01 - NEUROGASTROENTEROLOGY

NEUROGASTROENTEROLOGYNeeraj Kumar

ABSTRACT

The interrelationship between neurology and the gastrointestinal system isdiscussed in this chapter, which is divided into four sections: (1) neurologicmanifestations of diseases that typically involve the gastrointestinal tract but mayinvolve the nervous system in association with or independent of gastrointestinalinvolvement (celiac disease, Whipple disease, and inflammatory bowel disease); (2)neurologic manifestations related to deficiency of key nutrients, such as vitaminB12, folate, copper, vitamin E, thiamine, and others; (3) nervous system disordersincluding cerebrovascular disease, extrapyramidal and spinal cord disorders, anddisorders of the peripheral and autonomic nervous system that are associated withgastrointestinal manifestations such as dysphagia, gastroparesis, and constipation;and (4) the increasingly important topic of neurologic complications related togastric surgery. The interested reader is directed to four recent reviews onneurogastroenterology for additional information (Kumar, 2007; Murray and Ross,2004; Perkin and Murray-Lyon, 1998; Skeen, 2002).

Continuum Lifelong Learning Neurol 2008;14(1):13–52.

NEUROLOGIC MANIFESTATIONSOF SPECIFIC GASTROINTESTINALDISORDERS

Celiac Disease

Celiac disease is an immune-mediatedenteropathy triggered by the ingestionof gluten-containing grains in genet-ically susceptible individuals (Craiget al, 2007; Farrell and Kelly, 2002;Rostom et al, 2006). It is characterizedby mucosal inflammation and resul-tant malabsorption. Celiac disease canpresent with intestinal or extraintesti-nal symptoms (like the skin rash ofdermatitis herpetiformis) or may evenbe detected in asymptomatic individ-uals. The diagnostic guidelines forceliac disease have required the pres-ence of characteristic lesions on smallbowel biopsy and demonstration ofclinical improvement following elimi-nation of gluten from the diet. Recentpopulation-based studies suggest thatsubclinical celiac disease may be muchmore common than previously recog-nized (Fasano et al, 2003). With aware-

ness of a high disease prevalence hascome the recognition of a broad spec-trum of clinical presentations.

Neurologic complications may occurin 10% of patients with well-establishedceliac disease. In earlier reports, neu-rologic manifestations associated withceliac disease were attributed to spe-cific nutrient deficiencies (iron, folate,calcium and vitamin D, vitamin A,vitamin E, copper, pyridoxine, vitaminK, and vitamin B12). More recentlythe focus has been on immunologicmechanisms. Severe malabsorption isgenerally rare in patients with a neuro-logic presentation. Documentation ofpatients with neurologic manifestationsand elevated autoantibodies associatedwith celiac disease (primarily antiglia-din), often without gastrointestinalmanifestations, has led to the sugges-tion that gluten sensitivity (as opposedto celiac disease) can cause neurologicmanifestations without gastrointestinalsymptoms or small bowel biopsychanges (Hadjivassiliou et al, 2002b).In some of these cases, neurologic

13

KEY POINT:

A Neurologic

complications

may occur in 10%

of patients with

well-established

celiac disease.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

manifestations may be followed by in-testinal manifestations.

Ataxia and peripheral neuropathy arethe best-characterized neurologic mani-festations of celiac disease (Chin et al,2003; Chin et al, 2006; Hadjivassiliouet al, 2002b). The types of neuropathydescribed include pure sensory, puremotor, or mixed; axonal or mixed axo-nal and demyelinating; multifocal orsymmetric; and small fiber or large fi-ber or mixed. In patients with smallfiber neuropathy, frequent facial in-volvement and a non–length-dependentpattern on skin biopsy findings maysuggest a sensory ganglionopathyor an immune-mediated neuropathy(Brannagan et al, 2005). Cognitiveimpairment, including rapidly pro-gressive dementia, may also be seenin association with celiac disease (Huet al, 2006). Other reported mani-festations include a wide spectrumof psychiatric disorders, myoclonicataxia, inflammatory myopathy, iso-lated ocular myopathy, inclusionbody myositis, neuromyotonia, cho-rea, headaches with transient deficitsand MRI evidence of white matterabnormalities, brainstem encephali-tis, multifocal leukoencephalopathy,myelopathy, neuromyelitis optica,internuclear ophthalmoplegia, epi-lepsy with or without occipital calci-fication, and others. The significanceof some of these associations isindeterminate.

