Chapter 41. Diseases of the Nervous System Caused by Nutritional Deficiency

Among nutritional disorders, those of the nervous system occupy a position of special interest and importance. The early studies of beriberi at the turn of the twentieth century were largely responsible for the discovery of thiamine and consequently for the modern concept of deficiency disease. A series of notable achievements in the science of nutrition followed the discovery of vitamins. Despite such progress, a number of diseases caused by nutritional deficiency, and particularly those of the nervous system, continue to represent a worldwide health problem of serious proportions. In some communities, where the diet consists mainly of highly milled rice, there is still a significant incidence of beriberi. In some developing countries, deficiency diseases are endemic, the result of chronic dietary deprivation. And the ultimate effects on the nervous system of intermittent mass starvation, involving large portions of the African continent, are alarming to contemplate.

It comes as a surprise to many physicians that deficiency diseases still occur in the United States and other parts of the developed world. To some extent this is attributable to the prevalence of alcoholism. Relatively less common causes are dietary faddism and impaired absorption of dietary nutrients, which occurs in patients with celiac sprue, pernicious anemia, or surgical exclusion of portions of the gastrointestinal tract for treatment of obesity, and the wasting syndromes of cancer and AIDS. Finally, there are iatrogenic deficiencies induced by the use of vitamin antagonists or certain drugs, such as isonicotinic acid hydrazide (INH), which is used in the treatment of tuberculosis and interferes with the enzymatic function of pyridoxine or methotrexate.

General Considerations

The term deficiency is used throughout this chapter in its strictest sense to designate disorders that result from the lack of an essential nutrient or nutrients in the diet or from a conditioning factor that increases the need for these nutrients. The most important of these are the vitamins, more specifically, members of the B group—thiamine, nicotinic acid, pyridoxine, pantothenic acid, riboflavin, folic acid, and cobalamin (vitamin B12). However, some deficiency diseases cannot be related to the lack of a single vitamin. Usually the effects of several vitamin deficiencies can be recognized (thiamine deficiency causing Wernicke disease and subacute combined degeneration [SCD] of the cord, as a result of vitamin B12 deficiency, are notable exceptions that are due to single deficiencies).

Furthermore, nutritional diseases of the nervous system are not simply a matter of vitamin deprivation. The general signs of undernutrition, such as circulatory abnormalities and loss of subcutaneous fat and muscle bulk, are usually associated and conversely, a total lack of vitamins, as in starvation, is rarely associated with the classic deficiency syndromes of beriberi or pellagra. In other words, a certain amount of food is necessary to produce them. In a similar way, excessive intake of carbohydrates relative to the supply of thiamine favors the development of a thiamine-deficiency state. All deficiency diseases, including those of the nervous system, are influenced by factors such as exercise, growth, pregnancy, neoplasia, and systemic infection, which increase the need for essential nutrients, and by disorders of the liver and the gastrointestinal tract, which may interfere with the synthesis and absorption of these nutrients.

As already mentioned, alcoholism is an important factor in the causation of nutritional diseases of the nervous system. Alcohol acts mainly by displacing food in the diet but also by adding carbohydrate calories (alcohol is burned almost entirely as carbohydrates), thus increasing the need for thiamine. There is some evidence as well that alcohol impairs the absorption of thiamine and other vitamins from the gastrointestinal tract.

In infants and young children, a reduction in protein and caloric intake (so-called protein-calorie malnutrition [PCM]) has a devastating effect on body growth. Whether or not PCM also hinders the growth of the brain, with consequent effects on intellectual and behavioral development, cannot be answered as readily. The data bearing on this matter are discussed in the last part of this chapter.

Characteristic of the nutritional diseases is the potential for involvement of both the central and peripheral nervous systems, an attribute shared only with certain metabolic disorders. In addition, there are several distinctive neurologic disorders in which nutritional deficiency may play a role, although this has not been proved. These include (1) "alcoholic" cerebellar degeneration, (2) Marchiafava-Bignami disease (degeneration of the corpus callosum), and (3) central pontine and extrapontine myelinolysis, which are more closely aligned with the rapid correction of hyponatremia, as discussed in Chap. 40.

Some comments will also be made in this chapter about PCM, the neurologic disorders consequent to intestinal malabsorption, and the rare hereditary vitamin-responsive diseases. Deficiencies of trace elements, because of their rarity, are not discussed; only iodine deficiency (cretinism) is of much importance in humans, and it was discussed in Chap. 40 on acquired metabolic diseases.

Wernicke disease and the Korsakoff amnesic state are common neurologic disorders that have been recognized since the 1880s. Wernicke disease is characterized by nystagmus, abducens and conjugate gaze palsies, ataxia of gait, and mental confusion. These symptoms develop acutely or subacutely and may occur singly or, more often, in combination. Wernicke disease is specifically the result of a deficiency of thiamine and is observed mainly, although far from exclusively, in alcoholics.

The Korsakoff amnesic state (Korsakoff psychosis) is a mental disorder in which retentive memory is impaired out of proportion to all other cognitive functions in an otherwise alert and responsive patient. This amnesic disorder, like Wernicke disease, is most often associated with the thiamine deficiency of alcoholism and malnutrition, but it may be a symptom of various other non-nutritional diseases that have their basis in structural lesions of the medial thalami or the hippocampal portions of the temporal lobes, such as infarction in the territory of branches of the posterior cerebral arteries, hippocampal damage after cardiac arrest, third ventricular tumors, and herpes simplex encephalitis. An almost equivalent type of memory disturbance may also follow acute lesions of the basal septal nuclei of the frontal lobe. Transient impairments of retentive memory of the Korsakoff type may be the salient manifestations of temporal lobe epilepsy, concussive head injury, and a unique disorder known as transient global amnesia. The anatomic basis of the Korsakoff amnesic syndrome is described in Chap. 21.

In the nutritionally deficient patient, Korsakoff amnesia is usually associated with and immediately follows the occurrence of Wernicke disease. For this reason and others elaborated in the following text, the term Wernicke disease or Wernicke encephalopathy is applied to a symptom complex of ophthalmoparesis, nystagmus, ataxia, and an acute apathetic–confusional state. If an enduring defect in learning and memory results, as it often does, the symptom complex is designated as the Wernicke-Korsakoff syndrome.

It is perhaps in part due to the emphasis in previous editions of this book that alcoholism has been inordinately associated with this disease complex. The disease arises in many other clinical settings. One of Wernicke's original cases, for example, occurred in a woman with hyperemesis gravidarum and such instances are still found. However, bariatric surgery, cancer chemotherapy, inanition in AIDS and from anorexia nervosa, and even in the frailty of older age, in nutritionally susceptible persons, starvation for economic and social reasons all may give rise to thiamine deficiency. Even the elderly and frail who subsist for years on "tea and toast" can acquire the disease. In addition, there are common medical circumstances in which a subclinical thiamine deficiency becomes manifest. Perhaps the most important of these is a carbohydrate load, particularly the administration of intravenous glucose to a malnourished individual; other precipitants are unbalanced intravenous hyperalimentation, refeeding syndrome, thyrotoxicosis, and hypomagnesemia.

The presence of this disease must be constantly emphasized. As summarized in the review by Sechi and Serra of published series from several countries, there is a discrepancy between the detection of the process in autopsy series, 0.5 to 3 percent, and the prevalence of the clinical diagnosis, 0.04 to 0.13 percent, indicating that approximately three-quarters of cases are not recognized during life.

Historical Note

In 1881, Carl Wernicke first described an illness of sudden onset characterized by paralysis of eye movements, ataxia of gait, and mental confusion. His observations were made in 3 patients, of whom 2 were alcoholics and 1 was a young woman with persistent vomiting following the ingestion of sulfuric acid. In each of these patients there was progressive stupor and coma culminating in death. The pathologic changes described by Wernicke consisted of punctate hemorrhages affecting the gray matter around the third and fourth ventricles and aqueduct of Sylvius; he considered these changes to be inflammatory in nature and confined to the gray matter, hence his designation "polioencephalitis hemorrhagica superioris." In the belief that Gâyet had described an identical disorder in 1875, the term Gâyet-Wernicke is used frequently by French authors. Such a designation is hardly justified insofar as the clinical signs and pathologic changes in Gâyet's patients differed from those of Wernicke's patients in all essential details.

The first comprehensive account of this disorder was given by the Russian psychiatrist S.S. Korsakoff in a series of articles published between 1887 and 1891 (for English translation and commentary, see reference by Victor and Yakovlev). Korsakoff stressed the relationship between "neuritis" (a term used at that time for all types of peripheral nerve disease) and the characteristic alcoholic disorder of memory, which he believed to be "2 facets of the same disease" and which he called "psychosis polyneuritica." But he also made the points that neuritis need not accompany the amnesic syndrome and that both disorders could affect nonalcoholic as well as alcoholic patients. His clinical descriptions were remarkably complete and have not been surpassed to the present day. It is of interest that the relationship between Wernicke disease and Korsakoff polyneuritic psychosis was appreciated neither by Wernicke nor by Korsakoff. Murawieff, in 1897, first postulated that a single cause was responsible for both. The intimate clinical relationship was established by Bonhoeffer in 1904, who stated that in all cases of Wernicke disease he found neuritis and an amnesic psychosis. Confirmation of this relationship on pathologic grounds came much later. For further details the reader is referred to the extensive monograph by Victor, Adams, and Collins.

Clinical Features

The incidence of the Wernicke-Korsakoff syndrome cannot be stated with precision, but it had been a common disorder as noted in the introductory comments. At the Cleveland Metropolitan General Hospital, for example, in a consecutive series of 3,548 autopsies in adults (for the period 1963 to 1976), our colleague M. Victor (1990) found the pathognomonic lesions in 77 cases (2.2 percent). The disease affects males slightly more often than females and the age of onset is fairly evenly distributed between 30 and 70 years. In the past few decades, the incidence of the Wernicke-Korsakoff syndrome has fallen in the alcoholic population, but it is being recognized with increasing frequency among nonalcoholic patients in a variety of clinical settings that are prone to include malnutrition, including iatrogenic ones.

The triad of clinical features described by Wernicke of ophthalmoplegia (with nystagmus), ataxia, and disturbances of mentation and consciousness is still clinically useful provided that the diagnosis is suspected and the signs are carefully sought. Often, the disease begins with ataxia, followed in a few days or weeks by mental confusion; or there may be confusion alone, or the more or less simultaneous onset of ataxia, nystagmus, and ophthalmoparesis with or without confusion. In approximately one-third of cases, one component of this triad may be the sole manifestation of the disease. Timely treatment with thiamine prevents the permanent Korsakoff-amnesic component of the disease. A schematic representation of the various features is shown in Fig. 41-1, adapted from the series of 131 autopsied proved cases described by Harper, Giles, and Finlay-Jones. The notable aspects are that all 3 of the typical signs were present in only 16 percent; 1 sign in 31 percent, usually confusion alone; 2 signs in 28 percent; and no signs reported or detected during life in 19 percent. A description of each of the major manifestations follows.

Oculomotor Abnormalities

The diagnosis of Wernicke disease is made most readily on the basis of the ocular signs. These consist of (1) nystagmus that is both horizontal and vertical and mainly evoked by gaze; this is the most common feature, (2) weakness or paralysis of the lateral rectus muscles, and (3) weakness or paralysis of conjugate gaze. Usually there is some combination of these abnormalities (see Chap. 14).

Next to nystagmus, the most frequent ocular abnormality is lateral rectus weakness, which is bilateral but not necessarily symmetrical and is accompanied by diplopia and internal strabismus. With complete paralysis of the lateral rectus muscles, nystagmus is absent in the abducting eyes and it becomes evident as the weakness improves under treatment. The palsy of conjugate gaze varies from merely a paretic nystagmus on extreme gaze to a complete loss of ocular movement in horizontal or vertical movements, abnormalities of the former being more frequent. An isolated paralysis of downward gaze does occur but is an unusual manifestation, and a pattern that simulates internuclear ophthalmoplegia has been seen. In advanced stages of the disease there may be a complete loss of ocular movements and the pupils, which are otherwise usually spared, may become miotic and nonreacting. Ptosis, small retinal hemorrhages, involvement of the near–far focusing mechanism, and evidence of optic neuropathy occur occasionally, but neither we nor our colleagues have observed papilledema that was included in Wernicke's original description. These ocular signs are highly characteristic of Wernicke disease and disappearance of nystagmus and an improvement in ophthalmoparesis within hours or a day of the administration of thiamine confirms the diagnosis.

