Although this group of diseases has been included for discussion in the chapter on viruses that affect the nervous system, it has been evident for some time that the cause of these diseases is neither a virus nor a viroid (nucleic acid alone, without a capsid structure). The transmissible, or "infectious" nature of prions was discovered by Gadjusek and Gibbs in the Fore tribes of New Guinea, who practiced ritual cannibalism and ate the brains of the deceased. The resulting disease, kuru, is described further on but the important point is that the aforementioned workers were able to transmit the disease to chimpanzees after a long latent period of years. Prusiner is credited with doggedly pursuing this problem, for which he was awarded the Nobel Prize. He (1993, 1994, 2001) has presented evidence that the transmissible pathogen is a proteinaceous infectious particle that is devoid of nucleic acid, resists the action of enzymes that destroy RNA and DNA, fails to produce an immune response, and electron microscopically does not have the structure of a virus. To distinguish this pathogen from viruses and viroids, Prusiner introduced the term prion.
Creutzfeldt-Jakob Disease (Subacute Spongiform Encephalopathy)
These terms refer to a distinctive cerebral disease in which a rapidly or subacutely progressive and profound dementia is associated with diffuse myoclonic jerks and a variety of other neurologic abnormalities, mainly visual or cerebellar. The major neuropathologic changes are found in the cerebral and cerebellar cortices, and the outstanding features are widespread neuronal loss and gliosis accompanied by a striking vacuolation or spongy state of the affected regions—hence the designation subacute spongiform encephalopathy (SSE). Less severe changes in a patchy distribution are found in cases with a briefer clinical course.
The widely used term Creutzfeldt-Jakob disease (CJD) may be an inappropriate eponym as it is most unlikely that the patient described by Creutzfeldt and at least three of the five patients described by Jakob did not have the same disease that we now recognize as subacute spongiform encephalopathy. However, decades of use make it virtually impossible to displace.
One of the more interesting aspects of the development of the prion concept has been the hypothesis that many conditions, most in the category of degenerative neurologic disease and characterized by the accumulation of specific proteins such as amyloid, tau, synuclein, and ubiquitin may have a similar mechanism in sequential, contiguous conformational change in protein aggregation.
Epidemiology and Pathogenesis
The disease appears in all parts of the world and in all seasons, with an annual incidence of 1 to 2 cases per million of population. The incidence is higher in Israelis of Libyan origin, in immigrants to France from North Africa, and perhaps in Slovakia. The incidence of spongiform encephalopathy is somewhat higher in urban than in rural areas, but a consistent temporal or spatial clustering of cases has not been observed, at least in the United States. A small proportion of all series is familial—varying from 5 percent reported by Cathala and associates to 15 percent of 1,435 cases analyzed by Masters and coworkers (1979). The occurrence of familial cases that are not in the same household probably indicates a genetic susceptibility to infection, although the possibility of common early exposure to the transmissible agent cannot be excluded. A small number of conjugal cases have also been reported. The only clearly demonstrated mechanism of spread of the usual type of CJD is iatrogenic, having occurred in a few cases after transplantation of corneas or dural grafts from infected individuals, after implantation of infected electroencephalographic depth electrodes, and after the injection of human growth hormone or gonadotropins that had been prepared from pooled cadaveric sources. At least one neurosurgeon is known to have acquired the disease. Of some interest is the finding by Zanusso and colleagues of the infectious prion protein in the nasal mucosa of all nine patients studied with the sporadic disease. This suggests a route for entry into the nervous system of the aberrant prion and also a potential diagnostic test. As noted further on, the tonsils of patients affected with variant CJD may also show immunostaining for prions.
