Deficiency Diseases of the Nervous System

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Chapter 57 Deficiency Diseases of the Nervous System

Yuen T. So, Roger P. Simon

Chapter Outline

Malnutrition causes a wide spectrum of neurological disorders (Table 57.1). Despite socioeconomic advances, nutritional deficiency diseases such as kwashiorkor and marasmus are still endemic in many underdeveloped countries. The problem in Western countries is usually the result of dietary insufficiency from chronic alcoholism or malabsorption due to gastrointestinal (GI) diseases. The B vitamins (thiamine, pyridoxine, nicotinic acid, and vitamin B₁₂), vitamin E, and perhaps folic acid are important for normal function of the nervous system. Emerging evidence also supports important roles of vitamin D and copper.

Table 57.1 Neurological Manifestations in Deficiency Diseases

Neurological Manifestations	Associated Nutritional Deficiencies
Dementia, encephalopathy	Vitamin B₁₂, nicotinic acid, thiamine, folate
Seizures	Pyridoxine
Myelopathy	Vitamin B₁₂, vitamin E, folate, copper
Myopathy	Vitamin D, vitamin E
Peripheral neuropathy	Thiamine, vitamin B₁₂, and many others
Optic neuropathy	Thiamine, vitamin B₁₂, and many others

Most causes of nutritional deficiency, whether dietary or malabsorptive, do not selectively deplete a single vitamin. This is especially true among the malnourished populations in underdeveloped countries where the diet may lack more than one nutrient, and overlapping neurological syndromes are the result. Individual vitamin requirements are influenced by many factors. The daily need for thiamine and nicotinic acid, important compounds in energy metabolism, increases proportionally with increasing caloric intake and energy need. For example, symptoms of thiamine deficiency may occur in at-risk patients during periods of vigorous exercise and high carbohydrate intake. Other factors such as growth, infection, and pregnancy may also worsen deficiency states.

Cobalamin (Vitamin B₁₂)

The terms vitamin B₁₂ and cobalamin are used interchangeably in the literature. Cobalamins are abundant in meat, fish, and most animal byproducts. Although vegetables are generally devoid of the vitamin, strict vegetarians seldom develop symptoms because only 1 mg is needed per day, and an adequate amount is available in legumes. Intestinal absorption of cobalamin requires the presence of intrinsic factor, a binding protein secreted by gastric parietal cells. Cobalamin binds to intrinsic factor, and the complex is transported to the ileum where it is absorbed into the circulation. A small amount of free cobalamin, about 1% to 5%, is also absorbed through the entire intestine without intrinsic factor. Once absorbed, cobalamin binds to a transport protein, transcobalamin, for delivery to tissues. As much as 90% of total body cobalamin (1-10 mg) is stored in the liver. Even when vitamin absorption is severely impaired, many years are needed to deplete the body store. A clinical relapse in pernicious anemia after interrupting cobalamin therapy takes an average of 5 years to be recognized.

Two biochemical reactions depend on cobalamin. One involves methylmalonic acid as precursor in the conversion of methylmalonyl coenzyme-A (co-A) to succinyl co-A. The importance of this to the nervous system is unclear. The other is a folate-dependent reaction in which the methyl group of methyltetrahydrofolate is transferred to homocysteine to yield methionine and tetrahydrofolate. The reaction depends on the enzyme methionine synthase, which uses cobalamin as a cofactor. Methionine is converted to S-adenosylmethionine (SAM), which is used for methylation reactions in the nervous system.

Causes of Deficiency

The classic disease, pernicious anemia, is caused by defective intrinsic factor production by parietal cells, leading to malabsorption. These patients may have demonstrable circulating antibodies to parietal cells or lymphocytic infiltrations of the gastric mucosa, suggesting an underlying autoimmune disorder. Another common cause of malabsorption is food-cobalamin malabsorption (Dali-Youcef and Andres, 2009). Under some clinical settings, the normal digestive process fails to release cobalamin from food or intestinal transport protein. Cobalamin remains bound and cannot be absorbed even in the presence of available intrinsic factors. Predisposing factors include atrophic gastritis and hypochlorhydria, and malabsorption may be seen with Helicobacter pylori infection, gastrectomy or other gastric surgeries, intestinal bacterial overgrowth, and prolonged use of H₂ antagonists, proton pump inhibitors, or biguanides (e.g., metformin). Patients with human immunodeficiency virus (HIV) are often observed to have a low serum cobalamin level, usually with normal homocysteine and methylmalonic acid. The significance of this association is unknown.

People who abuse nitrous oxide may develop a clinical syndrome of myeloneuropathy indistinguishable from that of cobalamin deficiency. The mechanism appears to be an interference with the cobalamin-dependent conversion of homocysteine to methionine. The other pathway, conversion of methylmalonyl co-A to succinyl co-A, is unaffected by nitrous oxide. Prolonged exposure to nitrous oxide is necessary to produce neurological symptoms in normal individuals. By contrast, patients who are already deficient in cobalamin may experience neurological deficits after only brief exposures during general anesthesia. Symptoms appear subacutely after surgery and resolve quickly with cobalamin treatment (Singer et al., 2008).

Clinical Features

The onset of symptoms is insidious, with paresthesias in the hands or feet experienced by most patients. Weakness and unsteadiness of gait are the next most frequent complaints. The Lhermitte sign may be present. Cerebral symptoms such as mental slowing, depression, confusion, delusions, and hallucinations are common, and occasionally patients present with only cognitive or psychiatric symptoms. Many patients also complain of dyspepsia, flatulence, altered bowel habits, or other GI symptoms.

On examination, signs of both peripheral nerve and spinal cord involvement may be present, although either can be affected first or disproportionately. Loss of vibration or joint position sense in the legs is common. If impaired position sense is severe, the Romberg sign may be present. Motor impairment, if present, results from pyramidal tract dysfunction and is most severe in the legs, ranging from mild clumsiness and hyperreflexia to spastic paraplegia and extensor plantar responses. Tendon reflexes are variably affected depending on the degree of pyramidal and peripheral nerve involvement. Visual impairment occasionally is encountered and may antedate other manifestations of vitamin deficiency; ophthalmological examination reveals bilateral visual loss, optic atrophy, and centrocecal scotomata. Brainstem or cerebellar signs, chorea, autonomic insufficiency, or even reversible coma may rarely occur.

