01 - NEUROGASTROENTEROLOGY

NEUROGASTROENTEROLOGYNeeraj Kumar

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ABSTRACTThe interrelationship between neurology and the gastrointestinal system is discussed in this chapter, which is divided into four sections: (1) neurologic manifestations of diseases that typically involve the gastrointestinal tract but may involve the nervous system in association with or independent of gastrointestinal involvement (celiac disease, Whipple disease, and inflammatory bowel disease); (2) neurologic manifestations related to deficiency of key nutrients, such as vitamin B12, folate, copper, vitamin E, thiamine, and others; (3) nervous system disorders including cerebrovascular disease, extrapyramidal and spinal cord disorders, and disorders of the peripheral and autonomic nervous system that are associated with gastrointestinal manifestations such as dysphagia, gastroparesis, and constipation; and (4) the increasingly important topic of neurologic complications related to gastric surgery. The interested reader is directed to four recent reviews on neurogastroenterology for additional information (Kumar, 2007; Murray and Ross, 2004; Perkin and Murray-Lyon, 1998; Skeen, 2002).Continuum Lifelong Learning Neurol 2008;14(1):1352.

Neurologic complications may occur in 10% of patients with well-established celiac disease.

NEUROLOGIC MANIFESTATIONS OF SPECIFIC GASTROINTESTINAL DISORDERS Celiac Disease Celiac disease is an immune-mediated enteropathy triggered by the ingestion of gluten-containing grains in genetically susceptible individuals (Craig et al, 2007; Farrell and Kelly, 2002; Rostom et al, 2006). It is characterized by mucosal inflammation and resultant malabsorption. Celiac disease can present with intestinal or extraintestinal symptoms (like the skin rash of dermatitis herpetiformis) or may even be detected in asymptomatic individuals. The diagnostic guidelines for celiac disease have required the presence of characteristic lesions on small bowel biopsy and demonstration of clinical improvement following elimination of gluten from the diet. Recent population-based studies suggest that subclinical celiac disease may be much more common than previously recognized (Fasano et al, 2003). With aware-

ness of a high disease prevalence has come the recognition of a broad spectrum of clinical presentations. Neurologic complications may occur in 10% of patients with well-established celiac disease. In earlier reports, neurologic manifestations associated with celiac disease were attributed to specific nutrient deficiencies (iron, folate, calcium and vitamin D, vitamin A, vitamin E, copper, pyridoxine, vitamin K, and vitamin B12). More recently the focus has been on immunologic mechanisms. Severe malabsorption is generally rare in patients with a neurologic presentation. Documentation of patients with neurologic manifestations and elevated autoantibodies associated with celiac disease (primarily antigliadin), often without gastrointestinal manifestations, has led to the suggestion that gluten sensitivity (as opposed to celiac disease) can cause neurologic manifestations without gastrointestinal symptoms or small bowel biopsy changes (Hadjivassiliou et al, 2002b). In some of these cases, neurologic

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" NEUROGASTROENTEROLOGY

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Ataxia and peripheral neuropathy are the bestcharacterized neurologic manifestations of celiac disease. The concept of gluten sensitivity and related neurologic disorders is controversial. Circulating IgG and IgA antibodies to gliadin are often present in patients with celiac disease. The specificity of antigliadin antibody for celiac disease is limited by the fact that up to 10% to 20% of the general population may have these antibodies. IgA antiendomysial antibody and IgG tissue transglutaminase antibody are more specific for the disease.

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manifestations may be followed by intestinal manifestations. Ataxia and peripheral neuropathy are the best-characterized neurologic manifestations of celiac disease (Chin et al, 2003; Chin et al, 2006; Hadjivassiliou et al, 2002b). The types of neuropathy described include pure sensory, pure motor, or mixed; axonal or mixed axonal and demyelinating; multifocal or symmetric; and small fiber or large fiber or mixed. In patients with small fiber neuropathy, frequent facial involvement and a nonlength-dependent pattern on skin biopsy findings may suggest a sensory ganglionopathy or an immune-mediated neuropathy (Brannagan et al, 2005). Cognitive impairment, including rapidly progressive dementia, may also be seen in association with celiac disease (Hu et al, 2006). Other reported manifestations include a wide spectrum of psychiatric disorders, myoclonic ataxia, inflammatory myopathy, isolated ocular myopathy, inclusion body myositis, neuromyotonia, chorea, headaches with transient deficits and MRI evidence of white matter abnormalities, brainstem encephalitis, multifocal leukoencephalopathy, myelopathy, neuromyelitis optica, internuclear ophthalmoplegia, epilepsy with or without occipital calcification, and others. The significance of some of these associations is indeterminate. The concept of gluten sensitivity and related neurologic disorders is controversial. Ataxia is the best-characterized neurologic manifestation of gluten sensitivity (Hadjivassiliou et al, 2003). MRI evidence of cerebellar atrophy is commonly seen. Antigliadin antibody (AGA) positivity is commonly seen in patients with apparently idiopathic sporadic ataxia. The ataxia is a result of immunologic damage to the cerebellum, posterior columns of the spinal cord, and peripheral nerves. AGAs

cross-react with epitopes on Purkinje cells, and patients with gluten ataxia may have antibodies against Purkinje cells (Hadjivassiliou et al, 2002a). Peripheral neuropathy is the second commonest manifestation of gluten sensitivity (Hadjivassiliou et al, 2006). Gluten sensitivity may be linked to a substantial number of idiopathic axonal neuropathies. Peripheral nerve involvement can be associated with cerebellar involvement or may occur independently. Circulating immunoglobulin (Ig) G and IgA antibodies to gliadin are often present in patients with celiac disease. The specificity of AGA for celiac disease is limited by the fact that up to 10% to 20% of the general population may have these antibodies. The precise pathogenic significance of these antibodies in nervous system disorders is unclear. Serum IgG AGA demonstrates good sensitivity, and IgA AGA has marginally better specificity for celiac disease. The combination is useful in screening patients at risk. Serologic abnormalities may resolve and histologic findings may improve with removal of gluten from the diet. IgA AGA testing is also useful to monitor dietary compliance. IgA endomysial antibody (EMA) and IgG tissue transglutaminase antibody (tTGA) are more specific for the disease. The reported specificity of these antibodies approaches 100% and over 95%, respectively. IgA deficiency is often associated with celiac disease. Hence, serologic testing for the IgA antibodies associated with celiac disease will be falsely negative in patients with selective IgA deficiency and celiac disease. In cases of selective IgA deficiency, IgG EMA and/or IgG tTGA may be obtained, but the IgG-based tests are less sensitive and specific than the IgA-based tests in those with normal levels of IgA. In patients with suspected celiac disease with a negative IgA EMA or IgA tTGA, serum IgA


determination should be the next step. AGAs have been described in patients with celiac disease and neurologic manifestations (Chin et al, 2003). The significance of this is unclear as these antibodies may be present in patients with celiac disease without neurologic symptoms. Approximately 95% of patients with celiac disease have HLA DQ2, and the remainder have HLA DQ8. If celiac disease is suspected despite negative serologic tests, the presence of these disease-associated alleles can be looked for and small intestinal mucosal biopsy considered. Multiple biopsies should be taken from the second part of the duodenum or beyond. The pathologic abnormality in the small intestine is characteristic, but not specific, and includes partial villous atrophy, crypt lengthening, increase in lamina propria, and intraepithelial lymphocytes. Reports in the literature on the effect of a gluten-free diet on neurologic manifestations are conflicting. Further, strict adherence to a glutenfree diet is difficult to achieve and is complicated by a lack of clear foodlabeling policy. Also, a group of patients with celiac disease is known to be resistant to a gluten-free diet (refractory sprue). While neurologic improvement on a gluten-free diet has been reported, persistence or progression of neurologic symptoms despite a gluten-free diet has often been noted. Generally, response of the neurologic manifestations is less robust to a gluten-free diet than that of gastrointestinal manifestations. In light of these uncertainties, the best approach seems to be to offer a gluten-free diet to patients with a recognized neurologic presentation and celiac disease. In some patients with neurologic manifestations, immunosuppressive therapy has been tried empirically (Chin et al, 2006). Coexisting vitamin or mineral deficiencies in association with celiac

disease should be looked for and appropriately treated (Case 1-1). Whipple Disease Whipple disease (WD) is a chronic, relapsing, multisystem disease due to infection with Tropheryma whipplei that has a predilection for middleaged men and affects the gastrointestinal, musculoskeletal, neurologic, cardiopulmonary, and lymphatic systems. Skin hyperpigmentation may be seen in up to a third of patients. A prodromal stage characterized by arthralgias and fever is followed by a steady-state stage with weight loss, diarrhea, and malabsorption. CNS symptoms may be seen in approximately 15% of patients with WD and in some can be the initial or only manifestation. Asymptomatic neurologic involvement has been shown by demonstration of DNA from T. whipplei in CSF by PCR assay (von Herbay et al, 1997). The CNS is also a site of symptomatic relapse following apparently successful therapy, often with antibiotics like tetracycline that have poor penetration into the CNS. A wide spectrum of neurologic manifestations may be seen (Fenollar et al, 2007; Louis et al, 1996) (Table 1-1). Psychiatric symptoms such as depression or personality change and cognitive impairment, including dementia, are commonly seen. Oculomasticatory myorhythmia and oculofacial-skeletal myorhythmia are considered pathognomic for CNS WD and are often accompanied by a supranuclear vertical gaze palsy. Oculomasticatory myorhythmia refers to pendular vergence oscillations that occur with slow rhythmic mouth and palatal movements. Oculofacial-skeletal myorhythmia refers to slow pendular vergence oscillations that occur synchronously with rhythmic movements of the mouth, face, and extremities and persist during sleep. Myoclonus is seen in one fourth of patients with

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CNS symptoms may be seen in approximately 15% of patients with Whipple disease and in some can be the initial or only manifestation. Oculomasticatory myorhythmia and oculofacialskeletal myorhythmia are considered pathognomic for CNS Whipple disease and are often accompanied by a supranuclear vertical gaze palsy.

