Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 affected individuals 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 pyridoxineand pantothenic acid-deficient swine, and Vilter and colleagues produced polyneuropathy in human subjects rendered pyridoxine deficient; these


Neurology_Adams

Neurology_Adams. degeneration of the peripheral nerves in pyridoxineand 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.


Neurology_Adams

Neurology_Adams. 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. 36). 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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. 15.


Neurology_Adams

Neurology_Adams. A pyridoxine-responsive seizure disorder (pyridoxine dependency) of the neonatal period is discussed in Chap. 15. 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. 15. Lifelong supplementation is required after the seizures are aborted with a large intravenous dose of the vitamin.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 the folate antagonist methotrexate is the underlying cause, supplemental folinic acid (leukovorin, citrovorum factor) is given orally. 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.


Neurology_Adams

Neurology_Adams. The spinal cord, brain, optic nerves, and peripheral nerves are all affected by vitamin B12 (cobalamin) deficiency, giving rise to a classic neurologic syndrome in which 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. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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).


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 reported by some patients but is 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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. 40-3. 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.


Neurology_Adams

Neurology_Adams. 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 HIV myelopathy 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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”).


Neurology_Adams

Neurology_Adams. 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;


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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 by Beck (1988).


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. The main differential diagnostic considerations of the combined sensory and motor features are cervical spondylosis (see Chaps. 10 and 42), multiple sclerosis of the cervical cord (see Chap. 35), non-B12-deficient combined system disease caused by low levels of serum copper (see Chap. 42), and rarities such as the female carrier state of adrenoleukodystrophy (see Chap. 36). The myelopathy associated with copper deficiency 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. 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 in which


Neurology_Adams

Neurology_Adams. 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 in which nitrous oxide was used as anesthesia.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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. 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 given excessive doses of the vitamin because the repletion of cobalamin tissue stores is a function of the dose.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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.


Neurology_Adams

Neurology_Adams. 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;


Neurology_Adams

Neurology_Adams. Satya-Murti et al). The same mechanism has been proposed to explain the neurologic disorders that sometimes complicate abetalipoproteinemia (see Chap. 36), fibrocystic disease (Sokol et al), celiac sprue disease, and extensive intestinal resections, intrinsic bowel syndromes, or cholestatic liver disease that cause malabsorption, even decades after the onset of surgery or of the medical disorder (Harding et al). Vitamin E deficiency has also been observed in young children with chronic cholestatic hepatobiliary disease (Rosenblum et al).


Neurology_Adams

Neurology_Adams. 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.


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Neurology_Adams. In addition to abetalipoproteinemia, there exists 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. 38). 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. The mutations and clinical manifestations have been variable, as pointed out in a study of 41 patients in 27 families carried out by Cavalier and colleagues. The age of onset ranged from 2 to 52


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Neurology_Adams. The mutations and clinical manifestations have been variable, as pointed out in a study of 41 patients in 27 families carried out by Cavalier and colleagues. The age of onset ranged from 2 to 52 year, but generally before age 20. Unexpected features such as head titubation and dystonia occurred in some cases but unlike Friedreich ataxia, cardiomyopathy was rare. 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).


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Neurology_Adams. 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 may provoke the syndrome of intracranial hypertension, or pseudotumor cerebri (see Chap. 29). 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.


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Neurology_Adams. 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.


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Neurology_Adams. 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. 42). A chronic tropical disease of the peripheral nerves, called “ataxic neuropathy of Nigeria,” has been attributed to the ingestion of inadequately detoxified cassava (Osuntokun) that contains cyanide. 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. 12)


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Neurology_Adams. 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


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Neurology_Adams. 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.


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Neurology_Adams. 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.


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Neurology_Adams. 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 strongly suggests that so-called tobacco–alcohol amblyopia is more likely caused by nutritional deficiency than 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


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Neurology_Adams. 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. The pathology of the optic nerve in amblyopia in the alcoholic has been described by Victor and colleagues (1960).


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Neurology_Adams. 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.


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Neurology_Adams. Recent outbreaks of an apparently nutritional or perhaps toxic optic neuropathy occurred in Cuba during the period of 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.


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Neurology_Adams. 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


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Neurology_Adams. 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


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Far East.

Neurology_Adams. Far East.


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Neurology_Adams. 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.


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Neurology_Adams. 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. We find it difficult to draw a sharp dividing line between the nutritional peripheral (and optic) neuropathy described previously and the Strachan syndrome.


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Neurology_Adams. 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


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Neurology_Adams. 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.


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Neurology_Adams. 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. 40-4) and MRI.