Laboratory Studies

Serum assays of vitamin B₁₂ and cobalamin-dependent metabolites provide direct measures of cobalamin homeostasis, although there are important limitations (Solomon, 2005). Blood cobalamins are bound to two transport proteins, transcobalamin and haptocorrin. The cobalamin bound to transcobalamin, known as holotranscobalamin, is the fraction that is available to tissues, although it accounts for only 10% to 30% of the serum level measured by standard laboratory methods. Serum levels are influenced by conditions that affect the concentrations of these transport proteins. Myeloproliferative and hepatic disorders may raise the concentration of haptocorrin and cause a falsely normal serum level. A misleadingly high serum level also may result from the presence of an abnormal cobalamin-binding protein. In contrast, pregnancy and contraceptives may give falsely low measurements in the absence of deficiency. Folate deficiency also causes a falsely low cobalamin serum level that corrects after folate replacement. These confounding factors diminish the sensitivity and specificity of the commonly used assay of total serum cobalamin in the diagnosis of deficiency state. Although measurement of holotranscobalamin is better in theory, available data suggest that its diagnostic accuracy is approximately equivalent to that of total serum cobalamin (Miller et al., 2006).

Homocysteine and methylmalonic acid are precursors of cobalamin-dependent biochemical reactions. These metabolites accumulate during deficiency state. Measuring these metabolites is useful in settings of nitrous oxide abuse and in inherited metabolic disorders in which cobalamin-dependent pathways are impaired despite normal serum level. Homocysteine and methylmalonic acid assays are also useful when the cobalamin concentration is in the lower range of normal, between 200 and 350 pg/mL. Homocysteine level should be measured either at fasting or after an oral methionine load. The blood sample should be refrigerated immediately after collection because the level increases if whole blood is left at room temperature for several hours. Elevated levels of homocysteine and methylmalonic acid are not specific for cobalamin deficiency, as there are many other causes of increase in these metabolites (Box 57.1). In cobalamin-deficient patients, these levels typically normalize within 2 weeks of treatment.

In patients with autoimmune gastritis and intrinsic factor deficiency, antibodies against parietal cell and intrinsic factor may be elevated. Anti–parietal cell antibodies are nonspecific and are present in other autoimmune endocrinopathies as well as occasional normal individuals. Anti–intrinsic factor antibodies are less sensitive (50%–70%) but are specific for pernicious anemia. Elevated serum gastrin level is a marker of atrophic gastritis and hypochlorhydria and is a sensitive (up to 90%) but nonspecific indicator of pernicious anemia. The Schilling test measures intestinal cobalamin absorption using radiolabeled cobalamin and intrinsic factor but has fallen out of favor, in part because the labeled cobalamin is not readily available. In food-cobalamin malabsorption, the routine Schilling test is normal, but a modified Schilling test using protein-bound cobalamin may show impaired absorption.

The classic hematological manifestation of pernicious anemia is a macrocytic anemia. Erythrocyte or bone marrow macrocytosis or hypersegmentation of polymorphonuclear cells may be present without anemia. Hematological abnormalities may be absent at the time of neurological presentation and are thus insufficiently sensitive for use in diagnosis.

Because most patients present with clinical features suggesting a myelopathy or encephalopathy, imaging studies are necessary to exclude structural causes. Results of magnetic resonance imaging (MRI) may be normal, or T2-signal abnormalities may be seen in the lateral or posterior columns in patients with subacute combined degeneration (Kumar and Singh, 2009) (Fig. 57.1). Both gadolinium enhancement and spinal cord swelling have been described. Patients with encephalopathy or dementia often have multiple foci of T2 signal abnormalities in the deep white matter that may become confluent with disease progression. Radiographic improvement is seen within a few months after initiation of treatment. Nonspecific abnormalities of electroencephalography, as well as visual and somatosensory evoked responses, are present in most patients with neurological abnormalities. Nerve-conduction studies show small or absent rural nerve sensory potentials in approximately half of patients, providing evidence for an axonal polyneuropathy.

Fig. 57.1 Vitamin B₁₂ deficiency myelopathy. Gadolinium-enhanced, T1-weighted cervical and upper thoracic magnetic resonance image showing marked enhancement of posterior cord of a 30-year-old African-American woman wheelchair-bound due to an 18-month history of progressive myelopathy; vitamin B₁₂ level: 60 pg/mL.

(Courtesy Dr. R. Laureno.)

Pathology

The term subacute combined degeneration of the spinal cord describes the pathological process seen in this disorder. Microscopically, spongiform changes and foci of myelin and axon destruction are seen in the white matter of the spinal cord. The most severely affected regions are the posterior columns at the cervical and upper thoracic levels (Fig. 57.2). Pathological changes also are seen commonly in the lateral columns, whereas the anterior columns are involved in only a small number of the advanced cases. The pathological findings of the peripheral nervous system are those of axonal degeneration, but in some cases there is evidence of demyelination. Involvement of the optic nerve and cerebral white matter also occurs.

Fig. 57.2 Subacute combined degeneration of the spinal cord in vitamin B₁₂ deficiency. Demyelination and loss of axons are more widespread in posterior than in lateral columns (Weigert stain).

(Courtesy Dr. Michael F. Gonzales.)

Treatment

Recommendations for treatment of cobalamin deficiency vary widely. A typical regimen uses intramuscular daily injections of 1000 µg for the first week, followed by weekly 1000 µg injections for 1 month, and monthly injections thereafter. These parenteral doses provide quantities considerably higher than the body requirement. There is no evidence that overdosing can speed neurological recovery, but high doses of cobalamin appear to be safe. Oral supplementation at 1000 µg daily has also been used with some success, even in patients with suspected malabsorption, although close monitoring is necessary to ensure adequacy of treatment.

With proper treatment, serum levels of homocysteine and methylmalonic acid return to normal in about 2 weeks. Neurological improvement is more delayed and may be incomplete. Most of the symptomatic improvement occurs during the first 6 to 12 months of therapy. The need for early diagnosis and treatment is underscored by the observation that remission correlates inversely with the time lapse between onset of symptoms and initiation of therapy.

Folate Deficiency and Homocysteine

Folate deficiency may produce the same neurological deficits as those seen in cobalamin deficiency because of its central role in the biosynthesis of methionine, SAM, and tetrahydrofolate (see Cobalamin Deficiency). Overt neurological manifestations are rare in folate deficiency, probably owing to alternative cellular mechanisms that are available to preserve SAM levels in times of folate scarcity.

