Chapter 39. Degenerative Diseases of the Nervous System

Because grouping of the degenerative diseases in terms of etiology is not entirely possible (except that a hereditary or genetic factor can be recognized in some), we resort for practical purposes to a division based on the presenting clinical syndromes and their pathologic anatomy. Although this is the most elementary mode of classification of naturally occurring phenomena, it is a necessary prelude to diagnosis and scientific study and preferable to a purely genetic or molecular classification. It is certainly an improvement on a haphazard listing of diseases by the names of the neurologists or neuropathologists who first described them. For reasons given in the introduction to this chapter, this approach remains the most effective in analyzing the problem presented by an individual patient. The main clinical categories are as follows:

Syndrome of progressive dementia, other neurologic signs absent or inconspicuous
Syndrome of progressive dementia in combination with other neurologic abnormalities
Syndrome of disordered posture and movement
Syndrome of progressive ataxia
Syndrome of slowly developing muscular weakness and atrophy
Sensory and sensorimotor disorders (neuropathies; see Chap. 46)
Syndrome of progressive blindness with or without other neurologic disorders (see Chap. 13)
Syndromes characterized by degenerative neurosensory deafness (see Chap. 15)

Diseases Characterized Mainly by Progressive Dementia

Alzheimer Disease

This is the most common and important degenerative disease of the brain, having an immense societal impact. Some aspects of the intellectual deterioration that characterize this disease were described in Chap. 21, under "The Neurology of Dementia," and the still ambiguous relationship of this disease to the aging process is mentioned above and in Chap. 29. There it was pointed out that some degree of shrinkage in size and weight of the brain, that is "atrophy," is an inevitable accompaniment of advancing age, but that these changes alone are of relatively slight clinical significance and uncertain structural basis (e.g., whether the loss of brain weight aging is the result of a simple depletion of neurons). By contrast, severe degrees of diffuse cerebral atrophy that evolve over a few years are associated with dementia, and the underlying pathologic changes in these cases most often prove to be those of Alzheimer disease. As also commented on in Chap. 29, the rate of cerebral atrophy, specifically of the hippocampus and medial parts of the temporal lobes, is accelerated in the early stages of Alzheimer disease, and longitudinal studies by magnetic resonance imaging can identify individuals who will subsequently develop the disease (Rusinick). Nevertheless, there is not a continuous increase in the deposition of plaques and tangles, the pathologic markers of Alzheimer disease, with increasing age. Therefore, Alzheimer changes are not an inevitable result of aging.

The now outdated practice of giving Alzheimer disease and senile dementia the status of separate diseases is attributable to the relatively young age (51 years) of the patient originally studied by Alois Alzheimer in 1907. Such a division is no longer tenable, as the 2 conditions, except for their age of onset, are clinically and pathologically indistinguishable. It is probably useful to consider as related but separable, the several heredofamilial forms of Alzheimer disease discussed below.

Epidemiology

Although Alzheimer disease has been described at every period of adult life, the majority of patients are in their sixties or older; a relatively small number have been in their late fifties or younger. It is one of the most frequent mental illnesses, making up a large proportion of persons in assisted living and skilled nursing facilities. The incidence of clinically diagnosed Alzheimer disease is similar throughout the world, and it increases with age, approximating 3 new cases yearly per 100,000 persons younger than age 60 years and a staggering 125 new cases per 100,000 of those older than age 60 years. The prevalence of the disease per 100,000 population is near 300 in the group aged 60 to 69 years; it is 3,200 in the 70- to 79-year-old group and 10,800 in those older than age 80. In the year 2008, there were estimated to be more than 2 million persons with Alzheimer disease in the United States. (It should be borne in mind that these are not pathologically proven cases and, while probably correct as an approximation, are likely combined with other diseases.) Prevalence rates, which depend also on overall mortality, are 3 times higher in women, although the incidence of new cases is only slightly disproportionate in women. The survival of patients with Alzheimer disease is reduced to half the expected rate, mainly because of respiratory and cardiovascular causes and inanition, but also for other reasons that are not entirely clear.

Several putative epidemiologic risk factors for Alzheimer disease, such as birth order, mother's age at birth, and a family history of Down syndrome seem marginal at best and in some instances may be a result of selection bias. Depression and possibly head injuries do seem to confer a somewhat increased risk later in life. Whether low educational attainment is a risk factor for the development of Alzheimer disease or, conversely, whether cognitively demanding occupations or higher intelligence protects against dementia is still under discussion. Provocative data indicating that inherent intellectual endowment is important were presented in Chap. 21 (Katzman; Cobb et al). Finally, associations between diabetes or hyperglycemia and dementia, in general, have emerged from epidemiologic studies, for example, one reported by Crane and coworkers, but the ostensible mechanism by which this confers risk has not been established. In their report, a higher than average glucose level over the preceding 5 years conferred a slightly increased risk of dementia but not necessarily of Alzheimer disease.

The familial occurrence of Alzheimer disease has been well established. In less than 1 percent of such cases there is a dominant inheritance pattern with a high degree of penetrance and appearance of disease at a younger age (Nee et al; Goudsmit et al; see further). Reports of substantial familial aggregations of dementia without a specific pattern of inheritance also suggest the operation of more than one genetic factor. Many studies have documented an increase in the risk of ostensibly sporadic Alzheimer disease among first-degree relatives of patients with this disorder. Again, this risk is disproportionately greater in females, adding to the evidence that women in general are at slightly higher risk for Alzheimer disease (Silverman et al). Li and coworkers have provided evidence that patients with an earlier age of onset of Alzheimer disease (before age 70 years) are more likely to have relatives with the disease than are patients with later onset. Genetic studies are difficult to carry out because the disease does not appear at the same age in a given proband. Even in identical twins, the disease may develop at the age of 60 years in one of the pair and at 80 years in the other. Death from other causes may prevent its detection. The other genetic contributions to the occurrence of Alzheimer disease are discussed extensively further on.

Clinical Features (See also Chap. 21)

The onset of mental changes is usually so insidious that neither the family nor the patient can date the time of its beginning and most patients come to attention months or years after the decline began. Occasionally, however, the process becomes manifest by an unusual degree of confusion in relation to a febrile illness, an operation, mild head injury, or the institution of a new medication. Other patients have as their initial complaints dizziness, mental fogginess, nondescript headaches, or other vaguely expressed and changeable somatic symptoms.

The gradual development of forgetfulness is the major symptom. Small day-to-day happenings are not remembered. Seldom-used names become particularly elusive. Little-used words from an earlier period of life also tend to be lost. Appointments are forgotten and possessions misplaced. Questions are repeated again and again, the patient having forgotten what was just discussed. It is said that remote memories are preserved and recent ones lost (the Ribot law of memory), but this is only relatively true and it is difficult to check the accuracy of distant personal memories. For example, Albert and associates, who tested Alzheimer patients' recognition of dated political events and pictures of prominent people past and present, found that some degree of memory loss extends to all previous decades of the person's life (neuropsychologic testing is discussed further on).

Once the memory disorder has become pronounced in the prototypic disorder, other failures in cerebral function become increasingly apparent. The patient's speech is halting because of failure to access the needed word. The same difficulty interrupts writing. Vocabulary becomes restricted, and expressive language becomes stereotyped and inflexible. Comprehension of spoken words seems at first to be preserved, until it is observed that the patient does not carry out a complicated request; even then it is uncertain whether the request was not understood because of inattention or because it was forgotten. Almost imperceptible at first, these disturbances of language become increasingly apparent as the disease progresses. The range of vocabulary and the accuracy of spelling are reduced. Finally, after many years of illness, there is a failure to speak in full sentences; the finding of words requires a continuous search; and little that is said or written is fully comprehended. There is a tendency to repeat a question before answering it, and later there may be a rather dramatic repetition of every spoken phrase (echolalia). The deterioration of verbal skills has by then progressed beyond a groping for names and common nouns to an obvious anomic aphasia. Other elements of receptive and executive aphasia are later added, but discrete aphasias of the Broca or Wernicke type are characteristically lacking. In general, there is a paucity of speech and a quantitative reduction in mentation.

Skill in arithmetic suffers a similar deterioration. Faults in balancing the checkbook, mistakes in figuring the price of items and in making the correct change; all these and others progress to a point where the patient can no longer carry out the simplest calculations (acalculia or dyscalculia).

In some patients, visuospatial orientation becomes defective. The car cannot be parked; the arms do not find the correct sleeves of the jacket or shirt; the corners of the tablecloth cannot be oriented with the corners of the table; the patient turns in the wrong direction on the way home or becomes lost. The route from one place to another cannot be described, nor can given directions be understood. As this state worsens, the simplest of geometric forms and patterns cannot be copied.

Late in the course of the illness, the patient forgets how to use common objects and tools while retaining the necessary motor power and coordination for these activities. The razor is no longer correctly applied to the face; the latch of the door cannot be unfastened; and eating utensils are used awkwardly. Finally, only the most habitual and virtually automatic actions are preserved. Tests of commanded and demonstrated actions cannot be executed or imitated. Ideational and ideomotor apraxia are the terms applied to the advanced forms of this motor incapacity as described in Chaps. 3 and 22.

As these many amnesic, aphasic, agnostic, and apraxic deficits declare themselves, the patient at first seems unchanged in overall motility, behavior, temperament, and conduct. Social graces, whatever they were, are retained in the initial phase of the illness, but troublesome alterations may gradually appear in this sphere as well. Imprudent business deals may be made. Restlessness and agitation or their opposites—inertia and placidity—become evident. Dressing, shaving, and bathing are neglected. Anxieties and phobias, particularly fear of being left alone, may emerge. A disturbance of the normal day and night sleep patterns is prominent in some patients. A poorly organized paranoid delusional state, sometimes with hallucinations, may become manifest. The patient may suspect his elderly wife of having an illicit relationship or his children of stealing his possessions. A stable marriage may be disrupted by the patient's infatuation with a younger person or by sexual indiscretions, which may astonish the community. The patient's affect coarsens; he is more egocentric and indifferent to the feelings and reactions of others. A gluttonous appetite sometimes develops, but more often eating is neglected, resulting in gradual weight loss. Later, grasping and sucking reflexes and other signs of frontal lobe disorder are readily elicited (Neary et al), sphincteric continence fails, and the patient sinks into a state of relative akinesia and mutism, as described in Chap. 21.

Difficulty in locomotion, a kind of unsteadiness with shortened steps but with only slight motor weakness and rigidity, frequently supervenes. Elements of parkinsonian akinesia and rigidity and a fine tremor can be perceived in patients with advanced stages of the disease. Ultimately, the patient loses the ability to stand and walk, being forced to lie inert in bed and having to be fed and bathed, the legs curled into a fixed posture of paraplegia in flexion (in essence, a persistent vegetative state).

The symptomatic course of this illness is quite variable but usually extends over a period of 5 or more years, but judging from pathology studies, the pathologic course has a much longer asymptomatic duration. This concept of a preclinical stage is supported by the detailed studies of Linn and colleagues, who found that a lengthy period (7 years or more) of stepwise decline in memory and attention span preceded the clinical diagnosis. In the dominantly inherited forms of disease, careful studies of biomarkers in the spinal fluid and by imaging show that changes occur 15 years or longer before the clinical manifestations are apparent (Bateman et al). Throughout this period, corticospinal and corticosensory functions, visual acuity, ocular movements, and visual fields remain intact. If there is hemiplegia, homonymous hemianopia, and the like, either the diagnosis of Alzheimer disease is incorrect or the disease has been complicated by a stroke, tumor, or subdural hematoma. Exceptions to this statement are rare. The tendon reflexes are little altered and the plantar reflexes almost always remain flexor. There is no sensory or cerebellar ataxia. Convulsions are rare until late in the illness, when up to 5 percent of patients reportedly have infrequent seizures. Occasionally, widespread myoclonic jerks or mild choreoathetotic movements are observed late in the illness. Eventually, with the patient in a bedfast state, an intercurrent infection such as aspiration pneumonia or some other disease mercifully terminates life.

The sequence of neurologic disabilities may not follow this described order and one or another deficit may take precedence, presumably because the disease process, after becoming manifest in the memory cortex of the temporal lobes, affects a particular part of the associative cortex earlier or more severely in one patient than in another. This allows a relatively restricted deficit to become the source of early medical complaint, long before the full syndrome of dementia has declared itself.

There are at least 4 limited deficits that may represent the opening features of Alzheimer disease but each of which alone may be mild enough to qualify as mild cognitive impairment (MCI). According to Petersen, who developed this concept, the MCI syndrome is defined by the presence of cognitive difficulties in one or all spheres that are not severe enough to interfere with daily life.

The early presentation of Alzheimer disease may manifest mainly as one of the following syndromes with the first, memory dysfunction being the most common and, even as other aspects of the disease advance, it tends to remain the most prominent.

Amnesia The early stages of Alzheimer disease are usually dominated by a disproportionate failure of episodic (autobiographical) memory, with integrity of other cognitive abilities. This may be the sole difficulty for many years. In such patients, immediate memory (essentially a measure of attention), tested by the capacity to repeat a series of numbers or words, is intact; it is the short-and long-term (retentive) memory that fails. Memory may become impaired but as a business executive, for example, the individual may continue to make acceptable decisions if the work uses long-established habit patterns and practices.
Dysnomia The forgetting of words, especially proper names, may first bring the patient to a neurologist. Later the difficulty involves common nouns and progresses to the point where fluency of speech is seriously impaired. Every sentence is broken by a pause and search for the wanted word; if the desired word is not found, a circumlocution is substituted or the sentence is left unfinished. When the patient is given a choice of words, including the one that was missed, there may be a failure of recognition. Repetition of the spoken words of others, at first flawless, later brings out a lesser degree of the same difficulty. The defect in naming is evident with even simple tests, for example, asking the patient to generate a list of farm animals or car brands—a test that may elicit only 3 or 4 responses. A more extensive examination entails asking the patient to name as many items as possible in each of 3 categories in 1 min—vegetables, tools, and clothing. Alzheimer patients fall well below a score of 50 items.
Visuospatial disorientation Parietooccipital functions are sometimes deranged in the course of Alzheimer disease and in a few cases may fail while other functions are relatively preserved. When it occurs in a pure form it is termed posterior cortical atrophy, as discussed in a later section (see Renner et al). As remarked above and in Chap. 22, prosopagnosia (impaired facial recognition), losing one's way in familiar surroundings or inability to interpret a road map, to distinguish right from left, or to park or garage a car, and difficulty in setting the table or dressing are all manifestations of a special failure to orient the schema of one's body with that of surrounding space. Exceptionally, there is a neglect of stimuli in one visual field. In the late states, some of these patients develop the Balint syndrome or Gerstmann syndrome (Tang-Wai et al; McMonagle et al).
Paranoia and personality changes Occasionally, at some point in the development of Alzheimer dementia, paranoia or bizarre behavior occasionally assumes prominence. This may appear before the more obvious memory or language defects announce themselves. The patient becomes convinced that relatives are stealing his possessions or that an elderly and even infirm spouse is guilty of infidelity. He may hide his belongings, even relatively worthless ones, and go about spying on family members. Hostilities arise, and wills may be altered irrationally. Many of these patients are constantly worried, tense, and agitated. Of course, paranoid delusions may be part of a depressive psychosis and of other dementias, but most of the elderly patients in whom paranoia is the presenting problem, seem not to be depressed, and their cognitive functions are for a time relatively well preserved. Social indiscretions, rejection of old friends, embarking on imprudent financial ventures, or an amorous pursuit that is out of character are examples of these types of behavioral change.
Executive dysfunction This may be the most disabling of the main aspects of the disease and when it appears early on, is not specific to Alzheimer dementia as it is a component of several other processes that affect the frontal lobes. These patients display early difficulties in coordinating and planning tasks and following complex conversations or instructions. They may become disinclined to participate in social activities and become withdrawn or quieter than usual. As the problem advances, simpler and formerly automatic actions such as driving become problematic for the patient; the degree of insight varies. Some are able to express that they feel "confused' but more often, it is the family that brings these changes to attention.

If one of the foregoing restricted deficits remains uncomplicated over a long period, one is justified in suspecting a cause other than Alzheimer disease, such as one of the lobar atrophies such as frontotemporal dementia (see further on), Binswanger disease, hydrocephalus, or embolic infarctions of the temporal or parietal lobes. Each of the restricted clinical disorders described above is only relatively pure. Careful testing of mental function—and this is of diagnostic importance—frequently discloses subtle abnormalities in several cognitive spheres. Initially, most patients have a disproportionate disorder of the temporoparietal cortices, reflected by an earlier impairment on the performance parts of the Wechsler Adult Intelligence Scale. Within a year or two, the more generalized aspects of mental deterioration become apparent, and the aphasic–agnosic–apraxic aspects of the syndrome become increasingly prominent. Although it is true that most patients with Alzheimer disease walk normally until relatively late in their illness, infrequently a short-stepped gait and imbalance draw attention to the disease and worsen slowly for several years before cognitive manifestations become evident. The general decrepitude in appearance that accompanies the middle and late stages of the disease in many patients is commented on in Chap. 21.

For research purposes and to establish certain inclusive and exclusive criteria for the diagnosis of Alzheimer disease, a working group of the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Diseases Association (ADRDA) had proposed the following criteria: (1) dementia defined by clinical examination, the Mini-Mental Scale (see Table 21-6), the Blessed Dementia Scale, or similar mental status examination; (2) patient older than age 40 years; (3) deficits in 2 or more areas of cognition and progressive worsening of memory and other cognitive functions, such as language, perception, and motor skills (praxis); (4) absence of disturbed consciousness; and (5) exclusion of other brain diseases (McKhann et al, 1984; Tierney et al, 1988). These criteria have essentially been reaffirmed by more recent consensus panels (see McKhann et al, 2011). Using these measures, the correct diagnosis is achieved in more than 85 percent of patients, but this is not surprising given that Alzheimer disease is overwhelmingly the most common cause of adult dementia. Most cases are identifiable without resorting to restrictive lists such as these, especially if the patient is observed serially over a period of months or years. There is strong interest in the addition of biomarkers to the diagnostic criteria for the disease but these have not reached the point of general clinical utility and the diagnosis remains predominantly a clinical one, aided by imaging and other tests.

Pathology

In the advanced stages of the disease, the brain presents a diffusely atrophied appearance and its weight is usually reduced by 20 percent or more. Cerebral convolutions are narrowed and sulci are widened. The third and lateral ventricles are symmetrically enlarged to varying degrees. Usually, the atrophic process involves the frontal, temporal, and parietal lobes, but cases vary considerably. The extreme atrophy of the hippocampus, the most prominent finding visible on MRI (mainly coronal images), is diagnostic in the proper clinical circumstances.

Microscopically, there is widespread loss of nerve cells. Early in the disease this is most pronounced in layer II of the entorhinal cortex. In addition to marked neuronal loss in the hippocampus, adjacent parts of the medial temporal cortex—namely, the parahippocampal gyri and subiculum—are affected. The anterior nuclei of the thalamus, septal nuclei, and diagonal band of Broca, amygdala, and particular brainstem parts of the monoaminergic systems are also depleted. The cholinergic neurons of the nucleus basalis of Meynert (the substantia innominata) and locus ceruleus are also reduced in number, a finding that has aroused great interest because of its putative role of the former in memory function (see below). In the cerebral cortex, the cell loss predominantly affects the large pyramidal neurons. Residual neurons are observed to have lost volume and ribonucleoprotein; their dendrites are diminished and crowd one another owing to the loss of synapses and neuropil. Astrocytic hypertrophy (more than proliferation) is in evidence as a compensatory or reparative process, most prominent in layers III and V.

Moreover, 3 microscopic changes give this disease its distinctive character: (1) The presence within the nerve cell cytoplasm of thick, fiber-like strands of silver-staining material, also in the form of loops, coils, or tangled masses (Alzheimer neurofibrillary changes or "tangles") (Fig. 39-1). These strands are composed of a hyperphosphorylated form of the microtubular protein, tau, and appear as pairs of helical filaments when studied ultrastructurally. (2) Spherical deposits of amorphous material scattered throughout the cerebral cortex and easily seen with periodic acid-Schiff (PAS); the core of the aggregates is the protein amyloid, surrounded by degenerating nerve terminals (neuritic plaques) that stains with silver. Amyloid is also scattered throughout the cerebral cortex in a nascent "diffuse" form, without organization or core formation and then is appreciated mainly by immunohistochemical methods, as well as deposition in the walls of small blood vessels near the plaques, so-called congophilic angiopathy. (3) Granulovacuolar degeneration of neurons, most evident in the pyramidal layer of the hippocampus. This last change is least important in diagnosis but there is uncertainty regarding its nature; it had been thought to be simply a reactive process but recent studies suggest it reflects a defect in phagocytosis of degraded proteins.

Figure 39-1.

Photomicrograph of Alzheimer amyloid plaques and neurofibrillary tangles. Bielchowsky silver stain.

Neuritic plaques and neurofibrillary changes are found in all the association areas of the cerebral cortex, but it is the neurofibrillary tangles and quantitative neuronal loss, not the amyloid plaques, that correlate best with the severity of the dementia (Arriagada et al). If any part of the brain is disproportionately affected, it is the hippocampus, particularly the CA1 and CA2 zones (of Lorente de Nó) and the entorhinal cortex, subiculum, and amygdala. These parts have abundant connections with other parts of the temporal lobe cortex and dentate gyrus of the hippocampus and undoubtedly account for the amnesic component of the dementia. The associative regions of the parietal lobes are another favored site. Only a few tangles and plaques are found in the hypothalamus, thalamus, periaqueductal region, pontine tegmentum, and granule-cell layer of the cerebellum.

Experienced neuropathologists recognize a form of Alzheimer disease, particularly in older patients (75 years), in which there are senile plaques but few or no neuronal tangles (about 20 percent of 150 cases reported by Joachim et al). Increasingly, other pathologic changes are being appreciated in Alzheimer cases with fewer plaques and tangles than anticipated for the degree of dementia; Lewy bodies in particular are found by sophisticated techniques. Another problem for the neuropathologist is to distinguish between the normal-aged brain and that of Alzheimer disease. It is not unusual to find a scattering of senile plaques in individuals who were ostensibly mentally normal during life. Anderson and Hubbard studied 27 demented individuals aged 64 to 92 years and 20 age-matched nondemented controls. In the former, 3 to 38 percent of the hippocampal neurons contained neurofibrillary tangles; in all but 2 of the controls, the number of hippocampal neurons with tangles fell below 2.5 percent. Moreover, an increased number of tangles in the aged are associated with mild cognitive impairment and a higher likelihood of progression to Alzheimer disease.

Many demented individuals with clinical features of Alzheimer disease have sufficient neuronal loss and Lewy bodies in cortex and the substantia nigra to justify a diagnosis on histopathologic grounds of Parkinson disease (see further on). Leverenz and Sumi found that 25 percent of their Alzheimer patients showed the pathologic (and clinical) changes of Parkinson disease, a much higher incidence than can be attributed to chance. Similarly, of 11 patients with progressive supranuclear palsy (also discussed further on) reported by Gearing and coworkers, 10 were demented and 5 had the neuropathologic features of Alzheimer disease. These mixed cases present problems not only of classification but also in understanding the neurobiology of these degenerative diseases. This subject is discussed further in the section on Parkinson disease.

It is of historical interest that Alzheimer was not the first to describe plaques, one of the hallmarks of the pathologic state. Miliary lesions (Herdchen) had been observed in senile brains by Blocq and Marinesco in 1892 and were named senile plaques by Simchowicz in 1910. In 1907, Alzheimer described the case of a 51-year-old woman who died after a 5-year illness characterized by progressive dementia. Throughout the cerebral cortex he found the characteristic plaques, but he also noted, thanks to the use of Bielschowsky's newly devised silver impregnation method, a clumping and distortion of fibrils in the neuronal cytoplasm, the neurofibrillary change that now, appropriately, carries Alzheimer's name.

Pathogenesis

Analyses of the plaques and neuronal fibrillary changes have been undertaken in an attempt to elucidate the mechanism of Alzheimer disease, but so far, to little avail. Several histologic techniques assist in this endeavor, including refined methods for silver impregnation that stain both amyloid and its main constituent (beta-amyloid protein [Aβ]); immunostaining using antibodies specific to such proteins as ubiquitin, neuronal tau protein, and beta-amyloid protein; and visualization of β-pleated protein sheets using thioflavine S and Congo red with ultraviolet and polarized light. Tau (composed chemically of beta2-transferrin) is a discrete cytoskeletal protein that promotes the assembly of microtubules, stabilizes their structure, and participates in synaptic plasticity in a yet to be defined manner. In the pathologic circumstances of Alzheimer disease, progressive supranuclear palsy, and frontotemporal dementia (see further on), tau is hyperphosphorylated and aggregates, resulting in paired helical filaments that make up the neurofibrillary tangles. Electrophoretically, tau moves with the β2-globulins and is thought to function as a transferrin, that is it binds iron and delivers it to the cell. Its concentration can be measured in the CSF and serum, but this has not yet proven clearly to be useful as a diagnostic test.

The Aβ protein is a small portion of a larger entity, the amyloid precursor protein (APP), which is normally bound to neuronal membranes. As shown in Fig. 39-2, the Aβ protein is cleaved from APP by the action of proteases termed α, β, and γ secretase. One current hypothesis, developed by Selkoe and others, focuses on the manner in which APP is cleaved by these enzymes to give rise to different-length residues of Aβ. During normal cellular metabolism, APP is cleaved by either α or β secretase. The products of this reaction are then cleaved by the γ-secretase isoform of the enzyme. The sequential cleavage by α and then γ produces tiny fragments that are not toxic to neurons. However, cleavage by β and then γ results in a 40-amino-acid product, Aβ40, and a longer 42-amino-acid form. The latter Aβ42 form is toxic in several models of Alzheimer disease, and it has been proposed that the ratio of Aβ42 to Aβ40 is critical to the neuronal toxicity of amyloid.

Figure 39-2.

Diagram of proteolysis of amyloid precursor protein (APP). When APP is cleaved sequentially by β secretase and then secretase, the resulting amyloid protein can be 40 (Aβ40) or 42 (Aβ42) amino acids in length. The latter favors the formation of aggregated fibrillary amyloid protein (fibrillogenesis) rather than normal APP degradation. The fibrillary form of amyloid is neurotoxic, a mechanism favored as the cause of cell damage in Alzheimer disease. Formation of Aβ42 is promoted by mutations, either in the APP gene itself or in the presenilins. In Down syndrome, excess production of APP and its product Aβ42 is caused by triplication of the long arm of chromosome 21, the location of the APP gene. The Apo E4 allele is associated with inadequate clearance of Aβ42 and is another mechanism that promotes fibrillogenesis. (Modified by permission from Sisodia SS, St. George–Hyslop PH: γ-Secretase, notch, Aβ and Alzheimer's disease: Where do the presenilins fit in? Nat Rev Neurosci 3:281–290, 2002.)

Several pieces of evidence favor the view that elevation of the levels of Aβ42 leads to aggregation of amyloid and then to neuronal toxicity. It appears that the diffuse deposition of Aβ42 precedes the formation of better-defined neurofibrils and plaques. The fact that the gene coding for APP is located on chromosome 21, one of the regions linked to one type of familial Alzheimer disease and the duplicated chromosome in Down syndrome, in which Alzheimer changes almost inevitably occur with aging (see further on), suggests that the overproduction of amyloid and all its Aβ residues are causative factors in the disease. Furthermore, the ratio of Aβ42 to Aβ40 is increased in Down syndrome. Another suggestive connection has been the finding that there are genetic defects in the genes encoding APP and in a pair of endosomal proteins termed presenilin 1 and 2 in some familial forms of Alzheimer disease. The presenilins interact with, or may be a component of, γ secretase, the enzyme that produces the Aβ42 fragment. Mutations of presenilin 1 and 2 also increase the relative levels of Aβ42. It should be noted that mutations of the APP and presenilin genes explain a very small proportion of Alzheimer cases (Terry). Transgenic mice that express human Alzheimer disease-associated mutations in APP or presenilin genes develop plaques with Aβ42 but not neurofibrillary tangles. Many of the relationships and mechanisms depicted in Fig. 39-2 are derived from the understanding of genetic forms of Alzheimer disease; the extent to which they will be implicated in the idiopathic disease is unknown. However, some form of disruption in these mechanisms is likely to be involved in the sporadic disease.

It must be emphasized, however, that there is still uncertainty regarding the relationship of amyloid deposition to the loss of neurons and brain atrophy. Alternatively, soluble oligomers of Aβ amyloid may be the toxic agents, whereas the emphasis until now has been on the effects of visible assemblies of insoluble amyloid fibrils. Similarly, TDP-43, the product of inadequate functioning of the progranulin gene, is also deposited in neurons and may play a substantial role in the severity of expression of Alzheimer disease; this protein has been implicated in the pathogenesis of frontotemporal dementia and motor neuron disease, both discussed later in the chapter. Others have questioned the amyloid hypothesis and pointed to the imprecise relationship between amyloid deposition and neuronal loss, even suggesting that aggregated amyloid is in some way a protective mechanism of cells.

The importance of neurofibrillary tangles has also been questioned, and the manner in which amyloid deposition relates to tangle formation is unclear. Unexplained also is prominent senile plaque formation in some cases and neurofibrillary tangles in others. One prevalent view is that the tangles are a secondary phenomenon. In their review, Hardy and Selkoe, authoritative investigators in this field, pointed out that "Although the amyloid hypothesis offers a broad framework to explain AD pathogenesis, it is currently lacking in detail, and certain observations do not fit easily with the simplest version of the hypothesis." Nonetheless, the amyloid hypothesis is currently the strongest.

In recent years, some of the subcellular mechanisms that are deranged by the presence of intracellular or extracellular amyloid have been elucidated. The finding of a reduced number and enlargement of synapses in affected cortex early in the disease by DeKosky and Scheff and others could be interpreted as either the first sign of neuronal death or the result of the neuronal loss. Amyloid deposition would then be a later, secondary phenomenon. These are complex and uncertain connections but they are among the most promising findings in this field of research.

It was long ago established that Alzheimer disease is not caused by any of the usual types of arteriosclerosis. On the other hand, several studies have indicated that the presence of cerebral infarctions, small or large, and nondescript ischemic white matter disease accelerates the deposition of amyloid and the development of neurofibrillary tangles in the brains of Alzheimer patients (see further on); the mechanism of these interactions is not understood. Not surprisingly, cerebrovascular disease also exaggerates the rate of progression and degree of dementia. How this relates to the entity of arteriosclerotic, multiinfarct, or vascular dementia is entirely clear. Without doubt, as discussed in Chap. 34, multiple cerebral strokes cause increasing deficits that cumulatively qualify as a dementia. At least some of the focal lesions that contribute to the cognitive syndrome can be identified clinically and there is a stepwise decline in function that corresponds to strokes. Admittedly, this type of vascular dementia may be more difficult to recognize when a number of the infarcts are of the relatively silent lacunar type; the mental capacities of such patients may then appear to fail in a gradual and continuous fashion. Memory is relatively spared in the early stages and usually a pseudobulbar state or deterioration in gait accompanies the dementia. The subcortical white matter change of Binswanger disease causes similar diagnostic problems. We are inclined toward the view expressed in Chap. 21 and summarized in the commentary by Jagust that there is an undefined, and perhaps synergistic, interaction between strokes and progressive mental decline in patients with Alzheimer disease. Most often, in our experience, it is the degenerative condition of Alzheimer that explains the dementia. A similar relationship between Alzheimer disease and previous head injuries is tentative but has led to speculation that several types of brain injuries are conducive to the development of neurofibrillary tangles and amyloid deposition, perhaps as if they were part of a reparative response.

No relationship to premorbid personality traits earlier in life has been established, but an intriguing finding from what has become known as the "nun study" and several similar studies suggests that poorer linguistic capability early in life corresponded to the development of Alzheimer disease with aging (D.A. Snowden et al). In this study, the autobiographies of 93 nuns, written in their twenties, were rated for linguistic and ideational complexity. Of 14 sisters who died in late life, deterioration of cognitive function and neuropathologically proven Alzheimer disease occurred in 7 who had a low "idea density" in their writings and in none of 7 whose writings were cognitively more complex. Obviously this type of correlation is subject to several interpretations, but the general notion of "cognitive reserve" having either a protective property or simply hiding mental decline, has emerged from numerous other studies. Also, there has been a general perception confirmed by a few studies such as the one by Verghese and colleagues, that an active mental life may reduce the severity of mental decline with aging, but firm conclusions cannot be made from the available information.

Neurotransmitter Abnormalities

Considerable interest was created in the late 1970s by the finding of a marked reduction in choline acetyltransferase (ChAT) and acetylcholine in the hippocampus and neocortex of patients with Alzheimer disease. This loss of cholinergic synthetic capacity was attributed to a reduction in the number of cells in the basal forebrain nuclei (mainly the nucleus basalis of Meynert), from which the major portion of neocortical cholinergic terminals originate (Whitehouse et al). However, a 50 percent reduction in ChAT activity has been found in regions such as the caudate nucleus, which shows neither plaques nor tangles (see review by Selkoe). The specificity of the nucleus basalis cholinergic changes has been questioned for other reasons as well. For one, Alzheimer brain also shows a loss of monoaminergic neurons and a diminution of noradrenergic, gabanergic, and serotonergic functions in the affected neocortex. The concentration of amino acid transmitters, particularly of glutamate, is also reduced in cortical and subcortical areas (Sasaki et al) and the concentration of several neuropeptide transmitters—notably substance P, somatostatin, and cholecystokinin are likewise low—but it has not been determined whether any of these biochemical abnormalities, including the cholinergic ones, are primary or secondary to heterogeneous neuronal loss. Nevertheless, the administration of cholinomimetics—either acetylcholine precursors (e.g., choline or lecithin), degradation inhibitors (e.g., physostigmine), or muscarinic agonists that act directly on postsynaptic receptors—have had a mild and unsustained therapeutic effect (see further under "Treatment").

Chase and associates have demonstrated a 30 percent reduction in cerebral glucose metabolism in Alzheimer disease, greatest in the parietal lobes, but this seems most likely to be secondary to tissue loss in these regions. Even if not of pathogenic significance, it finds value as a diagnostic marker of the disease. The role of aluminum in the genesis of neurofibrillary tangles, as was once proposed, has never been validated. It has been suggested that the use of estrogen by postmenopausal women or of antiinflammatory agents in men or women delayed the onset of the disease or reduced its occurrence, but neither of these have been corroborated by other studies.

Genetic Aspects of Alzheimer Disease (Table 39-1)

Of great importance was the aforementioned series of discoveries in patients with inherited forms of Alzheimer disease, of defective genes that code for errant APPs localized to chromosome 21 near the β-amyloid gene (St. George-Hyslop et al). As mentioned, this also provided an explanation for the Alzheimer changes that characterize the brains of practically all patients with the trisomy 21 defect (Down syndrome) who survive beyond their twentieth year; they overproduce amyloid as a result of the triplication of the gene. But gene defects on chromosome 21 are responsible for only a small proportion of familial cases and a minuscule percentage of disease overall. Other kindreds with familial Alzheimer disease have been linked to rare dominant mutations of the presenilin genes on chromosome 14 (presenilin 1; Sherrington et al), accounting in some series for up to 50 percent of familial cases, and on chromosome 1 (presenilin 2), which may account for many of the remaining ones (Levy-Lahad et al). These are summarized in Table 39-1. The age of onset of the disease in these familial forms, as in the Down cases, is earlier than that in sporadic forms. These cohorts of patients have provided great insight into long duration between the appearance of amyloid in the brain, approximately a decade, and the onset of clinical disease, and they suggest the potential use of imaging of chemical biomarkers for the disease (The Dominantly Inherited Alzheimer Network; see Bateman et al).

Table 39-1 Mutations and Modulating Factors Associated with Alzheimer Disease

Table 39-1 Mutations and Modulating Factors Associated with Alzheimer Disease

GENE

PROTEIN

INHERITANCE

AGE

CLINICAL FEATURES

APP

Amyloid precursor protein

Early

Rare but clinically simulates sporadic Alzheimer disease

PS1

Presenilin 1

Early

As above

PS2

Presenilin 2

Early

As above

Apo E

Apolipoprotein E

Haplotype

Late

Modifies susceptibility to Alzheimer disease; ϵ-4 allele represents risk

UBQLN1

Ubiquilin 1

SNP

Late

Familial cases only

TREM2

TREM2

SNP

Late

Modulating factor as for Apo E

AD, autosomal dominant; SNP, single nucleotide polymorphism.

It has been clear for some time that an excess or aberrant amyloid alone is an incomplete explanation for the disease. Certain sequence variants in normal genes confer an increased risk of the disease. The one first discovered was Apo E, a regulator of lipid metabolism that has an affinity for Aβ in Alzheimer plaques, has been found to modify the risk of acquiring Alzheimer disease. Of the several isoforms of Apo E, the presence of E4 (and its corresponding allele e4 on chromosome 19) is associated with a tripling of the risk of developing sporadic Alzheimer disease (Roses; Strittmatter et al; Polvikoski et al). This is the same allele that contributes to an elevated low-density lipoprotein fraction in the serum. Possession of two e4 alleles virtually assures the development of disease in those who survive to their eighties. The e4 allele also modifies the age of onset of some of the familial forms of the disease. In contrast, the e2 allele is underrepresented among Alzheimer patients. For these reasons it has been proposed that Apo E, by interacting with APP or tau protein in some way, modifies the formation of plaques. Indeed, possession of the e4 allele correlates with increased deposition of Aβ in the brain (McNamara). As pointed out by Hardy, Apo E appears to act at a point in the pathogenesis that is after the various genetic mutations have influenced the cellular pathology that ostensibly causes Alzheimer disease. However, these statistical relationships do not invariably connect an allele to the disease in a particular individual. In other words, the e4 allele does not act as a mendelian trait but as a susceptibility (risk) factor. It follows that many, if not most, individuals who develop Alzheimer disease do not have the risk allele. Moreover, many individuals with the e4 allele live into their seventies and eighties without developing Alzheimer disease. All that can be stated with certainty is that, on average, the presence of the e4 allele accelerates the appearance of Alzheimer disease by about 5 years.