The concept of gluten sensitivity andrelated neurologic disorders is contro-versial. Ataxia is the best-characterizedneurologic manifestation of glutensensitivity (Hadjivassiliou et al, 2003).MRI evidence of cerebellar atrophy iscommonly seen. Antigliadin antibody(AGA) positivity is commonly seen inpatients with apparently idiopathicsporadic ataxia. The ataxia is a resultof immunologic damage to the cere-bellum, posterior columns of the spi-nal cord, and peripheral nerves. AGAs

cross-react with epitopes on Purkinjecells, and patients with gluten ataxiamay have antibodies against Purkinjecells (Hadjivassiliou et al, 2002a). Pe-ripheral neuropathy is the secondcommonest manifestation of glutensensitivity (Hadjivassiliou et al, 2006).Gluten sensitivity may be linked toa substantial number of idiopathicaxonal neuropathies. Peripheral nerveinvolvement can be associated withcerebellar involvement or may occurindependently.

Circulating immunoglobulin (Ig) Gand IgA antibodies to gliadin are oftenpresent in patients with celiac disease.The specificity of AGA for celiac diseaseis limited by the fact that up to 10% to20% of the general population mayhave these antibodies. The precisepathogenic significance of these anti-bodies in nervous system disorders isunclear. Serum IgG AGA demonstratesgood sensitivity, and IgA AGA hasmarginally better specificity for celiacdisease. The combination is useful inscreening patients at risk. Serologic ab-normalities may resolve and histologicfindings may improve with removal ofgluten from the diet. IgA AGA testingis also useful to monitor dietary com-pliance. IgA endomysial antibody(EMA) and IgG tissue transglutaminaseantibody (tTGA) are more specific forthe disease. The reported specificity ofthese antibodies approaches 100% andover 95%, respectively. IgA deficiency isoften associated with celiac disease.Hence, serologic testing for the IgAantibodies associated with celiac dis-ease will be falsely negative in patientswith selective IgA deficiency and celiacdisease. In cases of selective IgAdeficiency, IgG EMA and/or IgG tTGAmay be obtained, but the IgG-basedtests are less sensitive and specific thanthe IgA-based tests in those withnormal levels of IgA. In patients withsuspected celiac disease with a negativeIgA EMA or IgA tTGA, serum IgA

14

KEY POINTS:

A Ataxia and

peripheral

neuropathy are

the best-

characterized

neurologic

manifestations

of celiac disease.

A The concept of

gluten sensitivity

and related

neurologic

disorders is

controversial.

A 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.

"NEUROGASTROENTEROLOGY


determination should be the next step.AGAs have been described in patientswith celiac disease and neurologicmanifestations (Chin et al, 2003). Thesignificance of this is unclear as theseantibodies may be present in patientswith celiac disease without neurologicsymptoms. Approximately 95% ofpatients with celiac disease have HLADQ2, and the remainder have HLADQ8. If celiac disease is suspecteddespite negative serologic tests, thepresence of these disease-associatedalleles can be looked for and smallintestinal mucosal biopsy considered.Multiple biopsies should be taken fromthe second part of the duodenum orbeyond. The pathologic abnormality inthe small intestine is characteristic, butnot specific, and includes partial villousatrophy, crypt lengthening, increasein lamina propria, and intraepitheliallymphocytes.

Reports in the literature on theeffect of a gluten-free diet on neuro-logic manifestations are conflicting.Further, strict adherence to a gluten-free diet is difficult to achieve and iscomplicated by a lack of clear food-labeling policy. Also, a group ofpatients with celiac disease is knownto be resistant to a gluten-free diet(‘‘refractory sprue’’). While neurologicimprovement on a gluten-free diet hasbeen reported, persistence or progres-sion of neurologic symptoms despite agluten-free diet has often been noted.Generally, response of the neurologicmanifestations is less robust to agluten-free diet than that of gastroin-testinal manifestations. In light of theseuncertainties, the best approach seemsto be to offer a gluten-free diet topatients with a recognized neurologicpresentation and celiac disease. Insome patients with neurologic mani-festations, immunosuppressive therapyhas been tried empirically (Chin et al,2006). Coexisting vitamin or mineraldeficiencies in association with celiac

disease should be looked for andappropriately treated (Case 1-1).

Whipple Disease

Whipple disease (WD) is a chronic,relapsing, multisystem disease due toinfection with Tropheryma whippleithat has a predilection for middle-aged men and affects the gastroin-testinal, musculoskeletal, neurologic,cardiopulmonary, and lymphatic sys-tems. Skin hyperpigmentation may beseen in up to a third of patients. Aprodromal stage characterized byarthralgias and fever is followed by asteady-state stage with weight loss,diarrhea, and malabsorption.