Causes of Deficiency

Absorption of folate occurs in the jejunum and to a lesser extent the ileum. Chronic alcoholism is an important cause of folate deficiency. Folate deficiency also may complicate small-bowel disease (e.g., sprue, Crohn disease, ulcerative colitis). Other populations at risk are pregnant women and patients receiving anticonvulsant drugs that interfere with folate metabolism. Sulfasalazine, methotrexate, triamterene, and oral contraceptives also may cause folate deficiency. Intrathecal methotrexate, in particular, causes a leukoencephalopathy associated with marked elevation of homocysteine levels in the cerebrospinal fluid (CSF).

Clinical Features

The majority of patients with laboratory evidence of folate deficiency do not have overt neurological findings. The classic syndrome of folate deficiency is similar to subacute combined degeneration seen in cobalamin deficiency. Presenting symptoms are limb paresthesias, weakness, and gait unsteadiness. These patients have megaloblastic anemia, impaired position and vibration sense, pyramidal signs, and possibly dementia. Chronic folate deficiency may result in mild cognitive impairment or increased stroke risk in adults, and in increased frequency of neural tube defects in babies born to folate-deficient mothers. Since 1998, the U.S. Food and Drug Administration mandates fortification of grain products with folate. The level of supplement, on the average, increases the dietary folate intake of adults by 100 mg/day.

Serum homocysteine is an important surrogate marker for folate metabolism, although there are other causes of elevated homocysteine levels. Hyperhomocysteinemia is a risk factor for vascular diseases and venous thrombosis. For cerebrovascular disease, the association is strongest for multi-infarct dementia and white-matter microangiopathy, but there is little or no association with cardioembolic or large-artery disease. Even a modestly increased serum level, in the range of 15 to 20 mmol/L, engenders a recognizable increase in vascular risk. On the other hand, it is as yet unclear whether folate supplementation can provide any reduction in vascular adverse outcomes.

Although low folate level is present in many elderly asymptomatic people, the prevalence seems to be higher in the psychiatric and Alzheimer disease populations. Moreover, a low folate level appears to correlate with depression and cognitive impairment. Even in healthy older adults, a low folate level is associated with subtle deficits in neuropsychological test performance.

Clinical observations in two inborn errors of metabolism reinforce our understanding of the role of homocysteine in neurological diseases. Hereditary deficiency of cystathionine β-synthase leads to hyperhomocysteinemia and hyperhomocysteinuria. The homozygous form presents with markedly elevated homocysteine levels, mental retardation, premature atherosclerosis, and seizures. Heterozygous individuals have milder elevations of homocysteine and also have increased risk of vascular disease. A much more common condition is a C-to-T substitution at codon 677 in the gene coding for N5, N10-methylenetetrahydrofolate reductase (MTHFR). Some 5% to 10% of the white population are homozygotes for this C677T mutation. These individuals have mildly elevated homocysteine levels and increased risk of vascular disease.

Laboratory Studies

Plasma and erythrocyte folate levels may be measured directly. Erythrocyte level is generally more reliable than plasma level because it is less affected by short-term fluctuation in intake. Serum homocysteine is increased in folate deficiency. Its measurement is discussed in Laboratory Studies under Vitamin B₁₂ Deficiency in this chapter.

Treatment

In patients with documented folate deficiency, the initial dose is usually 1 mg of folate several times per day, followed by a maintenance dose of 1 mg/day. For acutely ill patients, parenteral doses of 1 to 5 mg may be given. Even with oral doses as high as 15 mg/day, there is no substantiated report of toxicity. In women of childbearing potential with epilepsy, daily folate supplementation of 0.4 mg or more is recommended as prophylaxis against neural tube defects.

Vitamin E

Vitamin E refers to a group of tocopherols and tocoretinols, of which α-tocopherol is the most important. It is a free-radical scavenger and an antioxidant, and has attracted attention for its potentials in the prevention and treatment of a wide range of neurological diseases. Unfortunately, the value of vitamin E for these indications has yet to be proven. We limit discussion here to the neurological manifestations of vitamin E deficiency.

Like other fat-soluble compounds, vitamin E depends on the presence of pancreatic esterases and bile salts for its solubilization and absorption in the intestinal lumen. Neurological symptoms of deficiency occur most commonly in patients with fat malabsorption (Box 57.2). A reduced bile salt pool may be caused either by reduced hepatic excretion, as in congenital cholestasis, or by interruption of the enterohepatic reabsorption of bile, as in patients with extensive small-bowel resection. Pancreatic insufficiency contributes to malabsorption. Another setting is cystic fibrosis.

A rare familial form of fat malabsorption is abetalipoproteinemia (Bassen-Kornzweig syndrome), a disorder in which impaired chylomicron and lipoprotein synthesis is partly responsible for the impaired fat absorption. In addition to a neurological syndrome similar to that seen in other vitamin E-deficient states, spiky red blood cells (acanthocytes) and retinal pigment changes are characteristic. Another hereditary cause of vitamin E deficiency may be a genetic defect in the assembly or secretion of chylomicrons, leading to a chylomicron retention disease that is demonstrable in the intestinal mucosa (Aguglia et al., 2000). A syndrome of ataxia with isolated vitamin E deficiency (AVED) occurs in patients without GI disease or generalized fat malabsorption. Mutations in the α-tocopherol transfer protein gene (TTPA) on chromosome 8q13 are responsible (Mariotti et al., 2004). This condition is inherited in an autosomal recessive manner. The defect appears to be impaired incorporation of the vitamin into hepatic lipoproteins that are necessary for delivery to tissues.

Clinical Features

Clinical symptoms typically do not begin until many years of malabsorption deplete the vitamin reserves. This takes 15 to 20 years in adults, but clinical onset as early as age 1 to 2 years may occur in children because of their small vitamin reserves. The usual presenting symptoms are weakness or gait unsteadiness. Neurological examination reveals a syndrome of spinocerebellar degeneration accompanied by peripheral nerve involvement. Some patients are diagnosed erroneously with Friedreich ataxia. The most consistent abnormalities are limb ataxia, areflexia, and loss of vibration and position sense. Cutaneous sensation usually is spared or affected to a lesser degree. About half of patients have nystagmus, ptosis, or partial external ophthalmoplegia. Mild to moderate proximal weakness is common, and some patients may have a myopathy. The pattern of weakness may also be diffuse or predominantly distal. Babinski sign may be present.

Laboratory Studies

The diagnosis is not difficult when the appropriate neurological syndrome and a low serum vitamin E level are both present. Serum level should be interpreted in light of the clinical findings. Some patients with low levels do not have demonstrable neurological deficits. Moreover, plasma vitamin E is largely incorporated into chylomicrons and is highly dependent on the concentrations of total plasma lipids, cholesterol, and very low-density lipoproteins.