Another polymorphism in TREM2 is quite rare in comparison to the aforementioned Apo E variants but confers an equivalent risk of Alzheimer disease that has been shown in several populations in (Guerreiro et al and Jonsson et al). In sporadic Alzheimer disease, the TREM2 polymorphism that is implicated in Alzheimer disease putatively causes inadequate phagocytic clearance of amyloid. Another rare modifying gene has been found in familial cases at the UBQLN1 (ubiquilin 1) site, coding for a protein that interacts with PS1 and PS2 and participates in proteasomal degradation.

Diagnostic Studies

Studies with CT and MRI are useful, but not definitive ancillary tests (Fig. 39-3). In patients with advanced Alzheimer disease, the lateral and third ventricles are enlarged to about twice the normal size and the cerebral sulci are proportionately widened. Coronal MRI of the medial temporal lobes may reveal a disproportionate atrophy of the hippocampi and a corresponding enlargement of the temporal horns of the lateral ventricles. Early in the disease, however, the changes do not exceed those found in many mentally intact old persons. For this reason, one cannot rely solely on imaging procedures for diagnosis and CT and MRI are most valuable in excluding alternative causes of dementia such as brain tumor, subdural hematoma, cerebral infarction, and hydrocephalus. The EEG undergoes mild diffuse slowing, but only late in the course of the illness; it is useful again, in the exclusion of alternative causes of mental decline that manifest themselves in seizure activity or changes typical of metabolic encephalopathy. The CSF is also normal, although occasionally the total protein is slightly elevated. Using the constellation of clinical data, cerebral imaging in the context of the age of the patient and time course of the disease, the diagnosis of dementia of Alzheimer type is made correctly in 85 to 90 percent of cases.

Figure 39-3.

Top: Coronal T1-weighted MRI of a 74-year-old man with moderate Alzheimer-type dementia. Diffuse cerebral and hippocampal atrophy with ex vacuo ventricular and cortical sulcal dilation is noted. Bottom: Coronal T1-weighted MRI of a 70-year-old woman with behavioral variant frontotemporal lobar dementia. Atrophy of the right greater than left temporal lobes is out of proportion to atrophy of the frontal and parietal lobes.

Of considerable value have been studies of cerebral blood flow single-photon emission computed tomography [SPECT]) and metabolism (positron emission tomography [PET]), which early in the illness often, but not always, show diminished activity in the parietal association regions and the medial temporal lobes. In most cases, when such changes are evident, the diagnosis was already obvious on clinical grounds. Newer PET ligand agents that bind to amyloid, such as the "Pittsburgh compound" and tau-ligands are more sensitive in identifying and observing the course of Alzheimer disease. Their main utility may be in detecting changes before brain atrophy is evident and in identifying patients who have the earliest changes of Alzheimer disease, whose disease course may be amenable to alteration by medications.

Neuropsychologic tests in the typical case show disproportionate deterioration in memory and verbal access skills. Testing is particularly useful when there is a serial decline in ability. Certain aspects of attention and executive function in Alzheimer disease that also show changes in Alzheimer disease were reviewed by Perry and Hodges. The use of these examinations is described in Chap. 21.

There are no established biologic markers of Alzheimer disease with the possible exception of the ratio of Aβ 42 to tau, in the cerebrospinal fluid (the ratio is low in Alzheimer disease). This test is used in some clinics, but may not be well enough validated for routine use (Maddalena et al). Schoonenboom and colleagues have shown that the incorporation of CSF phosphorylated tau (p-tau) with the typical CSF amyloid/tau ratio may provide additional specificity in distinguishing Alzheimer from other dementing diseases.

Differential Diagnosis of Alzheimer Disease (See also Table 21-3)

Formerly, when virtually all forms of dementia were untreatable, there was little advantage to either the patient or the family in ascertaining the cause of the cerebral disease. There are now adequate treatments for a number of diseases and conditions that cause cognitive decline, putting a premium on proper diagnosis.

The currently potentially treatable forms of dementia are those caused by normal-pressure hydrocephalus; chronic subdural hematoma; the dementia of AIDS; paraneoplastic and related autoimmune encephalitis; nutritional deficiencies (thiamine—Wernicke-Korsakoff syndrome, Marchiafava-Bignami disease, pellagra, vitamin B12 deficiency); chronic intoxication (e.g., alcohol, sedatives); multiple cerebral infarctions; certain endocrine and metabolic disorders (myxedema, Hashimoto encephalopathy), neurosyphilis and other chronic meningitides, Cushing disease, chronic hepatic encephalopathy; frontal and temporal lobe tumors; vascular dementia, cerebral vasculitis; sarcoidosis; progressive multifocal leukoencephalopathy (PML), Whipple disease; multiple sclerosis; and sometimes neglected, the pseudodementia of depression. Exclusion of most of these diseases is readily accomplished by careful history, sequential clinical evaluations, and testing of blood and CSF, EEG, CT, MRI, and neuropsychologic testing can be undertaken. We have regularly but infrequently incorporated the results of metabolic brain imaging (both FDG-PET and amyloid-ligand imaging) as well as CSF amyloid-tau ratio. We anticipate that these tests or similar ones may find more frequent use. In exceptional situations, brain biopsy may be justified in the diagnosis of dementia, almost limited to rapidly progressive cases. A perspective, albeit from a sample that cannot be generalized to practice, has been given by Warren and colleagues of 90 consecutive brain biopsies performed between 1989 and 2003 for the evaluation of dementia. More than half provided a diagnosis, mostly Alzheimer, Creutzfeldt-Jakob disease, and inflammatory disorders. However, reasonable assurances must be given to the neurosurgeon that prion disease is unlikely.

One problem in differential diagnosis is the distinction between a late-life depression and a dementia, especially when some degree of both is present. Observation over several weeks or more, and the patient's demeanor, makes the distinction clearer. Multiinfarct dementia is usually not difficult to separate from Alzheimer dementia, as discussed further on. The dementia of normal-pressure hydrocephalus may also be confused with Alzheimer dementia (see Chap. 30). The problem of distinguishing Alzheimer disease from a more "benign" form of memory decline associated with aging comes up frequently in practice, as discussed further on. These treatable conditions are discussed in Chaps. 21, 30, and 34 and the important topic of depression is addressed in Chap. 52. Often we have been confident on clinical grounds that a patient had Alzheimer disease, only to have revealed at autopsy that progressive supranuclear palsy, Lewy-body disease, Pick disease, another non-Alzheimer degeneration of the frontal lobes, or cortical-basal-ganglionic degeneration was the cause. All are discussed later in this chapter.

Treatment

There is no evidence that any of the formerly proposed therapies for Alzheimer disease—cerebral vasodilators, stimulants, L-dopa, massive doses of vitamins B, C, and E, gingko biloba, hyperbaric oxygen, intravenous immunoglobulin, and many others—have any salutary effect. Trials of oral physostigmine, choline, and lecithin have yielded mostly negative or uninterpretable results.

The effect of the currently used cholinergic precursors and agonists and acetylcholinesterase inhibitors, such as donepezil, is modest. With regard to the latter group of drugs, several large trials have demonstrated a slight prolongation of the patient's ability to sustain an independent life, but such evidence generally requires that the medications be taken for 6 to 12 months. For example, a meta-analysis of the drugs collectively demonstrated a mean improvement of 2 to 3 points on the 70-point Alzheimer Disease Assessment Scale and a slight delay in progression. Despite some trials that have failed to demonstrate benefit (c.f., AD 2000 Collaborative Group), the balance of evidence favors the use of these medications in practice, but only in mildly or moderately affected patients.

Side effects of the aforementioned class of drugs may include nausea and less often, vomiting. The families of our patients report from time to time that the medication caused insomnia or increased confusion. It is worth mentioning that when the acetylcholine receptor antagonist succinylcholine is used prior to general anesthesia, its effects may be prolonged in patients taking the above drugs. The use of trazodone, haloperidol, thioridazine, risperidone, and related drugs may suppress some of the aberrant behavior and hallucinations when these are problems, making life more comfortable for both patient and family, but several trials suggest that their general application causes more problems than it solves and they must often be discontinued in response to adverse effects. The randomized trial conducted by Schneider and coworkers found that olanzapine, quetiapine, and risperidone for the treatment of psychosis, aggression, or agitation with Alzheimer disease were approximately as good as placebo in relieving these symptoms, but largely because the drugs were not tolerated. Olanzapine was slightly preferable in those who continued taking the medication. The clinician is left with little recourse but to use this class of medications or haloperidol to control unmanageable behavior. Small doses of diazepines, such as lorazepam, are useful when sleep is severely disturbed, but they often increase confusion as well.

The N-methyl-D-aspartate (NMDA) glutaminergic antagonists, specifically memantine (20 mg daily), have also been tried. In a study of memantine by Reisberg and colleagues of 252 patients (187 of whom completed the trial), there were better results on a few scales that reflected functional behavior compared to the use of placebo, but there was no change in 3 main measures of cognitive performance. Because the side effects were ostensibly minor, this drug has been approved for use in late-stage Alzheimer disease and in conjunction with cholinergic drugs. Nevertheless, hallucinations or agitation may occur and require discontinuation. The combination of memantine and donepezil in moderately to severely affected patients offered no benefit over either drug alone (Howard et al). The effects of these drugs in later stages of the disease are, in any case, minimal.

A provocative series of studies using a small molecule inhibitors of the enzyme γ-secretase (semagacestat; see Doody et al, 2013), and a monoclonal antibody directed at soluble forms of amyloid (solanezumab; see Doody et al, 2014) have failed to demonstrate clear benefit in early Alzheimer disease. The presumption is that such agents might be useful if started in the presymptomatic stages of disease.

A series of animal experiments that demonstrated the possibility of removal of plaques by immunization against amyloid has led to human studies with a similar vaccination. One trial was stopped because of the occurrence of an immune encephalitis in a small number of patients, but in autopsy material there were indications that this novel approach may have had the desired effect of reducing amyloid deposition (Orgogozo et al). Revised vaccines are being formulated for further testing of this approach.

Given the state of therapeutics for Alzheimer disease, always important is the general management of the demented patient, which should proceed along the lines outlined in Chap. 21, keeping in mind that the physician's counsel is often the family's main resource for important medical and social decisions.

Associated Pathologic States

As indicated earlier, the histologic changes of Alzheimer disease have a number of interesting associations. Amyloid plaques and tangle deposition are far more common in the brains of patients with Parkinson disease (20 to 30 percent) than in the brains of age-matched controls (Hakim and Mathieson). These findings partly explain the high incidence of dementia in patients with Parkinson disease (see further on). As mentioned, with the advance of Alzheimer disease, extrapyramidal features may emerge. In such cases, Burns and colleagues have found changes in the substantia nigra including accumulation of synuclein and tau representative of Lewy bodies. Another association between the 2 diseases is apparent in the Guamanian Parkinson–dementia complex, which is also discussed below. In this entity, the symptoms of dementia and parkinsonism are related to neurofibrillary changes in the cerebral cortex and substantia nigra, respectively; senile plaques and Lewy bodies are unusual findings. What can be deduced from the crossover syndromes is that multiple degenerative changes can occur in these diseases and give rise to heterogeneity in clinical presentation.

The finding of neurofibrillary tangles (and to a lesser extent of plaques) in boxers ("punch-drunk" syndrome, or dementia pugilistica) is another interesting ramification of the Alzheimer disease process in that trauma appears to be able to elicit one of the core features of the disease as discussed in Chap. 35. Some cases of primary progressive aphasia (see further on) have Alzheimer change and amyloid plaque deposition as the primary pathologic change. There are other unusual and meaningful associations, such as dementia with motor neuron disease or the cases of familial dementia with spastic paraplegia reported by Worster-Drought and by van Bogaert and their associates (see later in this chapter). Here, neurofibrillary change is the most prominent feature whereas amyloid plaques are negligible in number or absent.

Another provocative connection is the already mentioned interrelationship between cerebrovascular disease and Alzheimer disease. This is a complex area that at one time, considered the 2 processes to be intimately related and later, was rejected, only to now be resurrected with clearer focus, as discussed Chap 34.

Lobar Atrophies (Frontotemporal Lobar Degeneration, Posterior Lobar Degeneration)

This broad category of disease has evolved and the nosology is confusing because type of selective atrophy of a cerebral lobe may be caused by several different histopathologic changes. The notion of lobar atrophy was introduced in 1892 when Arnold Pick of Prague described a special form of cerebral degeneration in which the atrophy was circumscribed (most often in the frontal or temporal lobes), with involvement of both gray and white matter; hence the term he applied was lobar rather than cortical sclerosis. In 1911, Alzheimer presented the first careful study of the microscopic changes, followed by even more complete analyses of the pathologic changes by the prominent neuropathologists of the age. As mentioned the pathologic change associated may be any one of several types: Pick inclusion bodies, neurofibrillary tangles, other inclusions, or with no characteristic changes except for neuronal loss. Contrariwise, gliosis and mild spongiform changes in the superficial layers of cortex, and even typical plaque and tangle pathology, have all been associated with syndromes of gross atrophy of the frontal or temporal lobes. What has emerged since his work is that the most common and important of the lobar atrophies is a group of frontotemporal degenerations that have diverse clinical and pathologic profiles.

In contrast to Alzheimer disease, in which the atrophy is relatively diffuse, the pathologic change in lobar atrophy is circumscribed and often asymmetrical. The parietal lobes are involved less frequently than the frontal and temporal lobes. The affected gyri become paper thin, resembling, in the advanced stages, the kernel of a dried walnut. The cut surface reveals not only a marked narrowing of the cortical ribbon but a grayish appearance and reduced volume of the underlying white matter. The corpus callosum and anterior commissure share in the atrophy but almost certainly as secondary phenomena. The overlying pia-arachnoid is often thickened, and the ventricles are enlarged. The pre- and postcentral, superior temporal, and occipital convolutions are relatively unaffected and stand out in striking contrast to the wasted parts.

The more common frontotemporal lobar degenerations (FTLDs) (to which Pick's name was attached) may display any one of several pathologic changes and reflect different genetic causes. For example, the behavioral or the aphasic variants of FTD, which are described below, may be the result of the deposition of tau, progranulin, amyloid, or synuclein. It is not clear to us if the term "Pick disease" is worth retaining to denote a unique process aside from the unusual type that is due to deposition of argyrophilic intracytoplasmic inclusions (Pick bodies) and diffusely staining ballooned neurons (Pick cells). In other respects, it is simply one of the large group of FTLDs. It is the lobar atrophy and marked changes in the underlying white matter that provide the unifying elements of this group of diseases.

Clinical and Pathologic Features

The descriptive terms frontotemporal lobar atrophy and frontotemporal dementia are used by neurologists and neuropathologists to refer to a clinical syndrome that is associated with degeneration of the frontal and temporal lobes. Some of the clinical aspects of frontotemporal dementia were discussed in Chap. 21, but broadly speaking, there are 2 main types: a behavioral variant and a language variant, the latter being divided into semantic dementia, progressive nonfluent aphasia, and a logopenic variant, all described below.

Behavioral Variant FTLD

Patients under consideration with behavioral changes present with personality and related abnormalities that include apathy, disinhibition, perseveration, poor judgment and limited ability for abstraction, loss of empathy, bizarre affect, eating disorders, and a general disengagement. Insight is almost always impaired and some subjects become euphoric or display repetitive compulsive behaviors. An initial diagnosis of depression has been common. Other psychiatric symptoms such as sociopathic and disinhibited behavior with aspects of hyperorality and hyperphagia may predominate late in the illness. Utilization behavior (the compulsive use of implements and tools put before the patient) is also displayed in advanced cases.

CT, MRI, and functional imaging demonstrate a disproportionate atrophy and hypofunction in the frontal lobes, usually asymmetric. A proportion of patients with this type of frontotemporal dementia have parkinsonian features. A form of motor neuron disease is also linked to frontotemporal dementia in a small number of cases. This is particularly the case in the Guamanian (now called western Pacific) variety and in the heredofamilial frontotemporal atrophy linked to a mutation on chromosome 17.

In some writings on this subject, the term frontotemporal dementia has come to be used in a highly restricted sense, being assigned to cases that show only tau-staining material in neurons. Most of the cases are sporadic, but the inherited variety linked to chromosome 17, in which parkinsonism is prominent, supports its distinction as a separate entity; it is in these cases that the intraneural deposition of tau is most striking, in both the frontotemporal cortex and the substantia nigra. In a few familial cases, this process is attributable to mutations in the gene on chromosome 17 that encodes the tau protein. These mutations alter the proportions of different isoforms of this protein and lead both to tau accumulation and its hyperphosphorylation. Indeed, many cases of frontotemporal dementia are associated with tau gene mutations. However, abnormal aggregates of tau have been identified in practically all neurodegenerative atrophies and, of course, form the main constituent of the paired helical filaments (neurofibrillary tangles) of Alzheimer disease, and in progressive supranuclear palsy where they are abundant, although of slightly different structure. From the observations of Brun and Passant and of Neary and associates, pure tau-reactive cases outnumber Pick disease when the latter is strictly defined by the cortical white matter degeneration and Pick inclusions.

Nonetheless, a frontotemporal dementia identical to that of the tau-reactive cases has been observed in others without any tau or synuclein staining of neurons. Many of the frontally predominant cases have shown deposition of the protein progranulin, consisting mainly of a ubiquitin neuronal inclusion consisting of TDP-43 (TAR DNA-binding protein), the result of PGRN mutations.

Primary Progressive Aphasias (PPA)

Focal disturbances, particularly aphasia and apraxia, occur early and prominently in certain patients with lobar degenerations, indicating a lesion in the left frontal or temporal lobes. Viewed from another perspective, a prominent language disorder has been described in almost two-thirds of all patients with temporal lobe atrophy.

Several types of this disturbance have been delineated. In the first, progressive nonfluent aphasia, the patient initially speaks less and has word-finding difficulty (anomia), but language structure is intact (Mesulam, 1982); later, he may forget and misuse words and soon fails to understand much of what is heard or read. Sentences are short and telegraphed. Later, dysarthria and apraxia become apparent and finally, the patient is virtually mute, seemingly without impulse to speak, and with an inability to form words (Snowden et al, 1992).

A second type, semantic dementia, is characterized by early difficulty naming items, people, and words, followed by verbal perseveration, but fluency is retained. There is considerable difficulty in generating lists of words of a given category, such as animals. These individuals are quite aware that they are having trouble finding words. Eventually the patient loses not just the use of names of people and objects, but also their meaning, or the conceptual knowledge of the word. Some may develop severe prosopagnosia, especially if the atrophy is predominantly right sided. Memory for day-to-day events is preserved.

A third type has been proposed, logopenic aphasia, that shares most aspects of nonfluent aphasia but in which the meaning of words is retained.

According to Mesulam (2003), who has studied the condition extensively, 60 percent of these cases show no characteristic pathologic change, 20 percent have Pick bodies, and a similar proportion show the typical changes of Alzheimer disease in the affected cortical region. A clear familial tendency has not been found. Chapter 23 can be consulted for details of the aphasic disorders.

Posterior Cortical Atrophy

This regional variant of lobar degeneration has been slightly less frequent than primary progressive aphasia in our practices. The fundamental feature is the progressive loss of the ability to understand and use visual information. The result is progressive and ultimately severe visuospatial difficulty with a relative preservation of memory. Prosopagnosia, achromatopsia, and dyslexia emerge, or, there may be difficulty with depth perception, reaching for objects and an inordinate sensitivity to bright light. Patients under our care have initially had a vague sense of visual disorientation followed over months by difficulty in seeing or recognizing objects in front of them. Many have alexia with agraphia while others have acalculia or the other elements of the Gerstmann syndrome. Several eventually become cortically blind. The syndrome is essentially that of an apperceptive visual disturbance that includes fragments of the Balint and the Gerstmann syndromes. The average age of onset is about 60 years. The most common pathologic change in most reports has been characteristic of Alzheimer disease.

Lewy-Body Dementia (Diffuse Lewy-Body Disease)

Next to Alzheimer disease, diffuse Lewy-body disease, or Lewy-body dementia, has been the most frequent pathologic diagnosis established in many series of globally demented patients. Reports of this condition have been increasing steadily since the original communication by Okazaki and colleagues in 1961 (see review by Kosaka). The disease is defined by the diffuse involvement of cortical neurons with Lewy-body inclusions and by an absence or inconspicuous number of neurofibrillary tangles and amyloid plaques. To some extent, increased recognition of this disorder is a result of improved histologic techniques, particularly the ability to detect ubiquitin and synuclein, main components of the Lewy body, by immunostaining. With this improved detection has come a better definition of the clinical syndrome and its distinctions from Alzheimer and other dementias. Because the Lewy bodies in cortical neurons are not surrounded by a distinct halo, as they are in the substantia nigra in cases of Parkinson disease (see further on for discussion and photomicrograph of a typical Lewy body) they were not readily appreciated. Aggreagated α-synuclein is the main component of the Lewy body an observation that will prove important in understanding both Parkinson disease and Lewy-body dementia.

Clinical Features

The disease in its typical form is marked by parkinsonian features, dementia, and a tendency to episodic delirium, especially nocturnally, and rapid eye movement (REM) sleep behavior disorder (described below and in Chap. 19). Diagnostic criteria have been offered by a working group, requiring 2 of 3 of the following: a parkinsonian syndrome (usually symmetric), fluctuations in behavior and cognition, and recurrent hallucinations (McKeith et al). The latest recursion of this group's criteria emphasizes the presence of the REM sleep behavior disorder and severe neuroleptic sensitivity.

In an analysis of 34 cases of diffuse Lewy-body disease, Burkhardt and colleagues, found that the most characteristic syndrome was one of progressive dementia in an elderly patient with the additional late onset of parkinsonism in many cases. In Lennox's summary of 75 cases, parkinsonism, particularly with limb and axial rigidity, was a prominent feature in 90 percent once the illness was fully developed, and almost half had tremor of the parkinsonian type (this is somewhat different from other series). Byrne and associates, as have many others, pointed out that episodic confusion, hallucinations, and paranoid delusions were features of Lewy-body dementia; such psychotic aspects are generally uncharacteristic of Alzheimer and lobar dementias, and only then, in advanced stages. In Lennox's review, one-third of patients had these swings in behavior, but as the illness advanced, amnesia, dyscalculia, visuospatial disorientation, aphasia, and apraxia differed little from those of Alzheimer disease. In the cases reported by Fearnley and coworkers, there was a supranuclear gaze palsy simulating that of progressive supranuclear palsy. These overlapping clinical features make diagnosis difficult unless the specific feature of episodic hallucinations is evident. Difficulty in diagnosis also arises because the parkinsonian disorder may be either mild or prominent and may occur as an early or a late manifestation.

The parkinsonian features can respond favorably to L-dopa, but only for a limited time and sometimes at the expense of causing an agitated delirium or hallucinations that would be uncharacteristic of early Parkinson disease (Hely et al); in others, the response to L-dopa is inconsistent or inapparent. Some patients also have orthostatic hypotension corresponding to cell loss and Lewy bodies in the intermediolateral cell column of the spinal cord or in the sympathetic ganglia, thereby simulating striatonigral degeneration or Shy-Drager syndrome (see further on). Others have commented on an extreme sensitivity of such patients to neuroleptic drugs, including increased confusion and greatly worsening parkinsonism or the development of the neuroleptic malignant syndrome.

In our experience with Lewy-body disease, the parkinsonian symptoms have been more prominent than they are in progressive supranuclear palsy, and the most characteristic feature besides the movement disorder and a slowly advancing dementia has been a vacuous, anxious state with intermittent psychotic or delirious behavior.

At least one randomized trial has described benefit from the anticholinesterase inhibitor, rivastigmine, in reducing delusions, hallucinations, and anxiety (McKeith and colleagues, 2000). With regard to diagnostic testing, the finding of reduced activity in the posterior parietal cortical regions on PET scans (as in Alzheimer disease) has been found as a relatively consistent, but not invariable, feature.

Other Degenerative Dementias

Argyrophilic Grain Disease

This obscure entity has been connected with a late-life dementia in which behavioral disturbances precede memory difficulty. Whether the finding of argyrophilic grains in the mediotemporal lobe, different from tau-laden neurofibrillary tangles and from the glial inclusions (putatively a defining feature of multiple system atrophy), constitutes a specific entity is not clear to the authors. The finding overlaps with the deposition of other materials that are more closely associated with dementing diseases such as phosphorylated tau and Lewy bodies. Probst and Tolnay remarked that these small argyrophilic inclusions are not found in nondemented individuals. It is unlikely that the condition can be identified in life; if it is a genuine entity, it must be rare. The interested reader may consult the review by Ferrer.

Neuroserpinopathy

There have been infrequent case reports of dominantly inherited, adult-onset dementia with a fulminant evolution suggestive of encephalopathy and the special feature of seizures. The distinctive feature has been the presence at autopsy of large eosinophilic, PAS-positive intraneuronal inclusions that contain aggregates of neuroserpin, thus the initial description of "familial encephalopathy with neuronal inclusion bodies." The serpins are a family of protease inhibitors that include neuroserpin, a protein expressed exclusively in neurons, and α1-antitrypsin. The neuronal inclusions are densest in the deep layers of the cortex and in the substantia nigra. Missense mutations in the gene encoding neuroserpin have been identified as the cause. This entity is reviewed by Lomas and Carrell.

Dementing Diseases in Which Other Neurologic Abnormalities Are Prominent

Huntington Disease (Huntington Chorea)

This disease, distinguished by the triad of dominant inheritance, choreoathetosis, and dementia, commemorates the name of George Huntington, a medical practitioner of Pomeroy, Ohio. In 1872, his paper, read before the Meigs and Mason Academy of Medicine and published later that year in the Medical and Surgical Reporter of Philadelphia, gave a succinct and graphic account of the disease that was based on observations of patients that his father and grandfather had made in the course of their practice in East Hampton, Long Island. Reports of this disease had appeared previously (see DeJong for historical background) but they lacked the completeness of Huntington's description. In 1932, Vessie was able to show that practically all the patients with this disease in the eastern United States could be traced to about 6 individuals who had emigrated in 1630 from the tiny East Anglian village of Bures, in Suffolk, England. One remarkable family was traced for 300 years through 12 generations, in each of which the disease had expressed itself.

To quote Huntington, the rule has been that "When either or both of the parents have shown manifestations of the disease, one or more of the offspring invariably suffer of the disease, if they live to adult life. But if by any chance these children go through life without it, the thread is broken and the grandchildren and great grandchildren of the original shakers may rest assured that they are free from disease." Davenport, in a review of 962 patients with Huntington chorea, found only 5 who had descended from unaffected parents. Possibly, in these 5 patients, a parent had the trait, in very mild form, or parentage was in question, because spontaneous mutations are rare.

In university hospital centers, this is a regularly observed type of hereditary nervous system diseases and the main cause of progressive chorea at most ages. Its overall frequency is estimated at 4 to 5 per million, and 30 to 70 per million among whites of northern European ancestry. The usual age of onset is in the fourth and fifth decades, but 3 to 5 percent begin before the fifteenth year and some even in childhood, where it takes on special form. In approximately 30 percent, symptoms become apparent after 50 years. The progression of the disease is generally slower in older patients for reasons noted below. Once begun, the disease progresses relentlessly, until only a restricted existence is possible and a medical disease terminates life.

Exhaustive genealogic documentation many years ago established the cause to be an autosomal dominant gene with complete penetrance. Koller and Davenport made the observation that young patients usually inherit the disease from their fathers and older patients from their mothers. It has been observed beginning at almost the same age in identical twins.

The first important achievement in respect to the biologic understanding of Huntington disease was the discovery by Gusella and colleagues of a marker linked to the Huntington gene and localized to the short arm of chromosome 4. Subsequently, these investigators and others identified the mutation as an excessively long repeat of the trinucleotide CAG within the Huntington gene, the length (number) of which determines not only the presence of the disease, but also the age of onset, longer repeat lengths being associated with an earlier appearance of signs. At the Huntington gene locus there are normally 11 to 34 (median: 19) consecutive repetitions of the CAG triplet, each coding for glutamine. Individuals with 35 to 39 triplets may eventually manifest the disease but it tends to be late in onset and mild in degree, or limited to the below-mentioned "senile chorea." Those with more than 42 repeats almost invariably acquire the signs of disease if they live long enough. The rare alternative mutation, termed HDL2 (Huntington disease-like-2), is associated with CATCG repeat expansion of the juntophilin-3 gene, but it is so infrequent that few clinicians will encounter it (Margolis et al).

These discoveries have made possible the development of a genetic test for the measurement of the repeat length that confirms the diagnosis in symptomatic patients and allows screening of asymptomatic individuals. Because there is no treatment for the disease, testing raises certain ethical considerations that must be resolved before its widespread utilization.

Clinical Features

The mental disorder assumes several subtle forms long before the more obvious deterioration of cognitive functions becomes evident. In approximately half the cases, slight but annoying alterations of personality are the first to appear. Patients begin to find fault with everything, to complain constantly, and to nag other members of the family; they may be suspicious, irritable, impulsive, eccentric, untidy, or excessively religious, or they may exhibit a false sense of superiority. Poor self-control may be reflected in outbursts of temper, fits of despondency, slovenliness, alcoholism, or sexual promiscuity. Disturbances of mood, particularly depression, are common (almost half of the patients in some series) and may constitute the most prominent symptoms early in the disease. Invariably, sooner or later, the intellect begins to fail globally. The patient becomes less communicative and socially withdrawn. The emotional disturbances and changes in personality may reach such proportions as to constitute a virtual psychosis with persecutory delusions or hallucinations.

Diminished work performance, inability to manage household responsibilities, and disturbances of sleep may prompt medical consultation. There is difficulty in maintaining attention and concentration and in assimilating new material. Mental flexibility lessens. Simultaneously, there is loss of fine manual skills (see further on). The performance parts of the Wechsler Adult Intelligence Scale show greater loss than the verbal parts. Memory is relatively spared. This gradual dilapidation of intellectual function has been characterized as a "subcortical dementia," that is elements of aphasia, agnosia, and apraxia are observed only rarely and memory loss is not profound. Often the process is so slow, particularly in cases of late onset, that a fair degree of intellectual capacity seems to be retained for many years.

The abnormality of movement is subtle at first and most evident in the hands and face; often the patient is merely considered to be fidgety, restless, or "nervous." Slowness of movement of the fingers and hands, a reduced rate of finger tapping, and difficulty in performing a sequence of hand movements are early signs. Gradually these abnormalities become more pronounced until the entire musculature is implicated with chorea. The frequency of blinking is increased (the opposite of parkinsonism), and voluntary protrusion of the tongue, like other attempts at sustained posture, is constantly interrupted by unwanted darting movements. In the advanced stage of the disease the patient is seldom still for more than a few seconds. The choreic movements are slower than the brusque jerks and postural lapses of Sydenham chorea, and they involve many more muscles. They tend to recur in stereotyped patterns yet are not as stereotyped as tics. In advanced cases, they acquire an athetoid or dystonic quality. Muscle tone is usually decreased until late in the illness, when there may also be some degree of rigidity, tremor, and bradykinesia, elements suggestive of Parkinson disease. Parkinsonism with rigidity characterizes the Westphal or "rigid" variant, which is more common with a childhood onset, or the HDL2 genetic variant noted earlier. Tendon reflexes are exaggerated in one-third of patients, but only a few have Babinski signs. Voluntary movements are initiated and executed more slowly than normal, but there is no weakness and no ataxia, although speech, which becomes dysarthric and explosive because of incoordination between tongue and diaphragm, may convey the impression of a cerebellar disorder. Inability to hold the tongue protruded is characteristic. In late-onset cases there may be an almost constant rapid movement of the tongue and mouth, simulating the tardive dyskinesia that follows the use of neuroleptic drugs. These disorders of movement that characterize Huntington chorea are described more fully in Chap. 4.

Oculomotor function is subtly affected in most patients (Leigh et al; Lasker et al). Particularly characteristic are impaired initiation and slowness of both pursuit and volitional saccadic movements and an inability to make a volitional saccade without movement of the head. Excessive distractibility may be noticed during attempted ocular fixation. The patient feels compelled to glance at extraneous stimuli even when specifically instructed to ignore them. Upward gaze is often impaired as the illness progresses.

As Wilson stated, the relation of the choreic to the mental symptoms "abides by no general rule." Most often the mental symptoms precede the chorea but they may accompany or follow it, sometimes by many years. Once the movement disorder is fully established, there is nearly always some degree of cognitive abnormality. Exceptional cases have been reported in which the movement disorder existed for 10 to 30 years without mental changes (Britton et al); this would be most characteristic of patients with fewer CAG repeats. More typically after 10 to 15 years of symptoms, most patients deteriorate to a vegetative state, unable to stand or walk and eating little; in this late stage, a mild amyotrophy may appear. Noteworthy is the high suicide rate, as pointed out by Huntington himself (see also Schoenfeld et al). Because there is a higher-than-normal incidence of head trauma, chronic subdural hematoma is another common finding at autopsy.

The first signs of the disease may appear in childhood, before puberty (even younger than the age of 4 years), and several series of such early-onset cases have been described (Farrer and Conneally; van Dijk et al). Mental deterioration at this early age is more often accompanied by cerebellar ataxia, behavior problems, seizures, bradykinesia, rigidity, and dystonia than by chorea (Byers et al). However, this rigid form of the disease (Westphal variant) also occurs occasionally in adults as mentioned above, in some cases because of HDL2. Functional decline is much faster in children than it is in adults (Young et al).

The dementia is generally more severe in cases of early onset and with correspondingly longer repeat lengths (15 to 40 years of age) than in those of later onset (55 to 60 years of age). In adult patients with early onset, the emotional disturbance tends to be more prominent initially and precedes the chorea and intellectual loss by years; with older age of onset, choreiform features are more often the initial components; in the middle years, dementia and chorea have their onset at nearly the same age. At the other extreme of age, the first features may become evident in the eighties, with orofacial or other dyskinesias that are mistakenly attributed to an exposure to neuroleptic drugs or called "senile chorea" (see Chap. 4).

Pathology and Pathogenesis

Gross atrophy bilaterally of the head of the caudate nucleus and putamen is the characteristic abnormality, usually accompanied by a moderate degree of gyral atrophy in the frontal and temporal regions. The caudate atrophy alters the configuration of the frontal horns of the lateral ventricles in that the inferolateral borders do not show the usual bulge formed by the head of the caudate nucleus. In addition, the ventricles are diffusely enlarged (Fig. 39-4); in CT scans, the bicaudate-to-cranial ratio is increased, which corroborates the clinical diagnosis in the moderately advanced case.

Figure 39-4.

Axial CT from a 54-year-old mildly demented woman with a 10-year history of Huntington chorea. The bulge in the inferolateral border of the lateral ventricle, normally created by the head of the caudate nucleus, is obliterated. There is also diffuse enlargement of the lateral ventricles.

The early articles of Alzheimer and Dunlap and the more recent one of Vonsattel and DiFiglia contain the most authoritative descriptions of the microscopic changes. The latter authors have graded the disease into early, moderately advanced, and far advanced stages. In 5 early but genetically verified cases, no striatal lesion was found, which suggests that the first clinical manifestations are based on a biochemical or infrastructural change. This view is supported by the observation that Huntington patients studied with PET show a characteristic decrease in glucose metabolism in the caudate nuclei, which precedes the volumetric loss of tissue (Hayden et al). The striatal degeneration begins in the medial part of the caudate nucleus and spreads, tending to spare the nucleus accumbens. Of the 6 cell types in the striatum (a differentiation based on size, dendritic arborizations, spines, and axon trajectories), the smaller neurons are affected before the larger ones. Loss of dendrites of the small spiny neurons has been an early finding, while the large cells are relatively preserved and exhibit no special alterations.

The anterior parts of the putamen and caudate are more affected than the posterior parts. Some observers have noted changes in the globus pallidus, subthalamic nucleus, red nucleus, cerebellum, and in the pars reticulata of the substantia nigra. In the cerebral cortex, there is slight neuronal loss in layers 3, 5, and 6, with replacement gliosis. Cases are reported with typical striatal lesions but normal cortices in which only chorea had been present during late life. Several neuropathologists have observed marked cell loss and gliosis in the subthalamic nuclei in Huntington-affected children or young adults with chorea and behavior disorders. However, Hadzi and colleagues have determined that the pathologic changes in the striatum and the cortex evolve differently and have separate relationships to the CAG repeat length.

Mechanism of Disease

As mentioned above, there is a general relationship between the number of CAG repeats and the age of onset of symptoms. It has been found that it is the longer sequence on either of the 2 alleles that determines the age of onset, the size of the expansion of the normal allele exerting no influence (Lee et al, 2012). Earlier onset in successive generations (anticipation) is well described in the early writings on the subject and is now known to be attributable to increasing lengths of the CAG repeat sequence.