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Case 1-1A 46-year-old man is evaluated for a 5-year history of gait difficulty and a 2-year history of incoordination with his hands. He has no past or present history of gastrointestinal symptoms. His examination is remarkable for a wide-based ataxic gait and a positive finger-nose and heel-shin test. His speech has a scanning quality. Muscle strength testing, reflexes, and sensations are normal. His brain MRI shows moderate cerebellar atrophy. His laboratory investigations are positive for IgA AGAs. Comment. Circulating IgA antibodies to gliadin are often present in patients with celiac disease. However, the specificity of AGA detection is limited by the fact that up to 10% to 20% of the general population may have these antibodies. Hence, the presence of AGAs in a patient with a progressive cerebellar syndrome does not necessarily indicate that they are causative. Other causes of cerebellar ataxia, such as paraneoplastic cerebellar degeneration, should be sought. The significance of the positive AGAs should be further evaluated with IgA EMA and IgG tTGA, which are more specific for celiac disease. Approximately 95% of patients with celiac disease have HLA DQ2, and the remainder have HLA DQ8. For diagnostic clarification a small bowel biopsy or HLA typing may be indicated. Neurologic manifestations of celiac disease may precede gastrointestinal manifestations or occur in the absence of gastrointestinal symptoms. If celiac disease is diagnosed, the possibility of coexisting vitamin or mineral deficiencies should be investigated and, if present, appropriately treated. Generally severe malabsorption is rare. A gluten-free diet should be offered to patients with a recognized neurologic presentation of celiac disease. The role of immunosuppressive therapy has not been established. While neurologic manifestations can be seen in 10% of patients with celiac disease, the concept of neurologic disease and gluten sensitivity remains controversial.

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neurologic involvement. Symptoms suggestive of hypothalamic involvement such as polydipsia, hyperphagia, changes in the sleep-wake cycle, and a change in libido may be present. Cerebellar ataxia may be more common than was earlier recognized (Matthews et al, 2005). Other neurologic manifestations that have been reported to occur in CNS WD include pyramidal and extrapyramidal manifestations, headache, progressive deafness, a strokelike syndrome, and a proximal myopathy. Ocular manifestations may include uveitis with vitreous opacities and papilledema. Isolated cervical myelitis with a spinal presentation of WD is rare (Figure 1-1A) (Messori et al, 2001).

Diagnosis and treatment of definite CNS WD should be based on the presence of pathognomic signs (oculomasticatory myorhythmia or oculofacial-skeletal myorhythmia) or positive biopsy or PCR results (Table 1-2) (Louis et al, 1996). Because of the protean manifestations and variability in organ involvement, a high index of suspicion is required and the diagnosis usually depends on additional diagnostic studies. Possible CNS WD should be considered in the setting of unexplained systemic symptoms and neurologic signs (supranuclear vertical gaze palsy, rhythmic myoclonus, dementia with psychiatric symptoms, or hypothalamic manifestations).


TABLE 1-1

Clinical Features of Neurologic Whipple Disease 8471% 50% 51% 44% 37% 31% 25% 25% 23% 20% 20%

Number of PatientsCognitive changes Altered level of consciousness Supranuclear ophthalmoplegia Psychiatric signs Upper motor neuron signs Hypothalamic manifestations Cranial nerve abnormalities Myoclonus Seizures Ataxia Oculomasticatory or oculofacial-skeletal myorhythmia Sensory deficit

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sickle-shaped particles in the cytoplasm (von Herbay et al, 1997). Brain MRI may show a high signal intensity on T2-weighted images involving one or more of the following structures: the hypothalamus, optic chiasm, mamillary body, medial temporal lobes, uncus, and cerebellar or cerebral peduncles (Figure 1-1B) (Messori et al, 2001). Due to the patchy involvement, brain biopsy is often a low-yield procedure. Patients with possible CNS WD should undergo small bowel biopsy (Louis et al, 1996). Up to one third of patients with CNS WD may have a negative small bowel biopsy. Endoscopy may show pale yellow mucosa alternating with erythematous mucosa in the postbulbar region of the duodenum and jejunum (Marth and Raoult, 2003). Biopsy samples should be taken from the proximal and distal duodenum or the jejunum. Bowel wall infiltration is associated with widening and flattening of the villi, with dilated lacteals containing yellow lipid deposits. On

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Brain MRI in Whipple disease may show high signal intensity on T2-weighted images involving one or more of the following structures: the hypothalamus, optic chiasm, mamillary body, medial temporal lobes, uncus, and cerebellar or cerebral peduncles. Up to one third of patients with CNS Whipple disease may have a negative small bowel biopsy.

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Adapted from Louis ED, Lynch T, Kaufmann P, et al. Diagnostic guidelines in central nervous system Whipples disease. Ann Neurol 1996; 40(4):561568. Copyright # 1996, with permission of John Wiley & Sons, Inc.

Blood studies in WD may show anemia, leukocytosis, eosinophilia, elevation of acute-phase reactants, and laboratory evidence of malabsorption. Radiographic assessment undertaken because of gastrointestinal symptoms may show abdominal lymphadenopathy, thickening of mucosal folds, hepatosplenomegaly, or ascites. Mild elevations of CSF protein and mild pleocytosis are common, but the CSF may be normal. Increased CSF immunoglobulin production or oligoclonal bands may be seen. The CSF cytologic hallmark in WD is the presence of histiocytes with periodic acid-Schiff (PAS)-positive, granular, sometimes

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FIGURE 1-1

A, Sagittal fast spin-echo T2-weighted cervical spine MRI showing an enlarged and inhomogeneously hyperintense spinal cord in a patient with an unusual spinal presentation of Whipple disease. B, Axial fast spin-echo T2-weighted brain MRI showing hyperintense lesions involving the middle cerebellar peduncles in a patient with Whipple disease (same patient as in A; brain MRI showed abnormalities 3 years later).

Adapted from Messori A, Di Bella P, Polonara G, et al. An unusual spinal presentation of Whipple disease. AJNR Am J Neuroradiol 2001;22(5): 10041008. Copyright # 2001, American Society of Neuroradiology.



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Recent developments using molecular analysis have allowed PCR amplification of the 16s ribosomal RNA sequences that are specific for Whipple organism and permits identification of the infection from a variety of tissues or body fluids, including peripheral blood.

TABLE 1-2

Guidelines for Diagnostic Screening, Biopsy, and Treatment of CNS Whipple Disease

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Definite CNS Whipple Disease Must have any one of the following three criteria: (1) Oculomasticatory myorhythmia or oculofacialskeletal myorhythmia (2) Positive tissue biopsy (3) Positive PCR analysis If histologic or PCR analysis was not performed on CNS tissue, then the patient must also demonstrate neurologic signs. If histologic or PCR analysis was performed on CNS tissue, then the patient need not demonstrate neurologic signs (ie, asymptomatic CNS infection).

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Possible CNS Whipple Disease Must have one of four systemic symptoms not due to another known etiology: (1) Fever of unknown origin (2) Gastrointestinal symptoms (steatorrhea, chronic diarrhea, abdominal distention, or pain) (3) Chronic migratory arthralgias, or polyarthralgias

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(4) Unexplained lymphadenopathy, night sweats, or malaise Also must have one of four neurologic signs not due to another known etiology: (1) Supranuclear vertical gaze palsy (2) Rhythmic myoclonus (3) Dementia with psychiatric symptoms (4) Hypothalamic manifestationsAdapted from Louis ED, Lynch T, Kaufmann P, et al. Diagnostic guidelines in central nervous system Whipples disease. Ann Neurol 1996;40(4):561568. Copyright # 1996, with permission of John Wiley & Sons, Inc.

light microscopy examination, PASstained small biopsy specimen shows magenta-stained inclusions within macrophages of the lamina propria. The PAS-positive intracellular inclusions are nonspecific. The bacteria can be differentiated from the intracellular inclusions of Mycobacterium avium complex, which, unlike the Whipple bacterium, is acid-fast positive. Electron microscopy may detect the distinctive, rod-shaped, trilaminar cell wall of T. whipplei. Noncaseating, epithelioidcell, sarcoidlike granulomas may be present in lymphatic tissue, gastrointestinal tract, bone marrow, and other tissues. These are often PAS-negative. Immunohistochemical staining or autoimmunochemical staining for antibodies against T. whipplei is more sensitive and specific than PAS staining but is not widely available. Recent developments using molecular analysis have allowed PCR amplification of the 16s ribosomal RNA sequences that are specific for Whipples organism and permits identification of the infection from a variety of tissues or body fluids, including peripheral blood (Fenollar et al, 2007). When amplified product is detected, the presence of T. whipplei should be confirmed by sequencing or by using fluorescence-labeled oligonucleotide hybridization probes in a real-time PCR assay. Prevalence of T. whipplei in duodenal biopsy specimens, saliva, stool, and blood from healthy persons is controversial (Marth and Raoult, 2003). The prognosis for patients with CNS involvement is poor. One fourth of such patients die within 4 years, and one fourth have major sequelae. The recommended treatment is oral administration of 160 mg of trimethoprim and 800 mg of sulfamethoxazole twice per day for 1 to 2 years, usually preceded by parenteral administration of streptomycin (1 g per day) together with penicillin G (1.2 million U per day)