Other laboratory abnormalities, despite their nonspecific nature, help clarify the diagnosis. Stool fat is increased in many patients, and serum carotene concentration is often abnormally low, both reflecting a generalized state of fat malabsorption. CSF should be normal. Nerve conduction studies usually reveal a sensory polyneuropathy, although motor conduction abnormality and features of a demyelinating neuropathy have been reported rarely (Puri et al., 2005). Somatosensory and visual evoked responses are frequently abnormal, and there may be high signal lesions in the posterior columns on T2-weighted MRI.

Treatment

Pellagra (Nicotinic Acid Deficiency)

Nicotinic acid is converted in the body to two important coenzymes in carbohydrate metabolism: nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate. Niacin, another term for nicotinic acid, was introduced to avoid confusion with the alkaloid nicotine. Dietary deficiency of nicotinic acid produces pellagra (from the Italian pelle agra, meaning “rough skin”). Pellagra classically occurs in populations who consume primarily corn. Corn lacks nicotinic acid as well as tryptophan, a precursor that can be converted in the body to nicotinic acid. In underdeveloped countries, pellagra is still a common health problem. Even in the United States, pellagra was endemic until around 1940 in the South and in alcoholic populations. It has now largely disappeared, credited to the widespread consumption of bread enriched with niacin.

Pellagra affects three organ systems in the body: the GI tract, skin, and nervous system (hence the mnemonic of “three Ds”: diarrhea, dermatitis, and dementia). The chief GI symptoms are anorexia, diarrhea, stomatitis, and abdominal discomfort. Skin changes range from erythema to a reddish-brown hyperkeratotic rash distributed over much of the body, with the face, chest, and dorsal surfaces of the hands and feet being most involved.

The neurological syndrome of pellagra is not well defined. Reported cases, especially of patients with alcoholic pellagra, frequently are confounded by other coexisting central nervous system disorders. The primary early symptoms are neuropsychiatric (e.g., irritability, apathy, depressed mood, inattentiveness, memory loss) and may progress to stupor or coma. In addition to the confusional state, spasticity, Babinski sign, gegenhalten, and startle myoclonus may be prominent on neurological examination. Nonendemic pellagra occurs rarely in patients with alcoholism or malabsorption secondary to GI disease. The diagnosis of nonendemic pellagra can be made only on clinical grounds because there is no available method to make a blood niacin level determination, and diagnosis is frequently difficult because diarrhea and dermatological changes may be absent. Unexplained progressive encephalopathy in alcoholic patients not responsive to thiamine therapy (see Wernicke-Korsakoff Syndrome in this chapter) should raise the possibility of pellagra.

Vitamin B₆ (Pyridoxine)

Although the term pyridoxine often is used synonymously with vitamin B₆, two other naturally occurring compounds—pyridoxal and pyridoxamine—possess similar biological activities. All three compounds are converted to pyridoxal phosphate, the active coenzyme important for amino acid metabolism.

The first recognition of vitamin B₆ deficiency provides a useful lesson in nutrition. In the early 1950s, physicians in the United States encountered cases of an unusual seizure disorder in infants at the age of several weeks to a few months. These seizures were difficult to control with the usual anticonvulsants. In contrast, the response was dramatic when vitamin B₆ was given. It eventually became clear that the symptomatic infants were fed a commercial formula that contained approximately one-third the vitamin B₆ found in other infant formulas. The cause was then traced to a manufacturing process that reduced the pyridoxine content.

Even with better awareness of the problem, sporadic cases of infantile seizures from dietary vitamin B₆ deficiency still occur, most commonly as a result of breastfeeding by malnourished mothers from poor socioeconomic backgrounds or in underdeveloped countries. The typical patients have a normal birth history and are entirely healthy until the development of hyperirritability and an exaggerated auditory startle. Recurrent convulsions often occur abruptly, as may status epilepticus. Once the dietary insufficiency is corrected, patients become free of seizures and develop normally.

Another form of pyridoxine-responsive seizure occurs in infants with a hereditary dependency on pyridoxine due to a mutation of the antiquitin gene (Plecko et al., 2007). They develop symptoms despite a normal dietary supply of pyridoxine. In contrast to infants with dietary deficiency, most of these children manifest seizures earlier in life (within days of birth) and require much larger doses of pyridoxine (5-100 mg) to control their convulsions. Long-term administration of large amounts of pyridoxine is needed, generally in the range of 10 mg/day. Even after several years of successful treatment, seizures may reappear within days of pyridoxine withdrawal. This pyridoxine dependency should be considered in infants with undiagnosed seizures, especially in those with a poor response to anticonvulsants.

Adults are more tolerant of vitamin B₆ deficiency. In adults, chronic deficiency causes a subacute or chronic neuropathy. Antagonists of vitamin B₆ such as isoniazid, hydralazine, and penicillamine are responsible for many of the cases. As many as 50% of the slow inactivators of isoniazid may develop peripheral neuropathy if treated with the drug. Sensory symptoms appear first in the distal portion of the feet. If the drug is continued, symptoms then spread proximally to the knees and hands. Burning pain is disabling in some instances. On examination, there is distal weakness, depressed tendon reflexes, and impaired distal sensation. In patients taking isoniazid, pyridoxine supplementation of 50 mg/day prevents the development of neuropathy in nearly all patients. Acute overdose of isoniazid may rarely lead to coma, metabolic acidosis, and seizures, and pyridoxine provides a specific antidote.

Indiscriminate use of pyridoxine supplements may be harmful. The supplement has been touted for the treatment of carpal tunnel syndrome despite the lack of valid clinical evidence. What is clear is that high doses of pyridoxine (1000 mg/day or more) can reliably cause a sensory neuropathy within a few months. Patients ingesting a high dose for a prolonged period have been described to develop sensory ataxia with impaired sensation, areflexia, and Romberg sign. Many years of taking doses as low as 200 mg/day of pyridoxine have been associated with a mild predominantly sensory polyneuropathy, although a safety threshold for chronic lower-dose usage has not been established. In general, it is prudent to limit the daily dosage to 50 mg or less for the therapeutic use of pyridoxine.