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Neurology_Adams. 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 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


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Neurology_Adams. 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.


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Neurology_Adams. 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.


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Neurology_Adams. 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.


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Neurology_Adams. 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.


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Neurology_Adams. 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.


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Neurology_Adams. 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.


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Neurology_Adams. 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


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Neurology_Adams. 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.


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Neurology_Adams. 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.


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Neurology_Adams. 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


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Neurology_Adams. 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.


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Neurology_Adams. 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


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Neurology_Adams. 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.


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Neurology_Adams. PROTEIN-CALORIE MALNUTRITION AND DEVELOPMENTAL DELAY (SEE ALSO CHAP. 37) 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. Because 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.


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Neurology_Adams. The literature is too large to review here, but excellent critiques have been provided by Winick, Birchfield and coworkers, Latham, and Dodge and colleagues. In contrast to the devastating effect of protein-calorie malnutrition 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 protein-calorie malnutrition 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


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Neurology_Adams. 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 protein-calorie malnutrition 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.


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Neurology_Adams. 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.


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Neurology_Adams. Table 40-2, 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. 43. 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. 39. Unexplained seizures are also said to occur.


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Neurology_Adams. 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. INHERITED VITAMIN-RESPONSIVE NEUROLOGIC DISEASES (SEE TABLE 40-3 AND CHAP. 36)


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Neurology_Adams. 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


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Neurology_Adams. 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. 36. Rosenberg has listed the most important of these hereditary vitamin- responsive diseases, which we have abstracted for the reader in Table 40-3.


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Neurology_Adams. Adams RD, Kubik CS: Subacute degeneration of the brain in pernicious anemia. N Engl J Med 231:2, 1944. Agamanolis DP, Victor M, Harris JW, et al: An ultrastructural study of subacute combined degeneration of the spinal cord in vitamin B12 deficient rhesus monkeys. J Neuropathol Exp Neurol 37:273, 1978. Albin RL, Albers JW, Greenberg HS, et al: Acute sensory neuropathy- neuronopathy from pyridoxine overdosage. Neurology 37:1729, 1987. Allen RH, Stabler SP, Savage DG, Lindenbaum J: Diagnosis of cobalamin deficiencies: I. Usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Hematol 34:90, 1990. Amess JAL, Burman JF, Nancekievill DG, Mollin DL: Megaloblastic haemopoiesis in patients receiving nitrous oxide. Lancet 2:339, 1978. Antozzi C, Garavaglia B, Mora M, et al: Late-onset riboflavin-responsive myopathy with combined multiple acyl coenzyme A dehydrogenase and respiratory chain deficiency. Neurology 44:2153, 1994.


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Neurology_Adams. Antozzi C, Garavaglia B, Mora M, et al: Late-onset riboflavin-responsive myopathy with combined multiple acyl coenzyme A dehydrogenase and respiratory chain deficiency. Neurology 44:2153, 1994. Bean WB, Hodges RE, Daum KE: Pantothenic acid deficiency induced in human subjects. J Clin Invest 34:1073, 1955. Beck WS: Cobalamin and the nervous system. N Engl J Med 318:1752, 1988. Behse F, Buchthal F: Alcoholic neuropathy: Clinical, electrophysiological, and biopsy findings. Ann Neurol 2:95, 1977. Biehl JP, Vilter RW: The effect of isoniazid on vitamin B6 metabolism and its possible significance in producing isoniazid neuritis. Proc Soc Exp Biol Med 85:389, 1954. Bignami A: Sulle alterazione del corpo calloso e della commissura anteriore ritrovate in un alcoolista. Policlinico [Prat] 14:460, 1907. Birchfield RE: Postural hypotension in Wernicke’s disease: A manifestation of autonomic nervous system involvement. Am J Med 36:404, 1964.


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Neurology_Adams. Birchfield RE: Postural hypotension in Wernicke’s disease: A manifestation of autonomic nervous system involvement. Am J Med 36:404, 1964. Bomb BS, Bedi HK, Bhatnagar LK: Post-ischaemic paresthesiae in pellagrins. J Neurol Neurosurg Psychiatry 40:265, 1977. Botez MI, Peyronnard J, Charron L: Polyneuropathies responsive to folic acid therapy. In: Botez MI, Reynolds EH (eds): Folic Acid in Neurology, Psychiatry, and Internal Medicine. New York, Raven Press, 1979, pp 401–412. Carmel R: Subtle and atypical cobalamin deficiency states. Am J Hematol 34:108, 1990. Carmel R, Watkins D, Goodman SI, Rosenblatt DS: Hereditary defect of cobalamin metabolism (cb1G mutation) presenting as a neurologic disorder in adulthood. N Engl J Med 318:1738, 1988. Carney MWP: Neuropsychiatric disorders associated with nutritional deficiencies. CNS Drugs 3:279, 1995.