Ataxia

Essentially the ataxia is one of stance and gait; in the acute stage of the disease it may be so severe that the patient cannot stand or walk without support. Lesser degrees are characterized by a wide-based stance and a slow, uncertain, short-stepped gait; the mildest degrees are apparent only in tandem walking. In contrast to the gross disorder of locomotion is a relative infrequency of limb ataxia and of intention tremor; when present, they are more likely to be elicited by heel-to-knee than by finger-to-nose testing. Dysarthric, cerebellar-type scanning speech is present only rarely.

Disturbances of Consciousness and Mentation

These occur in some form in all but 10 percent of patients who have clinical signs. From Fig. 41-1 it can also be appreciated that when there is only one sign of Wernicke disease, it is usually a confusional state. Several related types of disturbed mentation and consciousness are recognized. By far the most common disturbance is a global confusional state. The next following in frequency is memory loss discussed as follows. The patient is apathetic, inattentive, and indifferent to his surroundings. Spontaneous speech is minimal and many questions are left unanswered, or the patient may suspend conversation and drift off to sleep, although he can be aroused without difficulty. Such questions as are answered betray disorientation in time and place, misidentification of those around him, and an inability to grasp the immediate situation. Many of the patient's remarks may be irrational and lack consistency from one moment to another. If the patient's interest and attention can be maintained long enough to ensure adequate testing, one finds that memory and learning ability are also impaired, in this way blending into the Korsakoff state. In response to the administration of thiamine, the patient rapidly becomes more alert and attentive and more capable of taking part in mental testing. If, however, the state is sustained, for some uncertain period, the most prominent abnormality becomes one of retentive memory (Korsakoff-amnesic state).

Drowsiness is a common feature of the Wernicke confusional state, but stupor and coma are rare as initial manifestations. If, however, the early signs of the disease are not recognized and the patient remains untreated, a progressive depression of the state of consciousness occurs with stupor, coma, and death in a matter of a week or two, just as occurred in Wernicke's original cases. Autopsy series of Wernicke disease are heavily weighted with cases of the latter type, often undiagnosed during life (Harper; Torvik et al).

Some patients are alert and responsive from the time they are first seen and already show the characteristic features of the Korsakoff amnesic state. In a small number of such patients, the amnesic state is the only manifestation of the syndrome, and no ocular or ataxic signs (other than possibly nystagmus) can be discerned.

The Amnesic State

As indicated in Chap. 21, the core of the amnesic disorder is a defect in learning (anterograde amnesia) and a loss of past memories (retrograde amnesia). The defect in learning can be remarkably severe. The patient may be incapable, for example, of committing to memory the simplest of facts (such as the examiner's name, the date, and the time of day) despite countless attempts; the patient can repeat each fact as it is presented, indicating that he understands what is wanted of him and that "registration" is intact, but by the time the third fact is repeated, the first may have been forgotten. However, certain nonverbal learning may take place; for example, with repeated trials, the patient may learn complex tasks such as mirror writing or how to negotiate a maze, despite no recollection of ever having been confronted with these tasks.

Anterograde amnesia is always coupled with a disturbance of past or remote memory (retrograde amnesia). The latter disorder is usually severe in degree, although not complete, and covers a period that antedates the onset of the illness by up to several years. A few isolated events and information from the past are retained, but these are related without regard for the intervals that separated them or for their proper temporal sequence. Usually the patient "telescopes" events into a brief period of time; sometimes the opposite occurs. This aspect of the memory disorder becomes prominent as the initial confusional stage of the illness subsides.

It is probably true that memories of the recent past are more severely impaired than those of the remote past (the rule of Ribot); language, computation, knowledge acquired in school, and all habitual actions are preserved. This is not to say that all remote memories are intact. As discussed in Chap. 21, these are not as readily tested as more recent memories, making the two difficult to compare. It is our impression that there are gaps and inaccuracies in memories of the distant past in practically all cases of the Korsakoff amnesic state, and serious impairments in many.

The cognitive impairment of the Korsakoff patient is not exclusively one of memory loss. Psychologic testing discloses that certain cognitive and perceptual functions that depend little or not at all on retentive memory are also impaired. As a rule, the Korsakoff patient has no insight into his illness and is characteristically apathetic and inert, lacking in spontaneity and initiative, and indifferent to everything and everybody around him. However, the patient has a relatively normal capacity to reason with data immediately before him.

Confabulation has generally been considered to be a specific feature of Korsakoff psychosis, but the validity of this view depends largely on how one defines confabulation, and there is no uniformity of opinion on this point. The observations of our colleague Victor and his colleagues (1959) do not support the oft-repeated statement that the Korsakoff patient fills the gaps in his memory with confabulation. In the sense that gaps in memory exist and that whatever the patient supplies in place of the correct answers fills these gaps, the statement is incontrovertible. It is hardly explanatory, however. The implication that confabulation is a deliberate attempt to hide the memory defect, out of embarrassment or for other reasons, is incorrect. In fact, the opposite seems to pertain: As the patient improves and becomes more aware of a defect in memory, the tendency to confabulate diminishes. Furthermore, confabulation can be associated with both phases of the Wernicke-Korsakoff syndrome: The initial one in which profound general confusion dominates the disease, and the convalescent phase in which the patient recalls fragments of past experience in a distorted fashion. Events that were separated by long intervals are juxtaposed or related out of sequence, so that the narrative has an implausible or fictional aspect. In the chronic state of the disease, confabulation is usually absent. These and other aspects of confabulation are discussed fully in the monograph by Victor and colleagues (1959).

Other Clinical Abnormalities

Approximately 15 percent of patients show signs of alcohol withdrawal, that is, hallucinations and other disorders of perception, confusion, agitation, tremor, and overactivity of autonomic nervous system function. These symptoms are evanescent in nature and usually mild.

Signs of peripheral neuropathy are found in more than 80 percent of patients with the Wernicke-Korsakoff syndrome. In most, the neuropathic disease is mild and does not account for the disorder of gait, but it may be so severe and particularly painful that stance and gait cannot be tested. In a small number, retrobulbar optic neuropathy is added. Despite the frequency of peripheral neuropathy, overt signs of beriberi heart disease are rare. However, indications of disordered cardiovascular function such as tachycardia, exertional dyspnea, postural hypotension, and minor electrocardiographic abnormalities are frequent; occasionally, the patient dies suddenly following only slight exertion. These patients may show an elevation of cardiac output associated with low peripheral vascular resistance, abnormalities that revert to normal after the administration of thiamine. Postural hypotension and syncope are common findings in Wernicke disease and are probably a result of impaired function of the autonomic nervous system, more specifically to a defect in the sympathetic outflow (Birchfield). There may be mild hypothermia, loss of libido, and erectile dysfunction.

Patients with the Korsakoff amnesic state may have a demonstrably impaired olfactory discrimination. This deficit, like the notable apathy present in most Wernicke's patients, is probably attributable to a lesion of the mediodorsal nucleus of the thalamus and its connections, and not to a lesion of the peripheral olfactory system (Mair et al). Vestibular function, as measured by the response to standard ice-water caloric tests, is universally impaired in the acute stage of Wernicke disease (Ghez), but vertigo is not a complaint. This vestibular paresis probably accounts for the severe disequilibrium in the initial stage of the illness.

Laboratory Findings

The acute lesions of the Wernicke-Korsakoff syndrome in the mammillary bodies, and other medial thalamic and periaqueductal areas can be demonstrated in most cases by magnetic resonance imaging (MRI) (Donnal et al; Varnet et al). The changes are most apparent on the fluid-attenuated inversion recovery (FLAIR), T2, and diffusion-weighted sequences (if there is hemorrhage), but they may also enhance as shown in Fig. 41-2. It is not clear to what extent gradient-echo MRI images can be expected to consistently reveal the small hemorrhagic lesions of the diencephalon and periventricular areas. Imaging is particularly useful in patients in whom stupor or coma has supervened or in whom ocular and ataxic signs are otherwise inevident (Victor, 1990), but in milder cases a normal MRI does not preclude the diagnosis. The typical MRI changes are observed in only 58 percent of cases according to Weidauer and colleagues. In the chronic state, the mammillary bodies may be shrunken if measured by volumetric techniques (Charness and DeLaPaz).

The cerebrospinal fluid (CSF) in uncomplicated cases of the Wernicke-Korsakoff syndrome is normal or shows only a modest elevation of the protein content. Protein values greater than 100 mg/dL or a pleocytosis indicates the presence of a complicating illness such as subdural hematoma, meningeal infection, or encephalitis.

Measurements of serum thiamine and red blood cell transketolase have been explored as aids to diagnosis but are not sufficiently sensitive for clinical use and they are not readily available. Before treatment with thiamine, patients with Wernicke disease show a marked reduction in transketolase. Restoration of these values and of thiamine di- and triphosphate toward normal occurs within a few hours of the administration of thiamine, and completely normal values are usually attained within 24 h.

There are suggestions that there is a hereditary factor in the susceptibility of Wernicke-Korsakoff disease and possibly explains why only a small proportion of nutritionally deficient alcoholics develop this disease. Candidates for this variability have been proposed to be in transketolase activity or in the thiamine transporter gene, possibly on an epigenetic basis, but other genetic regions have been studied and to our reading, there is no clarity on this subject.

Approximately half of patients with Wernicke-Korsakoff disease show electroencephalographic (EEG) abnormalities, consisting of diffuse mild to moderate slow activity. Total cerebral blood flow and cerebral oxygen and glucose consumption may be reduced in the acute stages of the disease and may still be present after several weeks of treatment (Shimojyo et al). These observations indicate that significant reductions in brain metabolism need not be reflected in EEG abnormalities or in depression of the state of consciousness and that the latter is more a function of the location of the lesion than of the overall degree of metabolic defect.

Course of the Illness

The mortality rate in the acute phase of Wernicke disease was 17 percent in the series of patients collected by Victor, Adams, and Collins (1989) many decades ago. The fatalities were attributable mainly to hepatic failure and infection (pneumonia, pulmonary tuberculosis, and septicemia being at that time the most common). Some deaths were undoubtedly a result of the cerebral or cardiac effects of thiamine deficiency that had reached an irreversible stage.

Most patients respond in a fairly predictable manner to the administration of thiamine, as detailed further on. The most dramatic improvement is in the ocular manifestations. Recovery often begins within hours or sooner after the administration of thiamine and practically always within several days. This effect is so constant that a failure of the nystagmus and ocular palsies to respond to thiamine should raise doubts about the diagnosis of Wernicke disease. Horizontal nystagmus sometimes disappears in minutes. Sixth-nerve palsies, ptosis, and vertical gaze palsies recover completely within a week or two in most cases, but vertical nystagmus may sometimes persist for several months. Horizontal gaze palsies recover completely as a rule, but in 60 percent of cases a fine horizontal nystagmus remains as a permanent sequela. In this respect, horizontal nystagmus is unique among the ocular signs.

In comparison with the ocular signs, improvement of ataxia is delayed. Approximately 40 percent of patients recover completely from ataxia. The remaining recover incompletely or not at all and are left with a slow, shuffling, wide-based gait and inability to walk tandem. The residual gait disturbances and horizontal nystagmus provide a means of identifying obscure and chronic cases of dementia as alcoholic-nutritional in origin. Vestibular function improves at about the same rate as the ataxia of gait, and recovery is usually but not always complete.

The early symptoms of apathy, drowsiness, and global confusion invariably recede, and as they do the defect in memory and learning stands out more clearly. However, the memory disorder, once established, recovers completely or almost completely in only 20 percent of patients. The remainder is left with varying degrees of permanent Korsakoff amnesia.

It is apparent from the foregoing account that Wernicke disease and Korsakoff amnesia are not separate diseases, but that the ocular and ataxic signs and the transformation of the global confusional state into an amnesic syndrome are successive stages in a single disease process. Of 186 patients in the series of Victor, Adams and Collins (1989) who survived the acute illness, 157 (84 percent) showed this sequence of clinical events. As a corollary, a survey of alcoholic patients with Korsakoff amnesia in a psychiatric hospital disclosed that in most patients the illness had begun with the symptoms of Wernicke disease and that approximately 60 percent of them still showed some ocular or cerebellar stigmata of Wernicke disease many years after the onset. The same continuum cannot be invoked to explain alcoholic-nutritional cerebellar degeneration that arises as an independent illness and is not as a residual of the ataxia of Wernicke disease (see further on).