From the molecular perspective, the pathogenesis of this disease is a direct, but still poorly understood, consequence of the aforementioned expansion of the polyglutamine region of huntingtin (the protein product of the Huntington gene). It has been shown that the mutant huntingtin protein aggregates in the nuclei of neurons. Moreover, the protein accumulates preferentially in cells of the striatum and parts of the cortex affected in Huntington disease. Evidence, particularly that given by Wetz (cited in the review by Bates), suggests that these aggregates may be toxic to neurons, either directly or in their protofibrillary (unaggregated) form. The situation is, however, likely to be more complex, as the bulk of huntingtin deposition is found in cortical neurons, whereas the neuronal loss is predominantly striatal. One theory supports the concept that the polyglutamine complex renders certain cell types unduly sensitive to glutamate-mediated excitotoxicity. More recently, 2 mechanisms have been proposed based on an interruption of protein transcription by the binding of mutant huntingtin to transcription proteins or that mitochondrial dysfunction occurs directly or through the same transcriptional mechanism, as summarized by Greenamyre. Because polyglutamine expansions are implicated in several neurodegenerative diseases (reviewed in corresponding sections of this chapter), treatments that block their effects on cellular function may be broadly effective in several degenerative diseases.

Diagnosis

Once the disease has been observed in its fully developed form, its recognition requires no great clinical acumen. The main difficulty arises in patients who lack a family history but who display progressive chorea, emotional disturbance, and dementia. This problem has been largely overcome since the mutation was identified. It is now possible to confirm or exclude the diagnosis by analysis of DNA from a blood sample. The presence of more than 39 CAG repeats at the Huntington locus essentially confirms the disease and gives some indication of the expected time of onset; lesser numbers of repeat length leave room for equivocation and strings between 39 and 42 may not be manifest if the patient does not live long enough to express the illness.

Chorea that begins in late life with only mild or questionable intellectual impairment and without a family history of similar disease is a source of diagnostic difficulty. A few cases are the result of the earlier mentioned HDL2 mutation and others derive from alternative degenerative conditions discussed below. Referring to the problem as "senile chorea" does not solve the problem. Indeed, senile chorea has many causes. We have seen it appear with infections, hyperglycemia, drug therapy, strokes, and thyrotoxicosis, only to disappear after a few weeks. A few times we have been confronted with the problem of an older patient who displays orolingual dyskinesias that are most characteristic of exposure to neuroleptic drugs but in whom there was no such history of exposures; testing usually disclosed Huntington disease.

Chorea in early adult life always raises the question of a late form of Sydenham chorea, of lupus erythematosus with antiphospholipid antibodies, or of cocaine use, but neither familial occurrence nor mental deterioration is part of these processes. A "benign inherited chorea," transmitted as an autosomal dominant trait without prolongation of a triplet sequence, has been traced to chromosome 14q. It is differentiated from Huntington disease by onset before age 5 years, progressing little, and having no associated mental deterioration (Breedveld et al). Other progressive neurologic disorders inherited as autosomal dominant traits and beginning in adolescence or adult life (e.g., polymyoclonus with or without ataxia, acanthocytosis with progressive chorea, and dentatorubropallidoluysian degeneration) can closely mimic Huntington disease, as described further on; sometimes only the genetic and pathologic findings settle the matter. A midlife progressive chorea without dementia (after more than 25 years of followup) that does not display the Huntington genotype has been reported. In at least one family in which this clinical picture is dominantly inherited, the fundamental defect is a mutation in the gene encoding the light chain of ferritin (Curtis). Affected individuals have axonal changes in the pallidum with swollen, ubiquitin- and tau-positive aggregates; serum ferritin levels may be depressed. The implication of this mutation is that perturbations of iron metabolism may be toxic to neurons, a feature that also characterizes Hallervorden-Spatz disease.

Dentatorubropallidoluysian atrophy (DRPLA), sometimes mistaken clinically for Huntington chorea, was described in European families by Warner and associates and is discussed further on. The extrapyramidal manifestations include chorea, myoclonus, and rigidity. Adult-onset chorea and dementia has been described with propionic acidemia; propionic acid is elevated in the plasma, urine, and CSF. This disorder must be added to other metabolic diseases described in Chap. 37 as causes of childhood chorea and dyskinesia—such as glutaric acidemia, keratin sulfaturia, calcification of basal ganglia, phenylketonuria, and Hallervorden-Spatz disease, now called PANK (Hagberg et al).

Other problems in differential diagnosis include prion disease, Wilson disease (see Chap. 37), acquired hepatocerebral degeneration (see Chap. 40), paraneoplastic chorea (see Chap. 31), and most often and especially, tardive dyskinesia (see Chap. 41). Many drugs in addition to the toxic effects of L-dopa and antipsychotic medications occasionally cause chorea (amphetamines, cocaine, tricyclic antidepressants, lithium, isoniazid, linezolid). The hyperglycemic–hyperosmolar state is known for producing a variety of generalized or local movement disorders, prominent among them being chorea.

Treatment

The dopamine antagonist haloperidol, in daily doses of 2 to 10 mg, is effective partially in suppressing the movement disorder. Because of the danger of superimposing tardive dyskinesia on the chronic disorder, the chorea should be treated only if it is functionally disabling, using the smallest possible dosages. Haloperidol may also help alleviate abnormalities of behavior or emotional lability, but it does not alter the progress of the disease. The authors have not been impressed with the therapeutic effectiveness of other currently available drugs. Levodopa and other dopamine agonists make the chorea worse and, in the rigid form of the disease, evoke chorea. Drugs that deplete dopamine or block dopamine receptors—such as reserpine, clozapine, and particularly tetrabenazine, which has been validated in a controlled study (Huntington Study Group)—suppress the chorea to some degree, but their side effects (drowsiness, akathisia, and tardive dyskinesia) usually outweigh their desired effects. They may be tried in difficult cases. The juvenile (rigid) form of the disease is probably best treated with antiparkinsonian drugs. Preliminary studies of the transplantation of fetal ganglionic tissue into the striatum have achieved mixed results. The psychologic and social consequences of the disease require supportive therapy, and genetic counseling is essential. Antidepression drugs are widely implemented because of the high incidence of depression and suicidality but their efficacy is not clear. Huntington disease pursues a steadily progressive course and death occurs as mentioned, on average 15 to 20 years after onset, sometimes much earlier or later.

Acanthocytosis with Chorea

There are 2 categories of neurologic disease associated with red blood cell acanthocytosis; one with a defect in the red cell lipid membrane (represented by Bassen-Kornzweig disease and the HARP [hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration] syndrome [see Chap. 37]) and a second group that lacks a lipid abnormality. This latter type of neuroacanthocytosis enters into the differential diagnosis of Huntington chorea or unexplained progressive choreas and has the following characteristics: (1) onset in adolescence or early adult life of generalized involuntary movements (described as chorea but including dystonia and tics), usually beginning as an orofacial dyskinesia and spreading to other parts of the body and to other neural systems; (2) mild to moderate mental deterioration with behavioral disturbance in some but not all cases; (3) decreased or absent tendon reflexes and evidence of chronic axonal neuropathy and denervation atrophy of muscles; and (4) the defining feature of acanthocytosis (thorny or spiky appearance of erythrocytes). The main syndrome, and the one to which the term neuroacanthocytosis had for a long time been applied, is caused by an autosomal recessive mutation. However, there are now 4 additional subtypes, one dominantly transmitted and another X-linked (McLeod type), which is discussed below. These are all in distinction to Bassen-Kornzweig disease that is caused by an inherent defect in the lipid layer of the red cell membrane (see further on).

In the series of 19 cases reported by Hardie and colleagues, the manifestations included dystonia, tics, vocalizations, rigidity, and lip and tongue biting; more than half had cognitive impairment or psychiatric features. The average age of onset was 32 years; 7 of the 19 cases were sporadic. The disease has been linked in almost all families to chromosome 9q, where there is a mutation in the gene encoding a large (3,100-amino-acid) protein designated chorein that is involved in cellular protein sorting and trafficking (Rampoldi). Some of the families with dominantly inherited neuroacanthocytosis have mutations in the chorein gene. There is atrophy and gliosis of the caudate nuclei and putamens but no neuronal loss in the cerebral cortex or other parts of the brain.

According to Sakai and coworkers, the acanthocytosis is the result of an abnormal composition of covalently (tightly) bound fatty acids in erythrocyte membrane proteins (palmitic and docosahexanoic acids increased and stearic acid decreased). The cells should be examined in a fresh preparation of blood and isotonic saline; it is likely to be overlooked in a conventional Wright stain. More than 5 percent of the red cells have the characteristic structural abnormality in affected individuals. The acanthocytosis may also be detected by scanning electron microscopy. The latter may be necessary to undertake in cases of unexplained chorea that have the other features of this disease as genetic testing for the gene (see below) is not widely available.

McLeod disease, another disorder with acanthocytosis and the gradual development of chorea in middle to late life, is characterized by degeneration of the caudate and putamen and a myopathy (elevated serum creatine phosphokinase [CPK]). These individuals have fewer facial tics and orofacial features than those with neuroacanthocytosis. McLeod syndrome arises from mutations in a gene on the X-chromosome that encodes the KX protein, which binds to surface Kell antigens on red cells. In addition to the primary KX gene mutations, these individuals show diminished Kell antigen expression on the red-cell surface.

Corticostriatospinal Degenerations

Included in this category are a heterogeneous group of degenerative diseases in which the symptoms of parkinsonism and corticospinal degeneration are present in various combinations. Some of the diseases that make up this group have not been sharply delineated and are difficult to separate from one another.

Variants of this category of disease continue to appear, all rare. The authors have observed several patients in whom extreme rigidity, corticospinal signs but no dementia, have developed over a period of several years. In the later stages of the disease, the patient, while alert, is totally helpless and unable to speak, swallow, or move the limbs. Only eye movements are retained, and even these are hampered by supranuclear gaze palsies in advanced cases. Intellectual functioning appears to be better preserved than movement but is difficult to assess. Other bodily functions are intact. The course is slowly progressive and ends fatally in 5 to 10 years. There is no family history of similar disease, and there are no clues as to causation. Gilbert and colleagues have described similar cases with signs of Parkinson disease, motor neuron disease, and dementia; in their cases, there were no senile plaques or Lewy bodies. The concurrence of typical motor neuron disease and Parkinson disease may be coincidental, but Qureshi and colleagues described 13 patients in whom both clinical phenomena began within a short time and they considered them to be related. In the variant described by Tandan and colleagues, an autosomal dominant syndrome of Charcot-Marie-Tooth polyneuropathy was combined with ptosis, parkinsonism, and dementia, again without Lewy bodies or amyloid plaques. Other variants have been described by Schmitt and coworkers and by Mata and colleagues. Hudson reviewed 42 sporadic cases in which ALS-parkinsonism-dementia were combined.

Under the title "Spastic Pseudosclerosis," Jakob, in 1921, described a chronic disease of middle to late adult life, characterized by abnormalities of behavior and intellect; weakness, ataxia, and spasticity of the limbs (chiefly the legs); extrapyramidal symptoms such as rigidity, slowness of movement, tremors, athetotic postures, and hesitant, dysarthric speech; and normal spinal fluid. The pathologic changes were diffuse and consisted mainly of an outfall of neurons in the frontal, temporal, and central motor gyri, striatum, ventromedial thalamus, and bulbar motor nuclei. In one of Jakob's cases, there were also prominent changes in the anterior horn cells and corticospinal tracts in the spinal cord like those of ALS. The latter finding gave rise to Wilson's concept of the disease as a corticostriatospinal degeneration. Some restricted cases bear a resemblance to the type of frontotemporal dementia that occurs with motor neuron disease.

A degenerative and probably familial disorder that had been described earlier by Creutzfeldt was considered by Spielmeyer to be sufficiently similar to the one of Jakob to warrant the designation Creutzfeldt-Jakob disease. As discussed in Chap. 33, the disorder originally described by Creutzfeldt and Jakob has been a source of endless controversy because of its indeterminate character. It has been confused with the subacutely evolving myoclonic dementia, or subacute spongiform encephalopathy, which is now known to be an infection caused by a prion agent. The latter disease bears at best only a superficial resemblance to the one described by Creutzfeldt and Jakob, and the 2 disorders should be separated. Unfortunately, the use of the eponym for the prion-related disease is so entrenched that attempts to delete it are futile and probably unnecessary. However, the term Jakob disease has been used for the degenerative type of corticostriatospinal degeneration.

The Guamanian Parkinson-dementia-ALS complex deserves separate comment because there have been many carefully studied cases with almost uniform clinical and pathologic features. The disease occurs in the indigenous Chamorro peoples of Guam and the Mariana islands, predominantly in men between the ages of 50 and 60 years. Progressive parkinsonism and dementia are combined with upper or lower motor neuron disease (ALS is also common among the Chamorro) leading to death in 5 years. The pathologic changes, described by Hirano and associates, consist of severe cortical atrophy with neurofibrillary tangles and a depopulation of the substantia nigra, but notably no Lewy bodies or amyloid plaques, even with sensitive neurochemical staining. Cases with amyotrophy show a loss of anterior horn cells. The cause of the Guamanian multisystem degeneration is not known, although several studies have incriminated one or more putative neurotoxins in the food supply (see Chap. 43). There are some clinical and pathologic similarities to the form of frontotemporal dementia with motor neuron disease.

Familial Dementia with Spastic Paraparesis

Occasionally, the authors have encountered families in which several members developed a spastic paraparesis and a gradual failure of intellectual function during the middle adult years. The patient's mental horizon narrowed gradually, and the capacity for high-level thinking diminished; in addition, the examination showed exaggerated tendon reflexes, clonus, and Babinski signs. In one such family, the illness had occurred in 2 generations; in another, 3 brothers in a single generation were afflicted. Skre described 2 recessive types of hereditary spastic paraplegia in Norway, 1 with onset in childhood, the other with onset in adult life. In contrast to the dominant form (see further on), the recessive types displayed evidence of more widespread involvement of the nervous system, including dementia, cerebellar ataxia, and epilepsy. Also, Cross and McKusick have observed a recessive type of paraplegia accompanied by dementia beginning in adolescence. They named it the Mast syndrome, after the afflicted family.

Worster-Drought and others reported the pathologic findings in 2 cases of this type. In addition to plaques and neurofibrillary changes, there was demyelination of the subcortical white matter and corpus callosum and a "patchy but gross swelling of the arterioles," which gave the staining reactions for amyloid ("Scholz's perivascular plaques"). van Bogaert and associates published an account of similar cases that showed the characteristic pathologic features of Alzheimer disease.

Another interesting association of familial spastic paraplegia is with progressive cerebellar ataxia. Fully one-third of the cases that we have seen with such a spastic weakness were also ataxic and would fall into the category of spinocerebellar degenerations. Yet another variant of this group of diseases has been described by Farmer and colleagues; the inheritance in their cases was autosomal dominant, and the main clinical features were deafness and dizziness, ataxia, chorea, seizures, and dementia, evolving in that order. Postmortem examinations of 2 patients disclosed calcification in the globus pallidus, neuronal loss in the dentate nuclei, and destruction of myelinated fibers in the centrum semiovale.

Adult Polyglucosan Body Disease

Under this title, Robitaille and colleagues have described a progressive neurologic disease in adults characterized clinically by spasticity, chorea, dementia, and a predominantly sensory polyneuropathy that is reviewed in more detail in Chap. 39. Structures that closely resembled Lafora bodies and corpora amylacea were found in large numbers in both central and peripheral neural processes (mainly in axons) and also in astrocytes. These basophilic PAS-positive structures were composed of glucose polymers (polyglucosans) and were readily demonstrated in sural nerve biopsies and therefore probably best termed polyglucosan bodies. Some of these structures were also found in the heart and liver.

More recently, Rifal and associates reviewed the findings in 25 cases of this disease—one observed by them and 24 reported previously. The dementia was relatively mild, consisting of impairment of retentive memory, dysnomia, dyscalculia, and sometimes nonfluent aphasia and deficits of "visual integration"; this was overshadowed by rigidity and spasticity of the limbs and the peripheral nerve disorder. Bladder dysfunction has been an early sign in many patients including a middle-aged woman under our care who had only diffuse white matter changes in the cerebral MRI and a moderate sensory neuropathy. Nerve conduction velocities were diminished and the leg muscles were denervated. Moderate degrees of generalized cerebral atrophy, multifocal areas of white matter rarefaction, and degeneration of the corticospinal system, disclosed by MRI. Some cases simulate motor neuron disease. The finding of polyglucosan axonal inclusion in biopsied nerves confirms the diagnosis. The disease has sometimes been misinterpreted as adrenoleukodystrophy. The disorder appears to be a glycogenosis that is allied with Anderson disease, as discussed in Chaps. 38 and 48.

Adult forms of metachromatic leukodystrophy, adrenoleukodystrophy, Krabbe disease, and neuronal ceroid lipofuscinosis (Kufs disease) may be present with a similar clinical picture of progressive dementia (see Chap. 37) as may Whipple disease or the Wernicke-Korsakoff disease. Quite rare instances of the same syndrome with adult onset have proved to be caused by phenylketonuria or other aminoacidopathies (see Chap. 37).

Diseases Characterized by Abnormalities of Posture and Movement

Parkinson Disease

This common disease, known since ancient times, was first cogently described by James Parkinson in 1817. In his words, it was characterized by "involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace, the senses and intellect being uninjured." Strangely, his essay contained no reference to rigidity or to slowness of movement and it stressed unduly the reduction in muscular power. The same criticism can be leveled against the term paralysis agitans, which appeared for the first time in 1841 in Marshall Hall's textbook Diseases and Derangements of the Nervous System and has fallen out of use, but was such a common term in the literature that it is included here.

The natural history of the disease is of interest. As a rule, it begins between 45 and 70 years of age, with the peak age of onset in the sixth decade. It is infrequent before 30 years of age, and most series contain a somewhat larger proportion of men. Trauma, emotional upset, overwork, exposure to cold, "rigid personality," and so on, were among many factors that had been suggested over the years as predisposing to the disease, but there is no evidence to support any such claims. Idiopathic Parkinson disease is observed in all countries, all ethnic groups, and all socioeconomic classes, although the incidence in African Americans is only one-quarter that in whites. There may be an increased incidence in rural compared to urban areas. In Asians, the incidence is one-third to one-half that in whites. The disease is frequent in North America, where there are approximately 1 million affected patients, constituting about 1 percent of the population over the age of 65 years. The incidence in European countries where vital statistics are kept is similar. A possible relationship to repeated cerebral trauma and to the "punch-drunk" syndrome (dementia pugilistica; chronic traumatic encephalopathy) has been particularly problematic and is unresolved despite several celebrated cases (Lees). A protective effect of smoking and coffee drinking has emerged in some epidemiologic studies but is marginal.

Clinical Features

A tetrad of hypo- and bradykinesia, resting tremor, postural instability, and rigidity are the core features of Parkinson disease. These are evident as an expressionless face, poverty and slowness of voluntary movement, "resting" tremor, stooped posture, axial instability, rigidity, and festinating gait. Much can still be gained from perusal of the often-cited study by Hoehn and Yahr, published in 1967 before the widespread use of L-dopa. Table 39-2 is reproduced from that paper. The manifestations of basal ganglionic disease are fully described in Chap. 4, and only certain diagnostic problems and variations of the clinical picture need be considered here.

Table 39-2 Initial Symptoms in Patients with Parkinson Disease

Table 39-2 Initial Symptoms in Patients with Parkinson Disease

Tremor

70%

Gait disturbance

11%

Stiffness

10%

Slowness

10%

Muscle aches

Loss of dexterity

Handwriting disturbance

Depression, nervousness, other psychiatric disturbance

Speech disturbance

Source: Adapted from Hoehn and Yahr's study of 183 idiopathic cases, 1967.

The early symptoms may be difficult to appreciate and are often overlooked by family members because they evolve slowly and tend to be attributed to the natural changes of aging. Speech becomes soft, monotonous, and cluttered. For a long time the patient may not be conscious of the inroads of the disease. At first the only complaints may be of aching of the back, neck, shoulders, or hips and of vague weakness. Slight stiffness and slowness of movement or a reduction in the natural swing of one arm during walking are ignored until one day it occurs to the physician or to a member of the family that the patient has the overall cast of Parkinson disease. Infrequency of blinking, as originally pointed out by Pierre Marie, is an early sign. The usual blink rate (12 to 20/min) is reduced in the parkinsonian patient to 5 to 10/min, and with it there is a slight widening of the palpebral fissures, creating a stare. A reduction in movements of the small facial muscles imparts the characteristic expressionless "masked" appearance (hypomimia). When seated, the patient makes fewer small shifts and adjustments of position than the normal person (hypokinesia), and the fingers straighten and assume a flexed and adducted posture at the metacarpophalangeal joints.

The characteristic tremor, which usually involves a hand, is often listed as the initial sign; but in at least half the cases observant family members will already have remarked on the patient's relative slowness of movement. In about one-quarter of cases the tremor is mild and intermittent, or evident in only one finger or one hand. The tremor of the fully developed case takes several forms, as was remarked in Chap. 6. The 4-per-second "pill-rolling" tremor of the thumb and fingers, although most characteristic, is seen in only about half the patients. It is typically present when the hand is motionless, that is not used in voluntary movement (hence the commonly used term resting tremor). Complete relaxation, however, reduces or abolishes the tremor, so that the term tremor in the position of repose is actually a more accurate description. Volitional movement dampens it momentarily. The rhythmic beat coincides with an alternating burst of activity in agonist and antagonist muscles in the electromyogram (EMG); hence the description alternating tremor is applied. The arm, jaw, tongue, eyelids, and foot are less often involved. Even the least degree of tremor is felt during passive movement of a rigid part (cogwheel phenomenon, or Negro sign, or at least this is the ostensible explanation for cogwheeling). The tremor shows surprising fluctuations in severity and is aggravated by walking and excitement, but its frequency remains constant (Hunker and Abbs). It bears repetition that one side of the body is typically involved before the other with tremor and rigidity, and the tremor in particular remains asymmetrical as the illness advances.

Lance and associates have called attention to the high incidence of a second essential type of tremor in Parkinson disease—a fine, 7- to 8-per-second, slightly irregular, action tremor of the outstretched fingers and hands. This tremor, unlike the slower one, persists throughout voluntary movement, is not evident with the limb in a resting position, and is more easily suppressed by relaxation. Electromyographically, it lacks the alternating bursts of action potentials seen in the typical tremor and resembles, if not equates with, essential tremor (see Table 6-1). It is subject to modulation by different medications than those used for the alternating Parkinson tremor. The patient may have either type of tremor or both.

Rigidity is less often an early finding. Once rigidity develops, it is constantly present and can be felt by the palpating fingers and as a salience of muscle groups even when the patient relaxes. When the examiner passively moves the limb, a mild resistance appears from the start (without the short free interval that characterizes spasticity) and it continues evenly throughout movement in both flexor and extensor groups, being interrupted to a variable degree only by the cogwheel phenomenon. Rigidity and its cogwheel component are elicited or enhanced by having the patient engage the opposite limb in a motor task requiring some degree of concentration, such as tracing circles in the air (termed Froment sign, or Noïka-Froment sign when the patient is asked to raise the other arm as high as possible, but this maneuver was actually utilized first to bring out cogwheeling in essential tremor) or touching each finger to the thumb. In the muscles of the trunk, postural hypertonus predominates in the flexor groups and confers on the patient the characteristic flexed posture. Other particulars of the parkinsonian appearance of muscle tone, stance, and gait are discussed in detail in Chaps. 4 and 7. There should be no pyramidal signs in Parkinson disease.

Here, a few additional points should be made regarding the quality of volitional and postural movements. The patient is slow and ineffective in attempts to deliver a quick hard blow; he cannot complete a rapid (ballistic) movement. On the EMG, the normal single burst of agonist–antagonist–agonist sequence of energizing activity is replaced by several sequential brief bursts, according to Hallett and Khoshbin. Alternating movements, at first successful, become progressively impeded if performed repetitively and, finally, they are blocked completely or adopt the rhythm of the patient's alternating tremor. The patient has great difficulty in executing 2 motor acts simultaneously. In the past the impaired facility of movement had been attributed to rigidity, but the observation that certain surgical lesions in the brain abolished rigidity without affecting movement refuted this interpretation. Thus slowness and lack of natural movements (bradykinesia and hypokinesia, respectively) are not derived from rigidity but are independent manifestations of the disease. The bradykinetic deficits underlie the characteristic poverty of movement, reflected also by infrequency of swallowing, slowness of chewing, a limited capacity to make postural adjustments of the body and limbs in response to displacement of these parts, a lack of small "movements of cooperation" (as in arising from a chair without first adjusting the feet), absence of arm swing in walking, and most of the other aspects of the parkinsonian countenance. Despite a perception of muscle weakness, the patient is able to generate normal or near-normal power, especially in the large muscles; however, in the small ones, strength is slightly diminished.

As the disorder of movement worsens, all customary activities show the effects. Handwriting becomes small (micrographia), tremulous, and cramped, as first noted by Charcot. Speech softens and seems hurried, monotonous, and mumbling (cluttered): The voice becomes less audible and, finally, the patient only whispers. Caekebeke and coworkers refer to the speech disorder as a hypokinetic dysarthria and attribute it to combined respiratory, phonatory, and articulatory dysfunctions. There is a failure to fully close the mouth. The consumption of a meal takes an inordinately long time. Each morsel of food must be swallowed before the next bite is taken.

Walking becomes reduced to a shuffle; the patient frequently loses balance, and in walking forward or backward seems to be "chasing" the body's center of gravity with a series of increasingly rapid short steps in order to avoid falling (festination). Defense and righting reactions are faulty. Falls do occur, but surprisingly infrequently given the degree of postural instability. Gait is improved by sensory guidance, as by holding the patient at the elbow. Obstacles such as door thresholds have the opposite effect, at times causing the patient to "freeze" in place. Getting in and out of a car or elevator or walking into a room or in a hall becomes particularly difficult. Difficulty in turning over in bed is a similarly characteristic feature as the illness advances, but the patient rarely volunteers this information. Several of our patients have fallen out of bed at a frequency that suggests a connection to their reduced mobility combined with slowed corrective or defensive postural movements. Shaving or applying lipstick becomes difficult, as the facial muscles become more immobile and rigid.

Persistent extension or clawing of the toes, jaw clenching, and other fragments of dystonia, often quite painful, may enter the picture and are sometimes early findings. (These are particularly resistant to treatment.) A special problem of camptocormia occurs in some Parkinson patients wherein an extreme forward flexion of the spine and correspondingly severe stooping occur. It appears to be a type of axial dystonia when it occurs with Parkinson disease. The deformity resolves when the patient is supine or pushes upward on the handles of a walker. This symptom is associated with a variety of other diseases, some of them muscular. We have not been impressed that it is ameliorated by L-dopa. Why some patients with Parkinson disease are extremely bent over and others are not at all affected is unknown.

As noted above, these various motor impediments and tremors characteristically begin in one limb (more often the left) and spread to one side and later to both sides until the patient is quite helpless. Yet in the excitement of some unusual circumstance (as escaping from a fire, for example), the patient with all but the most advanced disease is capable of brief but remarkably effective movement (kinesis paradoxica).

Regarding elicitable neurologic signs, there is an inability to inhibit blinking in response to a tap over the bridge of the nose or glabella (Myerson sign) but grasp and suck reflexes are not present unless dementia supervenes and buccal and jaw jerks are rarely enhanced. Commonly there is an impairment of upward gaze and convergence; if prominent or noted early in the disease, this sign suggests more the possibility of progressive supranuclear palsy. Bradykinesia may extend to eye movements, in that there is a delay in the initiation of gaze to one side, slowing of conjugate movements (decreased maximal saccadic velocity), hypometric saccades, and breakdown of pursuit movements into small saccades.

There are no sensory findings, but a wide variety of paresthetic and other sensory complaints and discomforts are common. These affect mainly the calves and abdomen and are among the most distressing of the nonmotor parkinsonian symptoms. Drooling is troublesome; an excess flow of saliva has been assumed, but actually the problem is probably one of failure to swallow with normal frequency. Seborrhea and excessive sweating are claimed to be secondary as well, the former due to failure to cleanse the face sufficiently, the latter to the effects of the constant motor activity but this explanation seems lacking to us; an autonomic disturbance is more plausible. Other nonmotor features are mostly in the category of autonomic disturbances and include most prominently constipation, abdominal pains and cramps, erectile dysfunction, joint aches, and various other sensory experiences that may be difficult for the patient to describe. There is a tendency in some patients to have orthostatic hypotension and sometimes syncope; this has been attributed by Rajput and Rozdilsky to cell loss in the sympathetic ganglia. However, these features are not as prominent as in multiple system atrophy (Shy-Drager syndrome). It is worth mentioning that several of our younger Parkinson patients with recurrent syncope proved to have cardiac arrhythmias; hence other causes of fainting must be considered.

Postural instability is a core feature of the illness; it can be elicited by tugging at the patient's shoulders from behind and noting the lack of a small step backward to maintain balance often with a fall or the initiation of backward festination. The tendon reflexes vary, as they do in normal individuals from being barely elicitable to brisk. Even when parkinsonian symptoms are confined to one side of the body, the reflexes are usually equal on the two sides, and the plantar responses are flexor. Exceptionally, the reflexes on the affected side are slightly brisker, which raises the question of corticospinal involvement, but the plantar reflex remains flexor. In these respects, the clinical picture differs from that of corticobasal ganglionic degeneration, in which rigidity, hyperactive tendon reflexes, and Babinski signs are combined with apraxia (see further on).

As mentioned earlier, Parkinson disease may be complicated by dementia, a feature described by Charcot. The reported frequency of this combination varies considerably based on the selection of patients and type of testing. An estimate of 10 to 15 percent (Mayeux et al) is the generally accepted figure and matches our experience. The incidence increases with advancing age and duration of disease, approaching 65 percent in Parkinson patients older than 80 years of age, but mental decline may become apparent in patients in their late fifties. The pathologic basis of the dementia is discussed below.

The overall course of the disease is quite variable. In the majority of patients, the mean period of time from inception of the disease to a chairbound state is 7.5 years, but with a wide range (Hoehn and Yahr; Martilla and Rinne). As much as 10 percent of cases remain relatively mild and only very gradually progressive, and such patients may remain almost stable for 10 years or more. These trajectories have been altered somewhat by modern therapies.

Hemiparkinson–Hemiatrophy Syndrome

Mentioned here is a rare syndrome described by Klawans and elaborated in a series of 30 patients by Wijemanne and Jankovic. The typical case shows atrophy in one or more body parts, including at times the face, often since childhood, and usually quite subtle. Signs of progressive parkinsonism or dystonia begin in midlife on the atrophic side and, for the most part, are responsive to L-dopa, but some, such as Klawans' original patients, are resistant. Several types of early life cerebral injury underlie the syndrome, but half of patients have no such lesion evident. Understanding of the idiopathic cases is limited. Those with deep brain lesions may be experiencing a slow degeneration of basal ganglia pathways.

Diagnosis

The 2 main difficulties are to distinguish typical Parkinson disease from the many parkinsonian syndromes caused by other degenerative conditions and by medications or toxins, and to distinguish the Parkinson tremor from other types, especially essential tremor. It is worth noting that Parkinson disease is far more common than any of the degenerative syndromes that resemble it. Bradykinesia and rigidity of the limbs and axial musculature are symptoms shared with other forms of parkinsonism, but it is mainly in Parkinson disease that one observes an early sign of "resting" alternating tremor that is more prominent in one arm.

When not all the typical signs are evident, there is no alternative but to reexamine the patient at several-month intervals until it is clear that Parkinson disease is present or until the characteristic features of another degenerative process become evident; these include early falls and vertical gaze impairment in progressive supranuclear palsy; dysautonomia with fainting, bladder, or vocal cord dysfunction in multiple system atrophy; early and rapidly evolving dementia or intermittent psychosis in Lewy-body disease; or apraxia in corticobasal ganglionic degeneration. Very symmetrical findings, particularly tremor, suggest an alternative to idiopathic Parkinson disease. Also, the constellation of features termed "lower half parkinsonism" consisting of difficulty purely with gait and stability, as discussed below and in Chap. 7, suggest a process other than Parkinson disease.

If the symptoms warrant, a beneficial and sustained response to levodopa or a dopamine agonist also gives a reasonably secure, although not entirely conclusive, indication of the presence of Parkinson disease (see further on). The other parkinsonian syndromes are for the most part changed only slightly or only for a few weeks or months by the drug. Conversely, although some experts disagree, we have adhered to the notion that complete resistance of the symptoms to L-dopa early in the illness makes the diagnosis unlikely. Furthermore, almost all patients with idiopathic Parkinson disease eventually acquire dyskinesias in response to L-dopa and the absence of this sign after approximately 3 to 5 years of use of the drug brings the diagnosis into question.

The epidemic of encephalitis lethargica (von Economo encephalitis) that spread over Western Europe and the United States after the First World War left great numbers of parkinsonian cases in its wake. No definite instance of this form of encephalitis had been recorded before the period 1914 to 1918, and very few have been seen since 1930; hence, this type of postencephalitic parkinsonism is no longer a diagnostic consideration. However, a Parkinson-like syndrome has been described following other forms of encephalitis, particularly with Japanese B virus, West Nile virus, and eastern equine encephalitis. In the few cases caused by these viruses that we have observed, there has been fairly symmetrical rigidity, hypokinesia, and little or no tremor.

An "arteriopathic" or "arteriosclerotic" form of Parkinson disease was at one time much diagnosed but we have never been entirely convinced of its reality, referring to damage to the substantia nigra as a result of vascular disease or to a syndrome that closely resembles Parkinson disease as a result of atherosclerotic white matter damage. Nonetheless, a number of authoritative clinicians are of the opinion that patients with a vascular cause have a predominantly "lower half" parkinsonism in which shuffling gait, stickiness on turning, and falling are disproportionate to other features. There is no tremor, and little or no response to L-dopa (see Winikates and Jankovic). MRI in such cases has shown substantial white matter changes in both cerebral hemispheres. In the few cases attributable to vascular parkinsonism that have come to our attention with autopsy material, there have been Lewy bodies in the appropriate locations. Pseudobulbar palsy from a series of lacunar infarcts or from Binswanger disease can cause a clinical picture that simulates certain aspects of Parkinson disease, but unilateral and bilateral corticospinal tract signs, hyperactive facial reflexes, spasmodic crying and laughing, and other characteristic features distinguish spastic bulbar palsy from Parkinson disease. Of course, the elderly parkinsonian patient is not impervious to cerebrovascular disease, and the 2 conditions overlap, but differentiating the predominantly gait or dementing disorders of widespread vascular brain damage from idiopathic Parkinson disease is not difficult.

Normal-pressure hydrocephalus can undoubtedly produce a syndrome resembling Parkinson disease, particularly in regard to gait and postural instability, and at times extending to bradykinesia; but rigid postures, slowness of alternating movements, hypokinetic ballistic movements, and resting tremor are not part of the clinical picture. The gait tends to be short-stepped but not shuffling and there is more of a tendency to retropulsion than there is in Parkinson disease. Sometimes a lumbar puncture gives surprising benefit, indicating hydrocephalus as the cause of the motor slowing and gait disorder.

Essential tremor is distinguished by its fine, quick quality, its tendency to become manifest during volitional movement and to disappear when the limb is in a position of repose, and the lack of associated slowness of movement or of flexed postures. Cogwheeling of minor degree may be associated. The head and voice are more often truly tremulous in essential tremor than in Parkinson disease. Some of the slower, alternating forms of essential tremor are difficult to distinguish from parkinsonian tremor; one can only wait to see whether it is the first manifestation of Parkinson disease. A markedly asymmetrical or unilateral tremor favors Parkinson disease. Also as noted, a faster oscillation is often mixed with the slow alternating Parkinson tremor, but the fast-frequency tremor is only occasionally an opening feature of the disease as discussed in Chap. 6.

Progressive supranuclear palsy (discussed in a section further on) is characterized by rigidity and dystonic postures of the neck and shoulders, a staring and immobile countenance, and a tendency to topple when walking—all of which are vaguely suggestive of Parkinson disease. Early and frequent falls are particularly suggestive of this disease, not being atypical of Parkinson disease until its late stages. Inability to produce vertical saccades and, later, paralysis of upward and downward gaze and eventual loss of lateral gaze with retention of reflex eye movements establish the diagnosis of PSP in most cases.

Paucity of movement, unchanging attitudes and postural sets, and a slightly stiff and unbalanced gait may be observed in patients with an anergic or hypokinetic type of depression. Because a fair proportion of parkinsonian patients are depressed, the separation of these 2 conditions is at times difficult. The authors have seen patients who were called parkinsonian by competent neurologists but whose movements became normal when antidepressant medication or electroconvulsive therapy was given. Several such patients have nonetheless insisted that levodopa helps them in some nondescript way.

The rapid onset of parkinsonism should suggest exposure to neuroleptic medications (used at times as antiemetics and gastric motility agents [metoclopramide]), a variant of Creutzfeldt-Jakob disease, an unusual postinfectious or paraneoplastic illness, or viral encephalitis. The implicated drugs may also evoke an inner restlessness, a "muscular impatience," an inability to sit still, and a compulsion to move about much like that which occurs at times in the parkinsonian patient (akathisia). Even the newer antipsychosis medications, favored specifically because of a putative lack of extrapyramidal effects, may be at fault.