CNS symptoms may be seen in ap-proximately 15% of patients with WDand in some can be the initial or onlymanifestation. Asymptomatic neurologicinvolvement has been shown by dem-onstration of DNA from T. whipplei inCSF by PCR assay (von Herbay et al,1997). The CNS is also a site of symp-tomatic relapse following apparentlysuccessful therapy, often with antibi-otics like tetracycline that have poorpenetration into the CNS. A wide spec-trum of neurologic manifestations maybe seen (Fenollar et al, 2007; Louis et al,1996) (Table 1-1). Psychiatric symp-toms such as depression or personal-ity change and cognitive impairment,including dementia, are commonlyseen. Oculomasticatory myorhythmiaand oculofacial-skeletal myorhythmiaare considered pathognomic for CNSWD and are often accompanied by asupranuclear vertical gaze palsy. Oculo-masticatory myorhythmia refers topendular vergence oscillations that oc-cur with slow rhythmic mouth andpalatal movements. Oculofacial-skeletalmyorhythmia refers to slow pendularvergence oscillations that occur syn-chronously with rhythmic movementsof the mouth, face, and extremitiesand persist during sleep. Myoclonusis seen in one fourth of patients with

15

KEY POINTS:

A CNS symptoms

may be seen in

approximately

15% of patients

with Whipple

disease and in

some can be

the initial or only

manifestation.

A Oculomasticatory

myorhythmia

and oculofacial-

skeletal

myorhythmia

are considered

pathognomic

for CNS Whipple

disease and

are often

accompanied by

a supranuclear

vertical gaze

palsy.


neurologic involvement. Symptoms sug-gestive of hypothalamic involvementsuch as polydipsia, hyperphagia, changesin the sleep-wake cycle, and a change inlibido may be present. Cerebellar ataxiamay be more common than was ear-lier recognized (Matthews et al, 2005).Other neurologic manifestations thathave been reported to occur in CNSWD include pyramidal and extrapyrami-dal manifestations, headache, progres-sive deafness, a strokelike syndrome, anda proximal myopathy. Ocular manifesta-tions may include uveitis with vitreousopacities and papilledema. Isolated cer-vical myelitis with a spinal presentation ofWD is rare (Figure 1-1A) (Messori et al,2001).

Diagnosis and treatment of definiteCNS WD should be based on thepresence of pathognomic signs (oculo-masticatory myorhythmia or oculofa-cial-skeletal myorhythmia) or positivebiopsy or PCR results (Table 1-2)(Louis et al, 1996). Because of theprotean manifestations and variabil-ity in organ involvement, a high in-dex of suspicion is required and thediagnosis usually depends on addi-tional diagnostic studies. Possible CNSWD should be considered in the set-ting of unexplained systemic symptomsand neurologic signs (supranuclearvertical gaze palsy, rhythmic myoclo-nus, dementia with psychiatric symp-toms, or hypothalamic manifestations).

16

Case 1-1A 46-year-old man is evaluated for a 5-year history of gait difficultyand a 2-year history of incoordination with his hands. He has no pastor present history of gastrointestinal symptoms. His examination isremarkable for a wide-based ataxic gait and a positive finger-noseand heel-shin test. His speech has a scanning quality. Muscle strengthtesting, reflexes, and sensations are normal. His brain MRI showsmoderate cerebellar atrophy. His laboratory investigations are positivefor IgA AGAs.

Comment. Circulating IgA antibodies to gliadin are often present inpatients with celiac disease. However, the specificity of AGA detectionis limited by the fact that up to 10% to 20% of the general populationmay have these antibodies. Hence, the presence of AGAs in a patientwith a progressive cerebellar syndrome does not necessarily indicatethat they are causative. Other causes of cerebellar ataxia, such asparaneoplastic cerebellar degeneration, should be sought. The significanceof the positive AGAs should be further evaluated with IgA EMA andIgG tTGA, which are more specific for celiac disease. Approximately 95%of patients with celiac disease have HLA DQ2, and the remainder haveHLA DQ8. For diagnostic clarification a small bowel biopsy or HLAtyping may be indicated. Neurologic manifestations of celiac diseasemay precede gastrointestinal manifestations or occur in the absence ofgastrointestinal symptoms. If celiac disease is diagnosed, the possibilityof 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 recognizedneurologic presentation of celiac disease. The role of immunosuppressivetherapy has not been established.