Neuropathologic Findings

Patients who die in the acute stages of Wernicke disease show symmetrical lesions in the paraventricular regions of the thalamus and hypothalamus, mammillary bodies, periaqueductal region of the midbrain, floor of the fourth ventricle (particularly in the regions of the dorsal motor nuclei of the vagus and vestibular nuclei), and superior cerebellar vermis. Lesions are consistently found in the mammillary bodies and less consistently in other areas. The microscopic changes are characterized by varying degrees of necrosis of parenchymal structures. Within the area of necrosis, nerve cells are lost, but usually some remain; some of these are damaged but others are intact. Myelinated fibers are more affected than neurons. These changes are accompanied by a prominence of the blood vessels, although in some cases there appears to be a primary endothelial proliferation and evidence of recent or old petechial hemorrhage. In the areas of parenchymal damage there is astrocytic and microglial proliferation. Discrete hemorrhages were found in only 20 percent of Victor's (1989) cases, and many appeared to be agonal in nature. The cerebellar changes consist of degeneration of all layers of the cortex, particularly of the Purkinje cells; usually this lesion is confined to the superior parts of the vermis, but in advanced cases the cortex of the most anterior parts of the anterior lobes is involved as well. Of interest is the fact that the lesions of Leigh encephalomyelopathy, a mitochondrial disorder implicating pyruvate metabolism, bear a resemblance to those of Wernicke disease but have a slightly different distribution and histologic characteristics.

The ocular muscle and gaze palsies are attributable to lesions of the sixth- and third-nerve nuclei and adjacent tegmentum, and the nystagmus to lesions in the regions of the vestibular nuclei. The latter are also responsible for the loss of caloric responses and probably for the gross disturbance of equilibrium that characterizes the initial stage of the disease. The lack of significant destruction of nerve cells in these lesions accounts for the rapid improvement and the high degree of recovery of oculomotor and vestibular functions. The persistent ataxia of stance and gait is caused by the lesion of the superior vermis of the cerebellum; ataxia of individual movements of the legs is attributable to an extension of the lesion into the anterior parts of the anterior lobes. Hypothermia, which occurs sometimes as an early feature of Wernicke disease, is probably attributable to lesions in the posterior and posterolateral nuclei of the hypothalamus (experimentally placed lesions in these parts have been shown to cause hypothermia or poikilothermia in monkeys).

The topography of the neuropathologic changes in patients who die in the chronic stages of the disease, when the amnesic symptoms are established, is much the same as the changes in the acute stages of Wernicke disease. Apart from the expected differences in age of the glial and vascular reactions, the only important difference has to do with the involvement of the medial dorsal and anterior nuclei of the thalamus. The medial parts of these nuclei were consistently involved in the patients who had shown the Korsakoff amnesic state during life; they were not affected in patients who had had no persistent amnesic symptoms in the series of Victor, Adams, and Collins (1989). The mammillary bodies were affected in all the patients, both those with the amnesic defect and those without. These observations suggest that the lesions responsible for the memory disorder are those of the thalami, predominantly of parts of the medial dorsal nuclei (and their connections with the medial frontal and temporal lobes and amygdaloid nuclei), and not those of the mammillary bodies, as is frequently stated. It is notable that the hippocampal formations, the site of damage in most other types of Korsakoff memory loss, are intact.

Treatment of the Wernicke-Korsakoff Syndrome

Wernicke disease constitutes a medical emergency; its recognition (or even the suspicion of its presence) requires the administration of thiamine. The prompt use of thiamine prevents progression of the disease and reverses those lesions that have not yet progressed to the point of fixed structural change. As emphasized earlier, in patients who show only ocular signs and ataxia, the administration of thiamine is crucial in preventing the development of an irreversible amnesic state.

Although 2 to 3 mg of thiamine may be sufficient to modify the ocular signs, much larger doses are needed to sustain improvement and replenish the depleted thiamine stores—initially, 50 to 200 mg intravenously and a similar dose mg intramuscularly—the latter being repeated each day until the patient resumes a normal diet. Certain writings indicate that initial doses of 500 mg are necessary to fully reverse the manifestations of Wernicke disease and prevent progression to the point of a Korsakoff syndrome. It appears that these higher doses, given for several days parenterally, are needed to replete vitamin levels in alcoholic and nutritionally deprived patients (see the articles by Thomson et al), but the need for high-dose regimens to reverse Wernicke disease is based on less-persuasive data. Nonetheless, current guidelines from the Royal College of Physicians, given by Thomson, promote high-dose regimens and seem advisable. The risks of administering parenteral thiamine have probably been overstated; anaphylactic reactions occurred in 0.1 percent of the series of Wrenn and colleagues and minor reactions in 1 percent.

To avoid precipitating Wernicke disease, it has become standard practice in emergency departments to administer 100 mg or more of thiamine in malnourished or alcoholic patients if intravenous fluids that contain glucose are being infused. Magnesium is given as well because it is required as cofactor for thiamine activity. It is similarly advisable to give B vitamins to alcoholic patients who are seen for other reasons in the emergency department so as to raise body stores of thiamine and other vitamins. The chronic alcoholic (or the nonalcoholic with persistent vomiting) exhausts thiamine in a matter of 7 or 8 weeks, during which time the administration of glucose may serve to precipitate Wernicke disease or cause an early form of the disease to progress rapidly. The further management of Wernicke disease involves the use of a balanced diet and all the B vitamins, as the patient is usually deficient in more than thiamine alone.

A different problem in management may arise once the patient has recovered from Wernicke disease and the amnesic syndrome becomes prominent. Only a minority of such patients (fewer than 20 percent in Victor's series) recover entirely; moreover, the time of recovery may be delayed for several weeks or even months, and then it proceeds very slowly over a period of many months. The extent to which the amnesic symptoms will recover cannot be predicted during the acute stages of the illness. Interestingly, the alcoholic Korsakoff patient, once more or less recovered, seldom demands alcohol but will drink it if it is offered.

Infantile Wernicke–Beriberi Disease

This designates an acute and frequently fatal disease of infants, which until recently was common in rice-eating communities of the Far East. It affects only breast-fed infants, usually in the second to the fifth months of life. Acute cardiac symptoms dominate the clinical picture, but neurologic symptoms (aphonia, strabismus, nystagmus, spasmodic contraction of facial muscles, and convulsions) have been described in many of the cases. This syndrome can be reversed dramatically by the administration of thiamine, so that some authors prefer to call it acute thiamine deficiency in infants. In the few neuropathologic studies that are available, changes like those of Wernicke disease in the adult have been described. Occasionally, there are outbreaks of this condition due to inadequately formulated baby foods that lack thiamine.

Infantile beriberi bears no consistent relationship to beriberi in the mother. Infants of mothers with overt signs of beriberi may be quite normal. The absence of beriberi in the mothers of affected infants suggests that infantile beriberi might be due to the result of a toxic factor in breast milk, but such a factor, if it exists, has never been isolated. The levels of thiamine in the breast milk of such mothers have not been measured, however.

Rarely, the clinical manifestations of beriberi in infancy represent an inherited (autosomal recessive) thiamine-dependent state, responding to the continued administration of massive doses of thiamine (Mandel et al; see also Table 41-3, further on).

(See also Chap. 46)

Most physicians in the Western world have only a dim notion about beriberi, which they recall as an ill-defined, predominantly cardiac disorder occurring among people whose diet was dominated by polished rice. The milling process, or "polishing," removes the husk that contains most of the vitamin nutrients. In fact, beriberi is a distinct clinical entity that is not confined to any particular part of the world. Essentially, it is a disease of the heart and of the peripheral nerves (which may be affected separately), with or without edema, the latter feature providing the basis for the old division into "wet" and "dry" forms. The cardiac manifestations range from tachycardia and exertional dyspnea to acute and rapidly fatal heart failure, the latter being the most dramatic but uncommon manifestation of beriberi. Here we emphasize the peripheral neuropathy, or neuropathic beriberi.

That beriberi is essentially a disorder of the peripheral nerves was established in the late nineteenth century by the studies of the Dutch investigators Eijkman, Pekelharing and Winkler, and Grijns. Only after beriberi gained acceptance as a nutritional disease (this followed Funk's discovery of vitamins in 1911) was it suspected that the neuropathy of alcoholics was also nutritional in origin. The similarity between beriberi and alcoholic neuropathy was commented upon by several authors, but it was Shattuck, in 1928, who first seriously discussed the relationship of the 2 disorders. He suggested that "polyneuritis of chronic alcoholism was caused chiefly by failure to take or assimilate food containing a sufficient quantity B vitamins and might properly be regarded as true beriberi." Convincing evidence that "alcoholic neuritis" is not a result of the neurotoxic effect of alcohol was supplied by Strauss. He allowed 10 patients to continue their daily consumption of whiskey while they consumed a well-balanced diet supplemented with yeast and vitamin B concentrates; the peripheral nerve symptoms improved in every case. The observations made by Victor (1984) support Strauss's contention that alcoholic polyneuropathy is essentially a nutritional disease.

Clinical Features

The symptomatology of nutritional polyneuropathy is diverse. In fact, many patients are asymptomatic and evidence of peripheral nerve disease is found only by clinical or electromyographic examination. The mildest neuropathic signs are thinness and tenderness of the leg muscles, loss or depression of the Achilles reflexes and perhaps of the patellar reflexes and at times, a patchy blunting of pain and touch sensation over the feet and shins.

Most patients, however, are symptomatic and have weakness, paresthesias, and pain as the usual complaints. The symptoms are insidious in onset and slowly progressive, but occasionally they seem to evolve or to worsen rapidly over a matter of days. The initial symptoms are usually referred to the distal portions of the limbs and progress proximally if the illness remains untreated. The feet are always affected earlier and more severely than the hands. Usually some aspect of motor disability is part of the chief complaint, but in about one-third of the patients the main complaints are pain and paresthesias. It is this painful syndrome that has been the most prominent feature in the patients we have encountered in recent years. The discomfort takes several forms: a dull, constant ache in the feet or legs; sharp and lancinating pains, momentary in duration, like those of tabes dorsalis; sensations of cramping or tightness in the muscles of the feet and calves; or band-like feelings around the legs. Coldness of the feet is a common complaint but is not corroborated by palpation. Far more distressing are feelings of heat or "burning" affecting mainly the soles, less frequently the dorsal aspects of the feet. These dysesthesias fluctuate in severity and characteristically are worsened by contactual stimuli, sometimes to the point where the patient cannot walk or bear the touch of bedclothes, despite the relative preservation of motor power (allodynia). The term burning feet has been applied to this syndrome, but it is not particularly apt, as the patient also complains of other types of paresthesias, dysesthesias, and pain, and these symptoms may involve the hands as well as the feet.

Examination discloses varying degrees of motor, sensory, and reflex loss. As the symptoms suggest, the signs are symmetrical, and more severe in distal than in proximal portions of the limbs, and often confined to the legs. In some cases, the disproportionate affection of motor power may be striking, taking the form of a foot- and wrist-drop, but the proximal muscles are usually affected as well (indicated, for example, by climbing stairs or by difficulty in arising from a squatting position). In a few patients, the weakness appears to be most severe in the proximal muscles. Absolute paralysis of the legs had been observed in the past only rarely; immobility caused by contractures at the knees and ankles in neglected patients was a more common occurrence. Tenderness of muscles on deep pressure is a highly characteristic finding, elicited most readily in the muscles of the feet and calves. In the arms, tendon reflexes are sometimes retained despite a loss of strength in the hands. In patients in whom pain and dysesthesias are prominent and motor loss is slight, the reflexes at knee and ankle may be retained or even of greater than average briskness. This attests to the predominant affection of the small nerve fibers.

Excessive sweating of the soles and dorsal aspects of the feet and of the volar surfaces of the hands and fingers is a common manifestation of alcohol-induced nutritional neuropathy. Postural hypotension is sometimes associated, all symptoms indicative of involvement of the peripheral sympathetic nerve fibers.

Sensory loss or impairment may involve all the modalities, although one may be affected out of proportion to the others, usually pain and temperature. One cannot predict from the patient's symptoms which mode of sensation might be affected disproportionately. In patients with impairment of superficial sensation (i.e., touch, pain, and temperature), the border between impaired and normal sensation is not sharp but shades off gradually over a considerable vertical extent of the limbs.