or ceftriaxone (2 g daily) for 2 weeks (Fenollar et al, 2007). Inflammatory Bowel Disease Extraintestinal manifestations and complications of inflammatory bowel disease (ulcerative colitis or Crohn disease) may precede or follow the gastrointestinal manifestations and occur independently of exacerbation of bowel symptoms. Neurologic manifestations seen in association with inflammatory bowel disease may be related to the primary disease, be coincidental, or be a consequence of disease complications or treatment. In a retrospective review of 638 patients with inflammatory bowel disease, neurologic involvement was noted in 10 patients with Crohn disease and 9 patients with ulcerative colitis (Lossos et al, 1995). In nearly three fourths of these patients, neurologic involvement started within 6 years of the diagnosis of inflammatory bowel disease. Over half of these patients had other extraintestinal manifestations. Peripheral nervous system disorders were most commonly seen and included acute inflammatory demyelinating polyneuropathy (3), mononeuritis multiplex (1), bibrachial plexopathy (1), myasthenia gravis (1), and myopathy (3). One patient had the Melkerson-Rosenthal syndrome (an idiopathic syndrome characterized by recurrent facial swelling, relapsing facial paralysis, and fissured tongue), and five had a myelopathy. Cerebrovascular manifestations included venous thrombosis sinus (2), recurrent transient ischemic attacks (1), and recurrent strokes (1). The incidence of arterial or venous thromboses is increased in patients with inflammatory bowel disease, and they often occur with disease exacerbation, possibly secondary to a hypercoagulable state or associated vasculitis. Patients with inflammatory bowel disease may also have chronic

inflammatory demyelinating peripheral neuropathy, multifocal motor neuropathy, small or large fiber sensory axonal sensory peripheral neuropathy, or large fiber axonal sensorimotor peripheral neuropathy (Gondim et al, 2005). Both demyelinating and axonal neuropathies may show response to immunotherapy (Gondim et al, 2005). Nonenhancing, hyperintense focal white matter lesions have been reported in the brain of patients with inflammatory bowel disease and may represent an extraintestinal manifestation (Geissler et al, 1995). They are more common in older patients and in those with longer disease duration and are unrelated to the presence of cardiovascular risk factors. An increased concurrence of inflammatory bowel disease and multiple sclerosis has been shown in Olmsted County using the database of the Rochester Epidemiology Project (Kimura et al, 2000). Tropical Sprue Tropical sprue is a chronic diarrheal illness of presumed infectious etiology that occurs in individuals who reside in or have been to the tropics. Neurologic manifestations of tropical sprue include subacute combined degeneration, peripheral neuropathy, myopathy, tetany, night blindness, and mental changes and are likely a consequence of nutrient deficiencies secondary to chronic malabsorption (Iyer et al, 1973). Campylobacter jejuni Infection Campylobacter jejuni is the most common cause of bacterial gastroenteritis in developed countries. Nonspecific prodromal symptoms are followed by a diarrheal illness, and after a brief incubation period Guillain-Barre syn drome may result. Up to 26% of patients with Guillain-Barre or Miller Fisher syndrome may have evidence of

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Neurologic manifestations seen in association with inflammatory bowel disease may be related to the basic disease, be coincidental, or be a consequence of disease complications or treatment. Peripheral nervous system involvement is common.

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Up to 26% of patients with Guillain-Barre or Miller Fisher syndrome may have evidence of Campylobacter jejuni infection. The resulting Guillain-Barre syndrome is associated with axonal degeneration, slow recovery, and residual disability.

C. jejuni infection (Rees et al, 1995). The resulting Guillain-Barre syndrome is associated with axonal degeneration, slow recovery, and residual disability. A seasonal form of acute motor axonal neuropathy in rural areas of China is also frequently associated with IgG and IgM antibodies against C. jejuni. NEUROLOGIC MANIFESTATIONS RELATED TO SPECIFIC NUTRIENT DEFICIENCIES Optimal functioning of the central and peripheral nervous systems is dependent on a constant supply of appropriate nutrients. Neurologic signs occur late in malnutrition. Neurologic consequences of nutritional deficiencies do not affect only individuals living in underdeveloped countries. Those at risk in developed countries include poor, homeless, and elderly individuals; patients on prolonged inadequate parenteral nutrition; individuals with food fads or eating disorders such as anorexia nervosa and bulimia; individuals suffering from malnutrition secondary to chronic alcoholism; and patients with malabsorption syndromes such as sprue, celiac disease, inflammatory bowel disease, and pernicious anemia (PA). Not infrequently multiple nutritional deficiencies coexist. Prognosis depends on prompt recognition and institution of appropriate therapy. Table 1-3 summarizes the salient features of neurologically significant nutrient deficiencies. Protein and calorie deficiency in infants and children in underdeveloped countries results in two related disorders: marasmus and kwashiorkor. Marasmus is due to caloric insufficiency and results in growth failure and emaciation in early infancy. Kwashiorkor presents with edema, ascites, and hepatomegaly and is due to protein deficiency. Generalized muscle wasting and weakness with hypotonia and

hyporeflexia are seen. Cognitive deficits may be permanent. Autopsy studies show cerebral atrophy and immature neuronal development. During the initial stages of dietary treatment, an encephalopathy may be seen. Numerous neuropathies and myeloneuropathies from the tropics have been described for which a nutritional cause has been postulated. Lack of multiple dietary components, in particular B-group vitamins, is the likely cause. Vitamin B12 Vitamin B12 or cobalamin (Cbl) is a water-soluble vitamin that is required as a cofactor in several enzymatic reactions. The two active forms of Cbl are methyl-Cbl and adenosyl-Cbl (Figure 1-2) (Kumar 2007; Tefferi and Pruthi, 1994). Figure 1-2 shows the biochemical pathways that are involved in Cbl metabolism. Figure 1-3 shows the gastrointestinal processing and absorption of Cbl (Perkin and Murray-Lyon 1998; Tefferi and Pruthi 1994). Cbl is transferred across the intestinal mucosa into portal blood where it binds predominantly to trans-Cbl II (TCII). The liver takes up approximately 50% of the Cbl, and the rest is transported to other tissues through receptors for TCII. Cells take up TCII-bound Cbl through receptor-mediated endocytosis. Intracellular lysosomal degradation releases Cbl for conversion to methylCbl or adenosyl-Cbl. Most of the Cbl secreted in the bile is reabsorbed. The estimated daily losses of Cbl are minute compared with body stores of 2500 mg. Hence, even in the presence of severe malabsorption, 2 to 5 years may pass before Cbl deficiency develops (Green and Kinsella, 1995). Similarly, a clinical relapse in PA after interrupting Cbl therapy takes approximately 5 years before it is recognized. Causes of deficiency. Many patients with Cbl deficiency have PA.

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TABLE 1-3

Summary of Sources, Causes of Deficiency, Neurologic Significance, Laboratory Tests, and Treatment for Deficiency States Related to Cobalamin, Folate, Copper, Vitamin E, Thiamine, Vitamin A, Niacin, Pyridoxine, and Vitamin DNeurologic Significance Associated With DeficiencyMyelopathy or myeloneuropathy, peripheral neuropathy, neuropsychiatric manifestations, optic neuropathy.

Nutrient SourcesCobalamin Meats, egg, milk, fortified cereals.

Major Causes of DeficiencyPernicious anemia, food-Cbl malabsorption (elderly), gastric surgery, acid-reduction therapy, gastrointestinal disease, parasitic infestation by fish tapeworm, hereditary enzymatic defects, nitrous oxide toxicity.

Laboratory TestsSerum Cbl, serum methylmalonic acid, plasma total Hcy, anemia, macrocytosis, neutrophil hypersegmentation, Schillings test, serum gastrin, intrinsic factor and parietal cell antibodies. Serum folate, red blood cell folate, plasma total Hcy.

TreatmentIM B12 1000 mg daily for 5 days and monthly thereafter.

Additional CommentsDecreased dietary intake is a rare cause of Cbl deficiency even in vegetarians.

Folate

Virtually all foods (grains and cereals are fortified with folic acid).

Alcoholism, gastrointestinal disease, folate antagonists.

Neurologic manifestations are rare and indistinguishable from those due to Cbl deficiency.

Oral folate 1 mg 3 times a day followed by a maintenance dose of 1 mg a day.

Food folate is in the polyglutamate form (bioavailability of less than 50%). Folic acid supplements are in the monoglutamate form (bioavailability approaching 100%).

Copper

Organ meats, seafood, nuts, cocoa, whole grain products. Vegetable oils, leafy vegetables, fruits, meats, nuts, unprocessed cereal grains. Enriched, fortified, or whole grain products, organ meats.

Gastric surgery, zinc toxicity, gastrointestinal disease.

Myelopathy or myeloneuropathy.

Serum copper and ceruloplasmin.

Oral elemental copper: 6 mg a day for 1 week followed by 4 mg a day for 1 week and 2 mg a day thereafter. Vitamin E ranging from 200 mg/d to 200 mg/kg/d (oral, IM).

Not infrequently, the cause of copper deficiency is unknown.

Vitamin E

Chronic cholestasis, pancreatic insufficiency, ataxia with vitamin E deficiency, homozygous hypobetalipoproteinemia, abetalipoproteinemia, chylomicron retention disease. Recurrent vomiting, gastric surgery, alcoholism, dieting, increased demand with marginal nutritional status.

Spinocerebellar syndrome with peripheral neuropathy, ophthalmoplegia, pigmentary retinopathy. Beriberi (dry, wet, infantile), Wernicke encephalopathy, Korsakoff syndrome.

Serum vitamin E. Ratio of serum a-tocopherol to sum of serum cholesterol and triglycerides.

Vitamin E deficiency is virtually never the consequence of a dietary inadequacy.

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Thiamine

50 mg to 100 mg Urinary thiamine, (IV, IM, oral). serum thiamine, erythrocyte transketolase activation assay, red blood cell thiamine diphosphate.

Reliance on the described triad of ophthalmoplegia, ataxia, and confusion and not recognizing thiamine deficiency in nonalcoholics may result in missing the diagnosis.