While neurologic manifestations can be seen in 10% of patients withceliac disease, the concept of neurologic disease and gluten sensitivityremains controversial.



Blood studies in WD may show ane-mia, leukocytosis, eosinophilia, ele-vation of acute-phase reactants, andlaboratory evidence of malabsorption.Radiographic assessment undertakenbecause of gastrointestinal symptomsmay show abdominal lymphadenop-athy, thickening of mucosal folds,hepatosplenomegaly, or ascites. Mildelevations of CSF protein and mildpleocytosis are common, but the CSFmay be normal. Increased CSF immu-noglobulin production or oligoclonalbands may be seen. The CSF cytolo-gic hallmark in WD is the presenceof histiocytes with periodic acid-Schiff(PAS)-positive, granular, sometimes

sickle-shaped particles in the cytoplasm(von Herbay et al, 1997). Brain MRImay show a high signal intensity onT2-weighted images involving one ormore of the following structures: thehypothalamus, optic chiasm, mamillarybody, medial temporal lobes, uncus,and cerebellar or cerebral peduncles(Figure 1-1B) (Messori et al, 2001).Due to the patchy involvement, brainbiopsy is often a low-yield procedure.Patients with possible CNS WD shouldundergo small bowel biopsy (Louiset al, 1996). Up to one third of patientswith CNS WD may have a negativesmall bowel biopsy. Endoscopy mayshow pale yellow mucosa alternatingwith erythematous mucosa in the post-bulbar region of the duodenum andjejunum (Marth and Raoult, 2003). Bi-opsy samples should be taken fromthe proximal and distal duodenum orthe jejunum. Bowel wall infiltration isassociated with widening and flatten-ing of the villi, with dilated lactealscontaining yellow lipid deposits. On

17

FIGURE 1-1 A, Sagittal fast spin-echo T2-weightedcervical spine MRI showing an enlarged andinhomogeneously hyperintense spinal cord

in a patient with an unusual spinal presentation of Whippledisease. B, Axial fast spin-echo T2-weighted brain MRIshowing hyperintense lesions involving the middle cerebellarpeduncles in a patient with Whipple disease (same patient asin A; brain MRI showed abnormalities 3 years later).

Adapted from Messori A, Di Bella P, Polonara G, et al. An unusual spinalpresentation of Whipple disease. AJNR Am J Neuroradiol 2001;22(5):1004–1008. Copyright # 2001, American Society of Neuroradiology.

TABLE 1-1 Clinical Featuresof NeurologicWhipple Disease

Number of Patients 84

Cognitive changes 71%

Altered level ofconsciousness

50%

Supranuclearophthalmoplegia

51%

Psychiatric signs 44%

Upper motor neuron signs 37%

Hypothalamicmanifestations

31%

Cranial nerveabnormalities

25%

Myoclonus 25%

Seizures 23%

Ataxia 20%

Oculomasticatory oroculofacial-skeletalmyorhythmia

20%

Sensory deficit 12%

Adapted from Louis ED, Lynch T, Kaufmann P,et al. Diagnostic guidelines in central nervoussystem Whipple’s disease. Ann Neurol 1996;40(4):561–568. Copyright # 1996, with permis-sion of John Wiley & Sons, Inc.

KEY POINTS:

A 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.

A Up to one third

of patients with

CNS Whipple

disease may have

a negative small

bowel biopsy.


light microscopy examination, PAS-stained small biopsy specimen showsmagenta-stained inclusions within mac-rophages of the lamina propria. ThePAS-positive intracellular inclusions arenonspecific. The bacteria can be dif-ferentiated from the intracellular in-clusions of Mycobacterium aviumcomplex, which, unlike the Whipplebacterium, is acid-fast positive. Electronmicroscopy may detect the distinctive,rod-shaped, trilaminar cell wall ofT. whipplei. Noncaseating, epithelioid-cell, sarcoidlike granulomas may bepresent in lymphatic tissue, gastrointes-tinal tract, bone marrow, and othertissues. These are often PAS-negative.Immunohistochemical staining or auto-immunochemical staining for antibodiesagainst T. whipplei is more sensitive andspecific than PAS staining but is notwidely available. Recent developmentsusing molecular analysis have allowedPCR amplification of the 16s ribosomalRNA sequences that are specific forWhipple’s organism and permits identi-fication of the infection from a variety oftissues or body fluids, including periph-eral blood (Fenollar et al, 2007). Whenamplified product is detected, thepresence of T. whipplei should beconfirmed by sequencing or by usingfluorescence-labeled oligonucleotidehybridization probes in a real-time PCRassay. Prevalence of T. whipplei induodenal biopsy specimens, saliva,stool, and blood from healthy personsis controversial (Marth and Raoult,2003).