Patients in whom pain is the outstanding symptom do not constitute a distinct group in terms of their neurologic signs. Pain and dysesthesias may be prominent in patients with either severe or slight degrees of motor, reflex, and sensory loss. The term hyperesthetic is used commonly to designate the exquisitely painful form of neuropathy but is not well chosen; as pointed out in Chap. 8, one is usually able, by using finely graded stimuli, to demonstrate an elevated threshold to painful, thermal, and tactile stimuli in the "hyperesthetic" zone. Once the stimulus is perceived, however, it has a painful and diffuse, unpleasant quality (hyperpathia). Tactile evocation of pain or burning is an example, as mentioned, of allodynia.

In most patients with nutritional polyneuropathy, only the limbs are involved and the abdominal, thoracic, and bulbar muscles are usually spared; however, we have encountered 2 cases in which there was sensory loss in the pattern of an escutcheon over the anterior thorax and abdomen. In the most advanced instances of neuropathy, hoarseness and weakness of the voice and dysphagia as a result of degeneration of the vagus nerves may be added to the clinical picture.

Some idea of the incidence of the motor, reflex, and sensory abnormalities and the combinations in which they occur can be obtained from Table 41-1, which is based on Victor's (1984) examination of 189 nutritionally depleted alcoholic patients. Noteworthy is the fact that only 66 (35 percent) of the 189 patients showed the clinical picture of polyneuropathy in its entirety, that is, a symmetrical impairment or loss of tendon reflexes, sensation, and motor power affecting legs more than the arms and the distal more than the proximal segments of the limbs. In the remaining patients, the motor-reflex-sensory signs occurred in various combinations.

Stasis edema and pigmentation, glossiness, and thinness of the skin of the lower legs and feet are common findings in patients with any severe form of neuropathy. Major dystrophic changes, in the form of perforating plantar ulcers and painless destruction of the bones and joints of the feet ("Charcot forefeet"), have been described but are rare. Repeated trauma to insensitive parts and superimposed infection are thought to be responsible for the neuropathic arthropathy, as discussed in Chaps. 8 and 46.

The CSF is usually normal, although a modest elevation of protein content is found in a small number. Findings of nerve conduction studies include mild to moderate degrees of slowing of motor and sensory conduction and a marked reduction in the amplitudes of sensory action potentials; the motor conduction velocities in distal segments of the nerves may be reduced, while conduction in proximal segments is normal. Denervated muscles show fibrillation potentials in a pattern that is consistent with more severe involvement peripherally.

Pathologic Features

The essential change is one of axonal degeneration, with destruction of both axon and myelin sheath. Segmental demyelination occurs only in a small proportion of fibers. The most pronounced changes are observed in the distal parts of the longest and largest myelinated fibers in the crural and, to a lesser extent, brachial nerves. In advanced cases, the changes extend into the anterior and posterior nerve roots. The vagus and phrenic nerves and paravertebral sympathetic trunks may be affected in advanced cases. Anterior horn and dorsal root ganglion cells undergo chromatolysis, indicating axonal damage. Secondary changes in the posterior columns are seen in some cases.

Pathophysiology

The nutritional factor(s) responsible for the neuropathy of alcoholism and beriberi has not been defined precisely. Because of the difficulty in producing peripheral neuropathy in mammals by means of a thiamine-deficient diet, the idea that thiamine is the antineuritic vitamin was questioned in the past. Very few of the animal experiments undertaken to settle this point were satisfactory from a nutritional and pathologic point of view. Nevertheless, several studies in birds and humans do indeed indicate that uncomplicated thiamine deficiency may result in peripheral nerve disease. The necessity of either accepting or rejecting the specific role of thiamine became less urgent when it was demonstrated, in both animals and humans; a deficiency of pyridoxine or of pantothenic acid could also result in degeneration of the peripheral nerves (Swank and Adams).

The question of whether polyneuropathy in the alcoholic patient might be a result of the direct toxic effects of alcohol and not of a nutritional deficiency has been raised from time to time (see the preceding text and Denny-Brown and Behse and Buchthal). The evidence for this view is not compelling, either on clinical or on experimental grounds, as already mentioned (see reference to Strauss, in introductory section on nutritional neuropathy). The data presented more recently by Koike and colleagues, ostensibly in favor of the existence of a true alcoholic neuropathy, in our view present no convincing support of a direct toxic effect of alcohol. In the end, we view alcoholic–beriberi neuropathy as a multiple B-vitamin deficiency. The interested reader will find a detailed critique of this subject in the chapters by Victor and by Windebank in the second and third editions, respectively, of Peripheral Neuropathy, edited by Dyck and coworkers.

Treatment and Prognosis

The first consideration is to supply adequate nutrition over a long period in the form of a balanced diet supplemented with B vitamins (equally important is to make certain that the patient follows the prescribed diet). If persistent vomiting or other gastrointestinal complications prevent the patient from eating, parenteral feeding becomes necessary; the vitamins may be given intramuscularly or added to intravenous fluids.

Where pain and sensitivity of the feet are the major complaints, the pressure of bedclothes may be avoided by placing a cradle support over the legs. Aching of the limbs may be related to their immobility, in which case they should be moved passively on frequent occasions. Aspirin or acetaminophen is usually sufficient to control hyperpathia and allodynia; occasionally codeine or methadone must be added. Obviously, opiates and addicting synthetic analgesics should be avoided if possible, but we have resorted to fentanyl patches for short periods in a few severely affected patients. Some of our patients with severe burning pain (similar to causalgia) in the feet had in the past been helped temporarily by blocking the lumbar sympathetic ganglia or by epidural injection of analgesics. The response to phenytoin, carbamazepine, and gabapentin has been inconsistent, but they are widely used. Adrenergic-blocking medication has been of little value and mexiletine, in our experience, of uncertain benefit.

The regeneration of peripheral nerves, which may take many months, will be of little avail if the muscles have been allowed to undergo contracture and the joints to become fixed. In cases of severe paralysis, molded splints should be applied to the arms, hands, legs, and feet during periods of rest. Pressure on the heels and elbows can be avoided by padding the splints and by turning the patient frequently or by asking the patient to do so. As function returns, more vigorous physiotherapeutic measures can be undertaken.

Recovery from nutritional polyneuropathy is a slow process. In the mildest cases there may be a considerable restoration of motor function in a few weeks. In severe forms of the disease, many months may pass before the patient is able to walk unaided. The sensory features and pain in particular may be slower to recover, having taken over a year in one of our recently observed patients. The slowness of recovery creates a special problem for the alcoholic patient, in whom the great danger to continued recovery is the resumption of drinking and inadequate diet.

Riboflavin Deficiency (Vitamin B2 Deficiency)

Whether or not riboflavin deficiency leads to neurologic symptoms has been controversial. In the past, there were claims that glossitis, cheilosis, and neuropathy were caused by riboflavin deficiency, but its effects were never isolated. It is a component of general malnutrition, making it difficult to separate the cause of various disorders. Night blindness seems, however, to be caused by B2 deficiency. Antozzi and coworkers reported that a metabolic disorder similar to the Reye syndrome can be caused by riboflavin deficiency and is correctable by administration of riboflavin alone. The affected infants in their studies were hypoglycemic, hypotonic, and episodically weak and unresponsive. Generally, 15 mg per day in divided doses is used for replacement, but restoration of a normal diet is paramount.

Antozzi and colleagues also recorded instances of disease in older children and adults, manifesting as a type of lipid storage polymyopathy as a result of either a deficiency or malabsorption of riboflavin. Presumably, a disorder of flavin metabolism had caused an impairment of both beta-oxidation of fatty acids and respiratory chain I and II complexes. Serum creatine phosphate was normal in these individuals, but carnitine was reduced. The oral administration of 200 mg of riboflavin and 4 g of carnitine per day relieved the symptoms. We have had no experience with such cases.

In the early 1900s, pellagra attained epidemic proportions in the southern United States and in the alcoholic population of large urban centers. Since 1940, it has diminished greatly because of the general practice of enriching bread with niacin. Nevertheless, among the vegetarian, maize-eating people of underdeveloped countries, and among the black population of South Africa, pellagra is still a common disease (Bomb et al; Shah et al; Ronthal and Adler). In developed countries, pellagra is practically confined to alcoholics (Ishii and Nishihara; Spivak and Jackson; Serdaru et al).

Clinical Features

In its fully developed form, pellagra affects the skin, alimentary tract, and hematopoietic and nervous systems. The early symptoms may be mistaken for those of a psychiatric disorder. Insomnia, fatigue, nervousness, irritability, and feelings of depression are common complaints; taken together they have the character of neurasthenia. Examination discloses mental dullness, apathy, and a mild impairment of memory. Sometimes an acute confusional psychosis dominates the clinical picture. Untreated, these symptoms may progress to a dementia. Pellagra may not only produce mental impairment but occasionally result from it, by virtue of anorexia and refusal of food. The dermatologic feature, often the aspect that permits one to make a confident diagnosis, is a scaly dermatitis in sun-exposed areas, followed by hyperpigmentation of these areas. Diarrhea and glossitis or other forms of mucous membrane disorder may be accompaniments (hence the alliterative triad dementia-dermatitis-diarrhea; the "3 Ds"). The spinal cord manifestations have not been clearly delineated, but in general, the signs are referable to both posterior and lateral columns, predominantly the former, and thereby simulating SCD. Signs of peripheral neuropathy are relatively less common and are indistinguishable from those of neuropathic beriberi.

Pathologic Changes

These are most readily discerned in the large cells of the motor cortex (Betz cells), and to a lesser extent in the smaller pyramidal cells of the cortex, the large cells of the basal ganglia, the cranial motor and cerebellar dentate nuclei, and the anterior horn cells of the spinal cord. The affected neurons are swollen and rounded, with eccentric nuclei and loss of the Nissl bodies that have the appearance of a secondary axonal reaction. However, in the pathologic material presented by Hauw and associates, these chromatolytic changes were most pronounced in the brainstem nuclei (upper reticular and pontine) and not in the Betz cells. They concluded that the neuronal changes were not caused by a retrograde axonal lesion but did not comment on the status of the spinal cord or nerves. The few studies of the peripheral nerves in pellagra have disclosed changes like those in alcoholics and other patients with nutritional deficiency.

The spinal cord lesions in pellagra take the form of a symmetrical degeneration of the dorsal columns, especially of Goll, and to a lesser extent of the corticospinal tracts. The posterior column degeneration is likely to be secondary to degeneration of the dorsal root ganglion cells or posterior roots. The reason for the corticospinal tract degeneration is not clear.

Etiology

It has been known since 1937, when Elvehjem and coworkers showed that nicotinic acid cured black tongue, a pellagra-like disease in dogs, that this vitamin is effective in the treatment of pellagra. Many years before, Goldberger had demonstrated the curative effects of dietary protein and proposed that pellagra was caused by a lack of specific amino acids (see Terris). Now it is known that pellagra may result from a deficiency of either nicotinic acid or tryptophan, the amino acid precursor of nicotinic acid. One milligram of nicotinic acid is formed from 60 mg of tryptophan, a process for which pyridoxine is essential. The relationship of niacin to tryptophan metabolism explains the frequent occurrence of pellagra in persons who subsist mainly on corn, which contains only small amounts of tryptophan and niacin, some of the niacin being in bound form and unavailable for absorption.

It should be pointed out that in experimental subjects, only the cutaneous-gastrointestinal-neurasthenic manifestations of pellagra have been produced by diets that are tryptophan or niacin deficient; neurologic abnormalities have not resulted from these diets (Goldsmith). As a corollary, only the dermal, gastrointestinal, and neurasthenic manifestations respond to treatment with niacin and tryptophan; neurologic disturbances in pellagrins have proved to be recalcitrant to prolonged treatment with the vitamin, although the peripheral nerve disorder may subsequently respond to treatment with thiamine. In monkeys, degeneration of peripheral nerves and the cerebrocortical changes of pellagra were induced by a deficiency of pyridoxine (Victor and Adams, 1956). Swank and Adams described degeneration of the peripheral nerves in pyridoxine- and pantothenic acid-deficient swine, and Vilter and colleagues produced polyneuropathy in human subjects rendered pyridoxine deficient; these subjects also showed seborrheic dermatitis and glossitis (indistinguishable from that of niacin deficiency) and the cheilosis and angular stomatitis that are usually attributed to riboflavin deficiency. The foregoing observations indicate that certain lingual and cutaneous manifestations of pellagra may be produced by a deficiency of pyridoxine or other B vitamins, and that the neurologic manifestations of pellagra are most likely caused by pyridoxine deficiency.