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Neurology_Adams. Carney MWP: Neuropsychiatric disorders associated with nutritional deficiencies. CNS Drugs 3:279, 1995. Cavalier L, Ouachi K, Kayden H, et al: Ataxia with isolated vitamin E deficiency: Heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet 62:301, 1998. Centers for Disease Control and Prevention: Epidemic neuropathy—Cuba, 1991–1994. MMWR Morb Mortal Wkly Rep 43:183, 189, 1994. Charness ME, DeLaPaz RL: Mamillary body atrophy in Wernicke’s encephalopathy: Antemortem identification using magnetic resonance imaging. Ann Neurol 22:595, 1987. Clayton PT, Smith I, Harding B, et al: Subacute combined degeneration of the cord, dementia, and parkinsonism due to an inborn error of metabolism. J Neurol Neurosurg Psychiatry 49:920, 1986. Crellin R, Bottiglieri T, Reynolds EH: Folate and psychiatric disorder: Clinical potential. Drugs 45:623, 1993.


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Neurology_Adams. Crellin R, Bottiglieri T, Reynolds EH: Folate and psychiatric disorder: Clinical potential. Drugs 45:623, 1993. Cuba Neuropathy Field Investigation Team: Epidemic optic neuropathy in Cuba—clinical characterization and risk factors. N Engl J Med 333:1176, 1995. Delay J, Brion S, Escourolle R, Sanchez A: Rapports entre la degenerescence du corps calleux de Marchiafava-Bignami et la sclerose laminaire corticale de Morel. Encephale 49:281, 1959. Denny-Brown DE: The neurological aspects of thiamine deficiency. Fed Proc 17(Suppl 2):35, 1958. Dodge PR, Prensky AL, Feigin R: Nutrition and the Developing Nervous System. St. Louis, Mosby, 1975. Donnal JF, Heinz ER, Burger PC: MR of reversible thalamic lesions in Wernicke syndrome. AJNR Am J Neuroradiol 11:893, 1990. Elvehjem CA, Madden RJ, Strong FM, Woolley DW: Relation of nicotinic acid and nicotinic acid amide to canine black tongue. J Am Chem Soc 59:1767, 1937.


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Neurology_Adams. Elvehjem CA, Madden RJ, Strong FM, Woolley DW: Relation of nicotinic acid and nicotinic acid amide to canine black tongue. J Am Chem Soc 59:1767, 1937. Fine EJ, Hallett M: Neurophysiological study of subacute combined degeneration. J Neurol Sci 45:331, 1980. Fisher CM: Residual neuropathological changes in Canadians held prisoners of war by the Japanese. Can Serv Med J 11:157, 1955. Gabsi S, Gouider-Khouja N, Belal S, et al: Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency. Eur J Neurol 8:477, 2001. Galler JR: Malnutrition—a neglected cause of learning failure. Postgrad Med 80:225, 1986. Gambini A, Falini A, Moiola L, et al: Marchiafava-Bignami disease: Longitudinal MR imaging and MR spectroscopy study. AJNR Am J Neuroradiol 24:249, 2003. Ghez C: Vestibular paresis: A clinical feature of Wernicke’s disease. J Neurol Neurosurg Psychiatry 32:134, 1969.


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Neurology_Adams. Ghez C: Vestibular paresis: A clinical feature of Wernicke’s disease. J Neurol Neurosurg Psychiatry 32:134, 1969. Goldsmith GA: Niacin-tryptophan relationships in man and niacin requirement. Am J Clin Nutr 6:479, 1958. Gotoda T, Arita M, Arai H, et al: Adult-onset spinocerebellar dysfunction caused by a mutation in the gene for the a-tocopherol-transfer protein. N Engl J Med 333:1313, 1995. Harding AE, Mathews S, Jones S, et al: Spinocerebellar degeneration associated with a selective defect of vitamin E absorption. N Engl J Med 313:32, 1985. Harper C: The incidence of Wernicke’s encephalopathy in Australia—a neuropathological study of 131 cases. J Neurol Neurosurg Psychiatry 46:593, 1983. Harper CG, Giles M, Finlay-Jones R: Clinical signs in the Wernicke-Korsakoff complex: A retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry 49:341, 1986.