The prognosis for patients with CNSinvolvement is poor. One fourth ofsuch patients die within 4 years, andone fourth have major sequelae. Therecommended treatment is oral admin-istration of 160 mg of trimethoprimand 800 mg of sulfamethoxazole twiceper day for 1 to 2 years, usuallypreceded by parenteral administrationof streptomycin (1 g per day) togetherwith penicillin G (1.2 million U per day)

18

TABLE 1-2 Guidelines forDiagnosticScreening, Biopsy,and Treatment ofCNS Whipple Disease

" Definite CNS Whipple Disease

Must have any one of thefollowing three criteria:

(1) Oculomasticatorymyorhythmia or oculofacial-skeletal myorhythmia

(2) Positive tissue biopsy

(3) Positive PCR analysis

If histologic or PCRanalysiswasnotperformed on CNS tissue, then thepatient must also demonstrateneurologic signs. If histologic orPCR analysis was performed onCNS tissue, then the patient neednot demonstrate neurologic signs(ie, asymptomatic CNS infection).

" Possible CNS Whipple Disease

Must have one of four systemicsymptoms not due to anotherknown etiology:

(1) Fever of unknown origin

(2) Gastrointestinal symptoms(steatorrhea, chronicdiarrhea, abdominaldistention, or pain)

(3) Chronic migratoryarthralgias, orpolyarthralgias

(4) Unexplainedlymphadenopathy, nightsweats, or malaise

Also must have one of fourneurologic signs not due toanother known etiology:

(1) Supranuclear vertical gaze palsy

(2) Rhythmic myoclonus

(3) Dementia with psychiatricsymptoms

(4) Hypothalamic manifestations

Adapted from Louis ED, Lynch T, Kaufmann P, et al.Diagnostic guidelines in central nervous system Whipple’sdisease. Ann Neurol 1996;40(4):561–568. Copyright# 1996, with permission of John Wiley & Sons, Inc.

KEY POINT:

A 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.



or ceftriaxone (2 g daily) for 2 weeks(Fenollar et al, 2007).

Inflammatory Bowel Disease

Extraintestinal manifestations and com-plications of inflammatory bowel dis-ease (ulcerative colitis or Crohndisease) may precede or follow thegastrointestinal manifestations and oc-cur independently of exacerbation ofbowel symptoms. Neurologic manifes-tations seen in association with inflam-matory bowel disease may be related tothe primary disease, be coincidental, orbe a consequence of disease complica-tions or treatment. In a retrospectivereview of 638 patients with inflam-matory bowel disease, neurologic in-volvement was noted in 10 patientswith Crohn disease and 9 patients withulcerative colitis (Lossos et al, 1995). Innearly three fourths of these patients,neurologic involvement started within6 years of the diagnosis of inflam-matory bowel disease. Over half ofthese patients had other extraintestinalmanifestations. Peripheral nervous sys-tem disorders were most commonlyseen and included acute inflamma-tory demyelinating polyneuropathy(3), mononeuritis multiplex (1), bibra-chial plexopathy (1), myasthenia gravis(1), and myopathy (3). One patient hadthe Melkerson-Rosenthal syndrome (anidiopathic syndrome characterized byrecurrent facial swelling, relapsing facialparalysis, and fissured tongue), and fivehad a myelopathy. Cerebrovascularmanifestations included venous throm-bosis sinus (2), recurrent transientischemic attacks (1), and recurrentstrokes (1). The incidence of arterialor venous thromboses is increased inpatients with inflammatory bowel dis-ease, and they often occur with diseaseexacerbation, possibly secondary to ahypercoagulable state or associatedvasculitis. Patients with inflammatorybowel disease may also have chronic

inflammatory demyelinating peripheralneuropathy, multifocal motor neurop-athy, small or large fiber sensory axonalsensory peripheral neuropathy, orlarge fiber axonal sensorimotor pe-ripheral neuropathy (Gondim et al,2005). Both demyelinating and axonalneuropathies may show response toimmunotherapy (Gondim et al, 2005).Nonenhancing, hyperintense focal whitematter lesions have been reported inthe brain of patients with inflammatorybowel disease and may represent anextraintestinal manifestation (Geissleret al, 1995). They are more common inolder patients and in those with longerdisease duration and are unrelated tothe presence of cardiovascular riskfactors. An increased concurrence ofinflammatory bowel disease and mul-tiple sclerosis has been shown inOlmsted County using the databaseof the Rochester Epidemiology Project(Kimura et al, 2000).