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TABLE 1-3

ContinuedNeurologic Significance Associated With DeficiencyBlindness.

Nutrient SourcesVitamin A Carrots, papayas, green leafy vegetables, liver. Meat, fish, poultry, enriched bread, fortified cereals.

Major Causes of DeficiencyNutritional deficiency in vulnerable populations, conditions associated with fat malabsorption. Corn as primary carbohydrate source, alcoholism, malabsorption, carcinoid, and Hartnup syndrome.

Laboratory TestsVitamin A levels.

Treatment

Additional Comments

Oral vitamin A Pseudotumor supplementation. cerebri due to excess ingestion.

Niacin

Encephalopathy. (Peripheral neuropathy.)

Urinary excretion of 25 mg to 50 mg of nicotinic acid methylated niacin (IM, oral). metabolites.

Pyridoxine

B6 antagonists, Meat, fish, eggs, alcoholism, soybeans, gastrointestinal disease. nuts, dairy products, starchy vegetables, noncitrus fruits, whole grain cereal products. Sunlight, liver, eggs, dairy products. Inadequate sun exposure, malabsorption, gastric bypass.

Infantile seizures, peripheral neuropathy. (Pure sensory neuropathy with toxicity.)

Plasma pyridoxal phosphate.

50 mg to 100 mg of pyridoxine daily (oral).

Milling of grain, cooking, and thermal processing can result in significant losses.

Vitamin D

Proximal myopathy, tetany.

Serum 25-hydroxy vitamin D, calcium, phosphorus, alkaline phosphatase, parathormone levels.

400 IU vitamin D a day prevents deficiency, 50,000 IU weekly may be required with clinical deficiency.

Vitamin D functions more like a hormone than a vitamin.

Cbl = cobalamin; Hcy = homocysteine.Adapted from Kumar N. Nutritional neuropathies. Neurol Clin 2007;25(1):209255. Copyright # 2007. Reprinted with permission from Elsevier.

22This is an autoimmune gastropathy targeting the parietal cells that produce acid and intrinsic factor. Cbl deficiency is particularly common in older adults. This is most likely because of the high incidence of atrophic gastritis and achlorhydria-induced food-Cbl malabsorption rather than reduced intake. Helicobacter pylori infection of the stomach may be associated with mucosal atrophy, hypochlorhydria, and impaired splitting of bound Cbl from food proteins. Cbl deficiency is commonly seen following gastric surgery. Other causes of Cbl deficiency include conditions associated with malabsorption such as ileal disease or resection, jejunal diverticulosis, bacterial overgrowth, pancreatic disease, and tropical sprue. Nitrous oxide (N2O) is a commonly used inhalational anesthetic that has been abused because of its euphoriant properties. N2O irreversibly oxidizes the cobalt core of Cbl and renders methyl-Cbl inactive. Clinical manifestations of Cbl deficiency appear relatively rapidly with N2O toxicity because the


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Cobalamin deficiency is particularly common in older adults. This is most likely due to the high incidence of atrophic gastritis and achlorhydriainduced foodcobalamin malabsorption rather than reduced intake.

FIGURE 1-2

Biochemistry of cobalamin (Cbl) and folate deficiency. Methyl-Cbl is a cofactor for a cytosolic enzyme, methionine synthase, in a methyl-transfer reaction that converts homocysteine (Hcy) to methionine. Methionine is adenosylated to S-adenosylmethionine (SAM), a methyl group donor required for biologic methylation reactions involving proteins, neurotransmitters, and phospholipids. Decreased SAM production leads to reduced myelin basic protein methylation and white matter vacuolization in Cbl deficiency. Methionine also facilitates the formation of formyltetrahydrofolate (THF) which is involved in purine synthesis. During the process of methionine formation methyl-THF donates the methyl group (CH3) and is converted into THF, a precursor for purine and pyrimidine synthesis. Impaired DNA synthesis could interfere with oligodendrocyte growth and myelin production. Adenosyl-Cbl is a cofactor for L-methylmalonyl coenzyme A (CoA) mutase, which catalyzes the conversion of L-methylmalonyl-CoA to succinyl CoA in an isomerization reaction. Accumulation of methylmalonate and propionate may provide abnormal substrates for fatty acid synthesis. The branched-chain and abnormal odd-number carbon fatty acids may be incorporated into the myelin sheath. The biologically active folates are in the THF form. Methyl-THF is the predominant folate and is required for the Cbl-dependent remethylation of Hcy to methionine. Methylation of deoxyuridylate to thymidylate is mediated by methylene-THF. Impairment of this reaction results in accumulation of uracil, which replaces the decreased thymine in nucleoprotein synthesis and initiates the process that leads to megaloblastic anemia. CH3 = methyl group; THF1 = monoglutamated form of tetrahydrofolate; THFn = polyglutamated form of tetrahydrofolate.

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Kumar N. Nutritional neuropathies. Neurol Clin 2007;25(1):209255. Copyright # 2007. Reproduced with permission from Elsevier. Adapted with permission from Tefferi A, Pruthi RK. The biochemical basis of cobalamin deficiency. Mayo Clinic Proc 1994;69(2):181186.



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Nitrous oxide irreversibly oxidizes the cobalt core of cobalamin and renders methylcobalamin inactive. The recognized neurologic manifestations of cobalamin deficiency include a myelopathy with or without an associated neuropathy, cognitive impairment, optic neuropathy, and paresthesias without abnormal signs.

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metabolism is blocked at the cellular level. They may, however, be delayed up to 8 weeks. Postoperative neurologic dysfunction can be seen with N2O exposure during routine anesthesia if subclinical Cbl deficiency is present (Kinsella and Green, 1995). N2O (laughing gas) toxicity due to inhalant abuse has been reported among dentists, other medical personnel, and university students. Clinical significance. Neurologic manifestations may be the earliest and often the only manifestation of Cbl deficiency (Healton et al, 1991). The severity of the hematologic and neurologic manifestations may be inversely related in a particular patient. Relapses are generally associated with the same

neurologic phenotype. The recognized neurologic manifestations may include a myelopathy with or without an associated neuropathy, cognitive impairment, optic neuropathy, and paresthesias without abnormal signs (Healton et al, 1991). The best-characterized neurologic manifestation of Cbl deficiency is a myelopathy that has commonly been referred to as subacute combined degeneration. The most severely involved regions are the cervical and upper thoracic posterior columns. Changes are also seen in the lateral columns. Involvement of the anterior columns is rare. The neurologic features typically include a spastic paraparesis, extensor plantar response, and impaired

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FIGURE 1-3

In the stomach, cobalamin (Cbl) bound to food is dissociated from proteins in the presence of acid and pepsin. The released Cbl binds to R proteins secreted by salivary glands and gastric mucosa. In the small intestine, pancreatic proteases partially degrade the R proteins-Cbl complex at neutral pH and release Cbl, which then binds with intrinsic factor (IF). IF is a Cbl-binding protein secreted by gastric parietal cells. The IF-Cbl complex binds to specific receptors in the ileal mucosa and is internalized. In addition to the IF-mediated absorption of ingested Cbl, a nonspecific absorption of Cbl occurs by passive diffusion at all mucosal sites. This is a relatively inefficient process by which 1% to 2% of the ingested amount is absorbed. OH = alkaline; H+ = acidic; TCII = transcobalamin II.

Reproduced with permission from Tefferi A, Pruthi RK. The biochemical basis of cobalamin deficiency. Mayo Clin Proc 1994;69(2):181186.


perception of position and vibration. Symptoms start in the feet and are symmetric. MRI abnormalities include a signal change in the subcortical white matter and posterior and lateral columns. Neuropsychiatric manifestations include decreased memory, personality change, psychosis, and, rarely, delirium (Healton et al, 1991; Lindenbaum et al, 1988). Clinical, electrophysiologic, and pathologic involvement of the peripheral nervous system has been described. In a recent study, Cbl deficiency was detected in 27 of 324 patients with a polyneuropathy (Saperstein et al, 2003). Clues to possible B12 deficiency in a patient with polyneuropathy included a relatively sudden onset of symptoms, findings suggestive of an associated myelopathy, onset of symptoms in the hands, macrocytic red blood cells (RBCs), and the presence of a risk factor for Cbl deficiency. Autonomic dysfunction with orthostatic hypotension has rarely been described. Electrophysiologic abnormalities include nerve conduction studies suggestive of a sensorimotor axonopathy, and abnormalities on somatosensory evoked potentials, visual evoked potentials, and motor evoked potentials. It is well known that serum Cbl can be normal in some patients with Cbl deficiency, and serum methylmalonic acid (MMA) and total homocysteine (Hcy) levels are useful in diagnosing patients with Cbl deficiency (Carmel et al, 2003; Green and Kinsella, 1995). The sensitivity of the available metabolic tests has facilitated the development of the concept of subclinical Cbl deficiency (Carmel et al, 2003). This refers to biochemical evidence of Cbl deficiency in the absence of hematologic or neurologic manifestations. These biochemical findings should respond to Cbl therapy. Its frequency is estimated to be at least 10 times that of clinical Cbl deficiency. The incidence

of subclinical Cbl deficiency increases with age. It is equally important to recognize that the presence of a low Cbl in association with neurologic manifestations does not imply cause and effect or indicate the presence of metabolic Cbl deficiency. The incidence of both cryptogenic polyneuropathy and Cbl deficiency increases with age, and the latter may be a chance occurrence rather than a cause of the neuropathy. The clinical impact of subclinical Cbl deficiency and its appropriate management are uncertain. Investigations. The older microbiologic and radioisotopic assays for serum Cbl determination have been replaced by immunologically based chemiluminescence assays. Though a widely used screening test, serum Cbl measurement has technical and interpretive problems and lacks sensitivity and specificity for the diagnosis of Cbl deficiency (Carmel et al, 2003). Levels of serum MMA and plasma total Hcy are useful as ancillary diagnostic tests in the diagnosis of Cbl deficiency (Carmel et al, 2003; Green and Kinsella, 1995). The specificity of serum MMA is superior to that of plasma Hcy. Although plasma total Hcy is a very sensitive indicator of Cbl deficiency, its major limitation is its poor specificity. Table 1-4 indicates causes other than Cbl deficiency that can explain abnormal levels of Cbl, MMA, and Hcy. A rise in the mean corpuscular volume may precede development of anemia. The presence of neutrophil hypersegmentation may be a sensitive marker for Cbl deficiency and may be seen in the absence of anemia or macrocytosis. In order to determine the cause of Cbl deficiency, tests directed at determining the cause of malabsorption are undertaken. Concerns regarding cost, accuracy, and radiation exposure have led to a significant decrease in the

KEY POINT:

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Clues to possible B12 deficiency in a patient with polyneuropathy include a relatively sudden onset of symptoms, findings suggestive of an associated myelopathy, onset of symptoms in the hands, macrocytic red blood cells, and the presence of a risk factor for cobalamin deficiency. Serum cobalamin can be normal in some patients with cobalamin deficiency and serum methylmalonic acid, and total homocysteine levels are useful in diagnosing patients with cobalamin deficiency. The specificity of serum methylmalonic acid is superior to that of plasma homocysteine.