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Neurology_Adams. Harper CG, Giles M, Finlay-Jones R: Clinical signs in the Wernicke-Korsakoff complex: A retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry 49:341, 1986. Hemmer B, Glocker FX, Schumacher M, et al: Subacute combined degeneration: Clinical, electrophysiologic, and magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry 65:822, 1998. Ishii N, Nishihara Y: Pellagra among chronic alcoholics: Clinical and pathological study of 20 necropsy cases. J Neurol Neurosurg Psychiatry 44:209, 1981. Jequier M, Wildi E: Le syndrome de Marchiafava-Bignami. Schweiz Arch Neurol Psychiatr 77:393, 1956. Jolliffe N, Bowman KM, Rosenblum LA, Fein HD: Nicotinic acid deficiency encephalopathy. JAMA 114:307, 1940. Kawamura M, Shiota J, Yagishita T, Hirayama K: Marchiafava-Bignami disease: Computed tomographic scan and magnetic resonance imaging. Ann Neurol 18:103, 1985.


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Neurology_Adams. Kawamura M, Shiota J, Yagishita T, Hirayama K: Marchiafava-Bignami disease: Computed tomographic scan and magnetic resonance imaging. Ann Neurol 18:103, 1985. King LS, Meehan MC: Primary degeneration of the corpus callosum (Marchiafava’s disease). Arch Neurol Psychiatry 36:547, 1936. Kinsella LJ, Green R: “Anesthesia paresthetica”: Nitrous oxide-induced cobalamin deficiency. Neurology 45:1608, 1995. Koike H, Iijima M, Sugiura M, et al: Alcoholic neuropathy is clinicopathologically distinct from thiamine-deficiency neuropathy. Ann Neurol 54:19, 2003. Latham MC: Protein-calorie malnutrition in children and its relation to psychological development and behavior. Physiol Rev 54:541, 1974. Layzer RB: Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet 2:1227, 1978. Lindenbaum J, Healton EB, Savage DG, et al: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 318:1720, 1988.


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Neurology_Adams. Lindenbaum J, Healton EB, Savage DG, et al: Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 318:1720, 1988. Mair RG, Capra C, McEntee WJ, Engen T: Odor discrimination and memory in Korsakoff’s psychosis. J Exp Psychol 6:445, 1980. Mandel H, Bernat M, Hazani A, Naveh Y: Thiamine-dependent beriberi in the thalamic-responsive anemia syndrome. N Engl J Med 311:836, 1984. Marchiafava E, Bignami A: Sopra un alterazione del corpo calloso osservata in soggetti alcoolisti. Riv Patol Nerv Ment 8:544, 1903. Mauritz KH, Dichgans J, Hufschmidt A: Quantitative analysis of stance in late cortical cerebellar atrophy of the anterior lobe and other forms of cerebellar ataxia. Brain 102:461, 1979. Mingazzini G: Der Balken. Berlin, Springer-Verlag, 1922. Morel F: Une forme anatomo-clinique particuliere de l’alcoolisme chronique: Sclerose corticale laminaire alcoolique. Rev Neurol 71:280, 1939.


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Neurology_Adams. Morel F: Une forme anatomo-clinique particuliere de l’alcoolisme chronique: Sclerose corticale laminaire alcoolique. Rev Neurol 71:280, 1939. Muller DPR, Lloyd JK, Wolff OH: Vitamin E and neurological function. Lancet 1:225, 1983. Nelson JS, Fitch CD, Fisher VW, et al: Progressive neuropathologic lesions in vitamin E deficient rhesus monkey. J Neuropathol Exp Neurol 40:166, 1981. Osuntokun BO: Cassava diet, chronic cyanide intoxication and neuropathy in the Nigerian Africans. World Rev Nutr Diet 36:141, 1981. Pallis CA, Lewis PD: The Neurology of Gastrointestinal Disease. Philadelphia, Saunders, 1974. Perkin CD, Murray-Lyon I: Neurology and the gastrointestinal system. J Neurol Neurosurg Psychiatry 65:291, 1998. Pincus JH: Folic acid deficiency: A cause of subacute combined system degeneration. In: Botez MI, Reynolds EH (eds): Folic Acid in Neurology, Psychiatry, and Internal Medicine. New York, Raven Press, 1979, pp 427–433.