In the special case of Hartnup disease in infants (which resembles pellagra in most respects including the dermatitis), a secondary niacin deficiency is believed to result from the high excretion of indicans and indole metabolites (see Chap. 37).

Treatment

The administration of niacin 500 mg per day for approximately 3 weeks reverses the process. If the patient is unable to take oral medications, intravenous doses of 100 mg per day for 5 to 7 days are utilized. If the patient is simultaneously deficient in pyridoxine, as for example when INH is used for tuberculosis treatment, the pyridoxine must also be replaced in order to allow the conversion of dietary tryptophan to endogenous niacin.

Nicotinic Acid-Deficiency Encephalopathy

Under this title, Jolliffe and coworkers, in 1940, described an acute cerebral syndrome in alcoholic patients consisting of clouding of consciousness, progressing to extrapyramidal rigidity and tremors ("cogwheel" rigidity) of the extremities, uncontrollable grasping and sucking reflexes, and coma. Some of their patients showed overt manifestations of nutritional deficiency, such as Wernicke disease, pellagra, scurvy, and polyneuropathy. These authors concluded that the encephalopathy represented an acute form of nicotinic acid deficiency, as most of their patients recovered when treated with a diet of low vitamin B content supplemented by intravenous glucose and saline and large doses of nicotinic acid. Sydenstricker and colleagues (1938) had previously reported the salutary effects of nicotinic acid on the unresponsive state observed in elderly undernourished patients, and Spillane (1947) described a similar syndrome and response to nicotinic acid in the indigent Arab population of the Middle East.

The status of this syndrome and its relation to pellagra are uncertain. The clinical, nutritional, and pathologic features were never delineated precisely. Serdaru and associates reported 22 presumed examples of this syndrome in the alcoholic population of the Salpêtriére clinic in Paris, all diagnosed retrospectively after the finding in postmortem material of pellagra-like changes in nerve cells. The prominent features were confusional states, paratonic rigidity, ataxia, and polymyoclonia, a picture somewhat like that described by Jolliffe and coworkers. Skin lesions were absent. We have not encountered identical cases among the undernourished patients in the alcoholic population.

Pyridoxine (Vitamin B6) Deficiency

Pyridoxine deficiency or excess has been associated with a sensory polyneuropathy. The occurrence of neuropathy caused by INH was recognized in the early 1950s, soon after the introduction of this drug for the treatment of tuberculosis. It was characterized by paresthesia and burning pain of the feet and legs, followed by weakness of these parts and loss of ankle reflexes. Rarely, with continued use of the drug, the hands were affected as well. The nature of INH-induced neuropathy was clarified by Biehl and Vilter who found that isoniazid causes a marked excretion of pyridoxine and that the administration of pyridoxine in conjunction with INH prevents the development of neuropathy. Because of this simple preventive measure, very few examples of INH-induced neuropathy are now observed. Hydralazine, closely related in structure to INH, when used in the past caused the formation of pyridoxal-isoniazid complexes (hydrazones), which make pyridoxal (the main form of vitamin B6) unavailable to the tissues. The neuropathy responds favorably to discontinuation of the drug and the administration of pyridoxine.

Pyridoxine deficiency also leads to homocystinemia because the vitamin is a coenzyme for the conversion of homocystine to cystathionine. Vascular thrombosis may result from the excess homocystine.

Severe pyridoxine deficiency in animals and humans also causes seizures. This was first observed in swine by Swank and Adams, and later in infants who were maintained on a milk formula lacking in pyridoxine. A pyridoxine-responsive seizure disorder (pyridoxine dependency) of the neonatal period is discussed in Chap. 16.

Treatment

For pyridoxine deficiency caused by malnutrition, the treatment is 50 mg per day orally for several weeks, followed by 2 mg per day and resumption of a normal diet. When the deficiency results from a pyridoxine antagonist such as INH, penicillamine, hydralazine, or cycloserine, the treatment is 50 mg per day, only when the antagonist is in use. Treatment for the inherited form with convulsions is discussed in the section on neonatal seizures in Chap. 16. Lifelong supplementation is required after the seizures are aborted with a large intravenous dose of the vitamin.

Pyridoxine Toxicity

Paradoxically, the consumption of large amounts of pyridoxine (mainly by vitamin faddists) may also cause a sensory peripheral neuropathy or ganglionopathy (Schaumburg et al; Albin et al). There is no weakness; the symptoms, including ataxia and areflexia, are purely sensory and can be quite disabling. Symptoms may extend to the trunk, scalp, and face. Improvement is the rule when the drug is withdrawn. This disorder is probably a direct toxic effect of pyridoxine on dorsal root ganglion cells.

Folate (B9 Deficiency)

Despite the frequency of folic acid deficiency and its hematologic effects, its role in the pathogenesis of nervous system disease has not been established beyond doubt (see reviews by Crellin et al and by Carney). However, folate antagonists such as methotrexate are known to cause a neuropathy that is probably predicated on the vitamin deficiency. The polyneuropathy that occasionally complicates the chronic administration of phenytoin has also been attributed, on uncertain grounds, to folate deficiency. Botez and colleagues have described a group of 10 patients with sensorimotor polyneuropathy (4 also had spinal cord disease) presumably because of intestinal malabsorption; all the patients improved over several months while receiving large doses of folic acid. This experience is unique, however. The possible role of folate deficiency in the pathogenesis of spinal cord disease was mentioned previously in relation to vitamin B12 deficiency, and its putative role in psychiatric disease has been discussed by Carney. In such cases of folate deficiency, if subacute combined degeneration or mental changes occur, they must be rare.

The folate deficiency of pregnancy is a special case that is known to increase the incidence of neural tube defects.

For nutritional folate deficiency, difficult to separate from the lack of other vitamins, replacement is with 1 mg per day. In pregnant women, higher doses are used, separately from a multivitamin preparation in order to avoid vitamin A toxicity. When a folate antagonists is the underlying cause, folinic acid (leukovorin, citrovorum factor) 15 mg orally is given every 6 h for 10 doses starting after methotrexate infusion.

Pantothenic Acid Deficiency

A predominantly sensory neuropathy also has been induced, again in swine, by Swank and Adams, and later in humans by a deficiency of pantothenic acid (a constituent of coenzyme A [CoA]), as reported by Bean and colleagues. In some patients, the administration of pantothenic acid has reportedly reversed the painful dysesthesias of the "burning foot" syndrome.

The spinal cord, brain, optic nerves, and peripheral nerves are all affected by vitamin B12 (cobalamin) deficiency, giving rise to a classic neurologic syndrome. The spinal cord is usually affected first and often exclusively. The term subacute combined degeneration (SCD) is customarily reserved for the spinal cord lesion of vitamin B12 deficiency and serves to distinguish it from other types of spinal cord diseases that happen to involve the posterior and lateral columns (loosely referred to as combined system disease). Whether a peripheral neuropathy is a primary component of the disease or is secondary to damage of the posterior root fibers of entry in the dorsal cord has been debated, but the available pathologic evidence favors the latter, except perhaps for a few advanced cases, in which other nutritional deficiencies could have been responsible.

The hematologic effects of vitamin B12 deficiency, when they result from pernicious anemia, are distinctive insofar as they usually result not from a dietary lack of vitamin B12 but from the failure to transfer minute amounts of this nutrient across the intestinal mucosa, "starvation in the midst of plenty," as Castle aptly put it. This failure derives from the chronic absence of an intrinsic factor, which is secreted (along with hydrochloric acid) by the parietal cells of the gastric mucosa and transports cobalamin ("extrinsic factor") to the ileum, where it is absorbed into the portal venous system. This is referred to as a conditioned deficiency, as it is conditional on the lack of an intrinsic factor. Minot and Murphy's clinical experiment that showed the cure of the neurologic process by the feeding of liver, or parenteral liver extract that contained an "extrinsic factor" later found to be cobalamin, was a remarkable feat of translational medicine. A movie can be seen depicting this work at: http://bloodjournal.hematologylibrary.org/content/107/12/4970.1/suppl/DC1. It was Castle, experimenting on himself, who isolated the "intrinsic factor" that facilitates absorption of the vitamin.

The hematologic and neurologic manifestations of vitamin B12 deficiency often complicate many of the malabsorptive disorders, including poor nutrition in the elderly, especially those with atrophic gastritis, but also individuals of any age with celiac sprue; gastric or ileal resections; overgrowth of intestinal bacteria in "blind loops," anastomoses, diverticula, and other conditions resulting in intestinal stasis; and infestation with cobalamin-metabolizing fish tapeworm (Diphyllobothrium latum). Uncommon instances of vitamin B12 deficiency are observed in lactovegetarians and in infants nursed by mothers deficient in vitamin B12; vitamin B12 deficiency may also be a result of a rare genetic defect of methylmalonyl-CoA mutase as discussed further on.

It should be further commented that interference with methionine synthetase, a methylcobalamin-dependent enzyme, can be produced by exposure to nitrous oxide. Chronic exposure can produce the entire subacute combined syndrome but more often, an individual is marginally deficient, often but not always elderly, and even short exposure may then induce symptoms. A megaloblastic anemic state, as well as the neurologic features of SCD, is thereby induced by the gas. This illness, cleverly named "anesthesia paresthetica" by Kinsella and Green, arises in operating room personnel (we have seen it in several anesthesia nurses), occasionally in dentists, and in abusers of the gas (whippets) to obtain a "high." Their serum B12 levels are usually in the low-normal range, and measurements of methylmalonic acid are greatly elevated (see further on).

Clinical Manifestations

Symptoms of nervous system disease occur in the majority of patients with pernicious anemia and in most with B12 deficiency of other sources. The patient first notices mild general weakness and paresthesias consisting of tingling, "pins and needles" feelings, or other vaguely described sensations. The paresthesias involve the hands and feet, more often and first in the hands, and tend to be constant and steadily progressive and the source of much distress. As the illness progresses, the gait becomes unsteady and stiffness and weakness of the limbs, especially of the legs, develop. If the disease remains untreated, an ataxic paraplegia evolves with variable degrees of spasticity.

Early in the course of the illness, when only paresthesia is present, there may be no objective sign. Later, examination discloses a disorder of the posterior and lateral columns of the spinal cord, predominantly of the former. Loss of vibration sense is the most consistent sign; it is more pronounced in the feet and legs than in the hands and arms and frequently extends over the trunk. Position sense is usually impaired in parallel. The motor signs, usually limited to the legs, include a mild symmetrical loss of strength in proximal limb muscles, spasticity, enhanced tendon reflexes, clonus, and extensor plantar responses. At first, the patellar and Achilles reflexes are diminished as frequently as they are increased; they may even be absent. This is most likely the result of a neuropathy due to multiple vitamin deficiencies as cases of pure cobalamin loss, for example due to nitrous oxide, almost never obliterate the tendon reflexes. This controversy regarding the presence of a polyneuropathy as a component of SCD has already been alluded to. The gait at first is predominantly ataxic, later ataxic and spastic.

Loss of superficial sensation below a segmental level on the trunk should suggest an alternative diagnosis involving the spinal cord. However, 2 of our patients have described a band-like sensation around the thorax. A defect of cutaneous sensation may take the form of impaired tactile, pain, and thermal sensation over the limbs in a distal distribution, implicating the small fibers of the peripheral nerves or the spinothalamic tracts, but such findings are relatively uncommon. The Lhermitte phenomenon (paresthesia down the spine or across the shoulders induced by rapid flexion of the neck) may be found if sought but is a sign more often allied with multiple sclerosis. The nervous system involvement in SCD is roughly symmetrical and distal, and sensory disturbances precede the motor ones; predominantly motor involvement from the beginning and a definite asymmetry of motor or sensory findings maintained over a period of weeks or months or prominent truncal or facial symptoms should always cast doubt on the diagnosis.

Cognitive symptoms and signs are frequent, ranging from irritability, apathy, somnolence, suspiciousness, and emotional instability to a marked confusional or depressive psychosis or dementia. Lindenbaum and coworkers have reported cases in which neuropsychiatric symptoms, responsive to vitamin B12, were present without spinal cord or peripheral nerve abnormalities. In our clinical material, symptoms of dementia or psychosis have not been frequent and always followed the spinal cord disorder. Perhaps a slight degree of mental illness is all that is seen in early stages.