Strict adherence to the diagnostic criteria for Parkinson disease also permits its differentiation from corticostriatospinal, striatonigral, and corticobasal ganglionic degeneration, calcification of the basal ganglia, Wilson disease, the acquired hepatolenticular degeneration of repeated hepatic coma, manganese poisoning, as well as Machado-Joseph disease, all of which are discussed in other parts of this chapter.

All in all, if one adheres to the standard definition of Parkinson disease—bradykinesia, hypokinesia "resting" tremor, postural changes and instability, cogwheel rigidity, and response to L-dopa—errors in diagnosis are few. Yet in a series of 100 cases, studied clinically and pathologically by Hughes and associates, the diagnosis was inaccurate in 25 percent. The ostensible explanation for this difficulty is that approximately one-quarter of Parkinson patients fail to display the characteristic tremor and approximately 10 percent are said to not respond to L-dopa. These authors noted that early dementia and autonomic disorder and the presence of ataxia or corticospinal signs were reliable guides to an alternate diagnosis.

Pathology and Pathogenesis

The most constant and pertinent finding in both idiopathic and postencephalitic Parkinson disease is a loss of pigmented cells in the substantia nigra and other pigmented nuclei (locus ceruleus, dorsal motor nucleus of the vagus). The substantia nigra is visibly pale to the naked eye; microscopically, the pigmented nuclei show a marked depletion of cells and replacement gliosis, and some of the remaining cells have reduced quantities of melanin, findings that enable one to state with confidence that the patient must have suffered from Parkinson disease. Also, many of the remaining cells of the pigmented nuclei contain eosinophilic cytoplasmic inclusions, surrounded by a faint halo, called Lewy bodies (Fig. 39-5). These are seen in practically all cases of idiopathic Parkinson disease. They were generally absent in postencephalitic cases, but there were neurofibrillary tangles within nigral cell in that disorder. Both these cellular abnormalities appear occasionally in the substantia nigra of aged, nonparkinsonian individuals. Possibly the individuals with Lewy bodies would have developed Parkinson disease had they lived a few more years. Many of the inherited forms of Parkinson disease also lack Lewy bodies.

Figure 39-5.

Photomicrograph of a round Lewy-body inclusion in the cytoplasm of a nigral neuron. (Hematoxylin and eosin [H&E] staining.) (Courtesy of Matthew Frosch, MD, PhD.)

Noteworthy is the finding by McGeer and colleagues that nigral cells normally diminish with age, from a maximal complement of about 425,000 to 200,000 at age 80 years. Tyrosine-hydroxylase, the rate-limiting enzyme for the synthesis of dopamine, diminishes correspondingly. However, these authors and others have found that in patients with Parkinson disease the number of pigmented neurons is reduced to 30 percent or less of that in age-matched controls. Using more refined counting techniques, Pakkenberg and coworkers estimated the average total number of pigmented neurons to be 550,000 and to be reduced in absolute numbers by 66 percent in Parkinson patients. (The number of nonpigmented neurons was reduced in Parkinson cases by only 24 percent.) Thus aging contributes importantly to nigral cell loss, but the cell depletion is so much more marked in Parkinson disease that some factor other than aging must also be operative.

Other regions of neuronal loss are widespread as mentioned, but their significance is less clear. There is neuronal loss in the mesencephalic reticular formation, near the substantia nigra. These cells project to the thalamus and limbic lobes. In the sympathetic ganglia, there is slight neuronal loss and Lewy bodies are seen. This is also true of the pigmented nuclei of the lower brainstem as well as of neuronal populations in the putamen, caudatum, pallidum, and substantia innominata. On the other hand, dopaminergic neurons that project to cortical and limbic structures, to caudate nucleus and nucleus accumbens, and to periaqueductal gray matter and spinal cord are affected little or not at all. The lack of a consistent lesion in either the striatum or the pallidum is noteworthy. An alternative hypothesis offered by Braak and Tredici, mentioned in an earlier section of this chapter and attributed to Braak and Braak, is that the substantia nigra compacta is affected only late in the pathobiology of Parkinson disease. Their study found that the earliest changes in the brain occur in the dorsal glossopharyngeal-vagal and anterior olfactory nuclei, and only later did they appear in the midbrain nuclei. This theory accommodates a variety of clinical features and potential environmental triggers to the disease. Lang has suggested that this distribution of cell loss explains some of the nondopaminergic features of the disease and offers other avenues for therapy.

Statistical data relating Parkinson and Alzheimer diseases are difficult to assess because of different methods of examination from one series to another. Nevertheless, the overlap of the 2 diseases is more than fortuitous, as indicated earlier in this chapter. The majority of the demented Parkinson patients show some Alzheimer-type changes but there are some in whom few plaques or neurofibrillary changes can be found and instead display cortical neuronal loss accompanied by widespread distribution of Lewy bodies, marking the process as Lewy-body dementia and not Parkinson disease.

Of interest had been the observation, both in humans and in monkeys, that a neurotoxin (known as MPTP [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]) produces irreversible signs of parkinsonism and selective destruction of cells in the substantia nigra. The toxin, an analogue of meperidine, which was self-administered by addicts, binds with high affinity to monoamine oxidase, an extraneural enzyme that transforms MPTP to a toxic metabolite, pyridinium MPP (1-methyl-4-phenylpyridinium). The latter is bound by the melanin in the dopaminergic nigral neurons in sufficient concentration to destroy the cells. The mechanism by which MPTP produces the clinical aspects of the Parkinson syndrome is unsettled. One hypothesis is that the inner segment of the globus pallidus is rendered hyperactive because of reduction of the influence of gamma-aminobutyric acid (GABA) of the subthalamic nucleus. The notion of some other environmental toxin as a cause of Parkinson disease has been stimulated by the MPTP findings (see Uhl et al; also the review by Snyder and D'Amato). For example, Parkinson disease is slightly more frequent in industrialized countries and in agrarian regions where organophosphates are commonly used, but its universal occurrence would argue against this hypothesis. Despite extensive study, no chemical toxin, heavy metal, or infection has been causally related to the disease. Some plausible theories hold that a toxin might be implicated only on a genetic background predisposing to the disease. The MPTP disease serves as a model for the neurophysiologic and neurochemical changes of Parkinson disease because of destruction of the substantia nigra, but in most other respects it does not reflect the naturally occurring disorder (including the absence of Lewy bodies).

Genetic Aspects

Considering its frequency, coincidence in a family on the basis of chance occurrence might be as high as 5 percent. However, careful epidemiologic studies suggest that a familial occurrence may be as high as 15 percent. A lack of concordance of Parkinson disease in twins was at first thought to negate the role of genetic factors, but a study of dopamine metabolism using PET scanning showed that 75 percent of asymptomatic twins of Parkinson patients had evidence of striatal dysfunction, whereas only a small portion of dizygotic twins showed these changes (Piccini et al). These data indicate a substantial role for inherited traits, even in cases of ostensibly sporadic Parkinson disease (see below regarding the better defined inherited forms). Some mutations and polymorphisms are more clearly modifying factors in producing the disease, but others act as dominant disease genes. These are summarized in Table 39-3. We have chosen to retain the nomenclature of the PARK genes for ease of exposition but, as the genes are sequenced, their names have replaced this generic notation in many summaries of the genetics of the disease.

Table 39-3 Main Genetic Defects Associated with Parkinson Disease

Table 39-3 Main Genetic Defects Associated with Parkinson Disease

NOTATION

GENE (PROTEIN)

INHERITANCE

AGE OF ONSET

LEWY BODIES

SPECIAL FEATURES

Park1 & Park4

SCNA (α-synuclein)

30–40 years

Two main mutations—A53T, A30P—promote oligomerization of α-synuclein.

Park2

PARK2 (parkin)

20–40 years

–

Accounts for 50% of early-onset inherited PD; 20% of "sporadic" early-onset cases.

Park3

PARK3

Late onset

Resembles idiopathic PD.

Park5

UCHL-1 (ubiquitin esterase)

SNP

50's

Two different polymorphisms confer risk of PD.

Mutations decreased recycling of ubiquitin monomers.

Park6

PINK1 (PTEN-induced putative kinase 1)

Varies

Mitochondrial gene.

Park7

PARK7 (DJ-1)

30's

Slow progression; gene plays role in cellular response to oxidative stress.

Park8

LRRK2 (leucine-rich repeat kinase 2)

Late

Ashkenazic Jews. Protein also called dardarin; related to Gaucher disease.

Park14

PLA2G6 (phospholipase A2)

Late

–

Dystonia-parkinsonism; late onset; other mutations cause neuroaxonal dystrophy.

NR4A2

NURR1 (nuclear receptor related protein 1)

Confers susceptibility to PD

Gene is implicated in the formation and identity of dopaminergic neurons.

AD, autosomal dominant; AR, autosomal recessive; PD, Parkinson disease.

Numerous observations have implicated the nuclear and synaptic protein α-synuclein, the main component of Lewy bodies in both the sporadic and inherited forms of Parkinson disease, as well as in Lewy-body disease. Synuclein, a normal component of the synapse, exists in a soluble unfolded form, but in high concentrations it aggregates into filaments, which are the main (but not the only) constituent of the Lewy body. Immunostaining techniques disclose additional less-specific proteins, such as ubiquitin and tau within the Lewy bodies. Furthermore, in families with a rare autosomal dominant form of Parkinson disease, several different mutations on chromosome 4 code for an aberrant form of synuclein that decreases its stability and promotes its aggregation (Polymeropoulos et al). A family has also been described in which the cause of Parkinson disease is an extra nonmutant copy of the α-synuclein gene (Singleton et al), comparable to the circumstance or triplication of chromosome 21 in the Alzheimer disease of Down syndrome. Additionally, some cases of familial parkinsonism result from mutations that control the removal of α-synuclein from the cell via proteasomal pathways. Together, these findings indicate that instability or misfolding of α-synuclein or its deficient removal may be a primary defect in the disease. The protofibrillary form of the protein (i.e., a soluble protein in the cytosol) is also toxic to dopaminergic neurons. These processes are accelerated by defects in heat shock proteins that chaperone α-synuclein into and out of the cell. Curiously, Lewy bodies are not found in patients with most of the parkin mutations.

Parkin is a ubiquitin protein ligase that participates in the removal of unnecessary proteins from cells through the proteasomal system (Fig. 39-6). Attachment of parkin and ubiquitin to cytosolic proteins is understood to be an obligatory step in the disposal of proteins by proteasomes. Mutations in the parkin gene lead either to an inadequacy or misfolding of synuclein, resulting in its accumulation, or to the disruption of disposal of proteins in dopamine-producing cells. The importance of the ubiquitination pathway in this disease is further highlighted by the report that parkinsonian features are present in a family with mutations in ubiquitin carboxyterminal hydrolase L1 (Park5, UCHL-1; Table 39-3). Figure 39-6 illustrates these relationships and the processing of synuclein in the cell. It must be emphasized that most of the mechanisms illustrated are speculative or are derived from the molecular study of familial Parkinson disease and therefore may not apply to the sporadic process.

Figure 39-6.

Schematic diagram of proposed mechanisms of α-synuclein toxicity in Parkinson disease. In this model, α-synuclein levels are elevated by (a) duplication of one copy of the α-synuclein gene; (b) point mutations in the α-synuclein gene that generate excessive accumulations of synuclein; or (c) mutations in parkin and UCH-L1 genes that reduce normal removal of synuclein by the proteosomes. The excess of synuclein polymerizes to form protofibrils, a process that is enhanced by defects in heat shock proteins (Hsps) or by the action of dopamine, which binds to synuclein. In turn, this leads to formation of Lewy bodies. This model attributes the neurotoxicity to either the protofibrils or the Lewy bodies. (Adapted by permission from Eriksen JL, Dawson TM, Dickson DW, Petrucelli L: Caught in the act: α-Synuclein is the culprit in Parkinson's disease. Neuron 40:453–456, 2003.)

A mutation that has received much attention has been at the LRRK2 (leucine-rich repeat kinase 2) site. It is implicated in both genetic and sporadic forms of the disease, particularly among those of Ashkenazic Jewish or North African origin. The LRRK2 protein (dardarin) is a cytoplasmic component that is widely distributed in the brain and peripheral nerves. It has been estimated that mutations in the gene (mainly one common one, G20195) are responsible for 1 percent of sporadic cases and are found in 5 to 8 percent of individuals with a first-degree relative who has the disease. The gene acts as a dominant trait but penetrance of the defect increases with age, being 85 percent at 70 years. Therefore, there may not be a family history. The clinical syndrome in most respects simulates the sporadic form of the disease according to Papapetropoulos and colleagues, but several other series have noted the absence of tremor. The genetics of this disorder, also called Park8, are reviewed by Brice.

Several other gene defects are of interest in familial parkinsonism. One is a dominantly inherited mutation in the gene Nurr1, whose normal function is to specify the identity of dopaminergic neurons. Another is in recessively inherited parkinsonism caused by defects in the gene DJ-1, a protein that is essential for the normal neuronal response to oxidative stress. Also, a disease-causing mutation in the gene termed PINK, corresponding to Park6, codes for a mitochondrial kinase, therefore implicating this cellular structure in some forms of Parkinson disease (Valente et al). Presumably, dopaminergic neurons are compromised in some manner by these defects.

There has also been emphasis on mutations on 1 of 12 exons in the so-called Park2 gene, which codes for the protein parkin (see Table 39-3). The most common types are point mutations or deletions in exon 7, but abnormalities of the other exons evince similar syndromes. Homozygous mutations generally give rise to early-onset disease, but certain hemizygous changes (in exon 7) are associated with a later onset. The resultant syndromes have been termed parkin disease to distinguish them from the idiopathic variety. It has been estimated by Khan and colleagues that 50 percent of families that display an early onset of Parkinson disease and 18 percent of sporadic cases with early onset (before age 40 years) harbor mutations in this gene. Perhaps of greater clinical interest is finding that up to 2 percent of late-onset cases are associated with parkin mutations, and 1 percent due to changes in the aforementioned LRRK2 gene. Sequencing of these genes is now available in commercial laboratories for the purposes of detecting mutations and polymorphisms.

From a clinical perspective, the presentation of the late-onset cases with parkin mutations has been quite variable. Collectively, they can often be identified by an extreme sensitivity to L-dopa, maintaining an almost complete suppression of symptoms over decades with only small doses of medication; also, they have a low threshold for dyskinesias induced by L-dopa. We can also corroborate from experience with our own patients an excellent response of tremor, postural changes, and bradykinesia to anticholinergic drugs. A second feature has been that most of these patients may enjoy a remarkable restorative benefit from sleep, which creates a diurnal pattern of symptoms. Several series, particularly those of Lohmann and associates and of Khan and colleagues, have indicated that there may be a wide variety of additional features: hyperreflexia, cervical, foot, or other focal dystonias, sometimes induced by exercise; and, less often, autonomic dysfunction, peripheral neuropathy, and psychiatric symptoms. The sensitivity to medication and sleep benefit have long been known as the distinguishing components of juvenile-onset parkinsonism with dopa-responsive dystonia (Segawa disease), which is discussed later in the chapter.

Of similar interest as a modulating factor in the development of the disease is strong association between mutations in the glucocerebrosidase gene (other mutations of which causes Gaucher disease) among Ashkenazi Jews (Sidransky et al), the same population predominantly affected by polymorphisms of LRRK2. Although population studies allow only limited conclusions about clinical correlations, the glucocerebrosidase mutation is present more often in patients with a family history of the disease, have an earlier onset that in patients with a normal gene and a lower incidence of resting tremor. Mutations have been present in 7 percent of Parkinson patients who had their genes fully sequenced, making it so far the most common genetic factor for the disease, and certainly in this ethnographic population.

It is hoped that the genetic mutations that give rise to Parkinson disease will expose the molecular pathophysiology of the disease. As discussed earlier, several sites are implicated in the familial forms of Parkinson disease, some related to the gene that codes for synuclein, the main component of the Lewy body.

Treatment

Although there is no current treatment that clearly halts or reverses the neuronal degeneration underlying Parkinson disease, methods are now available that afford considerable relief from symptoms. Treatment can be medical or surgical, although reliance is placed mainly on drugs, particularly on L-dopa (Table 39-4). The following sections are necessarily detailed so as to give the clinician a full comprehension of the use and side effects and interactions of these drugs.

Table 39-4 Drugs Commonly Used in the Treatment of Parkinson Disease

Table 39-4 Drugs Commonly Used in the Treatment of Parkinson Disease

MEDICATION

STARTING DOSE

TARGET DOSE

MAIN BENEFIT

SIDE EFFECTS

L-Dopa

Carbidopa-L-dopa

25/100 mg tid

Up to 50/250 mg q3h

Reduction of tremor and bradykinesia; less effect on postural difficulties

Nausea, dyskinesias, orthostatic hypotension, hallucinations, confusion

Controlled release carbidopa-L-dopa

25/100 mg tid

Up to 50/200 mg q4h

May prolong L-dopa effects

Dopamine agonists

Ropinirole

0.25 mg tid

9 to 24 mg/d

Moderate effects on all aspects; reduced motor fluctuations of L-dopa

Orthostatic hypotension, excessive and abrupt sleepiness, confusion, hallucinations

Pramipexole

0.125 mg tid

0.75 to 3 mg/d

As above

Glutamate antagonist

Amantadine

100 mg/d

100 mg bid–tid

Smoothing of motor fluctuations

Leg swelling, congestive heart failure, prostatic outlet obstruction, confusion, hallucinations, insomnia

Anticholinergics

Benztropine

0.5 mg/d

Up to 4 mg/d

Tremor reduction, less effect on other features

Atropinic effects: dry mouth, urinary outlet obstruction, confusion, and psychosis

Trihexyphenidyl

0.5 mg bid

Up to 2 mg tid

As above

COMT inhibitors

Entacapone

200 mg with L-dopa

Prolonged effect of L-dopa

Urine discoloration, diarrhea, increased dyskinesias

MAO-inhibitors

Rasagiline

0.5 mg

1 mg daily

Reduced "off" time, Potential neuroprotection

Hypertensive crisis with tyramine-rich foods and sympathomimetics

Selegiline

5 mg

5 mg bid

Potential neuroprotection

L-Dopa and L-Dopa–Modifying Drugs

At present, L-dihydroxyphenylalanine (L-dopa) is unquestionably the most effective agent for the treatment of Parkinson disease and the therapeutic results, even in those with far advanced disease, are much better than have been obtained with other drugs. The levodopa, or a dopamine agonist preparation as described below, is introduced when the symptoms begin to interfere with work and social life or falling becomes a threat, and then these drugs are used at the lowest possible dose. The theoretical basis for the use of this compound rests on the observation that striatal dopamine is depleted in patients with Parkinson disease but that the remaining diseased nigral cells are still capable of producing some dopamine by taking up its precursor, L-dopa. The number of neurons in the striatum is not diminished and they remain receptive to ingested dopamine acting through the residual nigral neurons. Over time, however, the number of remaining nigral neurons becomes inadequate and the receptivity to dopamine of the striatal target neurons becomes excessive, possibly as a result of denervation hypersensitivity; this results in both a reduced response to L-dopa and to paradoxical and excessive movements (dyskinesias) with each dose. The drug has an interesting history that includes many early trials that failed to persuade neurologists of its effectiveness; Barbeau's paper on this historical subject may be consulted by the interested reader.

Most patients tolerate the drug initially, experiencing few serious adverse effects and showing various degrees of improvement, sometimes dramatic, especially in hypokinesia and tremor after several days or sooner. However, the side effects and limitations of L-dopa become considerable as the drug therapy continues and the disease progresses, as discussed below.

By combining L-dopa with a decarboxylase inhibitor (carbidopa or benserazide), which is unable to penetrate the central nervous system (CNS), decarboxylation of L-dopa to dopamine is greatly diminished in peripheral tissues. This permits a greater proportion of L-dopa to reach nigral neurons and, at the same time, reduces the peripheral side effects of L-dopa and dopamine (nausea, hypotension, confusion). Combinations of carbidopa-levodopa are available in a 1:10 or 1:4 ratio and the benserazide-levodopa combination is available in a 1:4 ratio. The initial dose of carbidopa-levodopa is typically one-half to one of a 25/100-mg tablet given bid or tid and increased slowly until optimum improvement is achieved, usually up to 4 tablets administered 5 or more times daily as the disease advances, or a similar dose of the 25/250-mg combination.

A class of catechol-O-methyltransferase (COMT) inhibitors, typified by entacapone, extends the plasma half-life and the duration of L-dopa effect by preventing its breakdown (as opposed to increasing its bioavailability, as in the case of carbidopa). A combination of L-dopa, carbidopa, and a COMT inhibitor is available in a single pill.

Long-acting preparations of levodopa-carbidopa may provide slightly longer effect and reduce dyskinesias in some patients (Hutton and Morris) in the advanced stages of disease, but our experience with these drugs given earlier in the course of disease has given less-predictable results. The absorption of the long-acting drug, however, is approximately 70 percent and may be inconsistent, often necessitating a slight increase in total dose. To facilitate the treatment of morning rigidity and tremor, the long-acting tablet can be given late in the previous evening.

For patients who require very frequent but small doses of the drug because of severe motor fluctuations and dyskinesias, an oral suspension may be formulated that allows precisely measured doses to be delivered orally or through a nasogastric tube. The typical composition is 500 mg L-dopa (of carbidopa-L-dopa 10/100 or 25/100), 500 mg of ascorbic acid to stabilize the drug, and 250 mL of water, resulting in a concentration of L-dopa of 2 mg/mL, which is administered in small amounts. A gel preparation is also available for delivery through a duodenal tube.

Each patient requires empirical adjustment of the dose and timing of medication and then generally does well by maintaining a relatively regular medication schedule, supplemented by small intercalated doses when needed. The effect of L-dopa may be virtually immediate (i.e., after absorption, which occurs over 30 to 40 min) but there is a further cumulative effect over several days of consistent dosing. The principles that guide the adjustment of dosing (end-of-dose wearing off, dyskinesias, freezing, confusion) are discussed further on.

Dopamine Agonists

These drugs have a direct dopaminergic effect on striatal neurons, thereby partially bypassing the depleted nigral neurons. They have found a place both as the initial treatment, replacing L-dopa in this role, and in modulating the effects of L-dopa later in the illness. However, dopamine agonists are consistently less potent than L-dopa in managing the main features of Parkinson disease and, in higher doses and in older individuals, they produce undesirable motor and cognitive side effects (see further on). They are favored because they are associated with fewer dyskinetic motor complications, or at least, delay the need for L-dopa and its dyskinetic effects. Bromocriptine and lisuride are synthetic ergot derivatives whose action in Parkinson disease is explained by their direct stimulating effect on dopamine (D2) receptors located on striate neurons. The nonergot dopamine agonists ropinirole and pramipexole have a similar type and duration of effectiveness and are used more widely because of their minimal ergot-like effects. Pergolide and the related drug cabergoline are no longer used because of the risk of cardiac valvular damage, particularly at higher dose levels.

The dopamine agonists are introduced gradually. For example, the initial dose of pramipexole is 0.125 mg tid, following which the dosage is doubled weekly to a total of 3 to 4.5 mg/d if the medication is used without L-dopa. If an individual is already taking L-dopa, these drugs usually permit a gradual reduction in levodopa-carbidopa dose by approximately 50 percent. Their duration of action is slightly longer than that of L-dopa and they cause less nausea. These medications may be also useful in reducing the motor fluctuations of L-dopa.

Our experience is in general agreement with that of Marsden, who found that of 263 patients given dopamine agonists as the sole treatment, 181 had abandoned medication after 6 months because of lack of effect or adverse reactions. Nevertheless, the fact that a large enough proportion of patients continue to benefit for up to 3 to 5 years indicates that the initial use of dopamine agonists has merit (see also Rascol et al). A recent development of some interest is a transdermally absorbed dopamine agonist such as rotigotine. Several trials suggest that the transdermal system can maintain a stable plasma level of the drug. In the study by LeWitt and associates, the main effect was a doubling of "on" time without unwanted dyskinesias. The effects on the quality of life in Parkinson patients appear to be positive but minor in degree. Skin reactions are common and the sulfites used in the patch formulation can cause severe systemic reactions in sensitive individuals.

Even small doses of dopaminergic drugs, when first introduced, may induce orthostatic hypotension, but most patients are tolerant of them. They may also produce abrupt and unpredictable sleepiness, and patients should be warned of this possibility in relation to driving. In some individuals, particularly the elderly, dopamine agonists may produce hallucinosis or confusion; these problems are most profound in patients who are later determined to have Lewy-body disease (see further on). More data are required to judge the efficacy of the current trend of initiating therapy with a dopamine agonist rather than with L-dopa.

Many clinicians initiate treatment with small amounts of a dopamine agonist, at least as much for the putative delay of dyskinesias that they offer in comparison to starting L-dopa. Alternatively, carbidopa/L-dopa tid can be initiated and supplemented over a month with a dopamine agonist. The side effects and subtleties of dosing are explained in the sections above on each of these classes of drug. The issue of also starting an MAO inhibitor such as rasagiline early in the illness is discussed below.

Adjunctive Medications

Because of the side effects of levodopa and of dopaminergic agents, some neurologists avoid pharmacotherapies if the patient is in the early phase of the disease and the parkinsonian symptoms are not troublesome. When the predominant manifestation is tremor, very satisfactory results can be obtained in some patients for up to several years with anticholinergic agents alone. The anticholinergic drugs have limited effect on the postural, hypokinetic, and other manifestations of disease. Koller's study, which quantified the effect of anticholinergic medication on tremor and compared it to L-dopa, concluded that there was considerable variability in response between patients but that L-dopa was on average more effective. Nonetheless, anticholinergic agents have long been in use for the treatment of tremor in younger patients and we still use them occasionally, either in conjunction with L-dopa or in patients who cannot tolerate the latter drug. The optimum dosage level is the point at which the greatest relief from tremor is achieved within the limits of tolerable side effects, mainly dry mouth. In older patients, one must be alert to changes in cognitive function, hallucinations, and urinary outflow obstruction.

Several synthetic preparations of anticholinergic drugs are available, the most widely used ones being trihexyphenidyl (beginning with 1 to 2 mg/d and increased up to 6 to 8 mg over several weeks) and benztropine mesylate (1 to 4 mg/d in divided doses). When it has been available, we have also had success with the related agent ethopropazine (50 to 200 mg daily in divided doses; but it has become difficult to obtain). The effects on tremor are cumulative and may not be evident for several days. To obtain maximum benefit from the use of these drugs, they should be given in gradually increasing dosage to the point where toxic effects appear: dryness of the mouth (which can be beneficial when drooling of saliva is a problem), blurring of vision from pupillary mydriasis, constipation, and urinary retention as mentioned (especially with prostatism). The presence of angle closure glaucoma is a contraindication to its use. Tremor abates in several days and most of our patients have become tolerant to the dry mouth after several weeks. Pyridostigmine, propantheline, or glycopyrrolate can be given to reduce the oral dryness.

With higher dose ranges, mental slowing, confusional states, hallucinations, and impairment of memory in elderly patients—specifically if there is already some degree of forgetfulness—are side effects that limit usefulness. Occasionally, further benefit may accrue from the addition of another antihistaminic drug, such as diphenhydramine or phenindamine.

The antiviral agent amantadine (100 mg bid) has mild or moderate benefit for tremor, hypokinesia, and postural symptoms. In some patients, it reduces L-dopa–induced dyskinesias (see further on). Its mechanism of action is unknown but antagonism of NMDA or release of stored dopamine has been proposed. It should be noted that amantadine commonly causes leg swelling, may worsen congestive heart failure, and can have an adverse effect on glaucoma, as well as exaggerate the cognitive changes associated with anticholinergic medications. The use of the centrally acting anticholinesterase, donepezil, is being explored for a possible effect on improving gait stability but requires further study. Finally, the monoamine oxidase inhibitors, described just below as putative neuroprotective agents, have a beneficial effect on motor fluctuations induced by L-dopa and may have a slight beneficial effect on the main Parkinson symptoms as described in several trials, such as the one reported by Rascol and colleagues.

Neuroprotective Agents

An additional approach, still somewhat controversial, has been to initiate treatment early in the course of the disease with a monoamine oxidase-B inhibitor (MAO-B inhibitor), with the aim of reducing oxidative stress in dopaminergic neurons. The DTAATOP trial conducted by The Parkinson Study Group (1989) reported a slowing of disease progression but later followup showed little difference between treated and untreated groups. Other agents in this class, notably rasagiline, have given similar mixed results in brief studies including the ADAGIO trial reported by Olanow and coworker. The difficulty in assessing the benefit of these agents has to do with their mild but definite symptomatic benefit on motor function. A credible long-term study has reported that early initiation of treatment with bromocriptine (now little used) did not reduce mortality or motor disability over 14 years and that any reduction in motor complications was unsustained (Katzenschlager et al). Nonetheless, we institute one of these MAO-B inhibitors in many patients.

Following this same line of reasoning, several studies, most still disputed or unconfirmed, have suggested that ropinirole, pramipexole, and even L-dopa have "neuroprotective" effects in Parkinson disease. However, slowing of the progression of symptoms, as measured by a variety of scales, has not been corroborated. Technical problems in interpreting these results are discussed at length in the reviews by Wooten and by Clarke and Guttman. The uncertainties have to do with clinical grading systems, functional imaging techniques, and points of comparison to treatment with L-dopa.

The notion that the administration of L-dopa early in the disease might reduce the period over which it remains effective has been largely dispelled, but some neurologists continue to adhere to this idea. Cedarbaum and colleagues, who reviewed the course of the illness in 307 patients over a 7-year period, found no evidence that the early initiation of L-dopa treatment predisposed to the development of fluctuations in motor response or to dyskinesia and dementia. In fact, the findings of the "Elldopa" trial by The Parkinson Study Group (2004) were that functional and other measures were better in patients who had taken L-dopa for 40 weeks and then stopped the medications than in those who received no medication. Neuropathologic study of the substantia nigra in the brains of Parkinson patients and their medication histories also failed to corroborate a reduction in the number of pigmented neurons (Parkkinen et al). Also, the large multicenter study reported by Diamond and colleagues indicated that patients who were given L-dopa early in the disease actually survived longer and with less disability than those who began the medication late in the course; that is, L-dopa may have itself been neuroprotective. However, there have been many alternative interpretations of these data.

Finally, attempts to slow the disease by vitamin antioxidants such as vitamin E have met with mixed, but generally negative, results. A possible exception was the trial of coenzyme Q10 by Shults and colleagues. Massive doses of this agent, 1,200 mg/d, were found to offer marginal advantages on the progression over 6 to 18 months as measured by certain scores of overall daily function but not on most neurologic scales. Further study of this approach is advised.

Side Effects of Dopamine Treatment and Their Management

The side effects of L-dopa are at times significant to the degree that its continuation cannot be tolerated. Some patients are at first troubled by nausea, although this can be mitigated by taking the medication with meals. Nausea usually disappears after several weeks of continued use or can be allayed by the specific dopaminergic chemoreceptor antagonist domperidone. A few have mild orthostatic hypotensive episodes.

The most troublesome effects of L-dopa as the disease advances, usually after several years of treatment, are end-of-dose reduction in efficacy and the induction of involuntary "dyskinetic" movements—restlessness, head wagging, grimacing, lingual-labial dyskinesia, blepharospasm, and especially, choreoathetosis and dystonia of the limbs, neck, and trunk. A decline in efficacy at the end of the dose interval, typically 2 to 4 h, may be treated by more frequent dosing, the addition of dopaminergic agonist, or a COMT inhibitor.

The on–off or off phenomenon is a rapid and sometimes unpredictable change—in a matter of minutes or from 1 h to the next—from a state of relative freedom from symptoms to one of nearly complete immobility. Both dyskinesias and severe "off" periods appear in approximately 75 percent of patients within 5 years. Few patients escape these opposing effects, forcing an increased frequency of administration and usually a reduction in dosage.

If involuntary dyskinetic movements are induced by relatively small doses of L-dopa, the problem may be suppressed to some extent by the addition of direct-acting dopaminergic agents or by the concurrent administration of amantadine, or by the use of an oral suspension of L-dopa as mentioned earlier. The use of lower doses of long-acting preparations of L-dopa may be helpful in reducing dyskinesias and the atypical antipsychotic medications have been said to be useful for this purpose but carry their own risks.

The onset of psychiatric symptoms coincident with the use of L-dopa or dopamine agonists may also present problems and is to be expected eventually in 15 to 25 percent of patients, particularly in the elderly. Confusion and outright psychosis (hallucinations and delusions) are seen in advanced cases of Parkinson disease when high doses of L-dopa are required and the disease has been present for many years. This may first be treated by reducing the dose of the drug. If this is not tolerated, the atypical neuroleptics olanzapine, clozapine, risperidone, or quetiapine may be given in low doses. The side effects of these drugs include sleepiness, orthostatic hypotension, and sialorrhea. As noted above, clozapine has been said to provide an additional benefit of suppressing dyskinesias in advanced Parkinson disease, but its hematologic risks have led to limited use. Although useful in the treatment of frankly psychotic patients, these drugs tend to be far less effective once dementia has supervened. The antiepileptic drug, valproate is also said to be useful in this circumstance, but it has not been as effective as clozapine and related drugs. Despite its lesser tendency to produce rigidity, olanzapine, and probably the other similar agents, in high doses may slightly worsen motor disability.

Depression, although frequent, is only occasionally a serious problem, even to the point of suicide. Delusional thinking may also occur in these circumstances. This combination of movement and psychiatric disorders is difficult to treat, and one is faced with instituting an antidepressant regimen or perhaps using one of the newer classes of antipsychotic medications that have the least extrapyramidal side effects (see below). While the selective serotonin reuptake inhibitors have been useful in cases of apathetic depression, they may cause slight worsening of parkinsonian symptoms. Trazodone has been helpful in treating depression and insomnia, the latter also being a major problem in some patients. Excitement and aggressiveness appear in a few. A return of libido may lead to sexual assertiveness. Other curious effects of excessive drive from L-dopa and dopamine agonists have been pathologic gambling (the same has been seen in treatment of restless legs syndrome) and cross-dressing (Quinn et al, 1983).

Anticholinergic agents or L-dopa should not be discontinued abruptly in advanced Parkinson disease. If abruptly discontinued, the patient may become totally immobilized by a sudden and severe increase of tremor and rigidity; rarely, a neuroleptic syndrome, sometimes fatal, has been induced by such withdrawal. Reducing the medication dose over a week or so is usually adequate.

With progressive loss of nigral cells, there is an increasing inability to store L-dopa and periods of drug effectiveness become shorter. In some instances, the patient becomes so sensitive to L-dopa that 50 to 100 mg will precipitate dyskinesias; if the dose is lowered by the same amount, the patient may develop disabling rigidity. With the end-of-dose loss of effectiveness and the on–off phenomenon, which with time become increasingly frequent and unpredictable, the patient may experience pain, respiratory distress, akathisia, depression, anxiety, and even hallucinations. Some patients function quite well in the morning and much less well in the afternoon, or vice versa. In such cases, and for end-of-dose and on–off phenomena, one must titrate the dose of L-dopa and use more frequent dosing during the 24-h day; combining it with a dopamine agonist or a long-acting preparation may be helpful. Sometimes temporarily withdrawing L-dopa and at the same time substituting other medications may reduce the on–off phenomenon.

Based on the principle that alimentary-derived amino acids compete for absorption of L-dopa, the use of a low-protein diet has been advocated as a means of controlling the motor fluctuations (Pincus and Barry). Symptoms can sometimes be reduced by the simple expedient of eliminating dietary protein from breakfast and lunch. Moreover, this dietary regimen may permit the patient to reduce slightly the total daily dose of L-dopa. Such dietary manipulation is worth trying in appropriate patients; it is not harmful, and most of our patients with advanced disease who have persisted with this diet have reported improvement in their symptoms or an enhanced effect of L-dopa. A novel observation by Pierantozzi and colleagues has been that the absorption of L-dopa may be influenced by the presence of gastric Helicobacter pylori infection and that eradication of the organism was associated with longer "on" time.

Surgical Measures

Until recently, success with L-dopa had replaced the use of the ablative surgical therapy pioneered by Cooper 50 years ago. The surgical approaches involved the placement of lesions in the globus pallidus, ventrolateral thalamus, or subthalamic nucleus, contralateral to the side of the body chiefly affected. The best results were obtained in relatively young patients, in whom unilateral tremor or rigidity rather than akinesia were predominant. The symptoms that responded least well to surgical therapy in Cooper's patients were postural imbalance and instability, paroxysmal akinesia, bladder and bowel disturbances, dystonia, and speech difficulties.

More recently, through the work of Laitinen, Leksell, and others, this mode of therapy has been revived as a stereotactically guided procedure and advanced by the newer technique of implanted electrodes (deep brain stimulation, DBS). For the treatment of Parkinson disease, the electrodes are placed in the posterior and ventral (medial) parts of the subthalamic nucleus or in the internal segment of the globus pallidus. Most patients who have DBS experience enhanced responsiveness to L-dopa and a reduction of drug-induced dyskinesias. Bilateral stimulation of the subthalamic nucleus has produced improvement in all features of the disease, including in bradykinesia, that is lost after several years, but there is generally little benefit for impaired gait and balance (Limousin et al; Weaver et al, who conducted a more extensive study but for only 6 months). A study by the Deep-Brain Stimulation for Parkinson's Disease Group demonstrated at least short-term benefit in motor fluctuations after the bilateral implantation of stimulating electrodes in the subthalamic nuclei and the durability of this effect with continued DBS in subsequent studies ranged from 2 to 7 years.