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Neurology_Adams. New York, Raven Press, 1979, pp 427–433. Plant GT, Mtanda AT, Arden GB, Johnson GJ: An epidemic of optic neuropathy in Tanzania: Characterization of the visual disorder and associated peripheral neuropathy. J Neurol Sci 145:127, 1997. Ronthal M, Adler H: Motor nerve conduction velocity and the electromyograph in pellagra. S Afr Med J 43:642, 1969. Rosenberg LE: Vitamin-responsive inherited diseases affecting the nervous system. In: Plum F (ed): Brain Dysfunction in Metabolic Disorders. Vol 53. New York, Raven Press, 1974, pp 263–270. Rosenblum JL, Keating JP, Prensky AL, Nelson JS: A progressive neurologic syndrome in children with chronic liver disease. N Engl J Med 304:503, 1981. Satya-Murti S, Howard L, Krohel G, Wolf B: The spectrum of neurologic disorder from vitamin E deficiency. Neurology 36:917, 1986. Schaumburg H, Kaplan J, Windebank A, et al: Sensory neuropathy from pyridoxine abuse: A new megavitamin syndrome. N Engl J Med 309:445, 1983.


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Neurology_Adams. Schaumburg H, Kaplan J, Windebank A, et al: Sensory neuropathy from pyridoxine abuse: A new megavitamin syndrome. N Engl J Med 309:445, 1983. Sechi G, Serra A: Wernicke’s encephalopathy: New clinical settings and recent advances in diagnosis and management. Lancet Neurol 6:442, 2007. Serdaru M, Hausser-Hauw C, Laplane D, et al: The clinical spectrum of alcoholic pellagra encephalopathy. Brain 111:829, 1988. Shah DR, Singh SV, Jain IL: Neurological manifestations in pellagra. J Assoc Physicians India 19:443, 1971. Shattuck GC: Relation of beriberi to polyneuritis from other causes. Am J Trop Med Hyg 8:539, 1928. Shimojyo S, Scheinberg P, Reinmuth OM: Cerebral blood flow and metabolism in the Wernicke-Korsakoff syndrome. J Clin Invest 46:849, 1967. Sokol RJ, Butler-Simon N, Neubi JE, et al: Vitamin E deficiency neuropathy in children with fat malabsorption: Studies in cystic fibrosis and chronic cholestasis. Ann N Y Acad Sci 570:156, 1989.


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Neurology_Adams. Sokol RJ, Butler-Simon N, Neubi JE, et al: Vitamin E deficiency neuropathy in children with fat malabsorption: Studies in cystic fibrosis and chronic cholestasis. Ann N Y Acad Sci 570:156, 1989. Spillane JD: Nutritional Disorders of the Nervous System. Baltimore, Lippincott Williams & Wilkins, 1947. Spivak JL, Jackson DL: Pellagra: An analysis of 18 patients and a review of the literature. Johns Hopkins Med J 140:295, 1977. Strachan H: On a form of multiple neuritis prevalent in the West Indies. Practitioner 59:477, 1897. Strauss MB: Etiology of “alcoholic” polyneuritis. Am J Med Sci 189:378, 1935. Swank RL, Adams RD: Pyridoxine and pantothenic acid deficiency in swine. J Neuropathol Exp Neurol 7:274, 1948. Sydenstricker VP, Schmidt HL Jr, Fulton MC, et al: Treatment of pellagra with nicotinic acid: Observations in 45 cases. South Med J 31:1155, 1938.


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Neurology_Adams. Sydenstricker VP, Schmidt HL Jr, Fulton MC, et al: Treatment of pellagra with nicotinic acid: Observations in 45 cases. South Med J 31:1155, 1938. Thomson AD, Cook CC, Touquet R, et al: The Royal College of Physicians report on alcohol: Guidelines for managing Wernicke’s encephalopathy in the accident and emergency department. Alcohol Alcohol 37:513, 2002. Torvik A, Lindboe CF, Rogde S: Brain lesions in alcoholics: A neuropathological study with clinical correlations. J Neurol Neurosurg Psychiatry 56:233, 1982. Traber MG, Sokol RJ, Burton GW, et al: Impaired ability of patients with familial isolated vitamin E deficiency to incorporate a-tocopherol into lipoproteins secreted by the liver. J Clin Invest 85:397, 1990. Varnet O, De Seze J, Soto-Ares G, et al: Encéphalopathie de Gayet-Wernicke: Intérêt diagnostique et pronostique de l’Imagerie par Résonance Magnétique. Rev Neurol 158:1181, 2002.