Visual impairment caused by optic neuropathy occasionally may be an early or sole manifestation of pernicious anemia; examination discloses roughly symmetrical centrocecal scotomata and optic atrophy in the most advanced cases. That visually evoked potentials may be abnormal in vitamin B12-deficient patients without clinical signs of visual impairment suggests that the visual pathways are affected more often than is evident from the neurologic examination alone. A small number of patients have symptoms of autonomic dysfunction, including urinary sphincteric symptoms and impotence.

The CSF is usually normal; in some cases there is a moderate increase in protein. The nerve conduction studies may show slowing of sensory conduction or reduced-amplitude sensory potentials, but they are as often normal in early cases. Frequently, according to Hemmer and colleagues, somatosensory evoked potentials are delayed or absent; these changes are known to recover with treatment. Quite remarkable in corresponding to the locus of pathologic change, as these and other authors have indicated, is the finding on MRI of a T2 hyperintensity that demarcates the posterior columns of the cord and sometimes the lateral columns, as shown in Fig. 41-3. In a few of our patients these have taken the form solely of well-defined linear changes over a long extent of the posterior columns of the cervical cord.

Neuropathologic Changes

The pathologic process takes the form of a diffuse, although uneven, degeneration of white matter of the spinal cord and occasionally of the brain. The earliest histologic event is swelling of myelin sheaths, characterized by the formation of intramyelinic vacuoles and separation of myelin lamellae. This is followed by a coalescence of small foci of tissue destruction into larger ones, imparting a vacuolated, sieve-like appearance to the tissue, an appearance also observed in the myelopathy of AIDS and rarely in lupus erythematosus. The myelin sheaths and axis cylinders are both involved in the degenerative process, the former more obviously and perhaps earlier and more severely than the latter. There is relatively little fibrous gliosis in the early lesions, but in more chronic ones, particularly those in which considerable tissue is destroyed, the gliosis is pronounced. The changes begin in the posterior columns of the lower cervical and upper thoracic segments of the cord and spread from this region up and down the cord as well as forward into the lateral and anterior columns. The lesions are not limited to systems of fibers within the posterior or lateral columns but are scattered irregularly through the white matter, thereby representing a myelinopathy.

In rare instances, foci of spongy degeneration are found in the optic nerves and chiasm and in the central white matter of the brain (Adams and Kubik). The peripheral nerves may show a loss of myelin, but there is no unequivocal evidence that axons are significantly affected.

Agamanolis and colleagues (1978) showed that monkeys sustained on a vitamin B12-deficient diet for a prolonged period develop neuropathologic changes indistinguishable from those of SCD in humans. The time required for the production of nervous system changes in monkeys, 33 to 45 months, is comparable to the time required to deplete the vitamin B12 stores of patients with pernicious anemia in whom parenteral vitamin B12 therapy had been discontinued. It is noteworthy that vitamin B12-deprived monkeys do not become anemic despite the prolonged period of vitamin B12 deficiency. Also in distinction to the human condition, involvement of the optic nerves is particularly severe in the monkey and probably precedes the degeneration of the spinal cord. The optic nerve lesions appear first in the papillomacular bundles, in the retrobulbar portions of the nerves; it subsequently spreads beyond the confines of this bundle and caudally in the optic nerves, chiasm, and tracts. These changes are much the same as those of "Tobacco–Alcohol Amblyopia" (see the section on this subject further on). The peripheral nerves are not affected in the experimentally produced vitamin B12 deficiency.

Paresthesia, impairment of deep sensation, and ataxia are caused by lesions in the posterior columns. Weakness, spasticity, increased tendon reflexes, and Babinski signs depend on involvement of the corticospinal tracts. The spinothalamic tracts may rarely be involved in the pathologic process, which explains the rare finding of a sensory level for pain and temperature on the trunk. The distal and symmetrical impairment of superficial sensation and loss of tendon reflexes that occur in advanced cases, however, may be explained by involvement of peripheral nerves and are then reflected in nerve conduction studies (see further on, under "Diagnosis").

Pathogenesis

Methylcobalamin is an essential cofactor in the conversion of homocysteine to methionine. An impairment of this reaction caused by a deficiency of cobalamin is thought to cause a failure of DNA synthesis, accounting for the hematologic abnormalities, particularly for the production of megaloblasts. However, because neurons do not divide, this sequence of chemical events does not explain the central nervous system abnormalities. One of the better-understood functions of vitamin B12 is its role as a coenzyme in the methylmalonyl-CoA mutase reaction. In this reaction, which is a key step in propionate metabolism, methylmalonyl-CoA is transformed to succinyl-CoA, which subsequently enters the Krebs cycle. A lack of the cobalamin-dependent enzyme methylmalonyl-CoA mutase leads to the accumulation of methylmalonyl-CoA and its precursor, propionyl-CoA. According to this mechanism, propionyl-CoA displaces succinyl-CoA, which is the usual primer for the synthesis of even-chain fatty acids; this results in the anomalous insertion of odd-chain fatty acids into membrane lipids, such as are found in myelin sheaths. Conceivably, this biochemical abnormality underlies the lesions of myelinated fibers that characterize the disease. However, Carmel and associates described a hereditary form of cobalamin deficiency in which methylmalonyl-CoA mutase activity was normal, despite the presence of typical neurologic abnormalities. In their view, the primary failure is one of methylation of homocysteine to methionine, that is, a failure of the methionine synthetase reaction, for which the coenzyme methylcobalamin is necessary.

Evidence for the latter view comes also from the observations, mentioned earlier, that prolonged administration of nitrous oxide (N2O) may produce not only megaloblastic changes in the marrow (Amess et al), but also a sensorimotor polyneuropathy, often combined with signs of involvement of the posterior and lateral columns of the spinal cord (Layzer). Probably N2O produces its effects by inactivating the methylcobalamin-dependent enzyme, methionine synthetase. These and other hypotheses are discussed by Jandl, Carmel and colleagues, and Beck (1988).

The role of folate deficiency in the genesis of SCD is less certain. One known clinical mistake has been to treat pernicious anemia by giving folic acid; this corrects the anemia but may worsen or even evoke the spinal cord lesions. Nevertheless, there have been a few reported examples of cerebral and spinal cord lesions indistinguishable from those caused by vitamin B12 deficiency in patients with defective folate metabolism, both in adults with acquired deficiency (Pincus) and in children with an inborn metabolic error (Clayton et al). The current view, however, is that folate deficiency alone does not produce SCD.

Diagnosis

The main differential diagnostic considerations of the combined sensory and motor features are cervical spondylosis (see Chaps. 11 and 44), multiple sclerosis of the cervical cord (see Chap. 36), rarities such as the female carrier state of adrenoleukodystrophy (see Chap. 37), and, most importantly, non-B12-deficient combined system disease caused by low levels of serum copper (see Chap. 44). The last of these refers to a myelopathic process that affects the posterior and lateral columns subacutely in a manner identical to that of subacute combined degeneration but unassociated with any form of B12 deficiency or related enzyme derangement. Somewhat to our surprise, the copper disorder has been as frequent as the classic type caused by B12 deficiency in our clinics. This entity is described more extensively in Chap. 44. One remarkable circumstance, with which we have had experience, is the creation of severe SCD including paralysis in a B12-deficient patient whose myelopathic symptoms were misattributed to cervical spondylosis and who had an operation for spondylosis in which spondylosis in nitrous oxide was used as anesthesia.

The chief obstacle to early diagnosis of SCD is the lack of parallelism that may exist between the hematologic and neurologic signs, particularly in patients who have taken dietary or medicinal folate. Anemia may also at times be absent, sometimes for many months, even in patients who have not taken folate. For example, in a retrospective study of 141 patients with neuropsychiatric abnormalities caused by cobalamin deficiency, there were 19 patients in whom both the hematocrit and mean red blood cell volume were normal (Lindenbaum et al); in these patients, subtle morphologic abnormalities such as hypersegmented polymorphonuclear leukocytes and megaloblastosis in bone marrow smears were almost always found if carefully sought.

Laboratory Diagnosis

Serum cobalamin should be measured whenever the diagnosis of vitamin B12 deficiency is in question. Microbiologic assay (using Euglena gracilis) is the most accurate measurement, but the method is time-consuming and cumbersome and has been replaced by a commercial radioisotope dilution assay (the inexpensive chemiluminescence assay is an alternative but slightly less dependable). With the radioassay, a serum B12 level below 100 pg/mL is usually associated with neurologic symptoms and signs of vitamin B12 deficiency. A level below 200 pg/mL that is unassociated with symptoms calls for further investigation of cobalamin deficiency. However, even serum levels of 200 to 300 pg/mL may still be associated (in 5 to 10 percent of cases) with cobalamin deficiency. High serum concentrations of cobalamin metabolites, methylmalonic acid (normal range, 73 to 271 nmol/L), and homocysteine (normal range 5.4 to 16.2 mmol/L) are additional reliable indicators of an intracellular cobalamin deficiency and can be used to corroborate the diagnosis in cases of low-mid-range B12 levels (Allen et al; Lindenbaum et al). It must be emphasized that the serum cobalamin level is not a measure of total-body cobalamin. In a patient who stops absorbing ingested cobalamin, the serum levels may remain in the normal range for months or years despite decreasing tissue reserves. In patients who have received vitamin B12 parenterally, the 2-stage Schilling test is a more reliable indicator of cobalamin deficiency because it uncovers a defect in absorption of the vitamin; however, the Schilling test has been largely supplanted for routine diagnosis by the measurement of antibodies to intrinsic factor and parietal cells.

Achlorhydria is almost invariably present in patients with pernicious anemia; its presence can be inferred by measuring the serum gastrin level. Antibodies to gastric parietal cells are also present in as many as 90 percent of patients with cobalamin deficiency, specifically in those with pernicious anemia as opposed to those with diminished B12 intake, but this test, although diagnostically specific, is positive in only 60 percent of cases. A relationship between helicobacter gastritis and autoimmunity against gastric parietal cells is being explored.

Low cobalamin levels with or without the clinical signs of deficiency may occur in patients with atrophic gastritis or after subtotal gastrectomy as mentioned. The malabsorption in such cases is thought to be because of a failure to extract cobalamin from food rather than a failure of the intrinsic factor mechanism ("food-cobalamin malabsorption"). Because the absorption of free cobalamin is normal, the Schilling test is unimpaired (Carmel, 1990). Infection of the gastric mucosa with Helicobacter pylori has been implicated in some cases. There are also rare inherited defects in the gene for intrinsic factor that render it ineffective.

The results of nerve conduction tests have varied in vitamin B12-deficient patients. Early in the course of SCD, nerve conduction may be normal, but some patients have slowing of distal sensory conduction; others have found reduced amplitudes and minor signs of denervation, suggestive of axonal change. This again raises the controversy regarding the presence of a peripheral nerve disorder in uncomplicated B12 deficiency. Authoritative texts indicate that a neuropathy is present but certainly, such involvement is not integral to the disease as many patients with prominent neurological manifestations, particularly early in the course, have normal nerve conduction studies. In patients with normal peripheral nerve studies, the somatosensory evoked potentials usually show abnormalities attributable to central conduction delays, implicating the posterior columns as the cause of the sensory symptoms (Fine and Hallett). In advanced cases, motor conduction and late responses may be affected to a slight degree. These ambiguities reflect the inconsistent and poorly understood role of the peripheral neuropathic component of this disease.

The MRI lesions in the posterior columns were described earlier; they extend through the cervical and upper thoracic cords and, less often, to the lateral columns. The frequency of these findings, however, is not known, and their absence cannot be considered evidence against the diagnosis.

Treatment

The diagnosis of pernicious anemia demands the administration of vitamin B12 and the continuation of treatment for the rest of the patient's life. In cases of pernicious anemia, the patient is given 1,000 μg of cyanocobalamin or hydroxocobalamin intramuscularly each day for several days. The usual approach is to repeat the injection weekly for a month and then monthly for an indefinite period. Although most of the injected cobalamin is excreted, these patients must be flooded with the vitamin because the repletion of cobalamin tissue stores is a direct function of the dose.

In recent years, the notion that all forms of B12 deficiency must be circumvented by parenteral administration of the vitamin has been questioned and the use of oral cobalamin 500 to 1,000 μg daily has been used as an alternative, particularly for maintenance treatment. Several studies have indicated the effectiveness of this approach in elderly patients with poor B12 absorption and in persons with restricted diets, such as vegans, but we would express reservation regarding the use of oral replacement in the treatment of manifest subacute combined degeneration with neurologic manifestations until further studies have been published.