The ideal candidates for DBS are considered to be those in whom, after several years, there is a failure of medications to relieve symptoms but especially because of unmanageable dyskinesias that result from L-dopa. A randomized, blinded trial by Deuschl and colleagues confirmed this effect and demonstrated an overall improvement in the quality of life at 6 months. The benefit with bilateral stimulation of the globus pallidus has been essentially equivalent to results from subthalamic stimulation (Follett et al). Dystonia, when present as part of the native disease or as a result of medication, may also benefit from this treatment, perhaps more so with pallidal stimulation. Several groups have pointed out that cognitive function may decline slightly with DBS, but deterioration is not as prominent in some spheres of performance, such as speed of processing, with stimulation of the globus pallidus. Hemorrhage into the basal ganglia and local infection near the stimulator has occurred in a small number of patients so treated. Depression and suicides also appear as adverse events in some stimulation trials.

The typical patient who will derive benefit from deep-brain stimulation is considered to be one who, to maintain mobility, requires a dose of L-dopa that produces unacceptable dyskinesias and who is constantly cycling between on and off periods. More recently, DBS has been introduced earlier in the course of illness, when the patient is still largely responsive to L-dopa and before severe motor complications such as dyskinesias arise. These patients are, of course, younger and have had a shorter duration of disease. In a trial conducted by Schuepbach and coworkers, in patients with mean durations of illness of 7.5 years and 52 years of age, there was a significant and sustained benefit in quality of life measures, motor complications and on time, for subthalamic DBS.

The stimulator is inserted in a pouch that is created near the rostral pectoral muscle and inferior to the clavicle. An external controller allows the stimulator to be adjusted for which 4 electrodes on either side are activated and their polarity, voltage applied, frequency of pulses, and pulse duration are manipulated. All patients with implanted electrodes require frequent initial contact with a physician experienced in programming the stimulator. Some patients can make minor adjustments or even turn off the stimulator on their own with a small control device that has preset limits. The battery must be exchanged periodically, the duration of service depending on the voltage used over time and other parameters of use. A comprehensive review of the subject has been given by Okun, including comments on the controversies regarding the differences in cognitive disturbance and the reduction in L-dopa doses comparing stimulation of the globus pallidus with the subthalamic nucleus.

Presumably, the high-frequency electrical impulses cause a disruption of local neuronal activity that is the functional equivalent of an ablative lesion, but the effects of deep brain stimulation may be more complex by way of stimulating neurotransmitter release.

The cerebral implantation of fetal dopaminergic tissue provided a modest improvement in motor function for a limited period of time (Spencer et al; Freed et al). The study by Freed and colleagues found a small improvement on a global scale that measured functional, psychologic, and neurologic aspects only in younger patients but the effect waned by 1 year. These procedures are hampered by many difficulties, mainly in obtaining tissue and the failure of grafts to survive but also the problem of uncontrollable dyskinesias in some patients. Another provocative approach has been the delivery of neural trophic factors directly or in a viral vector through a small catheter; at least 2 trials have failed to show benefit. Similarly, the implantation of stem cells is being explored but has several obstacles.

Techniques of focused ultrasound energy to produce ablative lesions in deep nuclei are being developed. So far, they have found use for the treatment of essential tremor, such as in the trial conducted by Elias with thalamic lesions (ventral intermediate nucleus).

Ancillary Treatments

In the management of the patient with Parkinson disease, one must not neglect the maintenance of general health and neuromuscular efficiency by a program of exercise, activity, and rest; physical therapy and exercises such as those performed in yoga may be of help in achieving these ends. Sleep may be aided by soporific antidepressants. Postural imbalance and falls can be greatly mitigated by the use of a cane or walking frame. A number of excellent exercise programs have been devised specifically for patients with Parkinson disease, and measures such as massage and yoga have their advocates. Among these mechanical therapies that have been studied systematically, tai chi has been found to improve balance and reduce falls as measured by objective criteria (Li et al), indicating that these approaches are of substantial value. Several of our patients have taken up dancing and report that their balance in daily circumstances is improved. Our position has been that any activity that keeps the patient moving and committed is of great value. Speech exercises help the motivated patient.

Hypotensive episodes respond to fludrocortisone or midodrine given each morning. Focal dystonias of the foot are partially treatable with local injections of botulinum toxin. In addition, the patient often needs emotional support in dealing with the stress of the illness, with the anxiety that seems to be an integral part of the disease in some patients, in comprehending the future, and in carrying on courageously in spite of it.

Multiple System Atrophy (Striatonigral Degeneration, Shy-Drager Syndrome, Olivopontocerebellar Degeneration)

As the name multiple system atrophy indicates, this depicts a group of disorders characterized by neuronal degeneration mainly in the substantia nigra, striatum, autonomic nervous system, and cerebellum. Following a report in 1964 by Adams and colleagues of what was then called striatonigral degeneration, many patients were recognized in whom the changes of striatonigral and olivopontocerebellar degeneration were combined and who had symptoms and signs of cerebellar ataxia and parkinsonian manifestations. The pathologic changes were found by chance in 4 middle-aged patients, in 3 of whom a parkinsonian syndrome had been described clinically, none with a family history of similar disease. Rigidity, stiffness, and akinesia had begun on one side of the body, then spread to the other, and progressed over a 5-year period but with minimal characteristic tremor of idiopathic Parkinson disease. A flexed posture of the trunk and limbs, slowness of all movements, poor balance, mumbling speech, and a tendency to faint when standing were other elements. There was an early-onset cerebellar ataxia in the fourth patient that was later obscured by a Parkinson syndrome.

The postmortem examinations disclosed extensive loss of neurons in the zona compacta of the substantia nigra, but notably, there were no Lewy bodies or neurofibrillary tangles in the remaining cells. Even more striking were the degenerative changes in the putamina and to a lesser extent in the caudate nuclei. Secondary pallidal atrophy (mainly a loss of striatopallidal fibers) was present. In the patient with ataxia there was, in addition, advanced degeneration of the pons, olives, and cerebellum (see below in the discussion of olivopontocerebellar degeneration).

Recognizing that the clinical and pathologic features of striatonigral degeneration, with or without autonomic failure, can coexist with olivopontocerebellar atrophy, Graham and Oppenheimer proposed the term multiple system atrophy (MSA), which has gained wide acceptance. Several large series of cases of this complex syndrome have been published, providing a perspective on the frequency and nature of its component syndromes. Either parkinsonism or cerebellar ataxia may predominate. In many writings they are categorized as MSA-P and MSA-C, respectively, depending on whether they display predominantly parkinsonism or cerebellar ataxia. More than half of the patients with striatonigral degeneration have orthostatic hypotension, which proves at autopsy to be associated with loss of intermediolateral horn cells and pigmented nuclei of the brainstem. This combined parkinsonian and autonomic disorder, formerly referred to as the Shy-Drager syndrome, was alluded to in Chaps. 18 and 26 and is now termed MSA-A, for multiple system atrophy with autonomic changes. In addition to orthostatic hypotension, other features of autonomic failure include erectile dysfunction loss of sweating, dry mouth, miosis, and urinary retention or incontinence. Vocal cord palsy is an important and sometimes initial manifestation of the disorder; it may cause dysphonia or stridor and airway obstruction requiring tracheostomy. A dusky discoloration of the hands as a sign of this disorder was ascribed to poor control of cutaneous blood flow by Klein and colleagues. A diagnostic problem arises in that orthostatic hypotension is also observed in up to 15 percent of patients with Parkinson disease, a feature that may be exaggerated by medications, but the degree of drop in blood pressure is far greater and more frequent in patients with this form of multiple system atrophy.

In the Brain Tissue Bank of the Parkinson Disease Society of Great Britain, MSA accounted for 13 percent of patients who had been identified during life as having idiopathic Parkinson disease. All the patients with MSA had one or more symptoms of autonomic failure (postural hypotension, urinary urgency or retention, urinary or fecal incontinence, erectile dysfunction) and dysphonia or stridor. Babinski signs were present in half the patients and cerebellar ataxia in one-third. Tremor was rare. Males were affected more often than females. In a comparable series of 100 patients (67 men and 33 women) studied by Wenning and coworkers (1994), the disease began with a striatonigral-parkinsonian syndrome in approximately half; often it was asymmetrical at the onset. Mild tremor was detected in some but in only a few was it of the "resting" Parkinson type. In nearly half, the illness began with autonomic manifestations; orthostatic hypotension occurred eventually in almost all patients, but it was disabling in only a few. Cerebellar features dominated the initial stages of the disease in only 5 percent, but ataxia was eventually obvious in half the larger group. This ataxic clinical presentation of multiple system atrophy will be elaborated further in the section on the degenerative cerebellar ataxias.

The extrapyramidal illness, on the whole, is more severe than in Parkinson disease, as more than 40 percent of patients are confined to a wheelchair or otherwise severely disabled within 5 years. These observations generally match the findings in the group described by Quinn and colleagues (1986), but they emphasized that pyramidal signs were present in 60 percent.

Colosimo and colleagues reviewed the clinical findings in 16 pathologically verified cases of MSA and found that several signs, namely, relative symmetry of the signs and rapid course, the lack of response to L-dopa, absence or minimal amount of tremor, and the early presence of autonomic disorders, reliably distinguished this syndrome from Parkinson disease. These observations are in keeping with our own and we would add that abnormalities of eye movement are not prominent in MSA. Additional features occurring occasionally in MSA are remarked upon in other series; anterocollis or dystonia of the lower facial muscles, for example, is striking in a few cases. It is noteworthy that levodopa has had little or no effect or has made these patients worse early in the disease but we have seen exceptions. The lack of L-dopa effect is probably attributable to the loss of striatal dopamine receptors.

The diagnosis of MSA, especially the form with ataxia, has been aided by imaging techniques. Both MRI and CT scanning frequently show atrophy of the cerebellum and pons in those with cerebellar features. The putamina are hypointense on T2-weighted MRI and may show an increased deposition of iron in the parkinsonian form. In the cerebellar form, a "hot cross bun" sign has been emphasized on MRI; it reflects atrophy of the pontocerebellar fibers that manifest high T2 signal intensity in an atrophic pons. Studies with PET have disclosed impairment of glucose metabolism in the striatum and to a lesser extent in the frontal cortex, a reflection, no doubt, of the loss of functioning neuronal elements in these parts.

Finally, despite the concurrence of striatonigral degeneration, olivopontocerebellar degeneration, and the Shy-Drager syndrome, each of these disorders can occur in almost isolated clinical form; we therefore retain their original designations.

Although the cause of this process is not known, and the majority of cases are sporadic, The Multiple System Atrophy Research Collaboration identified a mutation in the COQ2 gene, coding for a protein involved in the synthesis of coenzyme Q10, in both familial cases and a very small proportion of sporadic ones.

Pathology

In recent years, attention has been drawn to the presence of abnormal staining material in the cytoplasm of astroglia and oligodendrocytes and in some neurons as well. These cytoplasmic aggregates have been referred to as glial cytoplasmic inclusions (Papp et al). Although they bear little resemblance morphologically to other discrete inclusions that have come to be accepted as characteristic of certain degenerative CNS diseases (e.g., Lewy bodies), they nonetheless contain α-synuclein (the main component of Lewy bodies). It is not clear to us whether these glial cytoplasmic accumulations represent a histopathologic hallmark of MSA as suggested by Chin and Goldman and by Lantos, as their presence is not specific; they have been identified in practically every degenerative disease that has been subjected to sensitive silver impregnation stains. Many types of inclusions are, of course, nonspecific, as, for example, α-synuclein–positive inclusions have been detected in several neurodegenerative syndromes. Appropriate control studies to determine whether the glial inclusions are found in nondegenerative lesions in brain (at the edge of an infarct, for example) are needed. Also lacking is information about the frequency of these cytoplasmic inclusions in relation to the aging brain.

Progressive Supranuclear Palsy

In 1963, Richardson, Steele, and Olszewski crystallized medical thought about a clinicopathologic entity—progressive supranuclear palsy (PSP)—to which there had been only ambiguous reference in the past. The condition is not rare. By 1972, when Steele reviewed the subject, 73 cases (22 with postmortem examinations) had been described in the medical literature. Rare familial clusters have been described in which the pattern of inheritance is compatible with autosomal dominant transmission (Brown et al; de Yébenes et al). Rojo and coworkers described 12 pathologically confirmed pedigrees and made note of the variable phenotypical expression of the disease even within a single pedigree. No toxic, encephalitic, racial, or geographic factor has been incriminated.

Clinical Features

The disease has its onset typically in the sixth decade (range: 45 to 75 years), with some combination of difficulty in balance, abrupt falls, visual and ocular disturbances (giving the syndrome its name), slurred speech, dysphagia, and sometimes vague changes in personality, including apprehensiveness and fretfulness suggestive of an agitated depression. The most common early complaint is unsteadiness of gait and unexplained falling without loss of consciousness. The patient has difficulty in describing his imbalance, using terms such as "dizziness," "toppling," or an ambiguous problem with walking. At first, the neurologic and ophthalmologic examinations may be unrevealing, and it may take a year or longer for the characteristic syndrome comprising supranuclear ophthalmoplegia, pseudobulbar palsy, and axial dystonia to develop fully.

Difficulty in voluntary vertical movement of the eyes, often downward but sometimes only upward, and later impairment of voluntary saccades in all directions are characteristic. A related but more subtle sign has been the finding of hypometric saccades in response to an optokinetic drum or striped cloth moving vertically in one direction (usually best seen with stripes moving downward). Later, both ocular pursuit and refixation movements are delayed and diminished in amplitude and eventually all voluntary eye movements are lost, first the vertical ones and then the horizontal ones as well. However, if the eyes are fixated on a target and the head is turned slowly, full movements can be obtained, demonstrating the supranuclear, nonparalytic character of paralysis of ocular pursuit. Other prominent oculomotor signs are sudden jerks of the eyes during fixation, "cogwheel" or saccadic choppiness of pursuit movements, and hypometric saccades of long duration (Troost and Daroff). The Bell phenomenon (reflexive upturning of eyes upon forced closure of the eyelids) and the ability to converge are also lost eventually, and the pupils become small but remain round and reactive to both light and to accommodative stimuli. The upper eyelids may be retracted, and the wide-eyed, unblinking stare imparts an expression of perpetual surprise. Blepharospasm and involuntary eye closure are prominent in some cases. In the late stages, the eyes may be fixed centrally and all oculocephalic and vestibular reflexes are lost. It should be emphasized, however, that a proportion of patients do not demonstrate these eye signs for a year or more after the onset of the illness. We have also followed several patients who had no disorder of eye movement during life but in whom the typical pathologic changes of PSP were nonetheless found. In one such patient, there was a subcortical type of dementia; in another, focal limb dystonia and parkinsonism. Furthermore, other degenerative conditions can manifest a supranuclear vertical gaze disorder, although never to the extent seen in PSP; these include corticobasal-ganglionic degeneration, Lewy-body disease, Parkinson disease, and Whipple disease.

The gait disturbance and repeated falling have proved difficult to analyze, as discussed in Chap. 7. Walking becomes increasingly awkward and tentative; the patient has a tendency to totter and fall repeatedly, but has no ataxia of gait or of the limbs and does not manifest a Romberg sign or orthostatic tremor. Some patients tend to lean and fall backward (retropulsion). One of our patients, a large man, fell repeatedly, wrecking household furniture as he went down, yet careful examination provided no clue as to the basic defect in this "toppling" phenomenon. Along with the oculomotor and balance disorders, there is a gradual stiffening and extension of the neck (in one of our patients it was sharply flexed in a manner consistent with camptocormia) but this is not an invariable finding. The face acquires a staring, "worried" expression with a furrowed brow (a result of the tonic contraction of the procerus muscle), made more striking by the paucity of eye movements. A number of our patients have displayed mild dystonic postures of a hand or foot, especially as the illness advanced but occasionally early on. The limbs may be slightly stiff and there are Babinski signs in a few cases.

The stiffness, slowness of movement, difficulty in turning and sitting down, and hypomimia may suggest a diagnosis of Parkinson disease. However, the facial expression of the PSP patient is more a matter of tonic grimace than of lack of movement, and the lack of tremor, the erect rather than stooped posture, and prominence of oculomotor abnormalities serve to distinguish the 2 disorders. The signs of pseudobulbar palsy are eventually prominent, and this feature, along with the eye movements, distinguishes the process most conspicuously from other degenerative conditions. The face becomes less expressive ("masked"), speech is slurred in a slowed spastic fashion, the mouth tends to be held open, and swallowing is difficult. Forced laughing and crying, said to be infrequent, have been present in about half of our cases late in the course. Many patients complain of sleep disturbances. The total sleep time and REM sleep are reduced, and spontaneous awakenings during the night are more frequent and longer than in normal individuals of the same age. Complaints of urinary frequency and urgency have also been frequent in advanced cases under our care.

The diagnosis often proves difficult to make if the main features are not outstanding. Other features, such as tremor, palilalia, myoclonus, chorea, orofacial dyskinesias, and disturbances of vestibular function, are observed in some cases. Finally the patient becomes anarthric, immobile, and quite helpless. Dementia of some degree is probably present in many cases, but is mild in most. Some patients do become forgetful and appear apathetic and slow in thinking; many others are irritable or at times euphoric. Dubois and colleagues proposed an "applause sign" as distinctive to this disease; the patient fails to stop clapping after being asked to do so only 3 times, but we are unable to corroborate this.

By MRI one can, in advanced cases, appreciate atrophy of the dorsal mesencephalon (superior colliculi, red nuclei) giving rise to a "mouse ears" configuration (Fig. 39-7), but these changes may not be evident early in the illness when diagnosis is most difficult. Several measurements of midbrain atrophy have been proposed as aiding diagnosis; for example, there is little overlap between PSP, multiple system atrophy, and Parkinson disease in the ratio of midbrain-to-pons cross-sagittal area, according to Oba and colleagues. The CSF remains normal. Nonetheless, the diagnosis continues to rest on the clinical features, mainly affecting eye movements.

Figure 39-7.

Progressive supranuclear palsy. T2-weighted axial MRI showing the atrophic dorsal midbrain that gives rise to the "mouse ears" (also "Mickey mouse") appearance.

Pathology

Postmortem examinations have disclosed a bilateral loss of neurons and gliosis in the periaqueductal gray matter, superior colliculus, subthalamic nucleus, red nucleus, pallidum, dentate nucleus, and pretectal and vestibular nuclei, and to some extent in the oculomotor nucleus. The expected loss of the myelinated fiber bundles arising from these nuclear structures has also been commented upon. The remarkable finding has been the neurofibrillary degeneration of many of the residual neurons. The neurofibrillary tangles are thick and often composed of single strands, either twisted or in parallel arrangement. The neurons of the cerebral cortex have been involved in some cases (shown by staining of tau protein), but these changes do not correlate with dementia. The cerebellar cortex is usually spared.

The cause and nature of this disease remain obscure. Though some clinical and pathologic heterogeneity is seen, the majority of cases of PSP conform to the typical pattern as we have just described. These interesting diagnostic and clinicopathologic aspects are summarized by Williams and Lees. Studies with PET demonstrate a decrease in blood flow, most marked in the frontal lobes, and a lesser extent of oxygen utilization in central structures (Leenders et al). Striatal dopamine formation and storage are significantly decreased when compared with control values. Much current interest has been directed to the neurofibrillary tangles and tau deposition in PSP and a potential link to the tau pathology displayed in frontotemporal dementia and in corticobasalganglionic degeneration (see below). As summarized by Golbe, certain tau gene haplotypes on chromosome 17p (the same site implicated in familial frontotemporal dementia) are more often associated with PSP than in unaffected individuals, but other factors, environmental or genetic, must also be involved. It is intriguing that the tau-gene haplotype of frontotemporal dementia is not found in PSP. A recent investigation into the mechanism of postural instability using functional imaging, showed a correlation between gait instability and decreased thalamic glucose metabolism and activation (Zwergal).

PSP should be suspected whenever an older adult inexplicably develops a state of imbalance, frequent falls with preserved consciousness, and variable extrapyramidal symptoms, particularly dystonia of the neck, ocular palsies, or a picture resembling pseudobulbar palsy. If the typical abnormalities of eye movements are present, the diagnosis is not difficult. When only a parkinsonian syndrome without tremor is apparent the main diagnostic consideration is striatonigral degeneration or the corticobasalganglionic syndrome, described below.

Treatment

L-Dopa has been of slight and unsustained benefit in some of our patients, and combinations of L-dopa and anticholinergic drugs have been entirely ineffective in others. A marked response to these drugs should, of course, suggest the diagnosis of Parkinson disease. Recently, the drug zolpidem, a gabanergic agonist of benzodiazepine receptors, has been reported to ameliorate the akinesia and rigidity of PSP (Daniele et al); however, these observations require corroboration. Benztropine or trihexyphenidyl has been somewhat helpful in reducing dystonia but botulinum injections may be a better alternative if there are focal signs. Treatments of the sleep difficulties and urinary incontinence are of great assistance to the patient and family. A feeding tube becomes necessary in advanced cases. Observing the decline of these patients and the limitations of treatment is a frustrating ordeal for all involved.

Corticobasal Degeneration

Most neurologists have observed elderly patients in whom the essential abnormality was a progressive asymmetrical extrapyramidal rigidity combined with signs of corticospinal disease. Sometimes a mild postural action tremor beginning unilaterally and suggestive in some respects of Parkinson disease has been added. The parkinsonism is generally unresponsive to L-dopa. These cases have come to be known by the names corticobasal-ganglionic or cortical-basal degeneration and like sounding terms. The clinical relation of such cases is indeterminate to corticostriatospinal degeneration described earlier, and based on the finding of tau inclusions, to frontotemporal lobar degeneration and to progressive supranuclear palsy.

Wenning and colleagues (1998) described a series of such patients in whom the diagnosis was confirmed at postmortem examination. The most common early symptom was an asymmetrical clumsiness of the limbs, in half of the patients, with rigidity and, in one-fifth, with tremor; these features are now considered to be the most characteristic early features of the process. As the illness progressed, almost all the patients developed an asymmetric or unilateral akinetic-rigid syndrome, which may be considered the essential motor disorder of this disease and various forms of gait disorder and dysarthria. Stimulus-induced or spontaneous myoclonus and pyramidal signs, mentioned in other reports and frequent in our cases, were not prominent in their series; limitations of vertical gaze and frontal lobe release signs eventually became apparent in half.

Eventually, although able to exert considerable muscle power, these patients cannot effectively direct their voluntary actions. Attempts to move a limb to accomplish some purposeful act might result in a totally inappropriate movement, always with great enhancement of rigidity in the limb and in other affected parts, or the limb may drift off and assume an odd posture, such as a persistent elevation of the arm without the patient's awareness—a kind of catalepsy. The disorder of limb function has some of the attributes of a limb-kinetic or an ideomotor apraxia (see Chap. 3), but the hand postures, involuntary movements, and changes in tone are at times more of the type described as "alien hand." Some patients exhibit anosognosia, Babinski signs, impaired eyelid or ocular motion (upgaze paresis or abnormal saccadic movements), lingual dyskinesias, frontal release signs, myoclonus, or dysarthria.

Another distinct group has dementia as an early feature, as described by Grimes and colleagues, but mental deterioration is more often late and may not occur in all patients. There are also rare patients who present with behavioral disturbance or nonfluent aphasias as early features, which are difficult to distinguish from subtypes of frontotemporal dementia (Lee and colleagues, 2011). Occasionally, there is some involvement of lower motor neurons with resulting amyotrophy. Several of our patients had myoclonus as an early feature, one displaying it only on one side of the face, the other in an arm. The condition progresses for 5 years or more before some medical complication overtakes the patient.

Postmortem examination of patients, originally reported by Rebeiz and colleagues, disclosed a combination of findings that differentiated the disease process from other neurodegenerative conditions. Cortical atrophy (mainly in the frontal motor–premotor and anterior parietal lobes) was associated with degeneration of the substantia nigra and, in one instance, of the dentatorubrothalamic fibers. The loss of nerve cells was fairly marked, but there was no gross lobar atrophy, as occurs in Pick disease. The neuronal degeneration was more on one side of the brain than the other. There was moderate gliosis in the cortex and underlying white matter. The disease is now clearly considered to be related to tau deposition in specific brain structures; however, the original authors were more impressed with ballooned and chromatolytic neurons with eccentric nuclei, a state that was called neuronal achromasia. The presence of these achromatic cells in posterior frontal and parietal neurons continues to be considered an essential feature of the disease, although the rounded areas within neurons stain for tau and resemble globose tangles that are found occasionally in Alzheimer disease (corticobasal bodies); in this way, CBD is connected to the other tau-related neurodegenerative diseases, "tauopathies." In addition, adjacent glia are filled with various configurations of tau protein, thereby linking the disease to frontotemporal lobar degeneration and PSP. Our colleague Feany, with Dickson, has identified one type of these as "plaques" in the cortex that are composed of tau aggregates within the distal processes of astrocytes.

Both CT and MRI have demonstrated asymmetrical cerebral and pontine atrophy, and PET studies have revealed thalamoparietal metabolic asymmetries—a greater reduction of glucose metabolism on the side of the most extensive lesion (Riley et al).

There are no clues as to the pathogenesis of this disease. There are rare familial types but no definite genetic cause has been identified. No organ other than the CNS is affected. The progression is relentless. None of the drugs in common use for spasticity, rigidity, and tremor has been helpful.

Dystonic Disorders

Dystonia Musculorum Deformans (Torsion Dystonia)

Dystonia as a symptom was discussed in Chaps. 4 and 6. Here we are concerned with a disease or diseases of which dystonia is the major manifestation. Schwalbe's account, in 1908, of 3 siblings of a Jewish family who were afflicted with progressive involuntary movements of trunk and limbs probably represents the first description of a disease in which severe and progressive dystonia was the sole manifestation. In 1911, Oppenheim contributed other cases and coined the term dystonia musculorum deformans in the mistaken belief that the disorder was primarily one of muscle and always associated with deformity. Flatau and Sterling, in the same year, first suggested that the disease might have a hereditary basis and gave it the more accurate name torsion dystonia of childhood. At first the condition was considered by some to be a manifestation of hysteria; only later was it recognized as a neurologic entity with a predilection for individuals of Eastern European Jewish origin. Soon thereafter, a second hereditary form of torsion dystonia, affecting non-Jews, was observed. The recessive form begins in early childhood, is progressive over a few years, and is restricted to Jewish patients. The dominant form begins later, usually in late childhood and adolescence, progresses more slowly, and is not limited to any ethnic group.

As indicated in Chap. 6, most instances of idiopathic (primary) dystonias that come to our attention, particularly the segmental or restricted types, do not conform to the classic hereditary disorders as defined above, although some may represent limited variants of the disease. In general, these more restricted types have a later onset and a relatively milder, more slowly progressive course, with a tendency to involve an axial or a distal region alone. Only the paravertebral, cervical, or cranial muscles may be involved (focal dystonia including torticollis and writer's cramp), with little change from year to year. The clinical classification of the predominantly adult-onset dystonias is made more complex by the fact that both the restricted and generalized forms may be sporadic or genetic. Molecular genetic studies, although still incomplete, hold the promise of clarifying the classification of the heritable dystonias. More than 10 types have been distinguished by genetic mapping, as summarized by Németh. The most important of these is an abnormal gene (DYT1, also known as TOR1A) on chromosome 9q, which codes for the protein, torsin A in both Jewish and non-Jewish families. The most common DYT1 mutation, causing deletion of a single glutamate from the torsin A peptide, is found in most cases of dystonia musculorum deformans. This disease is inherited in an autosomal dominant pattern. Although the penetrance of the clinical trait in these families is low, PET demonstrates hypermetabolism in the cerebellum, lenticular nuclei, and supplementary motor cortex in all carriers of the mutated gene.

The function of torsin A is not fully defined. It is present in neurons throughout the brain and has adenosine triphosphate (ATP) binding and nuclear localization. It may function as a chaperone protein that shuttles other proteins in and out of cells. A current speculation, shared with other degenerative disease, is that the absence of torsin A renders neurons unduly sensitive to oxidative stress (Walker and Shashidharan).

Although DYT1 mutations account for the majority of inherited cases of generalized dystonia, they are also implicated in a small proportion of the more restricted dystonias, particularly blepharospasm (see further on). Some individuals in families affected with generalized dystonia will demonstrate only localized forms (e.g., writer's cramp or torticollis). The general rule stated above still holds, namely, that the inherited variety (dystonia musculorum deformans) related to DYT1 manifests early in life and begins in one limb and then spreads to most muscles of the body, while in the common dystonias (mostly sporadic but some heritable) the disease remains confined to the craniocervical or another region, does not generalize, and has an adult onset.

Clinical Features

The first manifestations of the generalized disease may be rather subtle. Intermittently, and usually after activity (late in the day), the patient (usually a child between 6 and 14 years of age, less often an adolescent) begins to invert one foot, to extend one leg and foot in an unnatural way, or to hunch one shoulder, raising the question of a nervous tic. As time passes, the motor disturbance becomes more persistent and interferes increasingly with the patient's activities. Soon the muscles of the spine and shoulder or pelvic girdle become implicated in involuntary spasmodic twisting movements. The cardinal feature of these severe dystonic muscle contractions is the simultaneous contraction of both agonists and antagonists at a joint. These cocontraction spasms are intermittent at first; in intervals that are free of the dystonia, muscular tone and volitional movements are normal. In some instances, the muscles are hypotonic. Gradually, the spasms become more frequent; finally, they are continuous and the body may become grotesquely contorted, as shown in Fig. 4-5A. Lateral and rotatory scoliosis uniformly results as secondary deformities. For a time, recumbency relieves the spasms, but later on position has no influence. The hands are seldom involved, although at times they may be held in a fisted posture. Cranial muscles do not escape, and in a few instances a slurring, staccato-type speech was the initial manifestation. Uncontrollable blepharospasm was the initial disorder in one of our patients; in two others, severe dysarthria and dysphagia were the first signs, caused by dystonia of the tongue, pharyngeal, and laryngeal muscles.

Other manifestations include torticollis, tortipelvis, dromedary gait, propulsive gait, action tremor, myoclonic jerks during voluntary movement, and mild choreoathetosis of the limbs. Excitement worsens the dystonia and sleep abolishes it. As the years pass the postural distortion may become fixed to the point where it does not disappear even in sleep. Tendon reflexes are normal, corticospinal signs are absent, and there is no ataxia, sensory abnormality, convulsive disorder, or dementia.

Pathology

No agreement has been reached concerning the pathologic substrate of the disease. None of the features of symptomatic dystonia are found, such as the ferrocalcinosis of PKAN, the lesions of Wilson disease, kernicterus, état marbré of neonatal hypoxia, or the cavitation of familial striatal necrosis, lesions have been observed in the basal ganglia. However, in the hereditary forms of dystonia, which are the subject of this section, one cannot be certain of any specific lesions that would account for the clinical manifestations. The brain is grossly normal and ventricular size is not increased. According to Zeman, who reviewed all the reported autopsy studies up to 1970, there were no significant changes in the striatum, pallidum, or elsewhere. This means only that the techniques being used (qualitative analysis of random sections by light microscopy) are inadequate or the problem is subcellular. The report by McNaught and colleagues of perinuclear inclusions in periaqueductal neurons by the use of special immunostaining methods is provocative. There had been tentative interest in elevations of dopamine β-hydroxylase in patients with the autosomal dominant form of the disease, but the meaning of these findings is not clear.

Treatment

Early in the course of the illness, several drugs including L-dopa, bromocriptine, carbamazepine, diazepam, and tetrabenazine seem to be helpful, but only in a few patients, and the benefit is not lasting. Intrathecal baclofen has been somewhat more successful in children. The rare hereditary form of dystonia-parkinsonism (described below) responds well to small doses of L-dopa and dopamine agonists and is exceptional in this respect. Burke and coworkers advocate the use of very high doses (up to 30 mg daily or more) of trihexyphenidyl (Artane). Apparently, dystonic children can tolerate these high doses if the medication is raised gradually, by 5-mg increments weekly. In adults, high-dose anticholinergic treatment is less successful but worthy of a trial. Clonazepam is beneficial in some patients with segmental myoclonus.

Impressive results were obtained in the past by the use of stereotactic techniques that made lesions in the ventrolateral nuclei of the thalamus or in the pallidum-ansa lenticularis region. Some frightfully disabled children, unable to sit or stand, were restored to near normalcy for a time. Approximately 70 percent of the patients in Cooper's series in the 1950s were moderately to markedly improved by unilateral or bilateral operations and, based on a 20-year followup study, the improvement was usually sustained. More recent studies report a somewhat less favorable but nonetheless clear improvement (see Tasker et al; Andrew et al). The main risk of the operation was a corticospinal tract lesion, produced inadvertently by damaging the internal capsule. Bilateral lesions have sometimes been disastrous, causing pseudobulbar palsy. The production of lesions has been supplanted, with success over long periods, by bilateral stimulation of the internal segments of the globus pallidus (Vidailhet and colleagues).

Hereditary Dystonia-Parkinsonism (Segawa Syndrome, Juvenile Dopa-Responsive Dystonia)

This process is discussed here because its main characteristic is a dystonia that is responsive to L-dopa, but most cases also have features of parkinsonism, which is why it was also mentioned in the earlier discussion of hereditary forms of Parkinson disease, especially in young patients. Following the description of the syndrome by Segawa and colleagues in 1976, others drew attention to this unique form of hereditary dystonia (Allen and Knopp; Deonna; Nygaard and Duvoisin). The pattern of inheritance is autosomal dominant and there is no ethnic predilection. Nygaard and colleagues found a linkage to the gene on chromosome 14q for the protein GTP cyclohydrolase 1 (GCH1 gene) that is implicated in the synthesis of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase. It is likely that the mutation impairs the generation of dopamine, a prediction that accords with responsiveness of the parkinsonian and dystonic features to L-dopa. In one autopsied case (an accidental death), there was a reduction in the amount of tyrosine hydroxylase in the striatum and depigmentation but no cell loss in the substantia nigra (Rajput et al). The affected enzyme was reduced in the striatum, as was the level of dopamine.

The dystonic manifestations usually become evident in childhood, usually between 4 and 8 years of age; females outnumber males in a ratio of 3:2. Often the legs are first affected by intermittent stiffening, with frequent falls and peculiar posturing, sometimes the feet assuming an equinovarus position. The arms become involved as well as the truncal muscles; retrocollis or torticollis may appear. Within 4 to 5 years, all parts of the body, including the bulbar muscles, are involved. Mild parkinsonian features (rigidity, bradykinesia, postural instability) can usually be detected early in the course of the illness, but more characteristically they are added to the clinical picture several years later. In our own patients, and in several of those of Deonna, there was rigidity of the limbs as well as slowness of movement and a tremor at rest, all aspects more parkinsonian than dystonic. In still others, the clinical picture has been one of cerebral spastic diplegia.

A remarkable feature is the disappearance or marked subsidence of the symptoms after a period of sleep and worsening as the day progresses. This diurnal variation is shared with many of the inherited forms of Parkinson disease listed in Table 39-3. Fluctuations of symptoms with exercise and menses and in the first month of pregnancy have been observed in some cases.

The special feature of this juvenile dystonia-parkinsonism syndrome is the dramatic response of both the dystonic and parkinsonian symptoms to treatment with L-dopa. As little as 10 mg/kg/d may eliminate the movement disorder and permit normal functioning. Unlike idiopathic Parkinson disease, the medication can be continued indefinitely without the development of tolerance, wearing-off effects, or dyskinesias. Segawa disease accounts for some cases that had in the past been reported as juvenile Parkinson disease.

Torticollis and Other Restricted Dyskinesias and Dystonias (see Chap. 6)

With advancing age, a large variety of focal or regional movement disorders come to light. Various neurophysiologic abnormalities, summarized in Chap. 6, have been implicated. In the common restricted dystonias, localized groups of adjacent muscles manifest arrhythmic cocontracting spasms (i.e., agonist and antagonist muscles are activated simultaneously). The patient's inability to suppress the dystonia and the recognition that it is for the most part beyond voluntary control distinguishes it from tics, habit spasms, and mannerisms described in Chap. 6. If the muscle contraction is frequent and prolonged, it is accompanied by an aching pain that may mistakenly be blamed for the spasm and the involved muscles may gradually undergo hypertrophy. Worsening under conditions of excitement and stress and improvement during quiet and relaxation are typical of this group of disorders and contributed in the past to the mistaken notion that the spasms had a psychogenic origin.

The most frequent and familiar type is torticollis, wherein an adult, more often a woman, becomes aware of a turning of the head to one side while walking. Usually this condition worsens gradually to a point where it may be more or less continuous, but in some patients it remains mild or intermittent for years on end. When followed over the years, the condition is observed to remain limited to the same muscles (mainly the scalene, sternocleidomastoid, and upper trapezius). Rarely, the torticollis is combined with dystonia of the shoulder, arm, and trunk; tremor; facial spasms; or dystonic writer's cramp.