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Neurology_Adams. Varnet O, De Seze J, Soto-Ares G, et al: Encéphalopathie de Gayet-Wernicke: Intérêt diagnostique et pronostique de l’Imagerie par Résonance Magnétique. Rev Neurol 158:1181, 2002. Victor M: MR in the diagnosis of Wernicke-Korsakoff syndrome. AJNR Am J Neuroradiol 11:895, 1990. Victor M: Polyneuropathy due to nutritional deficiency and alcoholism. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R (eds): Peripheral Neuropathy, 2nd ed. Philadelphia, Saunders, 1984, pp 1899–1940. Victor M: Tobacco amblyopia, cyanide poisoning and vitamin B12 deficiency: A critique of current concepts. In: Smith JL (ed): Miami Neuro-ophthalmology Symposium. Vol 5. Hallandale, FL, Huffman, 1970, pp 33–48. Victor M, Adams RD: Neuropathology of experimental vitamin B6 deficiency in monkeys. Am J Clin Nutr 4:346, 1956. Victor M, Adams RD: On the etiology of the alcoholic neurologic diseases with special reference to the role of nutrition. Am J Clin Nutr 9:379, 1961.


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Neurology_Adams. Victor M, Adams RD: On the etiology of the alcoholic neurologic diseases with special reference to the role of nutrition. Am J Clin Nutr 9:379, 1961. Victor M, Adams RD, Collins GH: The Wernicke-Korsakoff Syndrome and Related Neurologic Disorders due to Alcoholism and Malnutrition, 2nd ed. Philadelphia, Davis, 1989. Victor M, Adams RD, Mancall EL: A restricted form of cerebellar degeneration occurring in alcoholic patients. Arch Neurol 1:577, 1959. Victor M, Mancall EL, Dreyfus PM: Deficiency amblyopia in the alcoholic patient: A clinicopathologic study. Arch Ophthalmol 64:1, 1960. Victor M, Yakovlev PI: S.S. Korsakoff’s psychic disorder in conjunction with peripheral neuritis: A translation of Korsakoff’s original article with brief comments on the author and his contribution to clinical medicine. Neurology 5:394, 1955. Vilter RW, Mueller JF, Glazer HS, et al: The effect of vitamin B6 deficiency induced by deoxypyridoxine in human beings. J Lab Clin Med 42:335, 1953.


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Neurology_Adams. Vilter RW, Mueller JF, Glazer HS, et al: The effect of vitamin B6 deficiency induced by deoxypyridoxine in human beings. J Lab Clin Med 42:335, 1953. Weidauer S, Nichtweiss M, Lanfermann H, et al: Wernicke’s encephalopathy: MR findings and clinical presentation. Eur Radiol 13:1001, 2003. Windebank AJ: Polyneuropathy due to nutritional deficiency and alcoholism. In: Dyck PJ, Thomas PK, et al (eds): Peripheral Neuropathy, 3rd ed. Philadelphia, Saunders, 1993, pp 1310–1321. Wrenn KD, Murphy F, Slovis CM: A toxicity study of parenteral thiamine hydrochloride. Ann Emerg Med 18:867, 1989. Figure 40-1. Clinical features of Wernicke-Korsakoff disease in a series of 131 autopsy proved cases. (Reprinted with permission from Harper CG, Giles M, Finlay-Jones R: J Neurol Neurosurg Psychiatry 49:341–345, 1986.) Figure 40-2. Axial T1-postgadolinium image of a 63-year-old woman with Wernicke encephalopathy showing abnormal enhancement of the mammillary bodies (arrow).


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Neurology_Adams. Figure 40-2. Axial T1-postgadolinium image of a 63-year-old woman with Wernicke encephalopathy showing abnormal enhancement of the mammillary bodies (arrow). Figure 40-3. Sagittal (left image) and axial (right image) T2 MRI of the cervical spine in subacute combined degeneration (SCD) showing abnormal hyperintensity in the posterior columns. The patient had markedly reduced vibration and position sense and a Romberg sign; the tendon reflexes were preserved and there were no corticospinal tract or peripheral nerve signs. Figure 40-4. Axial CT from a 60-year-old alcoholic patient showing prominence of midline cerebellar sulci (upper image). A broad-based gait and ataxia of the legs had been present for many years. Death was from myocardial infarction. The cerebellum, cut in the midsagittal plane (lower image), shows folial atrophy of the anterosuperior vermis, characteristic of alcoholic cerebellar degeneration.