Thiamine

Thiamine is synonymous with vitamin B₁. It is a water-soluble vitamin that plays a crucial role in the metabolism of carbohydrates, amino acids, and lipids. It is absorbed in the jejunum and ileum by active transport as well as passive diffusion. A continuous dietary supply is necessary; it is not stored to a significant extent in the body. Demand for thiamine increases during periods of high metabolic demands such as pregnancy and many systemic illnesses and also with high glucose intake. The minimum daily requirement of thiamine is 0.3 mg/1000 kcal dietary intake in normal subjects, but the requirement is higher during pregnancy and old age. For therapeutic purposes, a target of 50 to 100 mg/day is often used.

Diagnosis of thiamine deficiency is based on recognizing the appropriate clinical features on a background of nutritional deficiency or high metabolic demands. Thiamine levels in serum and urine may be decreased, although the levels do not reliably reflect tissue concentrations. Erythrocyte transketolase activity level is dependent on thiamine and provides an assay of functional status. Pyruvate accumulates during thiamine deficiency, and elevated serum level provides additional confirmation. A blood sample should be drawn before initiation of treatment because these laboratory abnormalities normalize quickly.

Thiamine Deficiency Neuropathy (Beriberi)

Beriberi literally means extreme weakness. It is caused by thiamine deficiency and affects the heart and peripheral nerves, producing congestive cardiomyopathy, sensorimotor polyneuropathy, or both. The classical wet and dry forms refer to the presence or absence of edema. The neuropathy generally develops over weeks or months. Affected patients complain of paresthesias or pain in the feet. Walking becomes difficult. The most common neurological finding is distal sensory loss. Weakness appears first in the finger and wrist extensors and the dorsiflexors of the ankle. Ankle reflexes are lost in most patients. When cardiac dysfunction is present, patients also experience tachycardia, palpitations, dyspnea, fatigue, and ankle edema.

Electrodiagnostic studies show an axonal neuropathy with reduced amplitude of sensory or motor responses, normal or mildly reduced conduction velocity, and neuropathic changes on electromyography. Lumbar puncture sometimes shows a mildly elevated opening pressure, a finding probably related to the presence of congestive heart failure. Findings of CSF examination are otherwise unremarkable. If cardiac impairment is present, electrocardiographic or other cardiac abnormalities may be seen.

Thiamine, 100 mg, may be given intravenously (IV) in the acute stage, especially if there is doubt about adequate GI absorption. Long-term treatment consists of a balanced diet with oral supplements of thiamine and other vitamins. Gradual return of sensory and motor function can be expected after thiamine replenishment. In severe cases, improvement may take many months and may be incomplete.

Infantile Beriberi

An acute syndrome of thiamine deficiency in infants occurs in the rice-eating populations of Asia, most frequently in breastfed infants younger than 1 year of age. Thiamine is often deficient in breast milk from mothers who eat primarily polished rice. Although the disorder is called infantile beriberi, it bears little resemblance to the adult form. Acute cardiac symptoms are common, often preceded by a prodrome of anorexia, vomiting, deficient weight gain, and restlessness. Dyspnea, cyanosis, and signs of heart failure follow and can lead rapidly to death. Arytenoid edema and recurrent laryngeal neuropathy may give rise to hoarseness, dysphonia, and eventually aphonia. Early signs of coughing and choking may be mistaken for respiratory tract infections. Central nervous system manifestations include drowsiness, ophthalmoplegia, and convulsions. These symptoms often begin abruptly and carry a grave prognosis. If given promptly, parenteral administration of 5 to 20 mg of thiamine can be life saving.

Wernicke-Korsakoff Syndrome

In 1881, Carl Wernicke described a syndrome of mental confusion, ophthalmoplegia, and gait ataxia in three patients, two of whom were alcoholics. At autopsy, multiple small hemorrhages were seen in the periventricular gray matter, primarily around the aqueduct and the third and fourth ventricles. Shortly after Wernicke’s original treatise, Korsakoff, a Russian psychiatrist, described an amnesia syndrome in 20 alcoholic men. At the time, neither Wernicke nor Korsakoff recognized the relationship between the encephalopathy and impaired memory. The clinical connection and the pathological similarity between the two conditions were not appreciated until 10 years later by other investigators. Korsakoff syndrome and Wernicke encephalopathy do not represent separate diseases but are different stages of one disease process (Wernicke-Korsakoff syndrome). Korsakoff syndrome typically follows Wernicke encephalopathy, emerging as ocular symptoms and encephalopathy subside.

Wernicke encephalopathy is due to thiamine deficiency. The most common clinical setting for this disorder is chronic alcoholism. However, a large number of cases occur in other conditions, with the only prerequisite being a poor nutritional state, either from inadequate intake, malabsorption, or increased metabolic requirement (Box 57.3). Wernicke encephalopathy may be precipitated acutely in at-risk patients by IV glucose administration or carbohydrate loading. Although the classic triad of confusion, ophthalmoplegia, and gait ataxia is still relevant in defining Wernicke encephalopathy, all three elements are recognized in only about one-third of all patients. Thus, the disorder should be considered in the differential diagnosis of all patients with acute encephalopathy.

Confusion is the most common symptom and develops over days or weeks. This is characterized by inattention, apathy, disorientation, and memory loss. Stupor or coma is rare. Gait ataxia is likely a result of cerebellar abnormality, peripheral neuropathy, and vestibular dysfunction. On examination, truncal ataxia is common, but limb ataxia is not—findings similar to those seen in alcoholic cerebellar degeneration. Ophthalmoplegia, when present, commonly involves both lateral recti, either in isolation or together with palsies of other extraocular muscles. Patients may have horizontal nystagmus on lateral gaze, and many also have vertical nystagmus on upgaze. Sluggish reaction to light, light-near dissociation, and other pupillary abnormalities are sometimes seen. The clinical findings reflect the localization of pathological abnormalities in this disease—namely, the prominent symmetrical involvement of periventricular structures at the level of the third and fourth ventricles. Lesions of the nuclei of cranial nerves III, VI, and VIII are responsible for the eye findings. Other frequent findings include hypothermia and postural hypotension, reflecting involvement of hypothalamic and brainstem autonomic pathways.

The Korsakoff syndrome follows repeated bouts of encephalopathy or an inadequately treated acute encephalopathy. As the acute encephalopathy subsides, it becomes obvious that the patient has an amnestic disorder. The memory impairment is out of proportion to other cognitive dysfunction and consists of both anterograde and retrograde amnesia. Affected patients have severe difficulty establishing new memories, always coupled with a limited ability to recall events that antedate the onset of illness by several years. Most patients are disoriented as to place and time. Alertness, attention, social behavior, and most other aspects of cognitive functioning are relatively preserved. Confabulation can be a prominent feature, especially in the early stages, although it may be absent in some patients. The memory disorder reflects the predilection of the lesions for the diencephalon and temporal lobes. Injury to these regions, regardless of cause (e.g., infarction, trauma, tumors, herpes encephalitis), can produce a syndrome indistinguishable from the amnesia syndrome seen in alcoholic patients.