Other restricted dyskinesias involve the neck in combination with facial muscles, the orbicularis oculi (blepharospasm and blepharoclonus), the throat and respiratory muscles (spastic dysphonia, orofacial dyskinesia, and respiratory and phonatory spasms), the hand in writer's cramp (graphospasm) or musician and other performing artist's dystonia, and proximal leg and pelvic-girdle muscles, where dyskinesia is elicited by walking. All these conditions and their treatments are discussed fully in Chap. 6.

Other Forms of Hereditary Dystonia

Several familial movement-induced (kinesogenic) dystonic syndromes and a type that is not kinesogenic and arises suddenly in adolescence, at times with parkinsonian features, have been described. There are other degenerative diseases that combine hereditary dystonia with neural deafness and intellectual impairment (Scribanu and Kennedy) and with amyotrophy in a paraplegic distribution (Gilman and Romanul). These are discussed in greater detail in Chap. 6.

Other important symptomatic dystonias that fall into the category of hereditary dystonia were described in Chap. 37. These are PKAN and calcification of the basal ganglia; of course, Wilson disease may have dystonia as a central feature. Many extrapyramidal diseases, including idiopathic Parkinson disease and progressive supranuclear palsy, may include fragmentary dystonias of the hand, foot, face, or periorbital muscles.

Syndrome of Progressive Ataxia

Wilson wrote that "the group of degenerative conditions strung together by the common feature of ataxia is one for which no very suitable classification has yet been devised," a statement that is not as appropriate today as when it was written 75 years ago. This topic was introduced in Chap. 5 and some of the congenital and acute acquired varieties are mentioned there. Here we consider the chronic, progressive forms of cerebellar disease. Although most of these are familial and are more or less confined to this part of the nervous system, a number of other systems may be involved to varying degrees. Most of the chronic progressive cerebellar diseases are subsumed under the "system atrophies," but no one classification designed to bring order to this category of diseases has proved satisfactory and a preferable genetic classification is emerging.

Setting aside those of congenital type and those caused by a metabolic disorder, Harding (1993) grouped the ataxias by age of onset, pattern of heredity, and associated features. A modification of the classifications of Greenfield and of Harding, which is included in the introductory listing of this chapter, still has clinical value. It divides the progressive cerebellar syndromes into 3 main groups: (1) the spinocerebellar ataxias, with unmistakable involvement of the spinal cord (Romberg sign, sensory loss, diminished tendon reflexes, Babinski signs); (2) the pure cerebellar ataxias, with no other associated neurologic disorders; and (3) the complicated cerebellar ataxias, with a variety of pyramidal, extrapyramidal, retinal, optic nerve, oculomotor, auditory, peripheral nerve, and cerebrocortical accompaniments including what is now referred to as multiple system atrophy.

Without doubt, the advances in molecular genetics of recent years have greatly altered our understanding of the inherited ataxias and have already disclosed a large number of unexpected relationships between mutations and other neural and nonneural disorders. These data are incorporated at appropriate points in the following discussion in Table 39-5, later in this section. Inherited ataxias of early onset (before the age of 20 years) are usually of recessive type; those of later onset are more likely to have a dominant pattern but may be autosomal recessive. Table 39-5 lists several types of ataxias that have a genetic basis. At the time of this writing, 29 types have been listed in the literature, many of limited clinical consequence and low incidence. We have included the main varieties that may be of interest to clinicians because they appear regularly or offer an insight into this class of disorders. At the same time, it should be emphasized that many patients with chronic progressive ataxia have no family history of an ataxia and may have had a spontaneous mutation; even then, the genetic aspects of many cases have not been elucidated.

Table 39-5 Genetic Defects Associated with Spinocerebellar Ataxias (SCA)

Table 39-5 Genetic Defects Associated with Spinocerebellar Ataxias (SCA)

NOTATION

GENE (PROTEIN)

INHERITANCE

AGE OF ONSET

CLINICAL FEATURES IN ADDITION TO ATAXIA

Progressive

Dentatorubropalli-doluysian atrophy (DRPLA)

ATN1 (atrophin1)

ADa

Childhood

Chorea, dystonia, seizures, dementia

SCA1

ATXN1 (ataxin-1)

ADa

Variable

10–25% of dominant ataxias; spasticity, polyneuropathy, ophthalmoparesis, dementia

SCA2

ATXN2 (ataxin-2)

ADa

Teens

Neuropathy, ophthalmoparesis, extrapyramidal features

SCA3 (Machado-Joseph)

ATXN3 (ataxin-3)

ADa

Teens

25% of dominant ataxias, spasticity, neuropathy, extrapyramidal features

SCA6

CACNA1A (alpha1A calcium channel)

ADa

Adult

20% of dominant ataxias; dysarthria, nystagmus, posterior column signs (see episodic ataxia below; gene implicated in familial hemiplegic migraine)

SCA7

ATXN7 (ataxin-7)

ADa

Late teens

Olivopontocerebellar atrophy and syndrome of retinal degeneration, hearing loss, ophthalmoplegia, spasticity; generational anticipation

Infantile

Fulminant, with large CAG expansion

SCA8

ATXN8 (ataxin-8; CTG repeat (noncoding)

AD, AR, sporadic

Adult

Slowly progressive sensory neuropathy, spasticity; known rapid infantile variant

SCA10

ATTCT repeat (ataxin-10)

Teens–adult

Seizures, personality change

SCA11

TTBK2 (serine/threonine kinase)

Adult

Mild phenotype, nystagmus, cerebellar ataxia, neuropathy, dystonia

SCA12

PPP2R2B (protein phosphatase 2A), CAG repeat, noncoding

Adult

Head and hand tremor

SCA13

KCNC3 (Kv3.3 channel)

Childhood

Developmental delay

SCA14

PRKCG (protein kinase C gamma)

Teens–adult

Myoclonus, tremor

SCA15 & 16

ITPR1 (ITPR1)

Varies

Head and hand tremor, gaze palsy

SCA17

TATA (TATA box binding protein, TBP)

ADa

Variable

Cognitive decline, seizures, extrapyramidal features

SCA with tremor

Fibroblast growth factor 14

Childhood

Tremor, cognitive defects, facial dyskinesia

Friedreich ataxia

FXN (frataxin)

Teens

Spinocerebellar ataxia, neuropathy, cardiomyopathy, arrhythmia

Vitamin E deficiency

TTPA (vitamin E transfer protein)

Childhood

Spinocerebellar ataxia, neuropathy, cardiomyopathy, arrhythmia

Episodic

Episodic ataxia with myokymia (EA1, EAM))

KCNA1 (Kv1.1)

Teens

Limb stiffness, dizziness, visual blurring

Paroxysmal episodic ataxia (EA2)

CACNA1A (Cav2.1)

Teens

Nystagmus, vertigo, weakness

Episodic ataxia (EA5)

CACNB4 (calcium channel beta-subunit)

Teens

Seizures, myoclonus, nystagmus

aCAG expansion. AD denotes autosomal dominant, AR autosomal recessive

Early-Onset Spinocerebellar Ataxias (Predominantly Spinal)

Friedreich Ataxia

This is the prototype of all forms of progressive spinocerebellar ataxias and accounts for about half of all cases of hereditary ataxias in most large case series (86 of 171 patients collected by Sjögren); its incidence among Europeans and North Americans is 1.5 cases per 100,000 per year. Friedreich, of Heidelberg, began in 1861 to report on a form of familial progressive ataxia that he had observed among nearby villagers. It was already known through the writings of Duchenne that locomotor ataxia was the prominent feature of spinal cord syphilis, that is tabes dorsalis, but it was Friedreich who demonstrated a nonsyphilitic hereditary type. This concept was greeted with skepticism, but soon Duchenne himself affirmed the existence of the new disease and other case reports appeared in England, France, and the United States. In 1882, in a thesis on this subject by Brousse of Montpelier, Friedreich's name was attached to the entity.

The pattern of inheritance is autosomal recessive. Genetic linkage studies led to the assignment of the gene mutation to chromosome 9q13-2 and subsequently, it was shown that in virtually all cases the mutation is an expansion of a GAA trinucleotide repeat within a gene that codes for the protein frataxin. (It is of interest that this mutation is within an intron). In a small proportion of cases, the mutation is a missense mutation rather than an expansion. In either case, the consequence of the mutation is a reduction in levels of frataxin and loss of its function. Cases in which the mutation allows the presence of some residual protein have a milder course. A current hypothesis is that frataxin is a mitochondrial matrix protein whose function is to prevent intramitochondrial iron overloading.

Clinical Features

Ataxia of gait is nearly always the initial symptom. Difficulties in standing steadily and in running are early symptoms. The hands usually become clumsy months or years after the gait disorder, and dysarthric speech appears after the arms are involved (this is rarely an early symptom). Exceptionally the ataxia begins rather abruptly after a febrile illness, and one leg may become clumsy before the other. In some patients, pes cavus and kyphoscoliosis (scoliosis) are evident well before the neurologic symptoms; in others, they follow by several years. The characteristic foot deformity takes the form of a high plantar arch with retraction of the toes at the metatarsophalangeal joints and flexion at the interphalangeal joints (hammertoes).

A notable feature in more than half of patients is a cardiomyopathy. The myocardial fibers are hypertrophic and may contain iron-reactive granules (Koeppen). Many of the patients die as a result of cardiac arrhythmia or congestive heart failure. For this reason, it is essential that affected individuals have a cardiologic assessment including electrocardiography and echocardiography. The cardiomyopathy of Friedreich disease can develop insidiously but with fulminant consequences. Kyphoscoliosis and restricted respiratory function are additional important contributory causes of death. Harding observed that approximately 10 percent of these patients have diabetes mellitus and a higher proportion have impaired glucose tolerance; there is both insulin deficiency and peripheral insulin resistance.

In the fully developed syndrome, the abnormality of gait is of mixed sensory and cerebellar type, aptly called tabetocerebellar by Charcot. According to Mollaret, the author of an authoritative monograph on the disease, the cerebellar component predominates, but in our relatively small series we have been as impressed almost as much with the sensory (tabetic) aspect. The patient stands with feet wide apart, constantly shifting position to maintain balance. Friedreich referred to the constant teetering and swaying on standing as static ataxia. In walking, as with all sensory ataxias, the movements of the legs tend to be brusque, the feet resounding unevenly and irregularly as they strike the floor, and closure of the eyes causes the patient to fall (Romberg sign). This is one component of the spinal aspect (posterior columns) of the disease. Attempts to correct the imbalance may result in abrupt, wild movements. Often there is a rhythmic tremor of the head. Eventually, the arms are grossly ataxic, and both action and intention tremors are manifest. Speech is slow, slurred, explosive, and, finally, almost incomprehensible. Breathing, speaking, swallowing, and laughing may be so incoordinated that the patient nearly chokes while speaking. Holmes (1907a) remarked on an ataxia of respiration that causes "curious short inspiratory whoops." Facial, buccal, and arm muscles may display tremulous and sometimes choreiform movements.

Although mentation is generally preserved, emotional lability has been sufficiently prominent to provoke comment. Torsional and vertical nystagmus is rare but "square wave jerks" are seen in the early stages of disease. Horizontal nystagmus may be present late in the course of the illness, but not early, but it is slight in amplitude. Ocular movements usually remain full, and pupillary reflexes are normal. The facial muscles may seem slightly weak, and deglutition may become impaired. Amyotrophy occurs late in the illness and is usually mild, but it may be extreme in patients with an associated neuropathy (see below). The tendon reflexes are abolished in nearly every case; rarely, they may be obtainable when the patient is examined early in the illness (see below). Plantar reflexes are extensor and flexor spasms may occur even with complete absence of tendon reflexes (another manifestation of the spinal component). The abdominal reflexes are usually retained until late in the illness. Loss of vibratory and position sense is invariable from the beginning; later, there may be some diminution of tactile, pain, and temperature sensation as well. Sphincter control is usually preserved.

Variants of Friedreich Ataxia

In one important variant of Friedreich ataxia the tendon reflexes are preserved or even hyperactive and the limbs may be spastic. It is the finding of the aberrant frataxin gene that links these unusual cases to Friedreich ataxia; some are associated with hypogonadism. Harding (1981) found 20 such cases among her 200 familial ataxias at the National Hospital, London. Nevertheless, the distinction between classic Friedreich ataxia and ataxia with retained tendon reflexes is an important one clinically, insofar as kyphoscoliosis and heart disease do not occur in the latter group and the prognosis is better. Two of our Friedreich patients had occasional seizures. There are many additional forms of spinocerebellar ataxia, most displaying mainly a cerebellar atrophy, that may simulate Friedreich disease, but due to different mutations. These are taken up below.

Laboratory Testing

Laboratory tests of diagnostic value are the measurement of sensory nerve conduction velocities and amplitudes, which for the most part are normal because peripheral neuropathy is not a component of the process. Electrocardiography and echocardiography may demonstrate the heart block and ventricular hypertrophy. The CT and MRI seldom reveal a significant degree of cerebellar atrophy but the spinal cord is small. There is no consistent abnormality of blood or CSF and no biochemical abnormalities have been demonstrated. Genetic testing for the length of the GAA trinucleotide repeat segment is available.

Pathology

The spinal cord is thin. The posterior columns and the corticospinal and spinocerebellar tracts are all depleted of myelinated fibers, and there is a mild gliosis that does not replace the bulk of the lost fibers. The nerve cells in the Clarke column and the large neurons of the dorsal root ganglia, especially lumbosacral ones, are reduced in number—but perhaps not to a degree that would fully explain the posterior column degeneration. The posterior roots are thin. Betz cells are also diminished in some cases, but the corticospinal tracts are relatively intact down to the medullary–cervical junction. Beyond this point, they are degenerated, but to a lesser degree than the posterior columns. The nuclei of cranial nerves VIII, X, and XII all exhibit a reduction of cells. Slight to moderate neuronal loss is seen also in the dentate nuclei, and the middle and superior cerebellar peduncles are reduced in size. Some depletion of Purkinje cells in the superior vermis and neurons in corresponding parts of the inferior olivary nuclei can be seen. Many of the myocardial muscle fibers degenerate and are replaced by fibrous connective tissue.

By way of exploring the anatomic basis of the clinical findings, pes cavus is not different from that seen in other neuromuscular diseases of early onset with mild hypertonus of the long extensors and flexors of the feet. There is also cause of amyotrophy of intrinsic foot muscles and foreshortening of the foot when the bones are still malleable. The kyphoscoliosis is probably a result of imbalance of the paravertebral muscles during development. The tabetic aspects of the disease are explained by the degeneration of large cells in the dorsal root ganglia and the large sensory fibers in nerves, dorsal roots, and the columns of Goll and Burdach. The loss of neurons in the sensory ganglia also causes abolition of tendon reflexes. Cerebellar ataxia is attributable to a combined degeneration of the superior vermis and the dentatorubral pathways but also the spinocerebellar tracts, in various combinations. Corticospinal lesions account for the weakness and Babinski signs and contribute to the pes cavus.

Diagnosis

Friedreich disease and its variants must be distinguished from familial cerebellar cortical atrophy described next, and from familial spastic paraparesis with ataxia, as well as from peroneal muscular atrophy and the Levy-Roussy syndrome, which are discussed also with the hereditary neuropathies in Chap. 46. It is advisable to assay serum vitamin E levels, as a rare (except in North Africa) but treatable inherited deficiency of a vitamin E transport protein causes a spinocerebellar syndrome with areflexia in children that resembles Friedreich disease (see Chap. 41). The absence of dysarthria and of skeletal or cardiac abnormalities in the vitamin-deficiency illness may be helpful. Exceptionally, a cardiac disturbance has been seen in the vitamin deficiency. A form of chronic inflammatory demyelinating polyneuropathy has long since overtaken tabes dorsalis as the most frequent type of areflexic ataxia. It bears a superficial resemblance to Friedreich ataxia when the onset is in early life, but lacks dysarthria and Babinski signs. A form of spinocerebellar degeneration related to human T-cell lymphotrophic virus type I (HTLV-I), causing so-called tropical spastic paraparesis, as well as the vacuolar myelopathy of AIDS multiple sclerosis, syringomyelia, neuroacanthocytosis, and cervical spondylosis, must be included in the differential diagnosis of late-onset cases. Genetic testing settles the matter.

Treatment

Not much can be said on this subject because there is little effective therapy. A double-blind crossover study by Trouillas and associates found that the administration of oral 5-hydroxytryptophan modified the cerebellar symptoms. This has not been tested in another study. Apart from this form of treatment, with which we have had no experience, no therapeutic measures are known to alter the course of the disease. In several small trials, idebenone, an antioxidant (the short-chain analogue of coenzyme Q10), reduced the progression of left ventricular hypertrophy, a risk factor for arrhythmias and sudden death in these patients, but this could not be confirmed in subsequent trials. These results are summarized in an article by Filla and Moss. Heart failure, arrhythmias, and diabetes mellitus are treated by the usual medical measures and it bears repetition that careful evaluation of the cardiac disorder may prevent premature death. Surgery for scoliosis and foot deformities may be helpful in selected cases.

Predominantly Cerebellar (Cortical, Holmes Type) Hereditary and Sporadic Ataxia

Soon after the publication of Friedreich's descriptions of a spinal type of hereditary ataxia, reports began to appear of somewhat different diseases in which the ataxia was related to degenerative changes in the cerebellum and brainstem rather than in the spinal cord. Claims of their independence from the spinal type were based largely on a later age of onset, a more definite hereditary transmission (usually of autosomal dominant type), the persistence or hyperactivity of tendon reflexes, and associations with ophthalmoplegia, retinal degeneration, and optic atrophy. Several of these clinical features, particularly briskness of tendon reflexes, are alien to the classic form of Friedreich ataxia.

By 1893, Pierre Marie thought it desirable to create a new category of hereditary ataxia that would embrace all of the non-Friedreich cases. He collated the familial cases of progressive ataxia that had been described by Fraser, Nonne, Sanger Brown, and Klippel and Durante (see both Greenfield and Harding [1993] for references) and proposed that all of them were examples of an entity to which he applied the name hérédo-ataxie cérébelleuse. Marie's proposition was based almost entirely on clinical observations not his own but those made by the aforementioned authors. Later, as members of these families died, postmortem examinations disclosed that Marie's hereditary cerebellar ataxia included not one but several disease entities. Indeed, as pointed out by Holmes (1907b) and later by Greenfield, in 3 of the 4 families the cerebellum showed no significant lesions at all. Yet there was by then no doubt of the existence of a separate class of predominantly cerebellar atrophies, some purely cortical and others associated with a variety of noncerebellar disorders.

Clinical Features

Holmes (1907a) described a family of 8 siblings, of whom 3 brothers and 1 sister were affected by a progressive ataxia, beginning with a reeling gait and followed by clumsiness of the hands, dysarthria, tremor of the head, and a variable nystagmus, but without additional features to implicate disease of the spinal cord or brainstem. It may be taken as the prototype of pure cerebellar cortical degeneration.

The ataxia begins insidiously, usually in the fourth decade but with wide variability in age of onset, and progresses slowly over many years. Ataxia of gait, instability of the trunk, tremor of the hands and head, and slightly slowed, hesitant speech is the usual clinical picture. Nystagmus is rare and intelligence is usually preserved. The patellar reflexes may be slightly increased but this may be apparent based on the pendular character of reflexes in cerebellar disease; the plantar reflexes are flexor and the ankle jerks are present but there are exceptions and probably mark the process as one of the other genetic ataxias.

This clinical syndrome probably can result from several genetically determined processes, some of which declare themselves as the illness progresses by displaying characteristic signs other than ataxia. The differential diagnosis in the nonfamilial cases is even broader, including many acquired types of ataxias discussed in Chap. 5 (see Table 5-1) and at the end of this section.

Pathology

Postmortem examination of the Holmes-type cases discloses symmetrical atrophy of the cerebellum involving mainly the anterior lobe and vermis, the latter being more affected. Purkinje cells are absent in the lingula, centralis, and pyramis of the superior vermis and reduced in number in the quadrangularis, flocculus, biventral, and pyramidal lobes. The other cerebellar cortical neurons and granule cells and dorsal and medial parts of the inferior olivary nuclei are diminished less so. The white matter is slightly pale in myelin stains. The vermian atrophy and that of adjacent parts of the cerebellum can be visualized with clarity in MRIs (Fig. 39-8).

Figure 39-8.

Familial cortical cerebellar atrophy. T1-weighted MRI in the sagittal plane showing marked atrophy of vermis and enlargement of fourth ventricle. The brainstem is only mildly atrophic and the posterior fossa is normal is size. Compare with Fig. 39-9 in which the cerebellum and pons are atrophic.

The vague similarity of the pathologic (and clinical) changes to those of alcoholic cerebellar degeneration is at once apparent and should raise the question of an alcoholic-nutritional cause in sporadic cases (see Chap. 41); in serious alcohol-nutritional disease, there usually is an accompanying polyneuropathy and reduced ankle reflexes.

Fragile X Tremor–Ataxic Premutation Syndrome

This type of developmental delay, caused by an unstable extended trinucleotide repeat sequence and breakage of the X-chromosome, is discussed in Chap. 38. Here we refer to an unusual variant of the degenerative process with onset in mid- or late adulthood, mainly but not exclusively in men, and consisting of gait or limb ataxia and mild tremor. The process affects carriers of a "premutation" who have 50 to 200 CGG repeat sequences in the FMR1 gene. In contradistinction to the full mutation of over 200 repeats, there is apparently a buildup of messenger ribonucleic acid (mRNA) in the adult form that interferes in some way with cellular function. Aggregating several studies, the frequency of this genetic abnormality among otherwise unassignable adult ataxia cases is less than 10 percent.

The entire clinical spectrum has yet to be defined but our experience with 2 patients featured mild progressive gait ataxia in the sixth decade that was misattributed to normal-pressure hydrocephalus and an intermittent hand tremor that was probably ataxic in nature. Some reports have included a parkinsonian syndrome and more consistently, a mild frontal dementia, making the distinction from frontotemporal dementia difficult. Many cases have been confused with multiple system atrophy.

T2 hyperintensity in the cerebellar peduncles are characteristic of some cases, but this was not found in our patients, which showed only midline cerebellar atrophy. A family history of developmental delay or autistic spectrum disorder may be a hint to diagnosis and some proportion of individuals with the premutation also have a nonprogressive cognitive deficiency.

A study of the neuropathology by Greco and colleagues showed cerebral and cerebellar spongiform white matter changes and both intranuclear and astrocytic inclusions. Their report demonstrated a correspondence between the quantity of trinucleotide repeats and the number of inclusion bodies.

Familial and Sporadic Forms of Combined Cerebellar Atrophy with Brainstem and Extrapyramidal Features

A sporadically occurring disorder closely resembling the Holmes type of cortical cerebellar degeneration but with additional features of brainstem atrophy was described in 1900 by Déjérine and André-Thomas, who named it olivopontocerebellar atrophy (OPCA). As more cases of this type were collected, an autosomal dominant hereditary pattern was evident in some, and one or more long tracts in the spinal cord were found to have degenerated. About half the cases later developed the parkinsonism with degeneration of nigral cells and, in a few, of striatal cells, thereby marking the disease as a form of striatonigral degeneration that is essentially a type of multiple system atrophy (MSA-C) as discussed in detail in an earlier section and also below.

Notable findings in both the sporadic and the familial forms of many of the variants of cerebellar atrophy are extensive degeneration of the middle cerebellar peduncles, cerebellar white matter, and pontine, olivary, and arcuate nuclei; loss of Purkinje cells has been variable. Most likely this degeneration represents a "dying back" of axons of the cerebellar, pontine, and olivary nuclei with secondary myelin degeneration. Extreme atrophy of the medullary olivary nuclei, evident on MRIs (Fig. 39-9), identifies a special process that represents the aforementioned OPCA.

Figure 39-9.

Olivopontocerebellar atrophy. MRI in the sagittal plane demonstrating both vermian atrophy (black arrow) and smallness of the pons (white arrow). (Reproduced by permission from Bisese JH: Cranial MRI. New York, McGraw-Hill, 1991.)

Although the associated features in each of the inherited cerebellar degenerations do not conform to newer genetic classifications, certain clinical constellations are nonetheless recognizable and clinically useful. Many texts use a genetic system exclusively to categorize these diseases. In the past, Konigsmark and Weiner subdivided them into several types, including a dominantly inherited OPCA (of Menzel); a recessive type (of Fickler-Winkler); a dominant type with retinal degeneration; one with spastic paraplegia and areflexia; and with dementia, ophthalmoplegia, and extrapyramidal signs. To these had been added cases of OPCA with neuropathy and slowed eye movements (Wadia type), of which we have seen 2 cases, and cases with dystonia and a variety of other clinical findings, most in single families (hemiballismus, athetosis, contractures of the legs, fixed pupils, ophthalmoplegia, ptosis, gaze palsy, deafness, retinal degeneration, mental retardation and epilepsy, claw foot and scoliosis, incontinence, parkinsonian symptoms and signs, plethora of presentations including a neonatal type). Some of these are detailed below.

Cases of sporadic olivopontocerebellar atrophy are more common than the familial variety and tend to occur at an older age; nystagmus, optic atrophy, retinal degeneration, ophthalmoplegia, and urinary incontinence are generally not observed. However, there are numerous cases that include mild extrapyramidal and neuropathic signs, slow eye movements, dystonia, impairment of vertical saccadic eye movements (thus simulating progressive supranuclear palsy), vocal cord paralysis, all of which probably mark the process as multiple system atrophy (MSA-C) or Machado-Joseph-Azorean disease (SCA3, discussed below), and some cases with deafness. The relationship of olivopontocerebellar atrophy to MSA was discussed in under "Multiple System Atrophy," but we emphasize that OPCA occurs as often independently of extrapyramidal degeneration for which reason we retain a separate designation.

Cerebellar Atrophy with Prominent Basal Ganglionic Features

Machado-Joseph-Azorean Disease (SCA3)

A special form of hereditary ataxia with brainstem and extrapyramidal signs has been described in patients mainly, but not exclusively, of Portuguese-Azorean origin. The disorder is characterized by an autosomal dominant pattern of inheritance and by a slowly progressive ataxia beginning in adolescence or early adult life in association with hyperreflexia, extrapyramidal features, dystonia, bulbar signs, distal motor weakness, and ophthalmoplegia. There is usually no impairment of intellect and in the examples the authors have seen, the extrapyramidal symptoms were mainly rigidity and slowness of movement. Early Machado-Joseph disease characteristically demonstrates the finding of dysmetric horizontal and vertical saccades, even before the ataxia is obvious (Hotson et al). This conjunction of a parkinsonian syndrome with cerebellar ataxia is suggestive of MSA except for an earlier age of onset and the prominence in some cases of dystonia, amyotrophy, and ophthalmoplegia in Machado-Joseph. Postmortem examination discloses a degeneration of the dentate nuclei and spinocerebellar tracts and a loss of anterior horn cells and neurons of the pons, substantia nigra, and oculomotor nuclei. Cancel and colleagues found an unstable number of CAG repeating sequences in a gene, ataxin-3, and named the disorder spinocerebellar ataxia type 3 (SCA3).

An affected Azorean family named Joseph was described in 1976 by Rosenberg and colleagues under the name of autosomal dominant striatonigral degeneration. Using the term Azorean disease of the nervous system (now better known as Machado-Joseph disease), Romanul and colleagues described yet another family of Portuguese-Azorean descent, many members of which were affected by a syndrome comprising a progressive ataxia of gait, parkinsonian features, limitation of conjugate gaze, fasciculations, areflexia, nystagmus, ataxic tremor, and extensor plantar responses; the pathologic changes closely resembled those described by Woods and Schaumburg. Romanul and coworkers compared the genetic, clinical, and pathologic features of their cases with those described in other Portuguese-Azorean families and concluded that all of them represent a single genetic entity with variable expression. This concept of the disease has been corroborated by the further observations of Rosenberg and of Fowler who studied 20 patients with the Machado-Joseph-Azorean disease over a 10-year period and more recently by genetic testing.

The disease is not limited to Azoreans. Cases conforming to the above descriptions have now been observed among African American, Indian, and Japanese families (Sakai et al; Yuasa et al; Bharucha et al). There are no signs of polyneuropathy, which is the main feature of another disease in Portuguese emigrants caused by amyloid deposition, described by Nakano and colleagues as "Machado disease," this being the name of the progenitor of the afflicted family.

In fully developed cases, the MRI findings are of reduced width of the superior and middle cerebellar peduncles, atrophy of the frontal and temporal lobes, and smallness of the pons and globus pallidus (Murata et al). There is no treatment of proven value.

Multiple System Atrophy with Predominant Ataxia (See Section Multiple System Atrophy)

This entity has been discussed with the degenerative disorders of the basal ganglia earlier in the chapter. Here it is pointed out that a number of cases of sporadic progressive ataxia in mid- and late life are attributable to this process and have been termed MSA-C to signify the predominant cerebellar feature. The extrapyramidal, corticospinal, or autonomic aspects of the illness may or may not become evident only with continued observation or by pathologic examination. Some guidance as to the frequency of MSA as the cause of otherwise undifferentiated sporadic ataxia is given in the study by Abele and colleagues who found that it accounts for almost one-third of cases, but the precise number is open to question as pathologic examinations were not made.

Dentatorubropallidoluysian Atrophy (DRPLA)

This is a rare familial disorder, described mostly in Japan and in small European pockets, in which symptoms of cerebellar ataxia are coupled with those of choreoathetosis and dystonia and, in a few instances, parkinsonism, myoclonus, epilepsy, or dementia. Pathologically there is degeneration of the dentatorubral and pallidoluysian systems. The main consideration when chorea is a prominent feature is the separation of this disorder from Huntington disease. The gene defect in DRPLA is an unstable CAG trinucleotide repeat in the gene that codes for the protein atrophin. This same mutation has been defined in affected families from throughout the world (e.g., Warner et al). As with Huntington chorea (where the expanded polyglutamine tract is in the protein huntingtin), this disease is inherited as an autosomal dominant trait and shows an inverse correlation between the age of onset and the size of the gene expansion (anticipation). When chorea predominates early in the illness, there may be difficulty distinguishing DRPLA from Huntington disease. The diagnosis is confirmed by sequencing of the affected gene.

Dentatorubral Degeneration

This is a rare and still nebulous entity but it is probably distinct from the condition described above. There are several instructive features. In 1921, Ramsay Hunt published an account of 6 patients (2 of whom were twin brothers) in whom myoclonus was combined with progressive cerebellar ataxia. The age of onset in the 4 nonfamilial cases was between 7 and 17 years, and the cerebellar ataxia followed the myoclonus by an interval of 1 to 20 years. Hunt named the disorder dyssynergia cerebellaris myoclonica. There were signs of Friedreich ataxia in the twin brothers; postmortem examination of one showed cerebellar atrophy, degeneration of the posterior columns and spinocerebellar tracts but not of the corticospinal tracts. In 1947, Louis-Bar and van Bogaert reported a similar case and noted, in addition to the above findings, degeneration of the corticospinal tracts and loss of fibers in the posterior roots. Thus the pathology was identical to that of Friedreich ataxia except for the more severe atrophy of the dentate nuclei.

Earlier (1914), under the title dyssynergia cerebellaris progressiva, Hunt had drawn attention to a progressive disease in young individuals manifest by what he considered to be a pure cerebellar syndrome but one of his cases was revealed at autopsy to be Wilson disease. Hunt's reports emphasize the hazard of classifying cerebellar ataxias on the basis of clinical findings alone, a point made effectively by Holmes.

Paroxysmal Ataxias (see Chap. 5)

Two adult forms of hereditary cerebellar ataxia are paroxysmal in nature. In one (EA-2 for "episodic ataxia, type 2"), the episodes occur without explanation and last several hours; vertigo is the prominent feature of the attacks. Between attacks the patient is normal or has only minimal ataxia and nystagmus (Griggs et al). These ataxic episodes are prevented strikingly by the administration of oral acetazolamide. The disorder has been found to be a mutation of the calcium channel gene on chromosome 19 as listed in Table 39-5.

A similar but physiologically and genetically unrelated paroxysmal ataxia (EA-1) is characterized by episodes that may be precipitated by exercise and by the presence of muscle myokymia (rippling) between attacks. Vertigo does not occur and acetazolamide is less effective or not effective at all. The disorder is caused by an abnormality of the potassium channel gene on chromosome 12 (see Table 39-5). Both of these episodic ataxias are therefore "channelopathies" (see Chap. 50). Also of interest is spinocerebellar atrophy type 6, a progressive condition in which a mutation has been traced to same gene implicated in the EA-2 acetazolamide-responsive paroxysmal ataxia, but this disorder is not paroxysmal and results in progressive ataxia, dysarthria, and loss of proprioception.

Genetics of the Heredodegenerative Ataxias (See Table 39-5)

The many familial degenerative ataxic disorders described in the preceding pages are genetically distinct. As indicated, the autosomal recessive type of Friedreich ataxia is the result of an expanded GAA repeat in the frataxin gene (Campuzano et al), quite different from the large number of dominant forms of inherited ataxia. The direct molecular test for the GAA expansion is useful for diagnosis, particularly for atypical cases with late onset (Dürr et al). The rarer recessive spinocerebellar ataxia associated with vitamin E deficiency arises from mutations in the gene that encodes an alpha tocopherol (vitamin E) transport protein, as mentioned above.

Among the common autosomal dominant cerebellar ataxias of later onset, molecular and gene studies have identified numerous mutations. Of these autosomal dominant ataxias, many are known to be caused by expanded CAG-trinucleotide repeats (including SCA types 1, 3, 6, and 7, 12, 17, as well as DRPLA). Undoubtedly others will be discovered. However, the mechanisms by which the expanded polyglutamine molecule leads to neuronal cell death or dysfunction remain uncertain. It is likely that differences in the clinical manifestations of these disorders will reflect differences in the patterns of expression of the affected proteins; that is each is expressed in different populations of neurons and at different stages in development. This raises the possibility that the cascade of events that triggers neuronal degeneration is similar in each of the diseases with a CAG expansion and that a therapy might be discovered that is effective in all of them.

The special case of fragile X premutation that may cause ataxia and tremor in adults is addressed in Chap. 38. Table 39-5 summarizes the genes, terminology, related neural abnormalities, and clinical features of the cerebellar atrophies.

Differential Diagnosis of the Degenerative Ataxias in Adults (See also Table 5-1)

Sporadic forms of cerebellar ataxia in adults are in some instances traceable to strokes involving cerebellar pathways (Safe et al). These are, of course, of acute onset. Some cases of ataxia are alcoholic-nutritional in origin, and a few are related to excessive use of drugs or therapeutic medications, especially antiepileptic drugs, which may in a few cases cause a slowly progressive and permanent ataxia. Organic mercury induces subacute cerebellar degeneration, and adulterated heroin causes a more abrupt and severe ataxic syndrome. The paraneoplastic variety of cerebellar degeneration often enters into the differential diagnosis; it occurs mostly in women with breast or ovarian cancers and evolves much more rapidly than any of the heredodegenerative forms. The more rapid onset of ataxia and the presence of anti-Purkinje cell antibodies (anti-Yo; see "Paraneoplastic Cerebellar Degeneration" in Chap. 31) are central to identifying the nature of this disease. From time to time one observes a similar idiopathic variety of subacute cerebellar degeneration, particularly in women who have no neoplasm and lack the specific antibodies of the paraneoplastic disease (Ropper). Rare cases of ataxia have been associated with celiac disease and Whipple disease, and metronidazole as noted in Chap. 5. Ataxia may also be an early and prominent manifestation of Creutzfeldt-Jakob disease caused by a prion (see Chap. 33) or of an inherited metabolic disease (see Chap. 37). Of the latter, late-onset GM2 gangliosidosis may simulate cerebellar degeneration in adults (see Chap. 37). Rare cases of aminoacidopathy manifesting for the first time in adult life have also provoked a cerebellar syndrome (see Chap. 37).

Hereditary Polymyoclonus

The syndrome of quick, arrhythmic, involuntary single or repetitive twitches of a muscle or group of muscles was described in Chap. 6, where it was pointed out that the condition has many causes. Chapter 37 discusses those caused by hereditary metabolic diseases. Familial forms are known, one of which, associated with cerebellar ataxia, was discussed earlier (dyssynergia cerebellaris myoclonica of Ramsay Hunt). But there is another disease, known as hereditary essential benign myoclonus, that occurs in relatively pure form unaccompanied by ataxia (termed essential, or familial, myoclonus; see Chap. 6). In this condition, it is difficult to evaluate coordination because willed movement is interrupted by myoclonus that may be mistaken for intention tremor. Only by slowing the voluntary movement can the myoclonus be reduced or eliminated. This myoclonic disease is inherited as an autosomal dominant trait. It becomes manifest early in life; once established, it persists with little or no change in severity throughout life, often with rather little disability. It can, by its natural course, be differentiated from some of the hereditary metabolic diseases such as the Unverricht and Lafora types of myoclonic epilepsy, the lipidoses, tuberous sclerosis, and myoclonic disorders that follow certain viral infections and anoxic encephalopathy. Of interest is the response of this form of movement disorder to certain pharmacologic agents, notably clonazepam, valproic acid, and 5-hydroxytryptophan, the amino acid precursor of serotonin, particularly when these agents are used in combination (postanoxic myoclonus responds to the same medications).

Another form of nonprogressive myoclonus, dominantly inherited, is associated with dystonia, which is due to a mutation in a sarcoglycan gene, SGCE.