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Neurology_Adams. Chapter 40 Diseases of the Nervous System Caused by Nutritional Deficiency Eye movementabnormalities (2.1%)Ataxia (1.0%)Confusion (34%)Confusion/ataxia(17.5%)Eye movementabnormalities/confusion (8.2%)Eye movementabnormalities/ataxia (2.1%)97 casesOne sign(37.1%)Two signs(27.8%)No signs(18.6%)Three signsClassic triad(16.5%)No signs(18.6%)One sign(37.1%)Two signs(27.8%) Disorders of the Nervous System Caused by Alcohol, Drugs, Toxins, and Chemical Agents


Neurology_Adams

Neurology_Adams. Disorders of the Nervous System Caused by Alcohol, Drugs, Toxins, and Chemical Agents Subsumed under this title is a diverse group of disorders of the nervous system that result from alcohol, drugs, and other injurious or poisonous substances. The neurologist must be concerned with the myriad of chemical agents that may adversely affect the nervous system; they abound in the environment as household products, insecticides, industrial solvents, and other poisons, as well as substances that may have therapeutic value but are used for their “recreational” psychotropic effects, or are conventional medications with known toxic effects. Also among the neurotoxins are those generated by bacteria and other infectious organisms, as well as toxins found in nature, such as marine toxins. Together, the effect of these agents and toxins on the nervous system constitutes the field of neurotoxicology.


Neurology_Adams

Neurology_Adams. It would hardly be possible within one chapter to discuss the innumerable drugs and toxins that affect the nervous system. The interested reader is referred to a number of comprehensive monographs and references such as Casarett and Doull’s Toxicology, edited by Klaassen and Occupational Neurology edited by Lotti and Bleecker. In addition, a current handbook of pharmacology and toxicology is a useful part of the library of every physician. The scope of this chapter is also limited because the therapeutic and adverse effects of many drugs are considered elsewhere in this volume in relation to particular symptoms and diseases. Thus, the adverse effects of antibiotics on cochlear and vestibular function and on neuromuscular transmission are discussed in Chaps. 14 and 46, respectively. Many of the undesirable side effects of the common drugs used in the treatment of extrapyramidal motor symptoms, pain, headache, seizure, sleep disorders, psychiatric illnesses, and so forth are also


Neurology_Adams

Neurology_Adams. Many of the undesirable side effects of the common drugs used in the treatment of extrapyramidal motor symptoms, pain, headache, seizure, sleep disorders, psychiatric illnesses, and so forth are also considered in the chapters dealing with each of these disorders and in the chapters that cover psychiatric diseases. Cyanide and carbon monoxide poisoning are discussed in relation to anoxic encephalopathy (see Chap. 39). A number of therapeutic agents that predictably damage the peripheral nerves (e.g., cisplatin, disulfiram, vincristine) are mentioned in this chapter but are discussed further in Chap. 43, and those that affect muscle are included in Chap. 45.


Neurology_Adams

Neurology_Adams. The presentation of this subject is introduced by some general remarks on the action of drugs on the nervous system and is followed by discussion of the main classes of agents that affect nervous function: 1. Alcohol and alcoholism 2. Opiates and synthetic analgesic drugs 3. Sedative-hypnotic drugs 4. Antipsychosis drugs 5. Antidepressant drugs 6. Stimulants 7. Psychoactive drugs and hallucinogens 8. Bacterial toxins 9. Plant poisons venoms, bites, and stings 10. Heavy metals and industrial toxins 11. Antineoplastic and immunosuppressive agents 12. Antibiotics The rational use of any drug requires knowledge of the best route of administration, the drug’s absorption characteristics, its distribution in the nervous system and other organs, and its biotransformations and excretion (pharmacokinetics). Because every drug, if given in excess, has some adverse effects, therapeutics and toxicology are inseparable.


Neurology_Adams

Neurology_Adams. All systems of neurons are not identical; each has its own vulnerabilities to particular drugs and toxic agents. This principle, originally enunciated by Oskar and Cecile Vogt in their theory termed pathoclisis is now embodied as “selective vulnerability.” For example, selective vulnerability explains the production of parkinsonism by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in which a synthetic toxin affects a progressive loss of melanin- bearing dopaminergic nigral neurons (see Chap. 38). Another example is the preferential effects of anesthetics on the neurons of the upper brainstem reticular formation. Not only may certain groups of nerve cells be selectively destroyed by a particular agent, but particular parts of their structure may be altered as well. Drugs may be targeted even to the terminal axons, dendrites, neurofilaments, or receptors on preand postsynaptic surfaces of neurons or to certain of their metabolic activities, whereby they synthesize


Neurology_Adams

Neurology_Adams. may be targeted even to the terminal axons, dendrites, neurofilaments, or receptors on preand postsynaptic surfaces of neurons or to certain of their metabolic activities, whereby they synthesize and release neurotransmitters or maintain their cellular integrity by the synthesis of RNA, DNA, and other proteins. An intriguing extension of this theme relates to the manner in which certain drugs or toxins affect individuals differently with a genetic disposition by way of single nucleotide polymorphisms; this is the field of pharmacogenetics.