Attention has been drawn to an outbreak of prion disease among cows in the British Isles ("mad cow disease," bovine spongiform encephalopathy, BSE). Cows elsewhere have sporadically been found to be infected. The mini-epidemic began in 1986, with putative transmission of the disease to some 24 humans. These patients were younger (average age of onset 27 years) than those with typical CJD (average age of onset 65 years) and manifested psychiatric and sensory symptoms as the first sign of illness; they did not exhibit the usual EEG findings even as the illness advanced to its later stages (Will et al). This has been called "new variant Creutzfeldt-Jakob disease (vCJD)." One reason for including a lengthy explanation of this illness is the potential for cases to appear in future years. It was shown that the prion strain in affected patients is identical to the one from affected cattle and different from the prion agent that causes sporadic CJD. The mode of transmission, presumed to be the ingestion of infected meat, is reminiscent of the propagation of kuru in New Guinea by ceremonial ingestion of brain tissue from infected individuals that opened the era of understanding of prion disease.
Prion (spongiform) encephalopathy or all types has now been firmly associated with the conversion of a normal cellular protein, PrPc to an abnormal isoform, PrPsc. The transformation involves a change in the physical conformation of the protein in which its helical proportion diminishes and the proportion of the β pleated sheet increases (see reviews by Prusiner). The current understanding is that the "infectivity" of prions and their propagation in brain tissue result from the susceptibility of the native PrP to alter its shape as a result of physical exposure to the abnormal protein, a so-called conformational disease. Conformationally altered prions have a tendency to aggregate, and this may be the mode of cellular destruction that leads to neuronal disease. In contrast, familial cases of prion disease are thought to be the result of one of several gene aberrations residing in the region that code for PrPc.
As the isoforms of the prions that causes the sporadic disease have been characterized, clinical patterns have emerged as more or less typical of certain protein configurations and their underlying genotypes. Several competing classification systems have been devised that are based on both the presence of methionine (M) or valine (V) at codon 129 of the prion protein and on which of two physicochemical properties it displays (termed types 1 or 2; see Parchi et al). The most common variant in most studies has been MM and the least common, VV, and type 1 is more frequent than type 2 (hence MM1 is the most common type overall, present in approximately two-thirds of sporadic cases). However, classification is complicated by the fact that some brain samples show more than one type of protein. Although several studies conflict on these points, a typical EEG pattern was most common in type 1 cases with at least one methionine, whereas MV2 cases were most likely to have MRI changes (see further on). Some studies have suggested that the MV2 subtype, comprising a small proportion of cases, was likely to present with ataxia, psychiatric changes, a lack of positive sharp waves on EEG, and a prolonged duration of disease, but none of the distinctions has been even close to absolute. There has also been controversy regarding the relationship of the genotype to the sensitivity of diagnostic tests discussed below. Details of these putative associations can be found in an extensive international study of 2,541 pathologically confirmed cases of CJD reported by Collins and colleagues.
Prion encephalopathy is in most cases a spontaneously occurring disease of late middle age, although it occurs in young adults. The sexes are affected equally. In the large series of pathologically verified cases reported by Brown and coworkers, prodromal symptoms—consisting of fatigue, depression, weight loss, and disorders of sleep and appetite lasting for several weeks—were observed in about one-third of the patients.
The early stages of the neurologic disease are characterized by a great variety of clinical manifestations, but the most frequent are changes in behavior, emotional response, and intellectual function, often followed by ataxia and abnormalities of vision, such as distortions of the shape and alignment of objects or impairment of visual acuity. Typically, the early phase of the disease is dominated by symptoms of confusion, with hallucinations, delusions, and agitation. In other instances, cerebellar ataxia (Brownell-Oppenheimer variant) or visual disturbances (Heidenhain variant) precede the mental changes and may be the most prominent features for several months. Headache, vertigo, and sensory symptoms are complaints in some patients but become quickly obscured by dementia and muteness.