The most important factor influencing the response to treatment is the duration of symptoms; age, sex, and the degree of anemia are of lesser importance. The greatest improvements occur in patients whose disturbance of gait has been present for less than 3 months and recovery is usually complete if therapy is instituted within a few weeks after the onset of symptoms. All neurologic symptoms and signs may improve, mostly during the first 3 to 6 months of therapy, and then at a slower tempo during the ensuing year or even longer. In practically all instances, there is some degree of improvement after treatment, although in cases of longest duration, the best that can be accomplished is an arrest of progression.

Vitamin E Deficiency

This occurs in 2 types: a defect in intestinal absorption and an inherent hepatic enzyme deficiency that blocks incorporation of vitamin E into lipoprotein. A rare neurologic disorder of childhood, sometimes later in life, consisting essentially of spinocerebellar degeneration in association with polyneuropathy and pigmentary retinopathy, has been attributed to a deficiency of vitamin E consequent to prolonged intestinal fat malabsorption (Muller et al; Satya-Murti et al). The same mechanism has been proposed to explain the neurologic disorders that sometimes complicate abetalipoproteinemia (see Chap. 37), fibrocystic disease (Sokol et al), celiac sprue disease, and extensive intestinal resections (Harding et al). Vitamin E deficiency has also been observed in young children with chronic cholestatic hepatobiliary disease (Rosenblum et al).

Ataxia, loss of tendon reflexes, ophthalmoparesis, proximal muscle weakness with elevated serum creatine kinase, and decreased sensation are the usual manifestations of vitamin E deficiency. These symptoms are referable to parts of the nervous system and musculature that are found to be diseased in animals deprived of vitamin E: degeneration of Clark columns, spinocerebellar tracts, posterior columns, nuclei of Goll and Burdach, and sensory roots (Nelson et al). Local differences in the natural concentration of vitamin E in various parts of the nervous system and musculature are believed to account for the distribution of the lesions. In affected children, neurologic function improves after long-term daily supplementation with high doses of vitamin E.

In recent years there have been reports of a form of spinocerebellar degeneration attributable to an inherited but conditioned deficiency of vitamin E that may closely mimic the phenotype of Friedreich ataxia ("familial isolated vitamin E deficiency" as discussed in Chap. 39). The onset is usually in early adolescence, but there is variability, particularly among different families. In these patients, absorption and transport of vitamin E to the liver is normal, but hepatic incorporation of tocopherol (the active form of vitamin E) into very-low-density lipoproteins is defective (Traber et al). The abnormality has been traced to a mutation in TTPA, the gene encoding α-tocopherol transfer protein (Gotoda et al). In a sense, this is a vitamin deficiency conditioned by a genetic mutation. An important feature of these cases is that chronic oral administration of large doses of vitamin E can halt and even reverse progression of the ataxia (Gabsi et al).

Vitamins A and D Deficiencies

Neurologic disorders caused by a lack or excess of these fat-soluble vitamins have been reported, but they are rare. Vitamin A deficiency sometimes occurs with malabsorption syndromes, causing impairment of vision. Excess of vitamin A in children or adults may result in the syndrome of pseudotumor cerebri (see Chap. 30). Vitamin D deficiency is associated with hypoparathyroidism or a malabsorption state that leads to hypocalcemia, proximal muscle weakness, and rickets.

Several related conditions of nutritional deficiency overlap in their presentations and have in common an uncertainty as to the primary cause. In all likelihood, there is a combination of factors, perhaps conditioned by genetic susceptibility. Here we refer especially to a syndrome of spastic ataxia, blindness, and a severe painful neuropathy with glossitis but there are other derivative syndromes that we discuss in this section.

Nutritional Spinal Spastic and Ataxic Syndrome

This syndrome is observed occasionally in nutritionally depleted alcoholics. The main clinical signs are spastic weakness of the legs, with absent abdominal and increased tendon reflexes, clonus, extensor plantar responses, and a loss of position and vibratory senses. In our experience, this syndrome has usually been associated with other nutritional disorders such as Wernicke disease and peripheral and optic neuropathy. In prisoner-of-war camps, the "spastic syndrome" was observed in association with mental and emotional changes and dimness of vision, and at times with widespread muscular rigidity, confusion, coma, and death. The latter syndrome has never been studied pathologically, so that it is impossible to state whether the lesions are the same as or different from those of pellagra or from Strachan syndrome, described further on.

The syndromes of tropical spastic paraparesis and of lathyrism, another form of spastic paraplegia common in India and certain parts of Africa, were for many years suspected of being nutritional in origin but are now known to be caused by a virus and a toxin, respectively. These and other types of tropical spastic paraplegia are discussed in greater detail with the spinal cord diseases (see Chap. 44). A chronic tropical disease of the peripheral nerves, called "ataxic neuropathy of Nigeria," has been attributed to the ingestion of inadequately detoxified cassava (Osuntokun). Another form of spastic ataxia, called "konzo," has been attributed to the production of cyanide by an ingested toxic glycoside in individuals who are protein deficient. The differential diagnosis of progressive spastic ataxia is quite broad and includes multiple sclerosis.

Nutritional Optic and Peripheral Neuropathy, "Tobacco–Alcohol Amblyopia," and Strachan Syndrome

(See also Chap. 13) These terms refer to a characteristic form of visual impairment that results from nutritional deficiency. The defect in vision is the result of a lesion of the optic nerves, more or less confined to the region of the papillomacular bundle. Typically, the patient complains of dimness or blurring of vision for near and distant objects, evolving gradually over a period of several days or weeks. Examination discloses a reduction in visual acuity because of the presence of central or centrocecal scotomata, which are larger for colored than for white test objects. Pallor of the temporal portion of the optic disc is observed in some cases. These abnormalities are bilateral and roughly symmetrical and, if untreated, may progress to blindness and irreversible optic atrophy. With normal diet and vitamin supplements improvement occurs in almost all cases but the most chronic ones; the degree of recovery depends on the severity of the amblyopia and particularly on its duration before therapy is instituted.

Although the precise deficiency responsible for this disease cannot be determined, its nutritional basis was established beyond doubt during World War II and the Korean War, when innumerable instances were observed in prisoners of war who had been confined for prolonged periods under conditions of severe dietary deprivation. Fisher described the optic nerve lesions in 4 such patients who had died of unrelated causes between 8 and 10 years after the onset of amblyopia. In each case, there was a loss of myelin and axis cylinders restricted to the region of the papillomacular fibers. Of the 4 cases, 3 also showed demyelination of the posterior columns of the spinal cord, no doubt an expression of the associated sensory polyradiculopathy.

In the Western world, a visual disorder indistinguishable clinically and pathologically from that observed in prisoners of war is observed infrequently, mainly among undernourished alcoholics. For many years this had been referred to as tobacco–alcohol amblyopia, with the implication that the visual loss is a result of the toxic effects of alcohol, tobacco, or both. Actually, the evidence is overwhelming that so-called tobacco–alcohol amblyopia is caused by nutritional deficiency and not by toxic exposure. A specific nutrient has not been identified, however. There are data in humans and animals that under certain conditions a deficiency of one or more of the B vitamins: thiamine, vitamin B12, and perhaps riboflavin, may cause degenerative changes in the optic nerves, a situation that pertains in the peripheral nerves as well. Part of the confusion in delineating a specific cause has been sporadic outbreaks of optic neuropathy in underdeveloped countries that may have been caused by a disseminated ingested toxin as described further on.

In the 1960s, a popular theory held that the combined effects of vitamin B12 deficiency and chronic poisoning by cyanide (generated in tobacco smoke) were responsible for "tobacco amblyopia." Vitamin B12 deficiency is a rare but undoubted cause of optic neuropathy, as noted further on, but the notion that cyanide or other substances in tobacco smoke have a damaging effect on the optic nerves is unsupported (see reviews of Potts and of Victor [1970]). Instances of Leber hereditary optic atrophy, a mitochondrial disorder, may be also mistaken for "tobacco–alcohol amblyopia," an error that should be made less often because Leber disease disorder can now be identified by mitochondrial DNA testing.

Recent outbreaks of an apparently nutritional or perhaps toxic optic neuropathy occurred in Cuba during the period 1991 to 1993 and in Tanzania. In both instances the optic neuropathy was frequently associated with peripheral neuropathy. The association of this epidemic with widespread dietary deprivation and the salutary response of both optic and peripheral nerve symptoms to treatment with B vitamins suggests a nutritional causation (see Centers for Disease Control and Prevention and the report of the Cuba Neuropathy Field Investigation Team), but a toxic cause could not be excluded. Shortly thereafter, Plant and colleagues reported on a similar outbreak of optic and peripheral neuropathy from Tanzania.

There remains to be considered a neuropathic syndrome that almost certainly is nutritional in origin but does not conform clinically to beriberi or pellagra, the classic deficiency diseases. This syndrome was originally observed by Strachan in 1897 among Jamaican sugarcane workers. The main symptoms in his patients were pain, numbness, and paresthesias of the extremities; objectively there was ataxia of gait, weakness, wasting, and loss of deep tendon reflexes and sensation in the limbs. Dimness of vision and impairment of hearing were common findings, as were soreness and excoriation of the mucocutaneous junctions of the mouth. This disorder, originally known as "Jamaican neuritis," was quickly recognized in other parts of the world, particularly in the undernourished populations of tropical countries. Subsequently, many cases of this syndrome were observed in the besieged population of Madrid during the Spanish Civil War and during World War II among prisoners of war in North Africa and the Far East.

The clinical descriptions from these varied sources are not entirely uniform, but certain features are common to all of them and occur with sufficient frequency to allow the delineation of the neurologic syndrome; it appears to be almost identical to the one described by Strachan. The core disorder is combined optic and peripheral neuropathy. The latter consists mainly of sensory symptoms and signs, and the former of the subacute evolution of failing vision, which, if untreated, progresses to complete blindness and pallor of the optic discs. Deafness and vertigo are uncommon, but in some outbreaks among prisoners of war, these symptoms were frequent enough to earn the epithet "camp dizziness." In all these respects, the syndrome differs from beriberi. Along with the neurologic signs there may be varying degrees of stomatoglossitis, corneal degeneration, and genital dermatitis (the orogenital syndrome). The mucocutaneous lesions are unlike those of pellagra and riboflavin deficiency.

There have been only a few neuropathologic studies of this syndrome. Aside from the changes in the papillomacular bundle of the optic nerve, which are similar to the deficiency amblyopia discussed previously, the most consistent abnormality has been a loss of myelinated fibers in each column of Goll adjacent to the midline. Fisher interpreted this change to indicate a degeneration of the central processes of the bipolar sensory neurons of the dorsal root ganglia (i.e., the dorsal roots). The fact that the primary sensory neuron is the main site of the neuropathic disorder is consistent with the predominantly sensory symptomatology. The present authors find it difficult to draw a sharp dividing line between the nutritional peripheral (and optic) neuropathy described previously and the Strachan syndrome.

"Alcoholic" Cerebellar Degeneration

This term refers to a common and uniform type of degeneration of the vermian and anterior lobes of the cerebellum in alcoholics. Its incidence was in the past about twice that of Wernicke disease, and like the latter, it is considerably more frequent in men than in women. It is characterized clinically by a wide-based stance and gait, varying degrees of instability of the trunk, and ataxia of the legs, the arms being affected to a lesser extent and often not at all. Nystagmus and dysarthria are infrequent. In addition to an ataxic (intention) tremor, there may be a tremor of the fingers or hands resembling 1 of the 2 types of parkinsonian tremor, but appearing only when the limbs are placed in certain sustained postures. Mauritz and coworkers demonstrated that the instability of the trunk in these cases consists of a specific 3-Hz rhythmic swaying in the anteroposterior direction; by contrast, patients with lesions of the cerebellar hemispheres show only slight postural instability without directional preponderance.

In most cases, the cerebellar syndrome evolves over a period of several weeks or months, after which it remains unchanged for many years. In others, it develops more rapidly or more slowly, but in these cases also the disease eventually stabilizes. Occasionally, the cerebellar disorder progresses in a saltatory manner, the symptoms worsening in relation to a severe infectious illness or an attack of delirium tremens.

The pathologic changes consist of a degeneration of all the neurocellular elements of the cerebellar cortex but particularly of the Purkinje cells in the anterior and superior aspects of the vermis. The cerebellar atrophy is readily visualized by CT (Fig. 41-4) and MRI.