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Neurology_Adams. The same mechanisms by which drugs and toxins act on particular steps in the formation, storage, release, uptake, catabolism, and resynthesis of neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine, and other catecholamines cannot be separated from their toxic effects. Johnston and Gross have summarized views of how these transmitters and modulating agents, by attaching to receptors at neuronal synapses, are able to increase or decrease the permeability of ion channels and stimulate or inhibit second cytoplasmic messengers (cyclic adenosine monophosphate [cAMP] and G-proteins). For example, drugs such as l-dopa, tryptophan, and choline enhance the synthesis of dopamine, serotonin, and acetylcholine, respectively, and may impart toxic effects through these same mechanisms. Baclofen modulates the release of gamma-aminobutyric acid (GABA), the main inhibitory transmitter in the central nervous system. Botulinum toxin prevents the release of acetylcholine in the


Neurology_Adams

Neurology_Adams. Baclofen modulates the release of gamma-aminobutyric acid (GABA), the main inhibitory transmitter in the central nervous system. Botulinum toxin prevents the release of acetylcholine in the neuromuscular junction and tetanus toxin does the same on GABA in Renshaw cells of the spinal cord. Benzodiazepines, bromocriptine, and methylphenidate are viewed as receptor agonists; the phenothiazines and anticholinergics act as receptor antagonists. Certain drugs enhance the activity of neurotransmitters by inhibiting their reuptake as, for example, the class of antidepressant drugs that has a relatively selective influence on the reuptake of serotonin. Others deplete existing neurotransmitters, and another class of drugs promotes the release of preformed synaptic transmitters; amphetamines and modafinil are examples in this class. Amantadine, an antiviral agent, may promote the release of dopamine. One must not assume that these are the exclusive modes of action of each of these drugs; for


Neurology_Adams

Neurology_Adams. modafinil are examples in this class. Amantadine, an antiviral agent, may promote the release of dopamine. One must not assume that these are the exclusive modes of action of each of these drugs; for example, cocaine acts as a direct stimulant and through the inhibition of reuptake of catecholamines.


Neurology_Adams

Neurology_Adams. A majority of drugs that act on the nervous system are ingested; factors that govern their intestinal absorption must therefore be taken into account. Small molecules usually enter the plasma by diffusion, larger ones by pinocytosis. The substances with which the drugs are mixed; the presence of food, other drugs, or intestinal diseases; and the age of the patient all influence the rate of absorption and blood concentrations. Different calculations are necessary for intramuscular, subcutaneous, and intrathecal routes of administration. To some extent, the solubilities of drugs (in lipid or water) determine the routes by which they can be given; some drugs, such as morphine, can be administered by numerous routes. Carried in the blood, the drug (or toxin) reaches many tissues, including the nervous system; protein binding in the plasma has an important influence on distribution. Many drugs and toxic substances bind to serum albumin and other serum proteins, limiting the availability of


Neurology_Adams

Neurology_Adams. nervous system; protein binding in the plasma has an important influence on distribution. Many drugs and toxic substances bind to serum albumin and other serum proteins, limiting the availability of the ionized form. The common drug and toxin transformations involve hydroxylation, deamination, oxidation, and dealkylation, which enhance their solubility and elimination mainly by the kidneys. Most of these catalytic processes occur in liver cells and utilize multiple enzymes.


Neurology_Adams

Neurology_Adams. To enter the extracellular compartment of the nervous system, a drug or toxic agent must transgress the tight capillary–endothelial barrier (blood–brain barrier) and the barrier between the blood and cerebrospinal fluid (blood–CSF barrier). Intrathecal injection circumvents these barriers, but then the agent tends to concentrate in the immediate subpial and subependymal regions. The process of movement from plasma to brain is by diffusion through capillaries or by facilitated transport. The solubility characteristics of the drug determine its rate of diffusion.


Neurology_Adams

Neurology_Adams. In the following discussion on neurotoxins, the reader will appreciate a number of phenomena: tolerance (lessening effect of increasing dose), dependence and addiction (insatiable need), habituation, drug-seeking behaviors, and abstinence with its associated withdrawal effects. Particularly difficult in reference to drugs such as nicotine is the separation of habituation from addiction, that is, of psychologic dependence from physical dependence (see further on). The few examples given earlier are intended to provide a glimpse of the complex interactions between chemical agents and the cells of the nervous system. For more specific information, the reader is referred to The Biochemical Basis of Neuropharmacology by Cooper, Bloom, and Roth, a text that we have consulted through its many editions and to Goodman and Gilman’s The Pharmacological Basis of Therapeutics.