As a rule, the disease progresses rapidly, so that obvious deterioration is seen from week to week and even day to day. Sooner or later, in almost all cases, myoclonic contractions of various muscle groups appear, perhaps unilaterally at first but later becoming generalized. Or, infrequently, the myoclonus may not appear for weeks or months after the initial mental changes. In a few patients, a startle response, that is elicitable for a brief period of time, is the only manifestation of myoclonus. In general, the myoclonic jerks are evocable by sudden sensory stimuli of all sorts, a startle response (to noise, bright light, touch) but they occur spontaneously as well. Twitches of individual fingers are typical but it should be emphasized that well-formed seizures are not a component of the illness. These changes gradually give way to a mute state, stupor, and coma, but the myoclonic contractions may continue to the end. Signs of degeneration of the pyramidal tracts or anterior horn cells, palsies of convergence and upgaze, and extrapyramidal signs occur in a small number of patients as the disease advances.
The clinical diagnosis during life rests mostly on the recognition of one of the clusters of typical clinical features, particularly the special rate of rapid progression of dementia—much more quickly than that of common degenerative diseases—coupled with stimulus-sensitive myoclonus and the characteristic MRI and EEG changes that occur in most patients (see below).
The disease is invariably fatal, usually in a few months and almost always less than a year from the onset. In approximately 10 percent of patients, the illness begins with almost stroke-like suddenness and runs its course rapidly, in a matter of a few weeks. At the other extreme, a small number of patients have reportedly survived for 2 to 10 years, but these reports should be accepted with caution; in some of them, the illness appears to have been superimposed on Alzheimer or Parkinson disease or some other chronic condition that predated the prion illness.
The routine CSF and other laboratory tests are normal—useful findings in that they exclude a number of chronic inflammatory causes of dementia such as neurosyphilis. In most patients, the EEG pattern is distinctive, changing over the course of the disease from one of diffuse and nonspecific slowing to one of stereotyped high-voltage slow- (1- to 2-Hz) and sharp-wave complexes on an increasingly slow and low-voltage background (see Fig. 2-5G). The high-voltage sharp waves, which give the appearance of periodicity (they have been called pseudoperiodic), are synchronous with the myoclonus, but may persist in its absence.
MRI of the brain has now been appreciated to show hyperintensity of the lenticular nuclei on T2-weighted and diffusion-weighted images in the basal ganglia and cortex when the disease is fully established (Fig. 33-5). Long contiguous segments of the cortex, as well as various parts of the basal ganglia, show these alterations in a pattern that is characteristic and mistakable only perhaps for the appearance of diffuse cerebral anoxia. According to Shiga and colleagues, these changes occur in 90 percent of cases (cortex more often than caudate or lenticular nuclei and sometimes both), making them potentially the most sensitive test for the disease but the proportion has been lower in our patients. Complicating the interpretation of the MRI findings in this disease have been reports from Japan of extensive white matter lesions in several autopsy-proven cases (Matsusue et al).
MRI showing T2 signal changes in the striatum in a patient with sporadic CJD (top) of 1 month's duration. DWI sequence showing restriction of diffusion in contiguous bands of cortex and in the striatum (bottom) in the same case.
There are helpful confirmatory diagnostic tests but they are not always necessary. Hsich and colleagues described a now widely used test of CSF—the finding by immunoassay of peptide fragments of normal brain proteins, termed "14-3-3." This test is particularly useful in separating CJD from other chronic noninflammatory dementing diseases but it has been sometimes disappointing on our wards, giving both false-positive and false-negative results. Several studies have given conflicting information on the sensitivity of the 14-3-3 test in relation to the various forms of prions and differing clinical presentations, but all seem to converge on the fact that repeated testing, up to three times is more likely to give positive results. A summary publication has indicated an overall sensitivity from pooled reports of 92 percent and specificity of 80 percent (report of the Guidelines Development Committee of the American Academy of Neurology). Also, enolase and neopterin concentrations in CSF are elevated in most cases, but the release of these substances is found with other types of brain lesions, particularly infarction. A number of other tests are emerging from specialized laboratories that are able to detect the specific abnormal PrPsc isoform of the prion protein in the spinal fluid. Prusiner's laboratory has been able to detect eight prion strains but it is not yet clear if this scientific advance can be put to clinical use.