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For the diagnosis of pernicious anemia, antiintrinsic factor antibodies are more specific than serum gastrin levels but lack sensitivity. They are found in approximately 50% to 70% of patients. Parietal cell antibodies are more commonly seen in pernicious anemia but lack specificity, particularly in individuals over the age of 70.

TABLE 1-4

Common Causes, Other Than Cobalamin Deficiency, for Abnormal Cobalamin, Methylmalonic Acid, and Homocysteine Levels Methylmalonic AcidIncreased by: Renal insufficiency Volume contraction (possible) Bacterial contamination of gut (possible) Methylmalonic coenzyme A mutase deficiency Methylmalonic acidrelated enzyme defects

CobalaminDecreased by: Pregnancy Transcobalamin I deficiency Folate deficiency Other diseases: HIV infection, myeloma Drugs: anticonvulsants, oral contraceptives Increased by: Renal failure Liver disease

HomocysteineIncreased by: Renal insufficiency Alcohol abuse Folate deficiency Vitamin B6 deficiency

Other diseases: hypothyroidism, renal transplant, leukemia, psoriasis Drugs: isoniazid Inborn errors of homocysteine metabolism Enzyme polymorphisms (eg, methylene tetrahydrofolate reductase)

Myeloproliferative disordersAdapted from Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology Am Soc Hematol Educ Program 2003:6281. This research was originally published in Blood. Copyright # the American Society of Hematology.

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availability of the Schilling test. An elevated serum gastrin and decreased pepsinogen I are seen in 80% to 90% of patients with PA, but the specificity of these tests is limited. Elevated gastrin levels are a marker for hypochlorhydria or achlorhydria, which are invariably seen with PA. Antiintrinsic factor antibodies are more specific but lack sensitivity and are found in approximately 50% to 70% of patients with PA. Parietal cell antibodies are more commonly seen in PA but lack specificity, particularly in individuals over the age of 70. Management. The goals of treatment are to reverse the signs and symptoms of deficiency, replenish body stores, ascertain the cause of de-

ficiency, and monitor response to therapy. With normal Cbl absorption, oral administration of 3 mg to 5 mg may suffice. In patients with food-bound Cbl malabsorption due to achlorhydria, 50 mg to 100 mg cyano-Cbl given orally is often adequate. Patients with Cbl deficiency due to achlorhydria-induced food-bound Cbl malabsorption show normal absorption of crystalline B12 but are unable to digest and absorb Cbl in food due to achlorhydria. The more common situation is one of impaired absorption where parenteral therapy is required. A short course of daily or weekly therapy is often followed by monthly maintenance therapy (Table 1-3). If the oral dose is large enough, even patients with an


absorption defect may respond to oral Cbl. Inappropriate therapy with folate may result in partial and transient hematologic improvement but continued neurologic deterioration with delayed recognition of the Cbl deficiency. Patients with B12 deficiency are prone to develop neurologic deterioration following N2O anesthesia. This is preventable by prophylactic B12 given weeks before surgery in individuals with a borderline B12 level who are expected to receive N2O anesthesia. IM B12 should be given to patients with acute N2O poisoning. With chronic exposure, immediate cessation of exposure should be ensured. Response to treatment may relate to extent of involvement and delay in starting treatment (Healton et al, 1991). Remission correlates inversely with the time lapsed between symptom onset and therapy initiation. Most of the symptomatic improvement occurs during the first 6 months. Response of the hematologic derangements is prompt and complete. Reticulocyte count begins to rise within 3 days and peaks around 7 days. RCB count begins to rise by 7 days and is followed by a decline in mean corpuscular volume, with normalization by 8 weeks. MMA and Hcy levels normalize by 10 days. Cbl levels rise after injection regardless of the benefit. Hence, MMA and Hcy are more reliable ways to monitor response to therapy. In patients with severe B12 deficiency, replacement therapy may be accompanied by hypokalemia due to proliferation of bone marrow cells that utilize potassium. Response of the neurologic manifestations is more variable and may be incomplete. Hydroxo-Cbl has superior retention and may permit injections every 2 to 3 months. Advantages of delivering Cbl by the nasal or sublingual route are unproven. Oral preparations of intrinsic factor (IF) are available but

not reliable. Antibodies to IF may nullify its effectiveness in the intestinal lumen. Folic Acid Folic acid and its metabolites are essential cofactors for DNA synthesis (Figure 1-2). Folate is absorbed by saturable and unsaturable mechanisms. Nonspecific, unsaturable absorption predominates in the ileum. The saturable process is specific, occurs in the proximal small intestines, and is mediated by the reduced folate carrier. In the enterocyte, folate is converted into methyl-tetrahydrofolate (THF), and a carrier-mediated mechanism exports it into the bloodstream. Following cellular uptake, folate undergoes polyglutamation that permits its attachment to enzymes. Daily folate losses may approximate 1% to 2% of body stores. Therefore, a few months of poor nutrition can result in folate deficiency. Clinically significant depletion of normal folate stores may be seen within 3 months, more rapidly with low stores or coexisting alcoholism. Serum folate falls within 3 weeks after decrease in folate intake or absorption; RBC folate declines weeks to months later. Causes of deficiency. Folate deficiency rarely exists in the pure state. It is often associated with conditions that affect other nutrients. Hence, attribution of neurologic manifestations to folate deficiency requires exclusion of other potential causes. Populations at increased risk of folate deficiency include alcoholics, premature infants, and adolescents. Increased folate requirements are also seen in pregnancy, lactation, and chronic hemolytic anemia. Folate deficiency is seen with small bowel disorders associated with malabsorption such as tropical sprue, celiac disease, bacterial overgrowth syndrome, giardiasis, and inflammatory bowel disease. Folate absorption may be decreased in conditions associated

KEY POINTS:

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If the oral cobalamin dose is large enough, even patients with an absorption defect may respond to oral cobalamin. Patients with B12 deficiency are prone to develop neurologic deterioration following nitrous oxide anesthesia. Folate deficiency rarely exists in the pure state. It is often associated with conditions that affect other nutrients. Hence, attribution of neurologic manifestations due to folate deficiency requires exclusion of other potential causes.

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with reduced gastric secretions such as gastric surgery (partial gastrectomy) and atrophic gastritis. A number of drugs, such as aminopterin, methotrexate (amethopterin), pyrimethamine, trimethoprim, and triamterene act as folate antagonists and produce folate deficiency by inhibiting dihydrofolate reductase. Clinical significance. In adults with acquired folate deficiency, neurologic manifestations are rare and mild. The reason for this is unclear since methionine synthase requires folate as cosubstrate. The megaloblastic anemia due to folate deficiency is indistinguishable from that seen in Cbl deficiency. The occurrence and frequency of neurologic manifestations of folate deficiency have been a matter of debate (Green and Miller, 1999; Reynolds, 2002). They are likely less common as compared with the myeloneuropathy and cognitive symptoms associated with Cbl deficiency. The myeloneuropathy or neuropathy seen in association with folate deficiency is indistinguishable from Cbl deficiency. Folate deficiency has been associated with affective disorders. Congenital errors of folate metabolism can be related either to defective transport of folate through various cells or to defective intracellular utilization of folate due to some enzyme deficiencies. These are often associated with severe central neurologic dysfunction. Metabolic folate deficiency, as suggested by elevated plasma total Hcy levels that improve with folate therapy, can be seen in asymptomatic individuals (Green and Miller, 1999). The increased Hcy seen with folate deficiency has been associated with an increased risk of cardiovascular and cerebrovascular disease, but the precise significance of this awaits further studies. Investigations. Serum folate levels between 2.5 mg/L and 5 mg/L may be

indicative of a mildly compromised folate status. Erythrocyte folate is more reliable than plasma folate because its levels are less affected by short-term fluctuations in intake. However, RBC folate assay is subject to greater variation depending on the method and laboratory. Reticulocytes have a higher folate content than mature RBCs. Their presence can affect RBC folate levels as can blood transfusions. Plasma Hcy levels have been shown to be elevated in many patients with clinically significant folate deficiency. Management. In women of childbearing age with epilepsy, daily folate supplement of 0.4 mg is recommended for prophylaxis against neural tube defects. With documented folate deficiency, higher doses are required. Daily doses as high as 20 mg may be necessary in patients with malabsorption. Acutely ill patients may need parenteral administration in a dose of 1 mg to 5 mg. Coexisting Cbl deficiency should be ruled out before instituting folate therapy. Reduced folates such as folinic acid (N5-formylTHF) are required only when folate metabolism is impaired by drugs such as methotrexate or by an inborn error of metabolism. Plasma Hcy is likely the best biochemical tool for monitoring response to therapy; it decreases within a few days of instituting folate therapy but does not respond to inappropriate Cbl therapy. Since folate deficiency is generally seen in association with a broader dietary inadequacy, the associated comorbidities need to be addressed. Copper Copper functions as a prosthetic group in metalloenzymes such as copper/zinc superoxide dismutase, cytochrome c oxidase, and dopamine b-monooxygenase. These enzymes have a critical role in maintaining the structure and function of the nervous system. Copper absorption occurs