Laboratory Studies

Brain MRI is very helpful in acute Wernicke encephalopathy. MRI typically shows signal abnormalities on T2-weighted FLAIR (fluid-attenuated inversion recovery) and diffusion-weighted images, symmetrically distributed around the periaqueductal regions, tectal plates, medial thalami, and bilateral mammillary bodies. Other regions such as the cerebellar vermis, pons, medulla, dentate nuclei, cranial nerve nuclei, and basal ganglia are also at times affected. Some lesions may show contrast enhancement. Hemorrhages are rarely seen. There are differences in the distribution of lesions between alcoholic and nonalcoholic patients, but there is a considerable overlap between the two groups (Zuccoli et al., 2009). Brain computed tomography (CT) may be used when MRI is unavailable but is much less sensitive in demonstrating abnormalities. MRI signal abnormalities typically resolve completely with prompt treatment, but shrunken mammillary bodies may be seen as a late residual finding. The CSF is either normal or shows a mild elevation in protein. Serum thiamine level and erythrocyte transketolase activity may be depressed, and there may be an elevation of serum pyruvate.

Pathology

The pathological process depends on the age of the lesions. Macroscopically, varying degrees of congestion, petechial hemorrhages, shrinkage, and discoloration are present (Fig. 57.3). Glial proliferation and myelin pallor characterize the more chronic lesions. The regions affected are the same as those observed to be involved on MRI. The frequency of Wernicke encephalopathy as estimated from various autopsy studies is approximately 0.8% to 2.8%, a figure far greater than that expected from clinical studies. Only 20% of the autopsy cases in one series were diagnosed during life. This is unfortunate because Wernicke encephalopathy is preventable and treatable. The underrecognition may result from an overemphasis on alcoholism as a cause (see Table 57.4) or a misconception that all three elements of the clinical triad are needed for a diagnosis. Wernicke encephalopathy occurring under other settings may be mistaken for encephalopathy of uremia, dialysis, sepsis, or other systemic diseases.

Fig. 57.3 Acute Wernicke disease. Hemorrhagic areas are seen adjacent to the fourth ventricle and aqueduct in the (from right to left) medulla, pons, and midbrain.

(Courtesy Dr. Michael F. Gonzales.)

Treatment

Treatment should not be delayed while waiting for laboratory confirmation of thiamine deficiency. Intravenous thiamine is safe, inexpensive, and effective in the treatment of Wernicke encephalopathy. Patients suspected to have the disorder should receive thiamine before administration of glucose to avoid precipitation of symptom worsening. A dose of 500 mg should be given IV in the acute stage, followed by 100 mg 3 times daily during the first week. Parenteral administration is preferable over oral supplements because intestinal absorption is unreliable in debilitated and alcoholic patients.

If left untreated, Wernicke encephalopathy is progressive. The mortality, even with thiamine treatment, was 10% to 20% in the early studies. With treatment, the majority of ocular signs resolve within hours, although a fine horizontal nystagmus persists in approximately 60% of patients. Apathy and lethargy improve over days or weeks. The gait disturbance resolves much more slowly, and in over one-third of the cases, gait may be abnormal even months after treatment. As the global confusional state recedes, some patients are left with the Korsakoff syndrome. The treatment of Korsakoff syndrome is usually limited to social support. Many patients require at least some form of supervision, either at home or in a chronic care facility. There are anecdotal reports of success treating the memory loss with acetylcholinesterase inhibitors or memantine, but controlled studies in small number of patients did not show a consistent benefit (Luykx et al., 2008).

Other Diseases Associated with Alcoholism

The diverse neurological consequences of alcohol abuse have been recognized for centuries. Alcohol is a potent central nervous system depressant. It facilitates the inhibitory neurotransmitter, γ-aminobutyric acid (GABA) and inhibits the excitation induced by N-methyl-d-aspartate (NMDA). It also has effects on the opioid, dopamine, and serotonin systems in the brain. Sustained heavy consumption of alcohol leads to dependency and increased tolerance, along with reduced sensitivity to GABA and increased sensitivity to NMDA. These alcohol abusers are also at risk for the development of withdrawal symptoms after cessation of alcohol consumption.

In addition to the increased susceptibility to withdrawal symptoms, dietary deficiency is common in alcohol abusers. Alcohol contains so-called empty calories because it does not provide significant amounts of protein and vitamins. A gram of pure ethanol contains 7 calories. A person who drinks a pint of 86-proof liquor daily consumes well over 1000 calories a day, approximately half of the daily caloric requirement. The alcohol consumption inevitably results in reduced intake of other foods. The problem is compounded further by malabsorption and abnormal metabolism of vitamins, both of which are common in alcoholics.

Despite the increased risk of malnutrition, only Wernicke-Korsakoff syndrome and rare cases of pellagra in alcoholics are clearly linked to nutritional deficiency. The pathogenesis of other neurological disorders is less clear (Box 57.4), though many have postulated a direct toxic effect of alcohol on both the central and peripheral nervous systems. For instance, neuropathy sometimes develops in alcohol abusers with normal nutritional status. The pattern of nerve fiber loss in these patients appears to be different from that in beriberi neuropathy from thiamine deficiency, thus suggesting a different pathological mechanism (Koike et al., 2003).

Alcohol-Withdrawal Syndromes

Alcohol-withdrawal syndrome typically occurs in patients with a long history of sustained alcohol use. Symptoms appear 4 to 12 hours after the last consumption of alcohol. The initial symptoms are insomnia, anxiety, tremulousness, palpitations, and diaphoresis. It is not uncommon for symptoms to appear even when there is a significant alcohol level in the blood. Mild cases of alcohol withdrawal are self-limiting, with symptoms peaking and resolving within 72 hours. Moderate to severe cases require urgent medical attention, as they are often complicated by withdrawal seizures, alcoholic hallucinosis, and delirium tremens.

Alcohol-withdrawal seizures are generalized clonic-tonic convulsions that usually occur between 12 and 48 hours from the last drink, though shorter or longer time intervals are possible. Most patients have either a single seizure or seizures occurring in a brief flurry. Status epilepticus is rare in isolated alcohol withdrawal, though alcohol withdrawal frequently complicates seizure disorders from other causes. The occurrence of status epilepticus or the presence of ominous features such as focal seizures or focal deficits in the postictal state should prompt an investigation into other structural, metabolic, or infectious causes. Although most alcohol-withdrawal seizures are self-limiting, recurrent or prolonged seizures require treatment. Benzodiazepines or phenobarbital are preferred over phenytoin, which is ineffective in withdrawal seizures.