Tonsillar material from patients with new variant Creutzfeldt-Jakob disease ("mad cow disease") stains with antibodies against abnormal prion protein, but this technique does not appear to be applicable to the early diagnosis of the sporadic disease (Hill). Whether the earlier-mentioned finding of infectious prion material in the nasal mucosa in the sporadic form will prove to have practical value in diagnosis is yet to be determined.
The National Prion Disease Pathology Surveillance Center, which was established at Case Western Reserve University, is available to assist clinicians by performing, free of charge, a variety of specific diagnostic tests (accessible through http://www.cjdsurveillance.com).
The disease affects principally the cerebral and cerebellar cortices, generally in a diffuse fashion, although in some cases the occipitoparietal regions are almost exclusively involved, as in those described by Heidenhain. In others, such as the cases of Brownell and Oppenheimer alluded to earlier, the cerebellum has been most extensively affected, with early and prominent ataxia. The degeneration and disappearance of nerve cells are associated with extensive astroglial proliferation; ultrastructural studies have shown that the microscopic vacuoles, which give the tissue its typically spongy appearance, are located within the cytoplasmic processes of glia cells and dendrites of nerve cells. The loss in particular of certain inhibitory neurons in the thalamic reticular nuclei seems to correspond to the presence of myoclonus and positive sharp waves in the EEG according to Tschampa and colleagues. Despite the fact that the disease is caused by a transmissible agent, the lesions show no evidence of an inflammatory reaction and no viral particles are seen.
The diagnosis of most cases presents no difficulty if the rapidity of progression and the myoclonus are recognized. Not infrequently, however, we have been surprised by a "typical" case that proves to be some other disease. Lithium intoxication, Hashimoto encephalopathy (as emphasized by Seipelt and colleagues who found a number of these cases in an epidemiologic survey of SSE; Chap. 40), Whipple disease (see Chap. 32), intravascular lymphoma, and carcinomatous meningitis—all of them characterized by myoclonus and dementia—may mimic CJD in the early weeks of illness. Contrariwise, the early mental changes of SSE may be misinterpreted as an atypical or unusually intense emotional reaction, as one of the major psychoses, as an unusual form of Alzheimer disease with myoclonus, corticobasal degeneration (see Chap. 39), or as Lewy-body disease. Despite the designation of CJD as a progressive dementia, the similarities to even rapidly developing Alzheimer disease are superficial. Also, diagnosis may be difficult in patients who present with dizziness, gait disturbance, diplopia, or visual disturbances until the rapidly evolving clinical picture clarifies the issue. Subacute sclerosing panencephalitis (see earlier in this chapter) in its fully developed form may resemble CJD, but the former is chiefly a disease of children or young adults, and the CSF shows elevation of gamma globulin (IgG), whereas the latter is essentially a disease of middle age and the presenile period and the CSF is normal. Limbic-brainstem-cerebellar encephalitis in patients with an occult tumor and AIDS dementia (discussed earlier) also figure in the differential diagnosis. Cerebral lipidosis in children or young adults can result in a similar combination of myoclonus and dementia, but the clinical course in such cases is extremely chronic and there are retinal changes that do not occur in spongiform encephalopathy. Well-formed convulsions should direct attention to another diagnosis.
No specific treatment is known. Antiviral agents have been ineffective. In view of the transmissibility of the disease from humans to primates and iatrogenically from person to person with infected materials, certain precautions should be taken in the medical care and handling of materials from affected patients. Special isolation rooms are unnecessary, and the families of affected patients and nursing staff can be reassured that casual contact poses no risk. Needle punctures and cuts are not thought to pose a risk, but some uncertainty remains. The transmissible agent is resistant to boiling, treatment with formalin and alcohol, and ultraviolet radiation but can be inactivated by autoclaving at 132°C (269.6°F) at 15 lb/in2 for 1 h or by immersion for 1 h in 5 percent sodium hypochlorite (bleach). Workers exposed to infected materials (butchers, abattoir workers, healthcare workers) should wash thoroughly with ordinary soap. Needles, glassware, needle electrodes, and other instruments should be handled with great care and immersed in appropriate disinfectants and autoclaved or incinerated. The performance of a brain biopsy or autopsy requires that a set of special precautions be followed, as outlined by Brown but this surgical procedure is not necessary as more diagnostic tools have become available. Obviously such patients or any others known to have been demented should not be donors of organs or corneas for transplantation or blood for transfusion.