Two particular forms of this syndrome have not been emphasized sufficiently. In one, the clinical abnormalities are limited to an instability of station and gait, individual movements of the limbs being unaffected. The pathologic changes in such cases are restricted to the anterosuperior portions of the vermis. A second type is strikingly acute but transient. Here, except for their reversibility, the cerebellar symptoms are identical to those that characterize the chronic, fixed form of the disease. In this transient type, the derangement is only one of function ("biochemical lesion") and has probably not progressed to the point of fixed structural changes. These forms of cerebellar disease, and particularly the restricted and reversible varieties, cannot be distinguished from the cerebellar manifestations of Wernicke disease either on pathologic or on clinical grounds. It is our opinion that the cerebellar ataxia of Wernicke disease and that referred to as alcoholic cerebellar degeneration are based on the same disease process, the former term being applicable when the cerebellar abnormalities are associated with ocular and mental signs and the latter when the cerebellar syndrome stands alone and becomes persistent. Alcoholic cerebellar degeneration is in all likelihood a result of nutritional deficiency and not of the toxic effects of alcohol, for reasons already indicated. Insofar as the cerebellar ataxia usually improves to some extent under the influence of thiamine alone (see earlier, under "Wernicke-Korsakoff Syndrome [Thiamine (B1) Deficiency]"), it is likely that a deficiency of this vitamin is in whole or part responsible for the cerebellar lesion, but this has not been proven.

Marchiafava-Bignami Disease (Degeneration of the Corpus Callosum)

In 1903, the pathologists Marchiafava and Bignami described a unique alteration of the corpus callosum in 3 alcoholic patients. In each case, coronal sectioning of the fixed brain disclosed a pink-gray discoloration of the central portion of the corpus callosum throughout the longitudinal extent of this structure. Microscopically, the lesion proved to be confined to the middle lamina (which makes up about two-thirds of the thickness of the corpus callosum), in which there was a loss of myelin and, to some degree, of the axis cylinders; macrophages were abundant in the altered zone, and astrocytic proliferation had followed. The clinical observations in these patients were few and incomplete. In 1907, Bignami described a case in which the corpus callosum lesion was accompanied by a similar lesion in the central portion of the anterior commissure.

These early reports were followed by a spate of articles that confirmed and amplified the original clinical and pathologic findings. By 1922, about 40 cases of this disorder had been described in the Italian literature (Mingazzini). With 1 exception, all the reported cases were in males, and all these men were insatiable drinkers. They drank red wine for the most part, but other forms of liquor as well. Beginning in 1936, with the report of King and Meehan, the disease came to be recognized throughout the world, and the notions that it had a predilection for drinkers of red wine and a special national predisposition or geographic locale were abandoned. The location of the white matter lesion was later appreciated by MRI to be variable with only a propensity for the corpus callosum.

Pathologic Features

Marchiafava-Bignami disease is more readily defined by its pathologic than its clinical features. The principal alteration, as mentioned, is usually in the middle portion of the corpus callosum, which on gross examination appears rarefied and sunken and reddish or gray-yellow in color, depending on its age. In the anterior portion of the corpus callosum, the lesion tends to be more severe in the midline than in its lateral parts; in the splenium, however, the opposite may pertain. The most chronic lesion takes the form of a centrally placed gray cleft or cavity, with collapse of the surrounding tissue and reduction in thickness of the corpus callosum. Microscopically, corresponding to the gross lesions, one observes clearly demarcated zones of demyelination, with variable involvement of the axis cylinders and an abundance of fatty macrophages with gliosis at the margins. Inflammatory changes are absent.

Infrequently, lesions of a similar nature are found in the central portions of the anterior and posterior commissures and the brachia pontis. These zones of myelin destruction are surrounded by a rim of intact white matter. The predilection of this disease process for commissural fiber systems has been stressed, but it is certainly not confined to these fibers. Symmetrically placed lesions have been observed in the columns of Goll, superior cerebellar peduncles, and cerebral hemispheres, involving the centrum semiovale and extending, in some cases, into the adjacent convolutional white matter. As a rule, the internal capsule and corona radiata, subcortical arcuate fibers, and cerebellum are spared. In several cases, the lesions of deficiency amblyopia (see earlier) have been added; in others, the lesions of Wernicke disease.

Many of the reported cases, as first pointed out by Jequier and Wildi, have involved cortical lesions of a special type: The neurons in the third layer of the frontal and temporal lobe cortices had disappeared and were replaced by a fibrous gliosis. Morel, who first described this cortical laminar sclerosis, did not observe its association with Marchiafava-Bignami disease. However, when Jequier and Adams reviewed his original cases (unpublished), all had Marchiafava-Bignami disease. In a subsequent report by Delay and colleagues comprising 14 cases of cortical laminar sclerosis, the cortical lesion was also consistently associated with a corpus callosum lesion. We believe the cortical lesions are best explained as secondary to the callosal degeneration.

Clinical Features

The disease affects persons in middle and late adult life. With few exceptions, the patients have been males and severe chronic alcoholics. The clinical features of the illness are otherwise quite variable, and a clear-cut syndrome has not emerged. Many patients have presented in a state of terminal stupor or coma, precluding a detailed neurologic assessment. In others, the clinical picture was dominated by the manifestations of chronic inebriation and alcohol withdrawal, namely tremor, seizures, hallucinosis, and delirium tremens. In some of these patients, following the subsidence of the withdrawal symptoms, no signs of neurologic disease could be elicited, even in the end stage of the disease, which lasted for several days to weeks. In yet another group, a progressive dementia has been described, evolving slowly over a year before death. Emotional disorders, dysarthria, slowing and unsteadiness of movement, transient sphincteric incontinence, hemiparesis, and apractic or aphasic disorders have been reported. The last stage of the disease is characterized by physical decline, seizures, stupor, and coma. An impressive feature of these varied neurologic deficits in some patients has been their tendency toward remission when nutrition was restored.

In 2 cases that have come to our attention, the clinical manifestations were essentially those of bilateral frontal lobe disease: motor and mental slowness, apathy, prominent grasping and sucking reflexes, gegenhalten, incontinence, and a slow, hesitant, wide-based gait. In both these cases, the neurologic abnormalities evolved over a period of about 2 months, and both patients recovered within a few weeks of hospitalization. Death occurred several years later as a result of liver disease and subdural hematoma, respectively. In each case, autopsy disclosed an old lesion typical of Marchiafava-Bignami disease confined to the central portion of the most anterior parts of the corpus callosum, but one had to look closely to see the gray line of gliosis.

In view of the great variability of the clinical picture and the obscuration in many patients of subtle mental and neurologic abnormalities by the effects of chronic inebriation and other alcoholic neurologic disorders, the diagnosis of Marchiafava-Bignami disease is understandably difficult. In fact, it is rarely made during life, but the CT and MRI have disclosed typical but unsuspected examples (see Kawamura et al). In some cases studied sequentially, MRI has disclosed demyelination, swelling, and necrosis of the corpus callosum with extension toward the subcortical white matter. In a few cases these findings have reversed over time after vitamin therapy, leaving residual callosal atrophy (Gambini et al). The occurrence, in a chronic alcoholic, of a frontal lobe syndrome or a symptom complex that points to a diagnosis of frontal or corpus callosum tumor but in whom the symptoms remit should suggest the diagnosis of Marchiafava-Bignami disease. The image appearance may be easily mistaken for multiple sclerosis, gliomatosis cerebri, or progressive multifocal leukoencephalopathy.

Pathogenesis and Etiology

Originally, Marchiafava-Bignami disease was attributed to the toxic effects of alcohol, but this is an unlikely explanation in view of the prevalence of alcoholism and the rarity of corpus callosum degeneration. Furthermore, the distinctive callosal lesions have not been observed with other neurotoxins. Very rarely, undoubted examples of Marchiafava-Bignami disease have occurred in abstainers, so that alcohol cannot be an indispensable factor. A nutritional etiology has been invoked, but the putative factor that is deficient has not been determined. This view is underscored by reports of improvement in a few, but not all, cases following administration of thiamine. The mechanisms involved in the selective demyelination and noninflammatory necrosis of particular areas of white matter remain to be elucidated. Perhaps, when its mechanism becomes known, Marchiafava-Bignami disease, like central pontine myelinolysis (which it resembles histologically), will have to be considered in a chapter other than one on nutritional disease.

(See also Chap. 38) There is increasing evidence that severe dietary deprivation during critical phases of brain development may result in permanent impairment of cerebral function and in developmental delay. Inasmuch as there are an estimated 100 million children in the world who are undernourished and suffer from varying degrees of protein, calorie, and other dietary inadequacies, this is one of the most pressing problems in medicine and society.

The literature is too large to review here, but excellent critiques have been provided by Winick, Birch and coworkers, Latham, and Dodge and colleagues. In contrast to the devastating effect of protein-calorie malnutrition (PCM) on body growth, brain weight is only slightly reduced. Nevertheless, on the basis of experiments in dogs, pigs, and rats, it is evident that prenatal and early postnatal malnutrition retards cellular proliferation in the brain. All cells are affected, including oligodendroglia, with a proportional reduction in myelin. Also, the process of dendritic branching may be retarded by early malnutrition. A limited number of studies in humans suggest that PCM has a similar effect on the brain during the first 8 months of life. In animals, varying degrees of recovery from the effects of early malnutrition are possible if normal nutrition is reestablished during the vulnerable periods. Presumably this is true for humans as well, although proof is difficult to obtain. In every series of severely undernourished infants and young children who have been observed for a period of many years, a variable proportion has been developmentally delayed to a modest degree; the majority recovers, however (Galler). Unfortunately, the neurologic and intellectual consequences of PCM have defied accurate assessment because of the difficulty of isolating the effects of severe malnutrition from those of infection, social deprivation, genetic mechanisms, and other factors.

Nutritional Deficiencies Secondary to Malabsorption

The vitamins known to be essential to the normal functioning of the central and peripheral nervous systems cannot be synthesized by the human organism. Each is ingested as an essential part of the normal diet and absorbed in certain regions of the gastrointestinal tract. Impairment or failure of absorption caused by diseases of the gastrointestinal tract gives rise to several malabsorption syndromes, some of which have already been referred to, for example, malabsorptive vitamin E deficiency. In these diseases, the site of the block in transport from the intestinal lumen varies; it may be at the surface of the enterocytes or at their interface with the lymphatic channels and portal capillaries.

Table 41-2, which is modified from Pallis and Lewis, lists the main malabsorptive diseases and their relationships to the intestinal abnormalities. Of all these diseases, celiac sprue (gluten enteropathy) is the most common. The neurologic complications of this disorder, in our experience, have taken the form of a symmetrical, predominantly sensory polyneuropathy, as described in Chap. 46. However, other complications have been described, notably a progressive cerebellar syndrome with cortical, dentatal, and olivary cell loss. The cerebellar changes may be coupled with a symmetrical demyelination of the posterior columns, producing a spinocerebellar disorder similar to that of vitamin E deficiency, but in the latter case, vitamin E supplementation has no consistent effect. Others have remarked on a high incidence of depression and other psychiatric disturbances in adult patients with celiac sprue, as also discussed in Chap. 40. Unexplained seizures are also said to occur.

Polyneuropathy and SCD of the spinal cord manifesting themselves many years after gastrectomy are encountered only rarely. The neurology of gastrointestinal disease has also been reviewed by Perkin and Murray-Lyon.

(See Table 41-3 and Chap. 37)

Although humans lack the capacity to synthesize essential vitamin molecules, they are nonetheless able to use them in a series of complex chemical reactions involved in intestinal absorption, transport in the plasma, entry into the organelles of many organs, activation of the vitamin into coenzyme, and, finally, their interaction with certain specific apoenzyme proteins. This compels consideration of another aspect of nutrition wherein one or more of these steps in vitamin utilization may be defective because of a genetic abnormality. Under these circumstances, the signs of vitamin deficiency result not from vitamin deficiency in the diet but from a genetically deranged control mechanism. In some instances the defect is only quantitative, and by loading the organism with a great excess of the vitamin in question, the biochemical abnormality can be overcome. The aforementioned special type of vitamin E deficiency that results from an inherited inability to incorporate the vitamin into lipoproteins falls into this category, the diseases of which, being of hereditary type, have already been described in Chap. 37. Rosenberg has listed the most important of these hereditary vitamin-responsive diseases, which we have abstracted for the reader in Table 41-3.