primarily in the small intestine. The Menkes P-type adenosine triphosphatase (ATPase) (ATP7A) is responsible for copper trafficking to the secretory pathway for efflux from enterocytes and other cells. Absorbed copper is bound to albumin and transported via the portal vein to the liver for uptake by liver parenchymal cells. Copper is then released into the plasma, and 95% of it is bound to ceruloplasmin. The Wilson P-type ATPase (ATP7B) is responsible for copper trafficking to the secretory pathway for ceruloplasmin biosynthesis and for endosome formation prior to biliary secretion. Excretion of copper into the gastrointestinal tract is the major pathway that regulates copper homeostasis and prevents deficiency or toxicity. Causes of deficiency. Because of coppers ubiquitous distribution and low daily requirement, acquired dietary copper deficiency is rare. Excessive zinc ingestion is a well-recognized cause of copper deficiency (Rowin and Lewis, 2005). Denture creams, if ingested in excess, can result in zinc-induced copper deficiency. Copper deficiency may occur in malnourished infants, nephrotic syndrome, and enteropathies associated with malabsorption. It may be a complication of prolonged total parenteral nutrition or enteral feeding. Copper deficiency following gastric surgery (for peptic ulcer disease or bariatric surgery) is increasingly recognized (Kumar et al, 2004a). Clinical significance. Menkes disease is the well-known copper deficiencyrelated disease in humans and is due to congenital copper deficiency. Copper deficiencyassociated myelopathy is well known in various animal species, but only in recent years have the neurologic manifestations of acquired copper deficiency in humans been recognized. The most common manifestation is that of a myelopathy or myeloneuropathy that

resembles the subacute combined degeneration seen with Cbl deficiency (Kumar, 2006; Kumar et al, 2004b; Rowin and Lewis, 2005) (Case 1-2). Also reported are CNS demyelination (Prodan et al, 2002) and optic neuritis (Gregg et al, 2002). Three reported patients had asymmetric weakness, distal sensory impairment, and electrodiagnostic evidence of denervation suggestive of lower motor neuron disease (Weihl and Lopate, 2006). Hyperzincemia of indeterminate significance may be present even in the absence of exogenous zinc ingestion (Kumar, 2006; Kumar et al, 2004b; Prodan et al, 2002). Copper and Cbl deficiency may coexist. Spinal cord MRI in patients with copper deficiency myelopathy may show increased signal on T2-weighted images, most commonly in the paramedian cervical cord (Figure 1-4A and 1-4B) (Kumar et al, 2006). The hematologic manifestations of acquired copper deficiency are well known and include anemia, neutropenia, and a left shift in granulocytic and erythroid maturation with vacuolated precursors, iron-containing plasma cells, and ringed sideroblasts in the bone marrow (Figure 1-4C, 1-4D, and 1-4E) (Gregg et al, 2002). The neurologic syndrome due to acquired copper deficiency may be present without the hematologic manifestations. Investigations. Laboratory indicators of copper deficiency include reduced serum copper or ceruloplasmin, and reduced urinary copper excretion, but these parameters are not sensitive to marginal copper status. Changes in serum copper usually parallel the ceruloplasmin concentration. Ceruloplasmin is an acute-phase reactant, and the rise in ceruloplasmin is probably responsible for the increase in serum copper seen in a variety of conditions such as pregnancy, oral contraceptive use, liver disease,

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Excessive zinc ingestion is a well-recognized cause of copper deficiency. Copper deficiency following gastric surgery is being increasingly recognized. The most common neurologic manifestation of acquired copper deficiency is that of a myelopathy or myeloneuropathy that resembles the subacute combined degeneration seen with cobalamin deficiency. Spinal cord MRI in patients with copper deficiency myelopathy may show increased signal on T2-weighted images, most commonly in the paramedian cervical cord.

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KEY POINT:

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The hematologic manifestations of acquired copper deficiency include anemia, neutropenia, and a left shift in granulocytic and erythroid maturation with vacuolated precursors, iron-containing plasma cells, and ringed sideroblasts in the bone marrow. The neurologic syndrome due to acquired copper deficiency may be present without the hematologic manifestations.

Case 1-2A 54-year-old woman is evaluated for a 2-year history of imbalance and distal lower limb paresthesias. She had gastric bypass surgery 14 years ago for obesity and since then has been on vitamin B12 replacement. Her neurologic examination is remarkable for a spastic ataxic gait with impaired perception of position at the toes and decreased perception of vibration up to the anterior superior iliac spine. Her ankle jerks are absent, knee jerks brisk, and plantar responses extensor. Her nerve conduction studies show a mild peripheral neuropathy. Somatosensory evoked potential studies show a central conduction delay that localizes to the cervical cord. Her spine MRI is unremarkable. Laboratory investigations show a mild normocytic anemia and neutropenia and normal B12 and MMA levels. Comment. Her clinical presentation is suggestive of a myeloneuropathy. Vitamin B12 deficiency is a common cause of a myeloneuropathy and is commonly seen after gastric bypass surgery. B12 supplementation is routinely recommended. A similar clinical presentation can also result from copper deficiency. Hence, it is imperative to look for copper deficiency in patients with a myeloneuropathy. Both copper and B12 deficiency can coexist, and a history of gastric surgery is a risk factor for both. In both conditions neurologic manifestations may be seen in the absence of hematologic derangement. Copper deficiency can also result from excess zinc ingestion. In some patients with copper-deficiency myelopathy, no cause for copper deficiency is evident. Even in patients with subacute combined degeneration due to B12 deficiency, deterioration despite adequate B12 supplementation should prompt a search for copper deficiency as a likely cause. The spine MRI may be normal or show an increased signal involving the dorsal column on T2-weighted MRI. Generally, oral copper supplementation improves copper levels. Response of the hematologic manifestations is prompt and complete, and neurologic deterioration is prevented.

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malignancy, hematologic disease, myocardial infarction, smoking, diabetes, uremia, and various inflammatory and infectious diseases. Treatment. In patients with zincinduced copper deficiency, discontinuing the zinc may suffice. Despite a suspected absorption defect, oral copper supplementation is generally the preferred route of supplementation. In most cases, oral administration of 2 mg of elemental copper a day seems to suffice. A comparable dose of elemental copper IV may be given. At times, prolonged oral therapy may fail to result in improvement, and parenteral therapy may be required. Initial parenteral administration followed by oral

therapy has also been used (Rowin and Lewis, 2005). A commonly employed regimen is administration of 6 mg of elemental copper a day orally for 1 week, 4 mg a day for the second week, and 2 mg a day thereafter (Kumar, 2006). Alternatively 2 mg of elemental copper IV may be administered for 5 days and periodically thereafter. Response of the hematologic parameters (including bone marrow findings) is prompt and often complete (Gregg et al, 2002; Kumar, 2006; Kumar et al, 2004b). Hematologic recovery may be accompanied by reticulocytosis. Recovery of neurologic signs and symptoms seen in association with copper deficiency is variable. Improvement in neurologic


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FIGURE 1-4

Sagittal (A) and axial (B) T2-weighted MRIs in a patient with copper deficiency showing increased signal in the paramedian aspect of the dorsal cervical cord. Bone marrow study (C, D, and E) in a patient with copper deficiency myelopathy showing vacuolated myeloid precursors (C). Iron staining (D and E) shows iron-containing plasma cells (D) and ringed sideroblasts (E).Panels A and B from Kumar N, Ahlskog JE, Klein CJ, Port JD. Imaging features of copper deficiency myelopathy: a study of 25 cases. Neuroradiology 2006;48(2):7883. Reprinted with permission from Springer Science and Business Media. Panels C and D reproduced with permission from Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc 2006;81(10):13711384. Panel E from Kumar N. Nutritional neuropathies. Neurol Clin 2007;25(1):209255. Copyright # 2007. Reprinted with permission from Elsevier.

Vitamin E deficiency may result from genetic defects in a-TTP (ataxia with vitamin E deficiency), in apolipoprotein B (homozygous hypobetalipoproteinemia), or in the microsomal triglyceride transfer protein (abetalipoproteinemia or Bassen-Kornzweig disease).

symptoms is generally absent although progression is typically halted (Kumar, 2006; Kumar et al, 2004b). Improvement, when present, is slight, often subjective, and preferentially involves sensory symptoms. Vitamin E The terms vitamin E and a-tocopherol are used interchangeably. Vitamin E serves as an antioxidant and free radical scavenger. Vitamin E is absorbed from the gastrointestinal tract by a nonenergy-requiring diffusion mechanism that requires bile acids, fatty acids, and monoglycerides for micelle formation. After uptake by enterocytes, all forms of dietary vitamin E are incorporated into chylomicrons. During chylomicron catabolism in plasma, vitamin E is transferred to circulating lipoproteins, which deliver it to tissues. The chylomicron remnants are taken up by the liver, which selects the a-tocopherol form for secretion into plasma in very low-density lipoproteins. This process requires the a-tocopherol transfer protein (TTP). Lipolysis of very lowdensity lipoprotein results in enrich-

ment of circulating lipoproteins with vitamin E, which is delivered to peripheral tissue. The majority of vitamin E in the human body is localized in the adipose tissue. Analysis of adipose tissue a-tocopherol content provides a useful estimate of long-term vitamin E intake. Most ingested vitamin E is eliminated by the fecal route. Causes of deficiency. Vitamin E absorption requires biliary and pancreatic secretions. Hence vitamin E deficiency is seen with chronic cholestasis and pancreatic insufficiency. Vitamin E deficiency is also seen with other conditions associated with malabsorption such as celiac disease, Crohn disease, cystic fibrosis, blind loop syndrome, bacterial overgrowth, and extensive small bowel resection. Vitamin E supplementation in total parenteral nutrition may be inadequate to maintain vitamin E stores. Vitamin E deficiency may also result from genetic defects in a-TTP (ataxia with vitamin E deficiency [AVED]), in apolipoprotein B (homozygous hypobetalipoproteinemia), or in the microsomal triglyceride transfer protein (abetalipoproteinemia or

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KEY POINT:

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The neurologic manifestations of vitamin E deficiency include a spinocerebellar syndrome with variable peripheral nerve involvement. The clinical features include cerebellar ataxia, hyporeflexia, proprioceptive, and vibratory loss, and in some patients an extensor plantar response. Ophthalmoplegia, ptosis, and pigmentary retinopathy have been reported. An associated myopathy may be present.