This is a rare, strongly familial disease inherited as an autosomal dominant trait. It begins insidiously in midlife and runs a chronic course (mean duration 5 years). The main characteristics are progressive cerebellar ataxia, corticospinal tract signs, dysarthria, and nystagmus. Dementia is often associated but is relatively mild.
Dysesthesias and proximal weakness of the legs have been emphasized as an early feature by Arata and colleagues. Their report may be consulted for details of 11 well-studied cases. The MRI is usually normal; with progression, generalized atrophy is found.
There are characteristic spongiform changes in brain tissue, as in CJD. Brain tissue from patients with this disease, when inoculated into chimpanzees, has produced a spongiform encephalopathy (Masters et al, 1981). Molecular genetic studies of affected family members demonstrate a mutation of the prion protein gene. This syndrome should be considered as a small familial subset of SSE, of slowly progressive type.
Fatal Insomnia (Familial and Sporadic)
This is another rare and usually familial disease in the spongiform encephalopathy group. It is characterized by intractable insomnia, sympathetic overactivity, and dementia, leading to death in 7 to 15 months (see also Chap. 16). The pathologic changes, consisting of neuronal loss and gliosis, are found mainly in the medial thalamic nuclei. Studies of a few families have shown a mutation of the prion protein gene and brain material was found to contain a protease-resistant form of the gene that is characterized by a mutation in the prion gene at codon 178 in conjunction with the presence of methionine at codon 129 on chromosome 20, the latter being a feature of sporadic CJD. Transmission of the disease by inoculation of infected brain material has not been accomplished (Medori et al). There is also a rare sporadic form of this disease and the configuration of the prion alteration is different from the familial variety.
This disease occurs exclusively among the Fore linguistic group of natives of the New Guinea highlands and is included here because of its historical interest as the first slow infection caused by an unconventional transmissible agent to be documented in human beings. Clinically the disease takes the form of an afebrile, progressive cerebellar ataxia, with abnormalities of extraocular movements, weakness progressing to immobility, incontinence in the late stages, and death within 3 to 6 months of onset. In some ways it is similar to the ataxic (Brownell-Oppenheimer) variant of CJD. The remarkable epidemiologic and pathologic similarities between kuru and scrapie in sheep were pointed out in 1959 by Hadlow, who suggested that it might be possible to transmit kuru to subhuman primates. This was accomplished in 1966 by Gajdusek and coworkers; inoculation of chimpanzees with brain material from affected humans produced a kuru-like syndrome in chimpanzees after a latency of 18 to 36 months. Since then the disease has been transmitted from one chimpanzee to another and to other primates by using both neural and nonneural tissues. The pioneering work in this field led to the awarding of a Nobel Prize to these workers and the same prize was awarded to Prusiner 23 years later, representing a landmark in which the Nobel was awarded twice for work regarding the same disease. Histologically there is a noninflammatory loss of neurons and spongiform change throughout the brain, but predominantly in the cerebellar cortex, with astroglial proliferation and periodic acid-Schiff–positive stellate plaques of amyloid-like material ("kuru plaques"). The transmissible agent has not been visualized, however.
Kuru has gradually disappeared because of the cessation of ritual cannibalism by which the disease had been transmitted. In this ritual, infected brain tissue was ingested and rubbed over the body of the victim's kin (women and young children of either sex), permitting absorption of the infective agent through conjunctivae, mucous membranes, and abrasions in the skin.