Tropical Sprue

Tropical sprue is a chronic diarrhealillness of presumed infectious etiologythat occurs in individuals who reside inor have been to the tropics. Neurologicmanifestations of tropical sprue includesubacute combined degeneration, pe-ripheral neuropathy, myopathy, tetany,night blindness, and mental changesand are likely a consequence of nutri-ent deficiencies secondary to chronicmalabsorption (Iyer et al, 1973).

Campylobacter jejuni Infection

Campylobacter jejuni is the mostcommon cause of bacterial gastroen-teritis in developed countries. Nonspe-cific prodromal symptoms are followedby a diarrheal illness, and after a briefincubation period Guillain-Barre syn-drome may result. Up to 26% ofpatients with Guillain-Barre or MillerFisher syndrome may have evidence of

19

KEY POINT:

A 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.


C. jejuni infection (Rees et al, 1995).The resulting Guillain-Barre syndromeis associated with axonal degeneration,slow recovery, and residual disability. Aseasonal form of acute motor axonalneuropathy in rural areas of China isalso frequently associated with IgG andIgM antibodies against C. jejuni.

NEUROLOGIC MANIFESTATIONSRELATED TO SPECIFIC NUTRIENTDEFICIENCIES

Optimal functioning of the central andperipheral nervous systems is depen-dent on a constant supply of appropri-ate nutrients. Neurologic signs occurlate in malnutrition. Neurologic con-sequences of nutritional deficienciesdo not affect only individuals living inunderdeveloped countries. Those atrisk in developed countries includepoor, homeless, and elderly individu-als; patients on prolonged inadequateparenteral nutrition; individuals withfood fads or eating disorders such asanorexia nervosa and bulimia; individ-uals suffering from malnutrition sec-ondary to chronic alcoholism; andpatients with malabsorption syn-dromes such as sprue, celiac disease,inflammatory bowel disease, and per-nicious anemia (PA). Not infrequentlymultiple nutritional deficiencies co-exist. Prognosis depends on promptrecognition and institution of appro-priate therapy. Table 1-3 summarizesthe salient features of neurologicallysignificant nutrient deficiencies.

Protein and calorie deficiency ininfants and children in underdevelopedcountries results in two related dis-orders: marasmus and kwashiorkor.Marasmus is due to caloric insufficiencyand results in growth failure and ema-ciation in early infancy. Kwashiorkorpresents with edema, ascites, and he-patomegaly and is due to protein de-ficiency. Generalized muscle wastingand weakness with hypotonia and

hyporeflexia are seen. Cognitive deficitsmay be permanent. Autopsy studiesshow cerebral atrophy and immatureneuronal development. During theinitial stages of dietary treatment, anencephalopathy may be seen. Numer-ous neuropathies and myeloneuropa-thies from the tropics have beendescribed for which a nutritional causehas been postulated. Lack of multi-ple dietary components, in particularB-group vitamins, is the likely cause.

Vitamin B12

Vitamin B12 or cobalamin (Cbl) is awater-soluble vitamin that is requiredas a cofactor in several enzymatic re-actions. The two active forms of Cbl aremethyl-Cbl and adenosyl-Cbl (Figure1-2) (Kumar 2007; Tefferi and Pruthi,1994). Figure 1-2 shows the biochemi-cal pathways that are involved in Cblmetabolism. Figure 1-3 shows thegastrointestinal processing and absorp-tion of Cbl (Perkin and Murray-Lyon1998; Tefferi and Pruthi 1994). Cblis transferred across the intestinal mu-cosa into portal blood where it bindspredominantly to trans-Cbl II (TCII).The liver takes up approximately 50%of the Cbl, and the rest is transportedto other tissues through receptors forTCII. Cells take up TCII-bound Cblthrough receptor-mediated endocyto-sis. Intracellular lysosomal degradationreleases Cbl for conversion to methyl-Cbl or adenosyl-Cbl. Most of the Cblsecreted in the bile is reabsorbed. Theestimated daily losses of Cbl are minutecompared with body stores of 2500 mg.Hence, even in the presence of severemalabsorption, 2 to 5 years may passbefore Cbl deficiency develops (Greenand Kinsella, 1995). Similarly, a clinicalrelapse in PA after interrupting Cbltherapy takes approximately 5 yearsbefore it is recognized.