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Bassen-Kornzweig disease). An additional cause is defect in chylomicron synthesis and secretion (chylomicron retention disease). AVED is an autosomal recessive disorder in which isolated vitamin E deficiency occurs without generalized fat malabsorption or gastrointestinal disease. The defect lies in impaired incorporation of vitamin E into hepatic lipoproteins for tissue delivery. Mutations in the a-TTP gene on chromosome 8q13 are responsible (Cavalier et al, 1998). Patients with hypobetalipoproteinemia or abetalipoproteinemia have impaired secretion of chylomicrons or other apolipoprotein B (ApoB)-containing lipoproteins, specifically very low-density lipoproteins and low-density lipoproteins. Patients with homozygous hypobetalipoproteinemia have a defect in the ApoB gene, and ApoB-containing lipoproteins secreted into the circulation turn over rapidly. Patients with abetalipoproteinemia have a genetic defect in the microsomal triglyceride transfer protein that prevents normal lipidation of ApoB, and the secretion of ApoBcontaining lipoproteins is nonexistent. In chylomicron retention disease, impaired assembly and secretion of chylomicrons and chylomicron retention in the intestinal mucosa are present. Clinical significance. The neurologic manifestations of vitamin E deficiency include a spinocerebellar syndrome with variable peripheral nerve involvement (Sokol, 1988). The phenotype is similar to that of Friedreich ataxia. The clinical features include cerebellar ataxia, hyporeflexia, and proprioceptive and vibratory loss, and in some patients an extensor plantar response. Ophthalmoplegia, ptosis, and pigmentary retinopathy have been reported. An associated myopathy may be present. The neuropathy associated with vitamin E deficiency preferentially involves centrally directed fibers of large myelinated neurons. It is rare for vitamin E deficiency

to present as an isolated neuropathy. Somatosensory evoked potential studies may show evidence of central delay, and nerve conduction studies may show evidence of an axonal neuropathy. With retinal pigmentary degeneration, abnormal electroretinograms may be seen. Spinal MRI in patients with vitamin E deficiencyrelated myeloneuropathy may show increased signal in the cervical cord dorsal column (Vorgerd et al, 1996). In children with cholestatic liver disease, neurologic abnormalities appear as early as the second year of life. In AVED, hypolipoproteinemia, and abetalipoproteinemia, neurologic manifestations start by the first or second decade. Development of neurologic symptoms in adults with acquired fat malabsorption syndromes takes decades. In Bassen-Kornzweig disease, abetalipoproteinemia is associated with low vitamins A and E, retinitis pigmentosa, ataxia, areflexia, acanthocytes, and steatorrhea. Investigations. Serum vitamin E levels are dependent on the concentrations of serum lipids, cholesterol, and very low-density lipoprotein. Hyperlipidemia or hypolipidemia can independently increase or decrease serum vitamin E without reflecting similar alterations in tissue levels of the vitamin (Sokol et al, 1984). Effective serum a-tocopherol concentrations are calculated by dividing the serum a-tocopherol by the sum of serum cholesterol and triglycerides. Serum a-tocopherol concentrations may be in the normal range in patients with a-tocopherol deficiency due to cholestatic liver disease, a disorder that is also associated with high lipid levels. In patients with neurologic manifestations due to vitamin E deficiency, the serum vitamin E levels are frequently undetectable. Additional markers of fat malabsorption such as increased stool fat and decreased serum carotene levels may be present. Vitamin E


determination in adipose tissue has also been used. Management. In AVED, oral supplementation with vitamin E in a dose of 600 IU twice daily raises plasma concentration levels to normal. In patients with cholestasis and malabsorption, larger oral doses or IM administration may be required. An empiric approach is to start with a lower dose, increase it gradually, and, based on the clinical and laboratory response, consider a higher dose or parenteral formulation. Doses of a-tocopheryl acetate ranging from 200 mg per day to 2 g per day have been used. Thiamine The terms vitamin B1 and thiamine are used interchangeably. Following cellular uptake, thiamine is phosphorylated into thiamine diphosphate, the metabolically active form that is involved in several enzyme systems in the metabolism of carbohydrates and branchedchain amino acids. Thiamine deficiency results in reduced synthesis of highenergy phosphates and lactate accumulation. After gastrointestinal uptake, thiamine is transported by portal blood to the liver. Because of its short half-life and absence of significant storage amounts, a continuous dietary supply of thiamine is necessary. A thiaminedeficient diet may result in manifestations of thiamine deficiency in 2 to 3 weeks. Prolonged cooking of food, baking of bread, and pasteurization of milk are all potential causes of thiamine loss. Causes of deficiency. Thiamine deficiency may be seen with persistent vomiting, anorexia nervosa, dieting, malnutrition, severe gastrointestinal or liver disease, gastrointestinal surgery including bariatric surgery, and AIDS (Reuler et al, 1985). Thiamine deficiency in alcoholism results from inadequate dietary intake, reduced gastrointestinal absorption, reduced

liver thiamine stores, and impaired phosphorylation of thiamine to thiamine diphosphate. Thiamine requirement is dependent on the bodys metabolic rate, with the requirement being the greatest during periods of high metabolic demand or high glucose intake. Symptoms of thiamine deficiency may be seen in high-risk patients during periods of vigorous exercise and high carbohydrate intake, as with IV glucose administration and refeeding. In patients with a marginal nutritional status, increased metabolic demand, as is seen in hyperthyroidism, malignancy, and systemic infections, may precipitate symptoms. Pregnant and lactating women have increased thiamine requirements, and infant beriberi may be seen in infants who are breast-fed by thiamine-deficient asymptomatic mothers. Maternal thiamine deficiency may result from eating a staple diet of polished rice with foods containing thiaminase or antithiamine compounds. Clinical significance. The bestcharacterized human neurologic disorders related to thiamine deficiency are beriberi, Wernicke encephalopathy (WE), and Korsakoff syndrome (KS) (Reuler et al, 1985). The three forms of beriberi are dry beriberi, wet beriberi, and infantile beriberi. Dry beriberi is characterized by a sensorimotor, distal, axonal peripheral neuropathy often associated with calf cramps, muscle tenderness, and burning feet. Autonomic neuropathy may be present. A rapid progression of the neuropathy may mimic Guillain-Barre syndrome. Pedal edema may be seen due to coexisting wet beriberi. Wet beriberi is associated with a high-output congestive heart failure with peripheral neuropathy. Shoshin beriberi is the name given to a fulminant form that presents with tachycardia and circulatory collapse. Infantile beriberi is seen between 2 and 6 months of age and

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Thiamine deficiency may be seen with persistent vomiting, anorexia nervosa, dieting, malnutrition, severe gastrointestinal or liver disease, gastrointestinal surgery including bariatric surgery, and AIDS. The bestcharacterized human neurologic disorders related to thiamine deficiency are beriberi, Wernicke encephalopathy, and Korsakoff syndrome.

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KEY POINTS:

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The clinical features of Wernicke encephalopathy include a subacute onset of ocular palsies, nystagmus, gait ataxia, and confusion. Involvement of the hypothalamic and brainstem autonomic pathways may be associated with hypothermia and orthostatic hypotension. Typical MRI findings in Wernicke encephalopathy include increased T2 or proton density or diffusionweighted imaging signal around the third ventricle, periaqueductal midbrain, dorsomedial thalami, and mamillary bodies. Korsakoff syndrome is an amnesticconfabulatory syndrome that follows Wernicke encephalopathy and emerges as ocular manifestations and encephalopathy subside.

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may present with the cardiac, aphonic, or pseudomeningitic forms. The clinical features of WE include a subacute onset of ocular motor disturbance, gait ataxia, and confusion. This classic triad is infrequently present. Involvement of the hypothalamic and brainstem autonomic pathways may be associated with hypothermia and orthostatic hypotension. Skin changes, tongue redness, features of liver disease, and truncal ataxia may be present. Over 80% of patients may have an associated peripheral neuropathy. Typical MRI findings include increased T2 or proton density or diffusion-weighted imaging signal around the third ventricle, periaqueductal midbrain, dorsomedial thalami, and mamillary bodies (Doherty et al, 2002) (Figure 1-5). In the early stages contrast enhancement may be seen. Rarely, symmetric cortical involvement may occur. The signal abnormalities resolve with treatment, but shrunken mamillary bodies may persist as sequelae. The frequency of WE in various autopsy studies is far in excess of what would be expected from clinical studies (Reuler et al, 1985).