The main clinical distinctions are from juvenile myoclonic epilepsy (see Chap. 16), drug-induced myoclonus, particularly lithium and opiates; renal failure and other acquired metabolic disorders; asterixis; and from the startle responses and some of the diseases that have this sign as their main characteristic (see Chap. 6). Creutzfeldt-Jakob subacute spongiform encephalopathy may cause difficulty in diagnosis initially but the course of illness clarifies the situation rapidly. Myoclonus is also one component of the complex movement disorder in corticobasal-ganglionic degeneration that was described in an earlier section.

Syndrome of Muscular Weakness and Wasting Without Sensory Changes

Motor Neuron Disease

This general term designates a group of progressive degenerative disorders of motor neurons in the spinal cord, brainstem, and motor cortex, manifest clinically by muscular weakness, atrophy, and corticospinal tract signs in varying combinations. It is for the most part a disease of middle life and progresses to death in a matter of 2 to 5 years or longer in exceptional cases.

Customarily, motor system disease is subdivided into several subtypes on the basis of the grouping of symptoms and signs. The most frequent form, in which amyotrophy and hyperreflexia are combined, is ALS (amyotrophy is the term applied to denervation atrophy and weakness of muscles). Less frequent are cases in which weakness and atrophy occur alone, without evidence of corticospinal tract dysfunction; for these the term progressive spinal muscular atrophy is used. When the weakness and wasting predominate in muscles innervated by the motor nuclei of the lower brainstem (i.e., muscles of the jaw, face, tongue, pharynx, and larynx), it is customary to speak of progressive bulbar palsy). In a small proportion of patients, the clinical state is dominated by spastic weakness, hyperreflexia, and Babinski signs, with lower motor neuron aspects becoming apparent only at a later stage of the illness, or not at all. This is designated primary lateral sclerosis, an infrequent form of motor system disease in which the degenerative process remains confined to the corticospinal pathways (Pringle et al). The pure spastic paraplegias without amyotrophy may represent a special class of disease hence they are described separately. There are also relatively common familial forms of spastic paraplegia in which the disease is confined to the corticospinal tracts or, in some cases, combined with posterior column or other neurologic signs.

Furthermore, an important group of special spinal muscular atrophies occurs in infancy and childhood and are the leading cause of heritable infant mortality and, after cystic fibrosis, the most frequent form of serious childhood autosomal recessive disease (Pearn). The best known is the Werdnig-Hoffmann type of infantile spinal muscular atrophy (SMA type I); but there are other forms beginning in later childhood, adolescence, or early adult life (SMA types II and III, or the Wohlfart-Kugelberg-Welander type). Despite the clinical heterogeneity of the heritable childhood spinal muscular atrophies, they all derive from mutations in the SMN gene (see below; see Gilliam et al; Brzustowicz et al). This group of early-onset spinal muscular atrophies is separate genetically from a familial form of ALS.

Amyotrophic Lateral Sclerosis

History

Credit for the original delineation of amyotrophic lateral sclerosis is appropriately given to Charcot. With Joffroy in 1869 and Gombault in 1871, he studied the pathologic aspects of the disease. In a series of lectures given from 1872 to 1874, he provided a lucid account of the clinical and pathologic findings. Although called Charcot disease in France, amyotrophic lateral sclerosis (the term recommended by Charcot) has been preferred in the English-speaking world. Duchenne had earlier (1858) described labioglossolaryngeal paralysis, a term that Wachsmuth in 1864 changed to progressive bulbar palsy. In 1869, Charcot called attention to the nuclear origin of progressive bulbar palsy, and in 1882 Déjérine established its relationship to ALS. Most authors credit Aran and Duchenne with the earliest descriptions of progressive spinal muscular atrophy, which they believed to be of myogenic origin. This interpretation was, of course, incorrect; Cruveilhier, a few years later, noted the slender anterior roots, and soon thereafter the disease was brought into line with ALS as a spinal muscular atrophy. The singular genetic discovery in relation to this disease has been of the mutation in the superoxide dismutase (SOD1) gene in familial cases of motor neuron disease.

Epidemiology

This is a disease commonly encountered by neurologists, with an annual incidence rate of 0.4 to 1.76 per 100,000 population. Men are affected nearly twice as often as women. Most patients are older than age 45 years at the onset of symptoms, and the incidence increases with each decade of life (Mulder). The disease occurs in a random pattern throughout the world except for a dramatic clustering of patients among inhabitants of the Kii peninsula in Japan and in Guam, where ALS is often combined with dementia and parkinsonism. In approximately 10 percent of cases the disease is familial, being inherited as an autosomal dominant trait with age-dependent penetrance. The familial cases do not differ fundamentally in their symptoms and clinical course from nonfamilial ones, although as a group the former have an earlier age of onset, an equal distribution in men and women, and a slightly shorter survival. Unusual environmental associations are reported from time to time, for example, an increased incidence among Italian professional football players (Chio et al, 2005) and among soldiers who had served in various regions. All of these are questionable on methodologic grounds (they are retrospective case control epidemiologic studies) but further exploration is warranted.

Clinical Features

In the most typical forms of disease, the onset is perceived by the patient as weakness in a distal part of one limb. This is noted first as an unexplained tripping from slight foot-drop, or by awkwardness in tasks requiring fine finger movements (handling buttons and automobile ignition keys), stiffness of the fingers, and slight weakness or wasting of the hand muscles on one side. In other words, features related to upper and to lower motor neuron degeneration (or both) may appear insidiously in one limb. Cramping beyond what seems natural and fasciculations of the muscles of the forearm, upper arm, and shoulder girdle may also arise. The earliest manifestation of the lower motor neuron component of this disease is sometimes volitional cramping—for example, leg cramps as the patient turns in bed during the early morning hours.

As the weeks and months pass, the other hand and arm become similarly affected with weakness, stiffness, slowness, atrophy or cramps. Before long, the triad of atrophic weakness of the hands and forearms, fasciculations, slight spasticity of the arms or legs, and generalized hyperreflexia—all in the absence of sensory change—leaves little doubt as to the diagnosis. Muscle strength and bulk diminish in parallel or there is a relative preservation of power early in the illness. Despite the amyotrophy, the tendon reflexes are notable for their liveliness. Babinski and Hoffmann signs are variably present; surprisingly, they may not appear even as the illness progresses. Abductors, adductors, and extensors of fingers and thumb tend to become weak before the long flexors, on which the handgrip depends, and the dorsal interosseous spaces become hollowed, giving rise to the "cadaveric" or "skeletal" hand. The muscles of the upper arm and shoulder girdles are typically involved later. There is a general tendency for adjacent areas to be involved before more distant ones. When an arm is the first limb affected, all this occurs while the thigh and leg muscles seem relatively normal, and there may come a time in some cases when the patient walks about with useless, dangling arms. Later the atrophic weakness spreads to the neck, tongue, pharyngeal, and laryngeal muscles, and eventually those in the trunk and lower extremities yield to the onslaught of the disease.

The affected parts may ache and feel cold, but true paresthesias, except from poor positioning and pressure on nerves, do not occur or are minor. Sphincteric control is well maintained even after both legs have become weak and spastic, but many patients acquire urinary and sometimes fecal urgency in the advanced stages of the disease. The abdominal reflexes may be elicitable even when the plantar reflexes are extensor. Extreme spasticity is rarely seen.

Coarse fasciculations are usually evident in the weakened muscles but may not be noticed by the patient until the physician calls attention to them. Fasciculations are almost never the sole presenting feature of ALS—a clinical truism with which one can reassure physicians and medical students who fear, on the basis of persistent focal muscle twitching in the thumb, face, foot, or forearm, that they are developing the disease.

The course of this illness, irrespective of its particular mode of onset and pattern of evolution, is progressive. There may be periods lasting weeks or months during which the patient observes no advance in symptoms but clinical changes can nonetheless be detected. Half the patients succumb within 3 years of onset and 90 percent within 6 years (Mulder et al). Several clinical variations that occur with regularity and have distinguishing clinical features are described below.

Other Patterns of Clinical Evolution

In addition to the special configurations discussed further on, there are many patterns of neuromuscular involvement other than the one just described. A leg may be affected before the hands. A foot-drop with weakness and wasting of the pretibial muscles may be incorrectly attributed to peroneal nerve compression until weakness of the gastrocnemius and other muscles betray more widespread involvement of lumbosacral neurons. In our experience, this crural amyotrophy has been less frequent than the brachial-manual type. Another variant is early involvement of thoracic, abdominal, or posterior neck muscles, the last being one of the causes of head lolling and camptocormia (forward bending of the neck and trunk) in older individuals. Yet another pattern is of early diaphragmatic weakness; such cases come to attention because of respiratory failure. A symmetrical proximal limb or shoulder-girdle amyotrophy with onset at an early age is also known and simulates muscular dystrophy (Wohlfart-Kugelberg-Welander disease, discussed later in this chapter). On several occasions we have observed a pattern involving the arm and leg on the same side, first with spasticity and then with some degree of amyotrophy; this has been called the hemiplegic or Mills variant. However, this clinical pattern more often turns out to be a result of multiple sclerosis of compression of the spinal cord from laterally, as occurs with a neurofibroma.

The first and dominant manifestations of motor neuron disease may be a spastic weakness of the legs, in which case a diagnosis of primary lateral sclerosis is tentatively made (discussed further on); only after a year or two do the hand and arm muscles weaken, waste, and fasciculate, making it obvious that both upper and lower motor neurons are diseased. Early on, a spastic bulbar palsy with dysarthria and dysphagia, hyperactive jaw jerk and facial reflexes, but without muscle atrophy, may be the initial phase of disease.

As the disease advances, very mild distal sensory loss may be observed in the feet without explanation, but, if the sensory loss is a definite and early feature, the diagnosis must remain in doubt. Approximately 5 percent of cases of ALS are observed in conjunction with a frontotemporal dementia; less commonly, there is an association with a Parkinson syndrome.

Progressive Muscular Atrophy

This purely lower motor neuron syndrome is more common in men than in women, reportedly in a ratio of 4:1. It probably encompasses several diseases of the lower motor neuron, but most of which are manifestations of ALS.

These purely lower motor neuron amyotrophies tend to progress at a slower pace than the usual case of ALS, some patients surviving for 15 years or longer. Chio and colleagues (1985), who analyzed the factors affecting life expectancy in 155 patients with progressive muscular atrophy (PMA), found that younger patients had a more benign course: The 5-year survival was 72 percent in patients with an onset before age 50 years and 40 percent in patients with onset after age 50 years. Some of the most chronic varieties of PMA are familial. It has been revealed that the original report of a familial variety of this illness by William Osler described a family now known to have had a mutation in the SOD1 gene, as discussed below. In about half the patients, the illness takes the form of a symmetrical (sometimes asymmetrical) wasting of intrinsic hand muscles, slowly advancing to the more proximal parts of the arms; less often, the legs and thighs are the sites of the initial atrophic weakness; or the proximal parts of the limbs are affected before the distal ones. Fascicular twitchings and cramping are variably present. Otherwise they differ from ALS only in that the tendon reflexes are diminished or absent, and signs of corticospinal tract disease cannot be detected. Nonetheless, many cases of ostensible PMA are found to have indications of corticospinal tract degeneration at autopsy (Ince et al).

The main disease to be distinguished from PMA is an immune-mediated motor neuropathy that occurs with or without multifocal block of electrical conduction (see Chap. 46), and various muscle diseases that produce a similar pattern of weakness, notably, inclusion body myopathy and polymyositis. The presence of a paraproteinemia, specifically immunoglobulin (Ig) M with antibodies against GM1 ganglioside, or the finding of focal conduction block or sensory nerve abnormalities on the EMG implies the presence of an autoimmune neuropathy disease rather than of a degenerative motor neuron type.

Progressive Bulbar Palsy

Here reference is made to a condition in which the first and dominant symptoms relate to weakness and laxity of muscles innervated by the motor nuclei of the lower brainstem, that is muscles of the jaw, face, tongue, pharynx, and larynx. This weakness gives rise to an early defect in articulation, in which there is difficulty in the pronunciation of lingual (r, n, l), labial (b, m, p, f), dental (d, t), and palatal (k, g) consonants. As the condition worsens, syllables lose their clarity and run together, until, finally, the patient's speech becomes unintelligible. In other patients, slurring is a result of spasticity of the tongue, pharyngeal, and laryngeal muscles; the speech sounds as if the patient were eating food that is too hot. Usually the voice is modified by a combination of atrophic and spastic weakness. Defective modulation with variable degrees of rasping and nasality is another characteristic. The pharyngeal reflex is lost, and the palate and vocal cords move imperfectly or not at all during attempted phonation. Mastication and deglutition become impaired; the bolus of food cannot be manipulated and may lodge between the cheek and teeth and the pharyngeal muscles do not force it properly into the esophagus. Liquids and small particles of food find their way into the trachea or nose. The facial muscles, particularly of the lower face, weaken and sag. Fasciculations and focal loss of tissue of the tongue are usually early manifestations; eventually the tongue becomes shriveled and lies useless on the floor of the mouth. The chin may also quiver from fascicular twitchings, but the diagnosis should not be made on the basis of fasciculations alone, in the absence of weakness and atrophy.

The jaw jerk may be present or exaggerated at a time when the muscles of mastication are markedly weak. In fact, spasticity of the jaw muscles may be so pronounced that the slightest tap on the chin will evoke clonus and blinking; rarely, attempts to open the mouth elicit a "bulldog" reflex (jaw snaps shut involuntarily). Spastic weakness of the oropharyngeal muscles may be the initial manifestation of bulbar palsy and may at times surpass signs of atrophic weakness; pseudobulbar signs (pathologic laughing and crying) may reach extreme degrees. This is the only common clinical situation in which spastic and atrophic bulbar palsy coexist. Strangely, the ocular muscles always escape.

As with other forms of motor system disease, the course of bulbar palsy is inexorably progressive. Eventually the weakness spreads to the respiratory muscles and deglutition fails entirely; the patient dies of inanition and aspiration pneumonia, usually within 2 to 3 years of onset. Approximately 25 percent of cases of motor system disease begin with bulbar symptoms, but rarely, if ever, does the sporadic form of progressive bulbar palsy run its course as an independent syndrome (pure heredofamilial forms of progressive bulbar palsy in the adult are known, e.g., Kennedy disease, discussed further on). In general, the earlier the onset of the bulbar involvement, the shorter the course of the disease.

Primary Lateral Sclerosis

This entity, like ALS, can be a form of motor neuron disease, although most cases appear to be examples of a unique degenerative process. Many patients in whom the signs of corticospinal tract degeneration suggest the presence of ALS will develop indications of lower motor neuron disease within 1 year, usually earlier. Approximately 20 percent, however, have a slowly progressive corticospinal tract disorder that begins with a pure spastic paraparesis; later, the arms and oropharyngeal muscles become involved and the disease remains one solely of the upper neurons. These cases have distinctive neuropathologic features and are designated as primary lateral sclerosis (PLS), a term originally suggested by Erb in 1875. A historical review of the subject appears in the article by Pringle and colleagues.

The typical case begins insidiously in the fifth or sixth decade with a stiffness in one leg, then in the other; there is a slowing of gait, with spasticity predominating over weakness as the years go on. Walking is still possible with the help of a cane for many years after the onset, but eventually this condition acquires the characteristic features of a severe spastic paraparesis. Over the years, finger movements become slower, the arms become spastic, and, if the illness persists for decades, speech takes on a pseudobulbar lilt. There are no sensory symptoms or signs. The legs are often found to be surprisingly strong, the difficulty in locomotion being attributable to rigid spasticity. About half the patients eventually acquire spasticity of the bladder. Pringle and associates suggest that a diagnostic criterion of the disease is progression for 3 years without evidence of lower motor neuron dysfunction.

Pathologic studies in a limited number of cases have disclosed a relatively stereotyped pattern of reduced numbers of Betz cells in the frontal and prefrontal motor cortex, degeneration of the corticospinal tracts, and preservation of motor neurons in the spinal cord and brainstem (Beal and Richardson; Fisher; Pringle et al). The corticospinal tract lesions are identical to those in typical ALS. Whether some of these cases are examples of late-onset familial spastic paraplegia (see further on) has not been extensively explored with molecular techniques.

Some patients who have only restricted bilateral signs of upper motor neuron disease prove to have multiple sclerosis, a slow compression of the spinal cord by spondylosis or meningioma, spinal dural arteriovenous fistula, or the myelopathic form of adrenoleukodystrophy (affected males or female carriers). In a few cases, tropical spastic paraplegia, HIV myelopathy, copper deficiency myelopathy, or a familial type of spastic paraplegia (described further on) will be uncovered. Exceptionally, progressive spastic paraparesis has been linked to an adult onset of phenylketonuria or other aminoacidopathies to vitamin B12 deficiency or to the fragile X premutation syndrome.

Laboratory Features of Motor Neuron Disease

Investigation provides useful confirmatory evidence even in the typical clinical syndrome. The EMG, as expected, displays widespread fibrillations (evidence of active denervation) and fasciculations and enlarged motor units (denoting reinnervation), and motor nerve conduction studies reveal only slight slowing, without focal motor conduction block. If the atrophic paresis is restricted to an arm or hand, raising the question of cervical spondylosis, evidence of denervation in many widely separated somatic segments favors the diagnosis of ALS. In questionable cases, it is good practice to insist that denervation be demonstrated in at least 3 limbs before concluding that the process is ALS. (The currently favored "El-Escorial" criteria that are used for the purposes of clinical research mandate that this finding be present.) Widespread denervation of the paraspinal muscles and of the genioglossus or facial muscles is also strongly suggestive of the disease but electromyographic testing of these muscles demands considerable experience and is uncomfortable for patients. A muscle biopsy is sometimes helpful in corroborating neurogenic denervation. Sensory nerve action potentials should be normal; tests of motor nerve conduction have a normal velocity, but the amplitudes become progressively lower as the disease progresses—in the earliest stages, they too may be normal. When in a typical case the amplitudes of sensory nerve action potentials are reduced, there is usually an underlying entrapment neuropathy, diabetes, or other late-life neuropathy. Sensory evoked potentials are mildly abnormal in a proportion of patients, but the explanation for this finding is unclear. (Sensory complaints and minimal sensory loss have been commented on above.)

The CSF protein is usually normal or marginally elevated. Serum creatine kinase is moderately elevated in patients with rapidly progressive atrophy and weakness, but it is just as often normal. Motor evoked potentials elicited from the cortex are also prolonged in patients with prominent corticospinal signs. In this group, the MRI may show slight atrophy of the motor cortices and wallerian degeneration of the motor tracts (Fig. 39-10). These changes may be diagnostically useful and appear as increased FLAIR and T2 signal intensity in the posterior limb of the internal capsule, descending motor tracts of the brainstem, and spinal cord, all of which are subtle and may be missed. All these laboratory findings, particularly the degeneration of the lateral columns of the cord and changes in the internal capsules, pertain also to primary lateral sclerosis with the notable exception of EMG findings of denervation and of elevations of creatine kinase (CK).

Figure 39-10.

Axial T2-weighted MRI showing abnormal hyperintensity reflecting wallerian change in the corticospinal tracts at the level of the internal capsule (top, arrow) and the pons (bottom) in a patient with ALS.

Pathology

The principal finding in ALS is a loss of nerve cells in the anterior horns of the spinal cord and motor nuclei of the lower brainstem. Large alpha motor neurons tend to be affected before small ones. In addition to neuronal loss, there is evidence of slight gliosis and proliferation of microglia cells. Many of the surviving nerve cells are small, shrunken, and filled with lipofuscin. It is not uncommon to detect ubiquitin inclusions in threads, skeins, or dense aggregates within the affected neurons by special stains. Occasionally, there is another ill-defined cytoplasmic inclusion that is present in neurons and glia. Most studies indicate that these are made up of TDP-43 and ubiquitin as discussed in the alter section on "Pathogenesis". According to some reports, swelling of the proximal axon is an early finding, presumably antedating visible changes in the cell body itself. The anterior roots are thin, and there is a disproportionate loss of large myelinated fibers in motor nerves (Bradley et al). The muscles show typical denervation atrophy of different ages. Whitehouse and coworkers found a depletion of muscarinic, cholinergic, glycinergic, and benzodiazepine receptors in regions of the spinal cord where motor neurons had disappeared.

The corticospinal tract degeneration is most evident in the lower parts of the spinal cord, but it can be traced up through the brainstem to the posterior limb of the internal capsule and corona radiata by means of fat stains, which show the macrophages that accumulate in response to chronic myelin degeneration. There is a loss of Betz cells in the motor cortex; this is manifest as a slight frontal lobe atrophy on the MRI, but it is not a prominent finding in most cases of ALS (Kiernan and Hudson). Other fibers in the ventral and lateral funiculi are depleted, imparting a characteristic pallor in myelin stains. Some pathologists have interpreted this as evidence of involvement of nonmotor neurons and hence object to the term motor system disease. However, this condition of more diffuse pallor may be a result of a loss of collaterals of motor neurons that contribute to the lamina propria. One observes the same effect in long-standing poliomyelitis. In cases of familial ALS resulting from mutations in the SOD1 gene, the nonmotor systems seem to be more affected (Cudkowicz et al).

Neuropathologic studies of cases of ALS with dementia are few in number. In addition to the usual loss of motor neurons, these cases have shown an extensive neuronal loss, gliosis, and vacuolation involving the frontal premotor area, particularly the superior frontal gyri and the inferolateral cortex of the temporal lobes. The histologic changes of Alzheimer or Pick disease have not been seen in our cases; neurofibrillary degeneration has been observed, but is inconsequential in comparison to that seen in the Guamanian Parkinson-dementia-ALS complex (Finlayson et al; Mitsuyama). Attempts to transmit this ALS–dementia syndrome to subhuman primates have been unsuccessful.

Diagnosis of ALS

The early clinical picture of motor system disease is closely simulated by a centrally placed cervical spondylotic bar or ruptured cervical disc, but with these conditions there is usually pain in the neck and shoulders, limitation of neck movements, and sensory changes, and the lower motor neuron changes are restricted to 1 or 2 spinal segments. The EMG is helpful if not decisive in differentiating these disorders. A mild hemiparesis or monoparesis because of multiple sclerosis may be, for a time, difficult to distinguish from early ALS and primary lateral sclerosis. Progressive spinal muscular atrophy may be differentiated from peroneal muscular atrophy (Charcot-Marie-Tooth neuropathy) by the lack of family history, the complete lack of sensory change, and different EMG patterns, as described in Chap. 46. Motor system disease beginning in the proximal limb muscles may be misdiagnosed as an inflammatory myopathy or a limb-girdle type of muscular dystrophy.

The main considerations in relation to progressive bulbar palsy are myasthenia gravis and, less often, inflammatory myopathy, muscular dystrophy, and especially the inherited (Kennedy) type of bulbospinal atrophy, which is discussed further on. The spastic form of bulbar palsy may suggest the pseudobulbar palsy of lacunar disease and can be a prominent part of the progressive supranuclear palsy described earlier in the chapter. A crural form of PMA may be confused with diabetic polyradiculopathy or polymyositis.

A major consideration is the differentiation of PMA from a chronic motor polyneuropathy, particularly the form that displays multifocal conduction block. Extensive nerve conduction studies and EMG examinations are necessary to distinguish the two; these neuropathic processes are discussed with the peripheral neuropathies in Chap. 46. The presence of an IgM monoclonal paraproteinemia or of specific antibodies directed against the GM1 ganglioside are usually indicative of the immune motor neuropathy, but in half of the cases these laboratory tests are negative. There is also a rare form of subacute poliomyelitis (possibly viral) in patients with lymphoma or carcinoma; it leads to an amyotrophy that progresses to death over a period of several months. Chapter 31 discusses this paraneoplastic variety of motor system disease in greater detail.

Because it may produce a motor-predominant radiculopathy, chronic Lyme infection is sometimes considered in the differential diagnosis of ALS. Some clinics screen for Lyme antibodies using both an enzyme-linked immunosorbent assay (ELISA) and the more sensitive and specific Western immunoblot, but we have never detected such a case and doubt there is much similarity. Infrequently, we have seen myelopathic motor findings and motor radiculopathy with vitamin B12 deficiency, and there are exceptional reports of myeloradiculopathy with lead poisoning; we sometimes include tests for these conditions. Another entity that may simulate ALS is inclusion body myositis (IBM), an atypical myopathy that begins asymmetrically and involves distal muscles, usually without much elevation of serum CPK levels. In a recent series of 70 patients with this condition, 13 percent were initially diagnosed as having ALS (Dabby et al). Features distinguishing the IBM cases included normal corticospinal function, preservation of deep tendon reflexes in weak muscles, and finger flexor weakness. One concludes from this series that a detailed, quantitative EMG and possibly a muscle biopsy are indicated in cases that display predominantly lower motor features. Fully developed ALS is difficult to confuse with these conditions. Acid maltase deficiency may also simulate ALS in causing fatigability and early respiratory failure.

Over the years, the authors have encountered young men with localized and asymmetrical amyotrophy of the leg or forearm that became arrested and did not advance over a decade or two. Several reports of such a partial cervical spinal amyotrophy have appeared in recent years (Hirayama et al; Moreno Martinez et al). In the type described by Hirayama and associates, young men are affected with progressive and asymmetrical amyotrophy of the forearm and hand that has been traced to ligamentous hypertrophy and buckling in the ventral spinal canal. This causes a compression of the cervical spinal cord gray matter, presumably by a chronic ischemic effect as discussed in detail in Chap. 44. In a familial variety of pure restricted amyotrophy, only the vocal cords became paralyzed over a period of years in adult life; only later were the hands affected.

Some patients who have recovered from paralytic poliomyelitis may develop progressive muscular weakness 30 or 40 years later; the nature of this relationship is obscure. We favor the explanation that atrophy of anterior horn cells with aging brings to light a critically depleted motor neuron population (see further on). It appears to progress little if at all.

An observation of interest is the finding of a form of progressive spinal muscular atrophy in patients with GM2 gangliosidosis, the storage disease that presents in infancy as Tay-Sachs disease (Kolodny and Raghavan). The onset is in late adolescence and early adult life and the atrophic paralysis is progressive, so that this condition is often mistaken for Wohlfart-Kugelberg-Welander disease or ALS. A number of cases of this type have been discovered in Ashkenazi Jews by the use of lysosomal enzyme analysis. The rare and incompletely characterized entity of polyglucosan disease, discussed in other sections of the book, has simulated ALS.

The differential diagnosis of the purely spastic state of primary lateral sclerosis is broad and has been listed earlier. An estimate of the frequency of all the aforementioned alternative diagnoses may be appreciated from a study of cases by Visser and colleagues that were initially presumed to be PMA but turned out to represent another process. In 17 of 89 patients the diagnosis proved to be anti-GM1 motor conduction block, chronic inflammatory demyelinating polyneuropathy, and various myopathies. This notwithstanding, ALS or the more discrete forms of motor system disease rarely offer any difficulty in diagnosis.

Pathogenesis

Insight into the sporadic form of the disease has been afforded by analyses of the approximately 10 percent of ALS cases that are familial and caused by identifiable mutations. They are inherited mainly in an autosomal dominant pattern (Table 39-6). Of these inherited forms, approximately 40 percent are associated with a hexanucleotide expansion in the C9orf72 gene, and provocatively, 4 to 8 percent of ostensibly sporadic cases have mutations in the gene. The mechanism of motor neuron death that results from this mutation is not known but may be associated with mishandling of RNA-binding proteins. Of similar interest are the TARDBP and FUS genes that each has an association with approximately 5 percent of familial cases and 2 percent of sporadic ones. These genetic and molecular influences are summarized by Andersen and Al-Chalabi. All 3 of the aforementioned genes have also been implicated in degenerative frontotemporal dementia and in the combination of this dementia with ALS. The SOD1 mutation, the first to be found in familial ALS, codes for the cytosolic enzyme Cu-Zn superoxide dismutase (SOD1; Rosen et al); it has also been implicated in a small proportion of sporadic cases. There are yet other mutations in this group that have associations, not necessarily causal, with small numbers of both sporadic and inherited cases (Table 39-7).

Table 39-6 Genetic Defects Associated with ALS

Table 39-6 Genetic Defects Associated with ALS

GENE

PROTEIN

INHERITANCE

AGE OF ONSET

CLINICAL FEATURES

SOD1

Superoxide dismutase 1

Adult

Clinically and pathologically similar to sporadic ALS

FUS

Fused sarcoma

Adult

ALS with frontotemporal dementia

TARDP5P

AD, rare recessive

DCTN

Dynactin

Adult

Slowly progressive with predominant bulbar features

CytoC

Cytochrome-c oxidase

Mitochondrial

Adult

Prominent spasticity

ALS2

GEF/alsin

Juvenile

Very slowly progressive, predominantly corticospinal

SETX

Senataxin

Juvenile

Very slowly progressive

VAPB

Vesicle-associated membrane protein

Adult

Similar to sporadic ALS

AD autosomal dominant; AR autosomal recessive

Table 39-7 Classification of the Spinal Muscular Atrophies (SMA)

Table 39-7 Classification of the Spinal Muscular Atrophies (SMA)

TYPE

INHERITANCE

AGE OF ONSET

CLINICAL FEATURES

PROGNOSIS

SMA I (infantile, Werdnig-Hoffmann)

Autosomal recessive

Two copies of SMN 2

Preterm to 6 months

Neonatal hypotonia (floppy baby), weakness of sucking and swallowing, may have arthrogryposis, unable to sit

Few survive 1 year

SMA II (intermediate type; Dubowitz disease)

Autosomal recessive

At least 3 copies of SMN 2

6 to 15 months

Proximal weakness, fasciculation, fine hand tremor, unable to stand

Variable; death from respiratory complications

SMA III (Wohlfart-Kugelberg-Welander)

Autosomal recessive or dominant

At least 3 copies of SMN 2

1 year to adolescence

Delayed motor development, proximal leg weakness

Slowly progressive, variable outcome

SMA IV

Autosomal recessive

At least 4 copies of SMN 2

After age 30

Proximal limb weakness and diaphragm

Slowly progressive; eventually wheelchair-bound but normal life expectancy

Kennedy syndrome (bulbospinal atrophy)

X-linked (CAG repeat expansion in the AR gene), less often autosomal dominant

Early adulthood

Scapuloperoneal or distal atrophy, oropharyngeal weakness, gynecomastia, oligospermia

Slowly progressive

Fazio-Londe disease

Autosomal recessive, rarely dominant, SLC52A3 gene

Childhood to early adolescence

Progressive bulbar and respiratory failure

Survival for years, respiratory failure

What has emerged from these genetic studies is the common feature of the accumulation of the TDP-43 and FUS proteins in neurons. The mechanisms that lead to cell death as a result of any of these mutations or the protein deposition are being sought.

A rare and recessively inherited childhood form of motor neuron disease (affecting corticospinal more than spinal motor neurons) has been attributed to mutations in a gene whose protein (alsin) is a component of the neuronal cell-signaling pathways. Yet another rare childhood-onset form of disease arises from mutations in the senataxin gene, a DNA helicase that probably assists in chromatin folding and unfolding. (It is of interest that a recessively inherited mutation in the same gene transmits a recessive form of ataxia with oculomotor disorder.) In several families, a mutation has been detected in a protein that is involved in the transport of vesicles in neurons. Table 39-6 summarizes these various genetic forms of motor neuron disease.

Trauma, particularly traction injury of an arm, but also repetitive head and spine injury has been reported occasionally as an antecedent event in patients with ALS, but a causative relationship has not been established. Younger and coworkers have found a higher incidence of paraproteinemia in patients with motor system disease than can be accounted for by chance. Many other examples of disordered immune function have been described but a coherent explanation of ALS as an autoimmune disease has not emerged. It has never been proved that intoxication with heavy metals (lead, mercury, aluminum) can cause motor system disease, although there are reports of concurrent myelopathic and radicular motor signs in patients with lead intoxication. There is little evidence that such cases represent a reactivation of a virus or the presence of some other infectious agent. The progressive weakness that occurs some 30 to 40 years after recovery from polio should not be confused with PMA, as already indicated. Finally, we have had occasion to see patients who, many years after a severe electrical injury that passed through the region of the cord, developed a progressive and severe amyotrophy of the arms; other such extraordinary cases are known but the concordance is considered coincidental by most authorities (see Chap. 44).

Treatment

With the exception of riluzole, discussed below, there is no specific treatment for any of the motor neuron diseases. Supportive measures, however, are exceedingly important. In initial office visits, it has been our practice to give the patient some idea of the seriousness of the condition; but in early discussions we avoid the devastating statement that ALS is invariably fatal. Typically, patients and family members will ask explicitly about these matters in subsequent visits; such data as are appropriate to the patient's circumstances and character can be conveyed at that time, usually with the caveat that any individual may outlive the standard survival statistics.

The antiglutamate agent riluzole was shown by Bensimon and colleagues to slow the progression of ALS and improve survival in patients with disease of bulbar onset. However, it added only 3 months of life at best. This claim has been confirmed in several followup studies, although again the benefit has been marginal. Several additional agents are reported to have been effective in genetic models of ALS. These are presently undergoing study in ALS patients. Guanidine hydrochloride and injections of cobra venom, gangliosides, interferons, high-dose intravenous cyclophosphamide, and thyrotropin-releasing hormone are but some of a long list of agents that were said to arrest the disease process, but these claims have been discredited.

An attempt can be made to reduce the spasticity with medications, such as baclofen or tizanidine, or by subarachnoid infusions of baclofen via an implanted lumbar pump. Initial intrathecal test doses are given to predict a response to the pump infusions of baclofen, but this test may fail; consequently, in severe cases it may be advisable to proceed with a constant infusion for several days. Some degree of improved comfort from a reduction in the extreme rigidity is usually the most that can be expected. Partial relief from spasticity may also be afforded by the use of benzodiazepines or sometimes dantrolene. These approaches are most suitable for cases of primary lateral sclerosis, which can be expected to progress slowly and for a long period.

At all stages of ALS, physical therapy is useful in maintaining mobility, but overwork of the muscles leading to fatigue and cramps should be avoided. Physical therapy is invaluable, for example, for avoiding contractures of the fingers and shoulders. Occupational therapy is likewise helpful, particularly assessments of the patient's function in the home.

Important in the management of ALS is periodic monitoring of respiratory function. We typically perform pulmonary function tests every few months after the first year or so of illness. Our experience has been that the vital capacity in cubic centimeters can be estimated by multiplying the highest number to which a patient can count with one deep breath by 100. Thus, the ability to count to 25 with a full effort in a single breath corresponds to a vital capacity of approximately 2.5 L. Significant practical advances have been made in the respiratory management of ALS. The introduction of bilevel positive airway pressure (BiPAP) has allowed patients to sleep better and reduce daytime somnolence. Many patients do not initially tolerate the device, usually because of maladjusted face masks or excessive applied airway pressures. Almost always, a seasoned pulmonary technologist can find solutions to these problems. It is appropriate to begin BiPAP at (or before) the earliest sign of carbon dioxide retention, a state that is heralded by disruption of sleep, nightmares, early morning headaches, and daytime drowsiness. With noninvasive respiratory assistance, it may be possible to defer tracheostomy for months or years. Ultimately, as the diaphragm fails, BiPAP is needed not only at night but also during the day. As BiPAP use approaches 20 to 24 h per day, patients must usually address the difficult question of tracheostomy and mechanical ventilation. We broach this subject early enough in the course of the disease to allow ample time for discussion and reflection. In practice, most patients elect not to undergo tracheostomy and full ventilation.

Another important issue regards nutrition. As oropharyngeal palsy progresses, food should be cut into small pieces and dry foods, such as toast should be avoided; milk shakes and preparations of the same consistency are ideal at this stage. Speech therapists are capable of teaching patients methods to adapt to declining bulbar function and at the same time minimizing aspiration. Ultimately, in our experience, most ALS patients will need a feeding tube to maintain normal hydration and caloric intake. Although we adopt a neutral position in discussions with patients regarding mechanical ventilation, we tend to urge patients to undergo placement of a feeding tube at the appropriate time. This presumably increases survival and improves quality of life by preventing dehydration and recurrent aspiration. Laparoscopic and radiologic technologies for the placement of a gastrostomy tube render the procedure swift and nearly painless. Some patients have tubes inserted as outpatients and then start gastric feeding within a day or two.

Other devices, often guided by the physical and occupational therapist, may be of great assistance to the patient and family as the disease progresses. These include a mechanized bed and structural accommodations in the home that facilitate entry of a wheelchair and the safe use of the bath or shower as well as thick-handled utensils. Ambulation aids, beginning with simple canes (first one, then two) followed by a walker (preferably with basket and seat) and then a wheelchair (manual or electric) are of value in maintaining a sense of independence and assuring safety.

The American Academy of Neurology has published explicit guidelines for management that have been of great aid to patients and physicians; they emphasize the complex and multidisciplinary needs of ALS patients (see Miller et al 2009a and 2009b).

Heredofamilial Forms of Progressive Muscular Atrophy

These diverse diseases are the concern mainly of child neurology. They are presented here because they fall within the category of system degenerations and are usually inherited.