With or without seizures, the initial symptoms of alcohol withdrawal may further progress to altered mentation. Visual and sometimes auditory and tactile hallucinations (alcoholic hallucinosis) often occur in the first 2 days after the last drink. They are then followed by delirium and agitation, accompanied by tachycardia, hypertension, fever, or diaphoresis (delirium tremens). Fluid and electrolyte disturbances often accompany delirium tremens. Hypovolemia, hypokalemia, hypomagnesemia, and hypophosphatemia are common and should be promptly treated if present. Other secondary complications may include cardiac failure, dysrhythmia, rhabdomyolysis, alcoholic pancreatitis, hepatitis, and pneumonia.

Benzodiazepines and supportive care are the mainstays in the treatment of a severe alcohol-withdrawal state (Korsten and O’Connor, 2003). A fast-acting benzodiazepine such as diazepam, lorazepam, or oxazepam should be given via the IV route. They are effective in controlling the agitation and sympathetic hyperactivity as well as any withdrawal seizures. This should be accompanied by aggressive support with IV fluids, nutritional supplementation (see Wernicke-Korsakoff Syndrome, earlier), treatment of coexisting complications, and close monitoring of vital signs, fluid status, and electrolytes. Less proven agents such as β-adrenergic antagonists, clonidine, and carbamazepine may also be used as adjunctive measures in controlling alcohol-withdrawal symptoms. The improvement of treatment has reduced the mortality rate of delirium tremens from over 30% at the beginning of the 20th century to the current rate of no more than 5%.

Alcoholic Neuropathy

Neuropathy is the most frequent neurological complication of alcoholism. Depending on the method of ascertainment, it may be diagnosed in 10% to 75% of alcoholic patients. Most affected patients are between age 40 and 60, and in essentially all cases, there is a history of chronic and heavy alcohol intake for many years.

Clinical Features

Alcoholic neuropathy is a mixed sensory and motor disorder that affects large- and small-diameter nerve fibers to varying degrees (Zambelis et al., 2005). Symptom onset is insidious, beginning in the feet and progressing proximally and symmetrically. Paresthesia is the most common presenting complaint. Many patients also complain of pain, either an aching discomfort in the calves or a burning sensation over the soles. Dysesthesia may be so severe that a light touch or gentle rubbing over the skin is intensely unpleasant. Interestingly, pain is more often a problem in those with milder neuropathy. On examination, both deep and superficial sensations are affected. Ankle tendon reflexes and sometimes knee reflexes are lost. Weakness and wasting are limited to the distal feet in mild cases but can involve the distal upper extremities in more severe cases. Rarely there may be vagus or recurrent laryngeal nerve involvement, with prominent hoarseness and weakness of voice. Both alcohol neurotoxicity and thiamine deficiency likely play important roles in alcoholic neuropathy. One study (Koike et al., 2003) suggests that pure alcoholic neuropathy without thiamine deficiency is more likely to be painful and has less motor involvement than that associated with concomitant thiamine deficiency.

Other manifestations of chronic alcoholism are often evident. Liver cirrhosis, hepatic encephalopathy, Wernicke-Korsakoff syndrome, alcoholic cerebellar degeneration, and alcohol-withdrawal symptoms all occur frequently at the time of evaluation. Trophic skin changes in the form of hyperpigmentation, edema, ulcers, and cellulitis in the distal part of the feet are sometimes encountered. There may be radiological suggestions of a distal neuropathic arthropathy (Charcot forefeet, acrodystrophic neuropathy), with phalangeal atrophy, bony resorption, and subluxation of small joints in the feet. Repeated trauma and infections to insensitive parts of the feet are probably responsible. This syndrome is prevalent in the south of France and Spain, where the term Thévenard syndrome is applied.

Laboratory Studies and Pathology

The pathology of alcoholic neuropathy is predominantly axonal loss. Nerve conduction studies show reduced amplitude of sensory nerve responses, with normal or mildly reduced conduction velocities. Electromyography may reveal signs of denervation and reinnervation in distal muscles of the lower extremities. Axonal degeneration of both myelinated and unmyelinated fibers is present on sural nerve biopsy. In some patients, autonomic dysfunction may be demonstrated by abnormalities in heart rate variation to deep breathing, Valsalva maneuver, and postural change.

Treatment

It is prudent to treat most affected patients with abstinence from alcohol, supplemental multivitamins, and a balanced diet. Even under ideal conditions, recovery is slow and incomplete.

Tobacco-Alcohol or Nutritional Amblyopia

Tobacco-alcohol amblyopia is a syndrome of vision loss caused by a selective lesion of the optic nerves. In Western countries, most affected patients are chronic and severe alcoholics, often with a history of poor dietary intake or marked weight loss. Vision loss occurs insidiously and painlessly, progressing in both eyes over a period of several weeks. The most common deficits are impaired visual acuity and the presence of central or centrocecal scotomata. Even in severely affected subjects, the optic discs may show only mild pallor. The commonly used term, tobacco-alcohol amblyopia, is likely incorrect, as neither agent has been proven to be directly responsible. The disease is probably identical to the nutritional amblyopia seen in prisoners of war and malnourished individuals who have no access to either alcohol or tobacco. Moreover, treatment with a combination of an adequate diet and B vitamins, despite the continuation of drinking and smoking, results in visual recovery. Dietary deficiencies of vitamin B₁₂, thiamine, folate, and riboflavin, all of which have been linked to optic neuropathy, may individually or together be responsible.

Marchiafava-Bignami Disease

In 1903, Marchiafava and Bignami, two Italian pathologists, described a syndrome of selective demyelination of the corpus callosum in alcoholic Italians who indulged in large quantities of red wine. The disease seems to affect primarily severe and chronic alcoholics in their middle or late adult life, with a peak incidence between ages 40 and 60. It is not restricted to any one ethnic group, and consumption of red wine is not an invariable feature. With the widespread use of MRI, there has been an increase in recognition of this previously rare disorder. A few cases have also been reported in nonalcoholics.