Causes of deficiency. Manypatients with Cbl deficiency have PA.

20

KEY POINT:

A 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.



21

continued on next page

TABLE 1-3 Summary of Sources, Causes of Deficiency, Neurologic Significance,Laboratory Tests, and Treatment for Deficiency States Related toCobalamin, Folate, Copper, Vitamin E, Thiamine, Vitamin A, Niacin,Pyridoxine, and Vitamin D

Nutrient SourcesMajor Causes ofDeficiency

NeurologicSignificanceAssociatedWithDeficiency

LaboratoryTests Treatment

AdditionalComments

Cobalamin Meats,

egg, milk,

fortified

cereals.

Pernicious anemia,

food-Cbl malabsorption

(elderly), gastric surgery,

acid-reduction therapy,

gastrointestinal disease,

parasitic infestation by

fish tapeworm,

hereditary enzymatic

defects, nitrous oxide

toxicity.

Myelopathy or

myeloneuropathy,

peripheral

neuropathy,

neuropsychiatric

manifestations,

optic neuropathy.

Serum Cbl, serum

methylmalonic

acid, plasma total

Hcy, anemia,

macrocytosis,

neutrophil

hypersegmentation,

Schilling’s test,

serum gastrin,

intrinsic factor

and parietal cell

antibodies.

IM B12 1000 mgdaily for 5 days

and monthly

thereafter.

Decreased 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.

Serum folate, red

blood cell folate,

plasma total Hcy.

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.

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.

Not infrequently,

the cause of

copper deficiency

is unknown.

Vitamin E Vegetable

oils, leafy

vegetables,

fruits,

meats, nuts,

unprocessed

cereal

grains.

Chronic cholestasis,

pancreatic insufficiency,

ataxia with vitamin E

deficiency, homozygous

hypobetalipoproteinemia,

abetalipoproteinemia,

chylomicron retention

disease.

Spinocerebellar

syndrome with

peripheral

neuropathy,

ophthalmoplegia,

pigmentary

retinopathy.

Serum vitamin E. Vitamin E

ranging from

200 mg/d to

200 mg/kg/d

(oral, IM).

Vitamin E

deficiency is

virtually never

the consequence

of a dietary

inadequacy.

Ratio of serum

a-tocopherol tosum of serum

cholesterol and

triglycerides.

Thiamine Enriched,

fortified, or

whole grain

products,

organ

meats.

Recurrent vomiting,

gastric surgery,

alcoholism, dieting,

increased demand with

marginal nutritional

status.

Beriberi (dry,

wet, infantile),

Wernicke

encephalopathy,

Korsakoff

syndrome.

Urinary thiamine,

serum thiamine,

erythrocyte

transketolase

activation assay, red

blood cell thiamine

diphosphate.

50 mg to 100 mg

(IV, IM, oral).

Reliance on the

described triad of

ophthalmoplegia,

ataxia, and

confusion and

not recognizing

thiamine

deficiency in

nonalcoholics

may result in

missing the

diagnosis.


This is an autoimmune gastropathytargeting the parietal cells that produceacid and intrinsic factor. Cbl deficiencyis particularly common in older adults.This is most likely because of the highincidence of atrophic gastritis andachlorhydria-induced food-Cbl malab-sorption rather than reduced intake.Helicobacter pylori infection of thestomach may be associated with mu-cosal atrophy, hypochlorhydria, andimpaired splitting of bound Cbl fromfood proteins. Cbl deficiency is com-monly seen following gastric surgery.

Other causes of Cbl deficiency includeconditions associated with malabsorp-tion such as ileal disease or resection,jejunal diverticulosis, bacterial over-growth, pancreatic disease, and tropi-cal sprue.

Nitrous oxide (N2O) is a commonlyused inhalational anesthetic that hasbeen abused because of its euphoriantproperties. N2O irreversibly oxidizesthe cobalt core of Cbl and rendersmethyl-Cbl inactive. Clinical manifesta-tions of Cbl deficiency appear relativelyrapidly with N2O toxicity because the

TABLE 1-3 Continued

Nutrient SourcesMajor Causes ofDeficiency

NeurologicSignificanceAssociatedWithDeficiency

LaboratoryTests Treatment

AdditionalComments

22

Vitamin A Carrots,

papayas,

green leafy

vegetables,

liver.