In some autopsy-confirmed cases of WE, the only clinical manifestation has been psychomotor retardation. Sudden death may occur and is related to hemorrhagic brainstem lesions. KS is an amnestic-confabulatory syndrome that follows WE and emerges as ocular manifestations and encephalopathy subside. Rarely, KS may be present without WE or may be present at the time of diagnosis of WE. Neuropathologic findings in WE include symmetric lesions of the periventricular regions of the thalamus and hypothalamus, mammillary bodies, nuclei at the level of the third and fourth ventricle, and superior cerebellar vermis. Investigations. Urinary thiamine excretion and serum thiamine levels may be decreased but do not accurately reflect tissue concentrations and are not reliable indicators of thiamine status. The preferred tests are the erythrocyte transketolase activation assay or measurement of thiamine diphosphate in RBC hemolysates using high-performance liquid chromatography. The erythrocyte transketolase activation assay is an assay of functional

34

A

FIGURE 1-5

Brain MRI (fluid-attenuated inversion recovery) in a patient with Wernicke encephalopathy with increased signal involving the mammillary body (A, long arrow), periaqueductal gray (A, short arrow), and medial thalamus (B, arrow head). C, Diffusion-weighted imaging in a patient with Wernicke encephalopathy showing increased signal involving the medial thalamus and hypothalamus that was associated with a reduced apparent diffusion coefficient. The signal change was less apparent on T2-weighted imaging.Reprinted with permission from Doherty MJ, Watson NF, Uchino K, et al. Diffusion abnormalities in patients with Wernicke encephalopathy. Neurology 2002;58(4):655657. Copyright # 2002, AAN Enterprises, Inc.


status and is based on measurement of transketolase activity in hemolysates of RBCs in the absence of (and in the presence of) added excess cofactor (thiamine diphosphate). Since these laboratory abnormalities normalize quickly, a blood sample should be drawn before initiation of treatment. Management. IV glucose infusion in patients with thiamine deficiency may consume the available thiamine and precipitate an acute WE. At-risk patients should receive parenteral thiamine prior to administration of glucose or parenteral nutrition. Patients suspected of having beriberi or WE should promptly receive parenteral thiamine. The recommended dose of thiamine in beriberi is 100 mg IV followed by 100 mg IM daily for 5 days and permanent oral maintenance. The parenteral form is used when doubt exists about adequate gastrointestinal absorption. In wet beriberi, a rapid improvement is seen with clearing of symptoms within 24 hours. Improvement in motor and sensory symptoms takes weeks or months. Patients with WE may need higher doses of thiamine. Response in WE is variable. Apathy and lethargy improve over days or weeks. Even with thiamine treatment the mortality is 10% to 20%. As the global confusional state recedes, some patients are left with a KS. Ophthalmoplegia improves rapidly, but a fine horizontal nystagmus may persist. Improvement in gait ataxia and memory is variable and often delayed. Vitamin A Vitamin A refers to retinol. The term retinoids refers to vitamin A derivatives such as retinal (vitamin A aldehyde), retinoic acid (vitamin A acid), and the carotenoids. Vitamin A is essential for visual function. It influences growth and tissue differentiation and is required for maintenance of epithelial cell integrity. In the intestinal mucosa, retinol is

esterified to retinyl palmitate, which is incorporated into chylomicrons and transported into the general circulation. Vitamin A is stored in the liver in the form of retinyl palmitate and released from the liver by hydrolysis. Causes of deficiency. Nutritional deficiency is seen when the diet consists of rice and wheat (grains lacking beta-carotene). Dietary deficiency may be seen in alcoholics, older adults, and individuals who are poor. Vitamin A deficiency is seen in conditions associated with fat malabsorption such as celiac disease, pancreatitis, and cholestatic liver disease. Clinical significance. Vitamin A deficiency causes night blindness and dryness and keratinization of the cornea and conjunctiva. White, foamy spots on the conjunctiva due to sloughed cells may be seen (Bitot spots). Other manifestations include impaired sense of taste, follicular hyperkeratosis of the skin, and keratinization of the respiratory, gastrointestinal, and urinary tracts. Excess ingestion of carotenes causes yellow skin pigmentation. Excess vitamin A ingestion causes dry skin, cheilitis, brittle nails, alopecia, petechiae, painful joints, anorexia, fatigue, nausea, diarrhea, and hepatotoxicity. Neurologic manifestations include headache, insomnia, irritability, papilledema, and pseudotumor cerebri. Investigations. Normal vitamin A levels range from 30 mg/dL to 65 mg/dL. Levels of less than 10 mg/dL are clearly low and over 100 mg/dL clearly high. Management. Prophylactically treating high-risk infants and children with large oral doses of vitamin A prevents development of a deficient state. In the setting of malabsorption, oral vitamin A supplementation is undertaken to normalize plasma levels. Niacin Niacin in humans is an end product of tryptophan metabolism. It is converted

KEY POINTS:

A

IV glucose infusion in patients with thiamine deficiency may consume the available thiamine and precipitate an acute Wernicke encephalopathy. At-risk patients should receive parenteral thiamine prior to administration of glucose or parenteral nutrition. Excess vitamin A ingestion causes dry skin, cheilitis, brittle nails, alopecia, petechiae, painful joints, anorexia, fatigue, nausea, diarrhea, and hepatotoxicity. Neurologic manifestations include headache, insomnia, irritability, papilledema, and pseudotumor cerebri.

A

35



KEY POINT:

A

Unexplained progressive encephalopathy in alcoholics that is not responsive to thiamine should raise the possibility of pellagra. The peripheral neuropathy seen in pellagra is indistinguishable from the peripheral neuropathy seen with thiamine deficiency.

36

into nicotinamide adenine dinucleotide (NAD) and its reduced form (NAD phosphate), coenzymes important in carbohydrate metabolism. Niacin and its amide are absorbed through the intestinal mucosa by simple diffusion. Niacin and nicotinamide are metabolized by separate pathways. Complexed and free niacin are taken up by tissue, and niacin is retained by metabolic trapping to NAD. Causes of deficiency. Pellagra, the condition caused by niacin deficiency, is rare in developed countries. Niacin deficiency is predominantly seen in populations dependent on corn as the primary carbohydrate source. Corn lacks niacin and tryptophan. Nonendemic pellagra may rarely be seen with alcoholism and malabsorption. Pellagra may also be seen in the carcinoid syndrome in which tryptophan is converted to serotonin instead of being used in niacin synthesis. Biotransformation of tryptophan to nicotinic acid requires several vitamins and minerals such as B2, B6, iron, and copper. Diets deficient in these nutrients can predispose to pellagra. Isoniazid (INH) depletes B6 and can trigger pellagra. Excess of neutral amino acids, such as leucine, in the diet can compete with tryptophan for uptake and predispose to niacin deficiency by impairing its synthesis from tryptophan. Hartnup syndrome is an autosomal recessive disorder characterized by impaired synthesis of niacin from tryptophan and results in pellagralike symptoms. Nicotinamide deficiency has also been described in some disorders of the alimentary tract. Bacterial colonization of the small intestines can lead to conversion of dietary tryptophan to indoles. Reversible nicotinamide-deficiency encephalopathy has been described in a patient with jejunal diverticulosis. Clinical significance. Pellagra affects the gastrointestinal tract, skin, and nervous system. Skin changes in-

clude a reddish-brown hyperkeratotic rash, which has a predilection for the face, chest, and dorsum of the hands and feet. Gastrointestinal manifestations include anorexia, abdominal pain, diarrhea, and stomatitis. Reported neurologic manifestations include a confusional state, which may progress to coma, spasticity, and myoclonus. Unexplained progressive encephalopathy in alcoholics that is not responsive to thiamine should raise the possibility of pellagra (Serdaru et al, 1988). The peripheral neuropathy seen in pellagra is indistinguishable from the peripheral neuropathy seen with thiamine deficiency. Nonendemic pellagra tends to lack dermatitis and has features similar to those of alcoholic pellagra (Serdaru et al, 1988). Investigations. The most reliable and sensitive measures of niacin status are urinary excretion of the methylated metabolites N1-methyl-nicotinamide and its 2-pyridone derivative (N1-methyl-2pyridone-5-carboxamide). No sensitive and specific blood measures of niacin status exist. It has been suggested that measures of erythrocyte NAD and plasma metabolites may serve as markers of niacin status. Management. Oral nicotinic acid in a dose of 50 mg 3 times a day or parenteral doses of 25 mg 3 times a day are used for treatment of symptomatic patients. Nicotinamide has comparable therapeutic efficacy in pellagra. Advanced stages of pellagra can be cured with IM nicotinamide given in doses of 50 mg to 100 mg 3 times a day for 3 to 4 days, followed by similar quantities orally. Vitamin B6 The term pyridoxine is generally used synonymously with vitamin B6. Pyridoxal and pyridoxamine are two other naturally occurring compounds that have comparable biological activity. All


three compounds are readily converted to pyridoxal phosphate, which serves as a coenzyme in many reactions involved in the metabolism of amino acids, lipids, nucleic acid, one-carbon units, and in the pathways of gluconeogenesis and neurotransmitter and heme biosynthesis. Meat, fish, eggs, soybeans, nuts, and dairy products are rich in vitamin B6. Starchy vegetables, noncitrus fruits, and whole grain cereal products are additional sources. Causes of deficiency. Vitamin B6 deficiency is seen with B6 antagonists such as INH, cycloserine, hydralazine, and penicillamine. Individuals at risk of developing vitamin B6 deficiency include chronic alcoholics, pregnant and lactating women, and older adults. Plasma pyridoxal phosphate levels are reduced in celiac disease, inflammatory bowel disease, and renal disease. Clinical significance. Dietary deficiency of pyridoxine or congenital dependency on pyridoxine may manifest as infantile seizures. In infants, pyridoxine deficiency may manifest as irritability and increased startle response. Adults are much more tolerant of pyridoxine defi

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