The neurological presentation is variable. The most common are an acute confusional state or a dementing syndrome. Patients may present with a variable combination of psychomotor slowing, behavioral changes, incontinence, dysarthria, and spasticity. Seizures, hemiparesis, and coma are sometimes seen. Pathologically, there is selective involvement of the central portion of the corpus callosum; the dorsal and ventral regions are spared or affected to a lesser degree. There also may be symmetrical involvement of other white-matter tracts. MRI is valuable and shows increased T2 and FLAIR signals along with restricted diffusion in the body of the corpus callosum, sometimes with extension into the genu or the splenium (Menegon et al., 2005). Abnormalities may also be seen in the subcortical white matter and cerebellar peduncles. Thinning of the corpus callosum is seen commonly in alcoholics without symptoms of Marchiafava-Bignami disease. It is unclear what causes the overt disease in susceptible individuals.

Treatment of Marchiafava-Bignami disease should be directed at supportive care, nutritional supplements, and rehabilitation from alcoholism. In those patients who recovered, it is not clear whether improvement was a result of nutritional supplementation or merely a reflection of the disease’s natural history.

Alcoholic Cerebellar Degeneration

Alcoholic cerebellar degeneration is likely the most common of the acquired degenerations of the cerebellum. Men are affected more frequently than women, and the incidence peaks in the middle decades of life. Alcohol abuse is long-standing in all patients, and alcoholic polyneuropathy accompanies most of them. The clinical syndrome is usually quite stereotyped. The presentation is a progressive unsteadiness in walking that evolves over weeks or months. Less commonly, a mild gait difficulty may be present for some time, only to worsen suddenly during binge drinking or an intercurrent illness. On examination, the most prominent finding is a truncal ataxia, demonstrated by a wide-based gait and difficulty with tandem walking. Limb ataxia, if present, is much milder than the truncal ataxia and more severe in the legs than in the arms. In contrast to Wernicke encephalopathy, nystagmus and ocular dysmetria are uncommon. Dysarthria, tremor, and hypotonia are rare findings.

The pathogenesis of cerebellar degeneration is unknown, though both nutritional deficiency and direct toxicity of alcohol may play a role. The pathological changes consist of selective atrophy of the anterior and superior parts of the cerebellar vermis, with the cerebellar hemispheres involved to a lesser extent. Cell loss involves all neuronal types in the cerebellum, although Purkinje cells are the most severely affected. A mild secondary loss of neurons is common in the deep cerebellar nuclei and the inferior olivary nuclei. In some patients, concomitant pathological changes of Wernicke encephalopathy may be present. Abstinence is the main treatment and can lead to a partial but incomplete improvement. With abstinence from alcohol and nutritional supplements, improvement in cerebellar symptoms occurs slowly but is often incomplete.

Vitamin A

Dietary deficiency of vitamin A is uncommon in Europe and the United States. Deficiency may occur rarely in fat malabsorption syndromes such as sprue, biliary atresia, and cystic fibrosis. A few cases have occurred in infants put on nondairy formula free of vitamin A. The earliest sign of deficiency is reduced ability to see in dim light. Retinol, an aldehyde form of vitamin A, binds with the protein, opsin, to form rhodopsin, which is responsible for vision at low light level. Xerosis, or keratinization, of the conjunctiva and cornea often accompanies night blindness. Some patients have the characteristic Bitot spots, which are white foam-like spots appearing at the side of the cornea. These eye findings are caused by metaplasia of epithelial cells and, if severe, can lead to permanent blindness. Rarely, infants may manifest a syndrome of raised intracranial pressure, bulging fontanelles, and lethargy.

Patients with signs of vitamin A toxicity or overdose are also likely to see a neurologist. The classic syndrome of toxicity is that of pseudotumor cerebri with headache and papilledema. The skin is often dry and pruritic, and patients may complain of generalized joint or bone pain. Especially in children, joint swelling and hyperostoses are often evident on roentgenography. Chronic daily consumption of more than 25,000 International Units may produce toxicity, although most reported patients consumed much higher doses over a shorter period of time. Unusual foods, such as polar bear liver and halibut liver, contain high concentrations of vitamin A and have caused acute toxicity. Serum retinol level is useful in the diagnosis. The generally accepted lower limit of normal is 20 mg/dL, whereas concentrations in excess of 100 mg/dL are suggestive of toxicity.

Vitamin D

Derangement in vitamin D and calcium metabolism may be caused by a diversity of systemic conditions including dietary insufficiency, inadequate sunlight exposure, immobility, anticonvulsant use, malabsorption, hypophosphatemia, and hyperparathyroidism. A common assay is the serum level of 25-hydroxyvitamin D. Levels below 10 ng/mL indicate deficiency, and levels between 10 and 20 ng/mL suggest some degree of insufficiency. Recent interest in the role of vitamin D arise from three lines of observation. First, around 50% of the elderly population may have insufficient amounts of vitamin D, most likely from a lack of adequate dietary intake and exposure to sunlight. Second, vitamin D has potentially diverse effects in the nervous system through its action on inflammatory cytokines, neurotrophins, and calcium-binding proteins. Third, low levels of 25-hydroxyvitamin D have been associated with a number of neurological diseases including multiple sclerosis, Parkinson disease, stroke, and cognitive decline (Miller, 2010). However, the observed associations do not prove a causative role of vitamin D deficiency in these neurological disorders. Whether vitamin D supplementation has any beneficial impact remains to be seen.

The best-documented syndrome attributable to overt vitamin D deficiency is a myopathy characterized by proximal weakness (Al-Said et al., 2009). Progressive weakness develops over many months. Weakness leads to difficulty in going upstairs and rising from a chair. When severe, some patients are wheelchair dependent. Diffuse bone pain, muscle pain, or back pain are common. Stretch reflexes and sensation are normal. Some patients may already have a diagnosis of osteomalacia. Serum creatine kinase level is usually normal or only mildly elevated. Serum alkaline phosphatase is abnormally high, and calcium and phosphorus may be normal or mildly decreased. Electromyography typically shows short-duration low-amplitude and polyphasic motor unit potentials without spontaneous activities; these features are similar to those of other metabolic myopathies. Nonspecific type II muscle fiber atrophy is seen on biopsy.

Initial treatment of deficiency consists of oral supplementation of vitamin D (cholecalciferol, 800 International Units daily) and dietary calcium (1200 mg daily). The underlying causes of vitamin D deficiency should be identified and corrected if possible. Dietary supplementation is continued for several months even after correction of the underlying cause. Once therapy is instituted, pain (if present) usually subsides, and laboratory abnormalities return to normal after a short period of vitamin D therapy. Satisfying recovery of muscle weakness follows over the subsequent months.