Spinal Muscular Atrophy (Werdnig-Hoffman Disease)

The classic form of spinal muscular atrophy was described by Werdnig in 1891 and 1894, by Hoffmann in 1893 and, at about the same time, by Thomsen and Bruce. The cases described by these authors were all in infants. Further clinical analyses, however, indicated the inadequacy of this narrow grouping for the large group of spinal muscular atrophies. Brandt, in his study of 112 Danish patients, found that in about one-third the weakness was present at birth, and in 97 the onset was in the first year of life; in 9 patients, the disease was not recognized until after the first year of life. In 1956, Walton, and later Wohlfart and colleagues and Kugelberg and Welander (see below), identified milder forms of spinal muscular atrophy in which the onset was between 2 and 17 years and walking was still possible in adult life. Byers and Banker, in a study of 52 patients, subdivided them into 3 groups on the basis of age of onset; in one group the disease was recognized at birth or in the first month or two of life; in a second, between 6 and 12 months; and in a third, after the first year. In their last group, it was not unusual for the patient to survive into adolescence and adult life. In a few of the late-onset types, signs of corticospinal tract involvement are conjoined, and Bonduelle has also included some patients with areflexia, pes cavus, Babinski signs, choreiform movements, and developmental delay in this group. More recently, the designations SMA I, II, and III have been introduced, based largely on the age of onset (see Table 39-7).

Genetic Aspects of Spinal Muscular Atrophies

Familial spinal muscular atrophy that begins in infancy and childhood is inherited mainly as an autosomal recessive trait. All the SMA phenotypes in children have been mapped to the same chromosome, 5q11.2-13.3 (Brzustowicz et al; Gilliam et al; Munsat et al). The mutations affect the gene at the "survival of motor neuron" (SMN) site. The SMN protein participates in forming protein-RNA complexes (small nuclear ribonucleoproteins and RNA) that are essential for gene splicing. Within the SMN locus there are 2 alleles: SMN1, which generates a full-length, fully functional form of SMN, and SMN2, which makes a truncated, partially functional SMN. The latter can partially compensate for the loss of SMN1. Making matters more complex, individuals vary in the number copies of SMN2. As a result, disease due to loss of both copies of SMN1 causes very severe SMA in individuals who carry only one copy of SMN2, while those with multiple copies of SMN2 have milder disease. Thus, the amount of SMN2 protein determines the severity and time of onset of disease.

Although affected siblings demonstrate very similar clinical patterns of disease, the same mutation may give rise to very different phenotypes in different families, so that additional modifying posttranscriptional or nongenetic attributes must be playing a role. Less often, autosomal dominant and X-linked patterns of inheritance have been found, resulting from mutations in UBA1, usually in adults. A rare autosomal dominant adult form is the result of mutations in VABP and a form that affects only the legs is associated with mutations in DYNC1H1.

Clinical Manifestations of Werdnig-Hoffmann Disease (SMA I)

The most frequent form of these spinal muscular atrophies, the severe infantile type, is a common disease, occurring once in every 20,000 live births. After cystic fibrosis, it is also the most frequent cause of death from a recessively inherited disease. Characteristically the infant, usually born normally, is noted from birth to be unnaturally weak and limp ("floppy"). Some mothers report that fetal movement in utero had been less than expected or lacking altogether. In severe cases, arthrogryposis at the ankles and wrists or dislocation of the hips is noted at birth (arthrogryposis and its differential diagnosis is discussed in Chap. 48 in the section on the congenital neuromuscular disorders). The muscle weakness in these children is generalized from the beginning, and death comes early, usually within the first year. Other infants seem to develop normally for several months before the weakness becomes apparent. In these, the trunk, pelvic, and shoulder-girdle muscles are at first disproportionately affected, while the fingers and hands, toes and feet, and cranial muscles retain mobility. Hypotonia accompanies the weakness, and because passive displacement of articulated parts in testing muscle tone is easier to judge than power of contraction at this early age, it may be singled out as the dominant clinical characteristic. As a rule, the tendon reflexes are unobtainable. Volume of muscle is diminished but is difficult to evaluate in the infant because of the coverings of adipose tissue. Fasciculations are seldom visible except sometimes in the tongue. Perception of tactile and painful stimuli is undiminished, and emotional and social development measures up to age.

As the months pass, the weakness and hypotonia progress gradually and spread to all the skeletal muscles except the ocular ones. Intercostal paralysis with a degree of collapse of the chest is the rule. Respiratory movements become paradoxical (abdominal protrusion with chest retraction). The cry becomes feeble, and sucking and swallowing are less efficient. Such infants are unable to sit unless propped, and they cannot hold up their heads without support and cannot roll over or support their weight when placed on their feet. Their posture is characteristic: arms abducted and flexed at the elbow, legs in the "frog position" with external rotation and abduction at hips and flexion at hips and knees. If the effects of gravity are removed, all muscles continue to contract; that is there is paresis, not paralysis. Until late in the illness, these children appear bright-eyed, alert, and responsive.

Infants in whom the disease becomes apparent only after several months of life have a less-rapid decline than those affected in utero or at birth. Some of the former become able to sit and creep and even to walk with support; those with later onset may survive for several years and even into adolescence or early adult life, as already mentioned.

Laboratory data of confirmatory value are few. Muscle enzymes in the serum are usually normal or rarely elevated. The EMG, if performed at a late enough stage of development, displays fibrillations, proving the denervative basis of the weakness. Motor unit potentials are diminished in number and, in the more slowly evolving cases, some are larger than normal (giant or polyphasic potentials reflecting reinnervation). Motor nerve conduction velocities are normal or fall in the low-normal range (these are normally slower in infants than in adults). Electrophysiologic studies performed in the first few months of life may give ambiguous results.

Pathologic Findings

Muscle biopsy after 1 month of age reveals a typical picture of group atrophy; shortly after birth this change is difficult to discern. Aside from denervative atrophy, the essential abnormalities are in the anterior horn cells in the spinal cord and the motor nuclei in the lower brainstem. Nerve cells are greatly reduced in number, and many of the remaining ones are in varying stages of degeneration; a few are chromatolytic and contain cytoplasmic inclusions. It is not unusual to see figures of neuronophagia. There is replacement gliosis and secondary degeneration in roots and nerves. Other systems of neurons, including the corticospinal and corticobulbar systems, are entirely unaffected.

Differential Diagnosis

The major problem in diagnosis is to distinguish Werdnig-Hoffmann disease from an array of other diseases that cause hypotonia and delayed motor development in the neonate and infant. The list of disorders that imitates spinal muscular atrophy constitutes a large part of the differential diagnosis of the so-called floppy infant. The congenital myopathies (as described in Chap. 48), the glycogenoses, neonatal myasthenia gravis, Prader-Willi syndrome, and disorders of fatty acid metabolism frequently present in this way. The preservation of tendon reflexes and relative lack of progression of muscle weakness distinguish the latter disorders. Because of the gravity of the diagnosis, muscle biopsy should be performed if there is any suspicion of spinal muscular atrophy. If studied properly, the biopsy usually yields the correct diagnosis.

Clinical disorders more or less similar to the spinal muscular atrophies may be identified occasionally in certain hereditary metabolic diseases. For example, Johnson and coworkers have described a patient who began experiencing weakness of the legs, cramping, and fasciculations during adolescence in what proved to be a variant of hexosaminidase A (GM2) deficiency, and biopsy of rectal mucosa showed nerve cells with the typical membranous cytoplasmic bodies of Tay-Sachs disease. Others have reported similar cases. A progressive motor neuron or motor nerve disorder has also been observed in glycogen storage disease affecting anterior horn cells. Motor nerve fibers also suffer damage in metachromatic and globoid body leukoencephalopathies.

Certain forms of muscular dystrophy, notably myotonic dystrophy, which is about twice as frequent as Werdnig-Hoffmann disease, may become manifest in the neonatal period and interfere with sucking and motor development (see Chap. 48). As a rule, the weakness is not as severe or diffuse as that in Werdnig-Hoffmann disease. The mother, but not the child, may display myotonia, either elicitable clinically or, if more subtle, with EMG recording. Also, a number of polyneuropathies may cause a serious degree of weakness in early childhood. Unfortunately, in respect to the latter, adequate sensory testing is not possible because of the patient's age, but the CSF protein is often elevated. Again, diagnosis is greatly facilitated by nerve-muscle biopsy and measurement of nerve conduction velocities. These velocities are reduced but must be interpreted with caution because of incomplete development of axons and of myelination in the first months of life. The needle EMG examination shows subtle signs of denervation that cannot be easily distinguished from the finding in the spinal muscular atrophies. Examination of parents and siblings may disclose a clinically inapparent neuropathy. Polymyositis of childhood may also simulate both muscular dystrophy and motor neuron disease. Finally nemaline and central core myopathy can manifest in infancy and early childhood and cause a floppy child syndrome.

Developmental delay with a flaccid rather than spastic weakness of the limbs is another major category of disease that must be distinguished. These include Down syndrome, cretinism, Prader-Willi syndrome, and achondrodysplasia. It should be commented that very sick children with celiac disease, cystic fibrosis, and other chronic diseases may be hypotonic to the point of simulating neuromuscular disease. Usually speech is not delayed and tendon reflexes are preserved in these purely medical states, and strength returns as the medical problem is corrected. Also, certain of the polioencephalopathies and leukodystrophies may weaken muscles and abolish tendon reflexes, but usually there is evidence of cerebral involvement.

There remains, after the assiduous study of the "floppy infant," a group of cases of hypotonia and motor underdevelopment that cannot be classified. The term amyotonia congenita (Oppenheim) was once applied to this entire group but is now obsolete. Walto proposed the term benign congenital hypotonia to designate patients who manifest limp and flabby limbs in infancy and a delay in sitting up and walking but who improve gradually, some completely and others incompletely. It is likely that among this group there are examples of congenital myopathy that await differentiation by application of modern histochemical, ultrastructural, and genetic techniques.

Chronic Childhood and Juvenile Proximal Spinal Muscular Atrophy (Wohlfart-Kugelberg-Welander Syndrome; SMA III)

This is a somewhat different form of heredofamilial spinal muscular atrophy, which, as the name indicates, involves the proximal muscles of the limbs predominantly and is only slowly progressive. It was first separated from other forms of motor system disease and from muscular dystrophy by Wohlfart and by Kugelberg and Welander in the mid-1950s. In about one-third of the cases the onset is before 2 years of age, and in half, between 3 and 18 years. Males predominate, especially among patients with juvenile and adult onset. The usual form of transmission is by an autosomal recessive pattern; most cases result from mutations in the SMN gene; as mentioned, multiple copies of the SMN2 gene partly rescue the loss of SMN1 and lead to this milder form of disease. Families with dominant and sex-linked inheritance have also been described.

The disease begins insidiously, with weakness and atrophy of the pelvic girdle and proximal leg muscles, followed by involvement of the shoulder girdle and upper arm muscles. Unlike the sporadic form of spinal muscular atrophy, the Wohlfart-Kugelberg-Welander variety (also listed in other books and monographs as Kugelberg-Welander disease) is bilaterally symmetrical from the beginning, and fasciculations are observed in only half the cases. Ultimately the distal limb muscles are involved and tendon reflexes are lost. Bulbar musculature and corticospinal tracts are spared, although Babinski signs and an associated ophthalmoplegia (presumably neural) have been reported in rare instances.

The presence of fasciculations and the EMG and muscle biopsy findings—all of which show the characteristic abnormalities of neural atrophy—permit distinction from muscular dystrophy. Cases that have been examined postmortem have shown loss and degeneration of the anterior horn cells.

The disease progresses very slowly, and some patients survive to old age without serious disability. In general, the earlier the onset, the less favorable the prognosis; however, even the most severely affected patients retain the ability to walk for at least 10 years after the onset. Admittedly, it is difficult to make a sharp distinction between these cases of Wohlfart-Kugelberg-Welander disease and certain milder instances of Werdnig-Hoffmann disease with onset in late infancy and early childhood and prolonged survival (Byers and Banker).

A form that is intermediate between the severe Werdnig-Hoffman type and the milder Wohlfart-Kugelberg-Welander is termed Dubowitz syndrome and designated SMA II.

Kennedy Syndrome (X-Linked Bulbospinal Muscular Atrophy)

An unusual pattern of distal muscular atrophy with prominent bulbar signs and, less often, ocular palsies was described by Kennedy and coworkers. The onset has varied from childhood to adult age, but symptoms typically begin in the third decade. Most cases have shown an X-linked pattern of inheritance and a lesser number, an autosomal dominant pattern. The proximal shoulder and hip musculature are involved first by weakness and atrophy, followed in about half of patients by dysarthria and dysphagia. Muscle cramps or twitching often precedes weakness. Facial fasciculations and mild weakness are characteristic and may be striking. The tendon reflexes become depressed and may be absent; a mild sensory neuropathy is almost universal. In the family described by Kaeser, in which 12 members in 5 generations were affected, the pattern of weakness was shoulder-shank, that is scapuloperoneal; it may therefore be mistaken for muscular dystrophy. Two-thirds of patients have gynecomastia, a feature that may first identify affected men in a kindred; oligospermia and diabetes are additional associations; therefore, the presence of genuine progeny virtually excludes the disease in a male. The CK level is elevated, sometimes tenfold, and physiologic studies reveal denervation and reinnervation as well as indications of a mild sensory neuropathy.

As in Huntington disease and certain of the spinocerebellar atrophies, the genetic defect is a CAG expansion, in this case in the gene (AR) that codes for the androgen receptor on the short arm of the X-chromosome (La Spada et al; see Table 39-7). Indeed, the first reported polyglutamine disease was Kennedy syndrome. Lengthened sequences correlate with an earlier age of onset (anticipation, as in Huntington disease) but have no relation to the severity of disease. Androgen receptors have been found on motor neurons of the spinal cord; the subpopulation of motor neurons that is susceptible to both Kennedy syndrome and ALS express abundant surface androgen receptors, but it is not clear whether this finding has direct pathogenic significance. Neuronal inclusions have been described, composed of aggregations of the abnormally long polyglutamine protein sequences that correspond to the CAG expansion. A family with the bulbospinal phenotype but without the CAG expansion has also been reported (Paradiso et al). Other features, such as optic atrophy and sensory neuronopathy, were present in some members of this kindred but are not features of typical cases. The diagnosis can be confirmed by genetic testing for the lengthened trinucleotide sequence. Prenatal diagnosis and identification of female carriers are also possible by this method.

Progressive Bulbar Palsy of Childhood (Fazio-Londe Syndrome)

Fazio in 1892, and Londe in 1893, described the development of a progressive bulbar palsy in children, adolescents, and young adults. There is progressive paralysis of the facial, lingual, pharyngeal, laryngeal, and sometimes ocular muscles. The illness usually presents with stridor and respiratory symptoms, followed by facial diplegia, dysarthria, dysphagia, and dysphonia. These features become increasingly pronounced until the time of death some years later. In a few patients there is a late development of corticospinal signs and sometimes ocular palsies. Occasionally, jaw and oculomotor paresis appears, and in one case, there was progressive deafness. The disease is rare, only several dozen well-described examples had been recorded in the medical literature by 1992 (McShane et al). Inheritance may be autosomal dominant, as in Fazio's original case, and rarely X-linked, but it is more likely to be autosomal recessive. Pathologic examination has shown a loss of motor neurons in the hypoglossal, ambiguus, facial, and trigeminal motor nuclei. In a few cases, the nerve cells in the ocular motor nuclei also were diminished. This disease, the 2 times we have encountered it, had to be differentiated from myasthenia gravis, a pontomedullary glioma, and brainstem multiple sclerosis.

The cause of the disease is interesting in that it results from mutations in SLC52A3, a riboflavin transporter, and some beneficial effect is derived from the administration of riboflavin (vitamin B2). The disease is allelic with Brown-Vialetto-Van Laere syndrome, another motor neuron degeneration, which includes deafness.

Hereditary Forms of Spastic Paraplegia

Hereditary Spastic Paraplegia (StrüMpell-Lorrain Disease)

This disease was described by Seeligmuller in 1874 and later by Strümpell in Germany and Lorrain in France; it has now been identified in nearly every part of the world. The pattern of inheritance is usually autosomal dominant, less often recessive (one family has shown X-linked inheritance), and the onset may be at any age from childhood to the senium. Harding (1993) divided the disease into 2 groups, the more common one beginning before age 35 with a very protracted course and the other with a late onset (40 to 60 years). The latter type often shows sensory loss, urinary symptoms, and action tremor.

The clinical picture is that of a gradual development of spastic weakness of the legs with increasing difficulty in walking. The tendon reflexes are hyperactive and the plantar reflexes extensor. In the pure form of the disease, sensory and other nervous functions are entirely intact. If the onset is in childhood, as many cases are, the foot arches become exaggerated, the feet are shortened, and there is a tightening (pseudocontracture) of calf muscles, forcing the child or adolescent to "toe-walk." This is a common orthopedic problem and may require surgical correction. In children, the legs appear to be underdeveloped, and in both children and adults they may become quite thin. Sometimes the knees are slightly flexed; at other times the legs are fully extended or hyperextended (genu recurvatum) and adducted. Weakness is variable and difficult to estimate. Sphincteric function is usually retained. Subtle sensory loss in the feet has been reported. The arms are variably involved. In some patients, the arms appear to be spared even though the tendon reflexes are lively. In others, the hands are stiff, movements are clumsy, and speech is mildly dysarthric. Conjoined findings such as nystagmus, ocular palsies, optic atrophy, pigmentary macular degeneration, ataxia (both cerebellar and sensory), sensorimotor polyneuropathy, ichthyosis, patchy skin pigmentation, epilepsy, and dementia have all been described in isolated families (see further on).

The few available pathologic studies have shown that, in addition to degeneration of the corticospinal tracts throughout the spinal cord, there is thinning of the columns of Goll, mainly in the lumbosacral regions, and of the spinocerebellar tracts, even when no sensory abnormalities had been detected during life. These were the pathologic findings described by Strümpell in his original (1880) report of 2 brothers with spastic paraplegia; one of them, in addition, had a cerebellar syndrome, but again, there were no sensory abnormalities. A reduction in the number of Betz and anterior horn cells has also been reported.

Genetic Aspects of Hereditary Spastic Paraplegia

Numerous genetic mutations have given rise to this disease. As of this writing, there were 52 hereditary spastic paraplegia (HSP) loci many of which are shown in Table 39-8. The disease types have been renamed under the designation "SPG" (for spastic paraplegia) and numbered in order of discovery of the associated gene. The common uncomplicated autosomal dominant form of disease has been linked to mutations in many proteins, the most common being (proteins in parentheses) SPAST (spastin) and ALT1 (atlastin); and the common recessive varieties, are in SPG7 (paraplegin); and X-linked in L1CAM and PLP1 (proteolipid protein). The common spastin variety, associated with a mutation on chromosome 2p, results in great variability of clinical presentation within and among families (see Nielsen et al). A high frequency of partial deletions of the SPAST gene has been found. The possible subcellular mechanisms by which these mutations cause degeneration of the corticospinal tracts have been reviewed by Blackstone.

Table 39-8 Genetic Defects Associated with Hereditary Spastic Paraplegia (HSP)

Table 39-8 Genetic Defects Associated with Hereditary Spastic Paraplegia (HSP)

HSP TYPE

GENE (PROTEIN)

GENETICS

AGE OF ONSET

CLINICAL AND MISCELLANEOUS FEATURES

ATL1 (atlastin)

Childhood

Guanylate-binding protein

Spastin

20's

40–50% of HSP; binds to microtubules

NIPA1

Teens

Golgi membrane protein

KIF5A (kinesin-1)

Childhood

Kinesin heavy chain–motor protein

HSP (heat shock protein)

Adult

Located in mitochondrial matrix

BSCL2 (seipin)

Variable

Silver syndrome: HSP with wasting of hands, feet

SPG7 (paraplegin)

Adult

Mitochondrial chaperone and metalloprotease; optic atrophy, neuropathy, myopathy

Spartin

HSP with wasting of distal limbs, hands, feet

SPG21 (maspardin)

Late teens

Endosomal protein involved in protein transport

L1CAM (L1 cell adhesion molecule)

Infancy

Developmental delay, hydrocephalus, callosal hypoplasia, spasticity

PLP (proteolipid protein)

Infancy

Cognitive impairment, spasticity, ataxia

AD autosomal dominant; AR autosomal recessive; XR X-linked recessive

Differential Diagnosis

In the diagnosis of this disorder, one should consider an indolent spinal cord or foramen magnum tumor, cervical spondylosis, a spinal from of multiple sclerosis (this was the clinical diagnosis in Strümpell's original cases), Chiari malformation, compression of the cord by a variety of congenital bony malformations at the craniocervical junction, and a number of chronic myelitides, among them, lupus erythematosus, sarcoidosis, AIDS, adrenomyeloneuropathy, primary lateral sclerosis (described earlier in this chapter), hypocupric myelopathy, spinal arteriovenous dural fistula, and especially, tropical spastic paraparesis (caused by the HTLV-1 virus as discussed in Chap. 33).

Variants of Familial Spastic Paraplegia

The literature contains a large number of descriptions of familial spastic paraplegia combined with other neurologic abnormalities. Some of the syndromes had developed early in life in conjunction with moderate degrees of mental retardation. In these, the rest of the neurologic picture appeared many years after birth and was progressive. Some idea of the number of these "hereditary paraplegia-plus" syndromes and the diverse combinations in which they may be present is conveyed in the review by Gout and colleagues. Again, it is hardly possible to describe each of these symptoms in any degree of detail. The list below includes the best-known entities but all are rare. But if the term hereditary spastic paraplegia is to have any neurologic significance, it should be applied only to the pure form of the progressive syndrome. The more common "atypical" or "syndromic" cases—with amyotrophy, cerebellar ataxia, tremors, dystonia, athetosis, optic atrophy, retinal degeneration, amentia, and dementia—should be put in separate categories and their identity retained for nosologic purposes until such time as additional biochemical and genetic data related to pathogenesis are forthcoming. The gene mutations found in some of the variant types have been summarized by Fink, but—as with all types of uncomplicated hereditary spastic paraplegia—the mechanisms of neuronal loss are not known. To be separated from these cases are all the congenital nonprogressive types of spastic diplegia and athetosis. The following list includes the best-known entities:

Hereditary spastic paraplegia with ataxia (Ferguson-Critchley syndrome) This syndrome is one of a collection of leg spasticity and generalized ataxia syndrome that may also be characterized by a disorder of gaze, or optic atrophy. Most impressive are the manifestations of spinocerebellar ataxia beginning during the fourth and fifth decades of life, accompanied by weakness of the legs, alterations of mood, pathologic crying and laughing, dysarthria and diplopia, dysesthesias of limbs, and poor bladder control. The tendon reflexes are lively, with bilateral Babinski signs. Sensation is diminished distally in the limbs. The whole picture resembles a chronic progressive form of multiple sclerosis. In other cases, running through several generations of a family, the extrapyramidal features were more striking; such cases overlap with the following syndromes. A dominant form of the disease is due to a mutation in SAX1.
Hereditary spastic paraplegia with extrapyramidal signs Action and static tremors, parkinsonian rigidity, dystonic tongue movement, and athetosis of the limbs have all been conjoined with spastic paraplegia. Gilman and Romanul have reviewed the literature on this subject. In the authors' experience, the picture of parkinsonism with spastic weakness and other corticospinal signs has been the most frequent combination.
Hereditary spastic paraplegia with optic atrophy This is known as Behr syndrome or optic atrophy-ataxia syndrome, since cerebellar signs are usually conjoined. Some patients also have athetosis. The syndrome is transmitted as an autosomal recessive trait, with onset in infancy and slow progression. The mutation is in OPA3. There may be a relationship to decreased excretion of 3-methylglutaconic aciduria of an optic atrophy and cataract syndrome (Costeff syndrome).
Hereditary spastic paraplegia with macular degeneration (Kjellin syndrome) Spastic paraplegia with amyotrophy, oligophrenia, and central retinal degeneration constitutes the syndrome described in 1959 by Kjellin. Although the developmental delay is stationary, the spastic weakness and retinal changes are of late onset and progressive. Mutations have been found in SPG11 and SPG15.
Hereditary spastic paraplegia with developmental delay or dementia Many of the children with progressive spastic paraplegia either have been developmentally delayed since early life or have appeared to regress mentally as other neurologic symptoms developed. Examples of this syndrome and its variants are too numerous to be considered here but are contained in the review by Gilman and Romanul. The autosomal recessive syndrome of Sjögren-Larsson, with the onset in infancy of spastic weakness of the legs in association with developmental delay, stands somewhat apart from the others in this large group because of the associated ichthyosis. The mutation for the latter is in ALDH3A2 that codes for fatty aldehyde dehydrogenase. This relates to both dry skin, itchy and discolored skin, and the myelinopathy that characterize Sjögren-Larsson syndrome.
Hereditary spastic paraplegia with polyneuropathy Our colleagues had observed several patients in whom a sensorimotor polyneuropathy was combined with unmistakable signs of corticospinal disease. The age of onset was in childhood or adolescence, and the disability progressed to the point where the patient was chairbound by early adult life. In two of the cases, a sural nerve biopsy revealed a typical hypertrophic polyneuropathy; in a third case there was only a depletion of large myelinated fibers. The syndrome resembles the myeloneuropathy of adrenoleukodystrophy.
Spastic paraparesis with distal muscle wasting (Troyer syndrome) This disorder is transmitted as an autosomal recessive trait in the Amish population. Onset is in childhood with amyotrophy of the hands, followed by spasticity and contractures of the lower limbs. Cerebellar signs (mild), athetosis, and deafness may be added. The mutation is in SPG20.

Syndrome of Progressive Blindness

(See Chap. 13) There are 2 main classes of progressive blindness in children, adolescents, and adults: progressive optic neuropathy and retinal degenerations (retinitis pigmentosa and tapetoretinal macular degeneration). Of course, there are many congenital anomalies and retinal diseases beginning in infancy that result in blindness and microphthalmia. Some of those of neurologic interest were described briefly in connection with the hereditary spastic paraplegias and in Chap. 13.

Leber Hereditary Optic Atrophy

Although familial amaurosis was known in the early eighteenth century, it was Leber, in 1871, who gave the definitive description of this disease and traced it through many genealogies. The family studies of Nikoskelainen and coworkers indicate that all daughters of carrier mothers become carriers themselves, a type of transmission that is determined by inheritance of defective mitochondrial DNA from the mother (Wallace et al). Common to all cases is the presence of a pathogenic mitochondrial DNA abnormality (Riordan-Eva et al), but the defect may occur at one of several sites as discussed in Chap. 37. Thus, Leber optic atrophy has been added to the growing list of mitochondrial diseases. Mutations in approximately 20 genes have been detected, together accounting for about half of cases.

In most patients, the visual loss begins between 18 and 25 years of age, but the range of age of onset is much broader. Usually the visual loss has an insidious onset and a subacute evolution, but it may evolve rapidly, suggesting a retrobulbar neuritis; moreover, in these latter instances, aching in the eye or brow may accompany the visual loss, just as it does in the demyelinative variety. Subjective visual phenomena are reported by some. Usually both eyes are affected simultaneously, although in some one eye is affected first, followed by the other after an interval of several weeks or months. In practically all cases, the second eye is affected within a year of the first. In the unimpaired eye, abnormalities of visual evoked potentials may antedate impairment of visual acuity (Carroll and Mastaglia).

Once started, the visual loss progresses over a period of weeks to months. Characteristically, central vision is lost before peripheral, and there is a stage at which bilateral central scotomata are readily demonstrated. Early on, perception of blue-yellow is deficient, while that of red and green is relatively preserved. In the more advanced stages, however, the patients are totally color-blind. Constriction of the fields may be added later. At first there may be swelling and hyperemia of the discs, but soon they become atrophic. Peripapillary vasculopathy, consisting of tortuosity and arteriovenous shunting, is the primary structural change; this has been present also in asymptomatic offspring of carrier females.

As visual symptoms develop, fluorescein angiography shows shunting in the abnormal vascular bed, with reduced filling of the capillaries of the papillomacular bundle. Although patients are left with dense central scotomata, it is of some importance that the visual impairment is seldom complete; in some patients, relative stabilization of visual function occurs. In a few, there may be a surprising improvement.

Examination of the optic nerve lesion shows the central parts of the nerves to be degenerated from papillae to the lateral geniculate bodies, that is the papillomacular bundles are particularly affected. Presumably axis cylinders and myelin degenerate together, as would be expected from the loss of nerve cells in the superficial layer of the retina. Both astrocytic glial and endoneurial fibroblastic connective tissue are increased. Tests for the 3 main mitochondrial mutations that give rise to the disorder are now available.

Congenital optic atrophy (of which recessive and dominant forms are known), retrobulbar neuritis, and nutritional optic neuropathy are the main considerations in differential diagnosis.

Retinitis Pigmentosa (See Chap. 13)

This remarkable retinal abiotrophy, known to Helmholtz in 1851, soon after he invented the ophthalmoscope, usually begins in childhood and adolescence. Unlike the optic atrophy of Leber, which affects only the third neuron of the visual neuronal chain, retinitis pigmentosa affects all the retinal layers, both the neuroepithelium and pigment epithelium (see Fig. 13-2). The incidence of this disorder is 2 or 3 times greater in males than in females. Inheritance is more often autosomal recessive than dominant; in the former, consanguinity plays an important part, increasing the likelihood of the disease by approximately 20 times. Sex-linked types are also known. It is estimated that 100,000 Americans are afflicted with this disease. Mutations in approximately 60 genes have been associated with the disorder but the most commonly affected in autosomal dominant cases is RHO; in recessive cases, USH2A, and in X-linked cases, RPGR and RP2.

The first symptom is usually an impairment of twilight vision (nyctalopia). Under dim light, the visual fields tend to constrict; but slowly, as the disease progresses, there is permanent visual impairment in all degrees of illumination. The perimacular zones tend to be the first and most severely involved, giving rise to partial or complete ring scotomata. Peripheral loss sets in later. Usually both eyes are affected simultaneously, but cases are on record where one eye was affected first and more severely. Ophthalmoscopic examination shows the characteristic triad of pigmentary deposits that assume the configuration of bone corpuscles, attenuated vessels, and pallor of the optic discs. The pigment is caused by clumping of epithelial cells that migrate from the pigment layer to the superficial parts of the retina as the rod cells degenerate. The pigmentary change spares only the fovea, so that eventually the world is perceived by the patient as though he were looking through narrow tubes.

The many and diverse syndromes to which retinitis pigmentosa may be linked include oligophrenia, obesity, syndactyly, and hypogonadism (Bardet-Biedl syndrome); hypogenitalism, obesity, and mental deficiency (Laurence-Moon syndrome); Friedreich and other types of spinocerebellar and cerebellar ataxia; spastic paraplegia and quadriplegia with Laurence-Moon syndrome; neurogenic amyotrophy, myopia, and color-blindness; polyneuropathy and deafness (Refsum disease); deaf mutism; Cockayne syndrome and Bassen-Kornzweig disease; and several mitochondrial diseases, particularly progressive external ophthalmoplegia and Kearns-Sayre syndromes.

Stargardt Disease

This is a bilaterally symmetrical, slowly progressive macular degeneration, differentiated from retinitis pigmentosa by Stargardt in 1909. In essence, it is a hereditary (usually autosomal recessive) tapetoretinal degeneration or dystrophy (the latter term being preferred by Waardenburg), with onset between 6 and 20 years of age, rarely later, and leading to a loss of central vision. The macular region becomes gray or yellow-brown with pigmentary spots, and the visual fields show central scotomata. Later the periphery of the retina may become dystrophic. The lesion is well visualized by fluorescein angiography, which discloses a virtually pathognomonic "dark choroid" pattern. Activity in the electroretinogram is diminished or abolished. Both recessively inherited Stargardt disease and the closely related cone-rod dystrophy have been linked to mutations of ABCA4 or ELOVL4 the former codes for a transporter protein (termed ABCR) of the photoreceptor.

This disease, with its selective loss of cone function, is in a sense the inverse of retinitis pigmentosa. According to Cohan and associates, it may be associated with epilepsy, Refsum syndrome, Kearns-Sayre syndrome, Bassen-Kornzweig syndrome, or Sjögren-Larsson syndrome, or with spinocerebellar and other forms of cerebellar degeneration and familial paraplegia.

Syndrome of Congenital or Progressive Deafness

(See Chap. 15) There is an impressive group of hereditary, progressive cochleovestibular atrophies that are linked to degenerations of the nervous system. These are the subject of an informative review by Konigsmark and are summarized below. Such neurotologic syndromes must be set alongside a group of 5 diseases that affect the auditory and vestibular nerves exclusively: dominant progressive nerve deafness; dominant low-frequency hearing loss; dominant midfrequency hearing loss; sex-linked, early-onset neural deafness; and hereditary episodic vertigo and hearing loss. The last of these is of special interest to neurologists because both balance and hearing are affected.

It should be pointed out that in 70 percent of cases of hereditary deafness, there are no other somatic or neurologic abnormalities. To date, 3 separate autosomal mutations have been identified that are associated with this pure "nonsyndromic" type of hereditary deafness, the most common of which is in the connexin gene, as discussed in Chap. 15. A number of mitochondrial disorders have been associated with deafness alone as well as with a number of the better-characterized mitochondrial syndromes (see Chap. 37). The age of onset of hearing loss in the pure forms has been variable, extending well into adulthood.

Hereditary Hearing Loss with Retinal Diseases

Konigsmark has separated this overall category into 3 subgroups: patients with typical retinitis pigmentosa, those with Leber optic atrophy, and those with other retinal changes. With respect to retinitis pigmentosa, 4 syndromes are recognized in which retinitis pigmentosa appears in combination: with congenital hearing loss (Usher syndrome); with polyneuropathy (Refsum syndrome); with hypogonadism and obesity (Alstrom syndrome); and with dwarfism, mental retardation, premature senility, and photosensitive dermatitis (Cockayne syndrome).

Hereditary hearing loss with optic atrophy forms the core of 4 special syndromes: dominant optic atrophy, ataxia, muscle wasting, and progressive hearing loss (Sylvester disease); recessive optic atrophy, polyneuropathy, and neural hearing loss (Rosenberg-Chutorian syndrome); optic atrophy, hearing loss, and juvenile diabetes mellitus (Tun-bridge-Paley syndrome); and opticocochleodentate degeneration with optic atrophy, hearing loss, quadriparesis, and developmental delay (Nyssen-van Bogaert syndrome).

Hearing loss has also been observed with other retinal changes, two of which are Norrie disease, with retinal malformation, hearing loss, and mental retardation (oculoacousticocerebral degeneration), and Small disease, with recessive hearing loss, mental retardation, narrowing of retinal vessels, and muscle atrophy. In the former, the infant is born blind, with a white vascularized retinal mass behind a clear lens; later the lens and cornea become opaque. The eyes are small, and the iris is atrophied. In the latter, the optic fundi shows tortuosity of vessels, telangiectases, and retinal detachment. The nature of the progressive generalized muscular weakness has not been ascertained.

In this group should be included Susac syndrome, ostensibly a microvasculopathy that causes characteristic changes in the white matter of the cerebral hemispheres, retinal vasculopathy, and progressive deafness as discussed in Chap. 34. The later onset and progressive nature of deafness in this and several other syndromes are distinguished from forms of congenital deafness that are typical of the group discussed below.

Hereditary Hearing Loss with Diseases of the Nervous System (See Table 15-1)

There are numerous conditions, mostly of childhood and including developmental abnormalities, in which congenital deafness accompanies disease of the peripheral or central nervous system. Those associated with mitochondrial encephalopathies have already been mentioned. The other main types with autosomal inheritance include the following:

Hereditary hearing loss with epilepsy The seizure disorder is mainly one of myoclonus. In one dominantly inherited form, photomyoclonus is associated with mental deterioration, hearing loss, and nephropathy (Hermann disease). In May-White disease, also inherited as an autosomal dominant trait, myoclonus and ataxia accompany hearing loss. Congenital deafness and mild chronic epilepsy of recessive type have also been observed (Latham-Monro disease).
Hereditary hearing loss and ataxia Here Konigsmark was able to delineate 5 syndromes, the first 2 of which show a dominant pattern of heredity, the last 3 a recessive pattern: piebaldism, ataxia, and neural hearing loss (Telfer-Sugar-Jaeger syndrome); hearing loss, hyperuricemia, and ataxia (Rosenberg-Bergstrom syndrome); ataxia and progressive hearing loss (Lichtenstein-Knorr syndrome); ataxia, hypogonadism, mental deficiency, and hearing loss (Richards-Rundle syndrome); ataxia, mental retardation, hearing loss, and pigmentary changes in the skin (Jeune-Tommasi syndrome).
Hereditary hearing loss and other neurologic syndromes These include dominantly inherited sensory radicular neuropathy (Denny-Brown); progressive polyneuropathy, kyphoscoliosis, skin atrophy, eye defects (myopia, cataracts, atypical retinitis pigmentosa), bone cysts, and osteoporosis (Flynn-Aird syndrome); chronic polyneuropathy and nephritis (Lemieux-Neemeh syndrome); congenital pain asymbolia and auditory imperception (Osuntokun syndrome); and bulbopontine paralysis (facial weakness, dysarthria, dysphagia, and atrophy of the tongue with fasciculations) with progressive neural hearing loss. The onset of the last syndrome occurs at 10 to 35 years of age; the pattern of inheritance is autosomal recessive. The disease progresses to death. It resembles the progressive hereditary bulbar paralysis of Fazio-Londe except for the progressive deafness and loss of vestibular responses. Regrettably, in most of these syndromes, there are no data regarding labyrinthine function.

The details of these many syndromes are contained in Konigsmark's review, of course, in the era before the genetic underpinnings of these diseases were accessible. The main syndromes are listed in Table 15-1 and are summarized above so as to increase awareness of the large number of hereditary-degenerative neurologic diseases for which the clue is provided by the detection of impaired hearing and labyrinthine functions.

References