Nutritional deficiency in

vulnerable populations,

conditions associated

with fat malabsorption.

Blindness. Vitamin A levels. Oral vitamin A

supplementation.

Pseudotumor

cerebri due to

excess ingestion.

Niacin Meat, fish,

poultry,

enriched

bread,

fortified

cereals.

Corn as primary

carbohydrate

source, alcoholism,

malabsorption,

carcinoid, and Hartnup

syndrome.

Encephalopathy. Urinary excretion of

methylated niacin

metabolites.

25 mg to 50 mg

of nicotinic acid

(IM, oral).(Peripheral

neuropathy.)

Pyridoxine Meat,

fish, eggs,

soybeans,

nuts, dairy

products,

starchy

vegetables,

noncitrus

fruits, whole

grain cereal

products.

B6 antagonists,

alcoholism,

gastrointestinal disease.

Infantile seizures,

peripheral

neuropathy.

Plasma pyridoxal

phosphate.

50 mg to 100 mg

of pyridoxine

daily (oral).

Milling of grain,

cooking, and

thermal

processing can

result in

significant losses.

(Pure sensory

neuropathy with

toxicity.)

Vitamin D Sunlight,

liver, eggs,

dairy

products.

Inadequate

sun exposure,

malabsorption,

gastric bypass.

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):209–255. Copyright # 2007. Reprinted with permission from Elsevier.



23

FIGURE 1-2 Biochemistry of cobalamin (Cbl) and folate deficiency. Methyl-Cbl is acofactor for a cytosolic enzyme, methionine synthase, in a methyl-transferreaction that converts homocysteine (Hcy) to methionine. Methionine

is adenosylated to S-adenosylmethionine (SAM), a methyl group donor required forbiologic methylation reactions involving proteins, neurotransmitters, and phospholipids.Decreased SAM production leads to reduced myelin basic protein methylation and whitematter vacuolization in Cbl deficiency. Methionine also facilitates the formation offormyltetrahydrofolate (THF) which is involved in purine synthesis. During the processof methionine formation methyl-THF donates the methyl group (CH3) and is convertedinto THF, a precursor for purine and pyrimidine synthesis. Impaired DNA synthesis couldinterfere with oligodendrocyte growth and myelin production. Adenosyl-Cbl is a cofactorfor L-methylmalonyl coenzyme A (CoA) mutase, which catalyzes the conversion ofL-methylmalonyl-CoA to succinyl CoA in an isomerization reaction. Accumulation ofmethylmalonate and propionate may provide abnormal substrates for fatty acid synthesis.The branched-chain and abnormal odd-number carbon fatty acids may be incorporatedinto the myelin sheath.

The biologically active folates are in the THF form. Methyl-THF is the predominant folate andis required for the Cbl-dependent remethylation of Hcy to methionine. Methylation ofdeoxyuridylate to thymidylate is mediated by methylene-THF. Impairment of this reactionresults in accumulation of uracil, which replaces the decreased thymine in nucleoproteinsynthesis and initiates the process that leads to megaloblastic anemia.

CH3 = methyl group; THF1 = monoglutamated form of tetrahydrofolate; THFn =polyglutamated form of tetrahydrofolate.

Kumar N. Nutritional neuropathies. Neurol Clin 2007;25(1):209–255. Copyright # 2007. Reproduced withpermission from Elsevier.

Adapted with permission from Tefferi A, Pruthi RK. The biochemical basis of cobalamin deficiency. Mayo ClinicProc 1994;69(2):181–186.

KEY POINT:

A Cobalamin

deficiency is

particularly

common in

older adults. This

is most likely

due to the high

incidence of

atrophic gastritis

and achlorhydria-

induced food-

cobalamin

malabsorption

rather than

reduced intake.


metabolism is blocked at the cellularlevel. They may, however, be delayedup to 8 weeks. Postoperative neuro-logic dysfunction can be seen with N2Oexposure during routine anesthesia ifsubclinical Cbl deficiency is present(Kinsella and Green, 1995). N2O(‘‘laughing gas’’) toxicity due to inhal-ant abuse has been reported amongdentists, other medical personnel, anduniversity students.

Clinical significance. Neurologicmanifestations may be the earliest andoften the only manifestation of Cbldeficiency (Healton et al, 1991). Theseverity of the hematologic and neuro-logic manifestations may be inverselyrelated in a particular patient. Relapsesare generally associated with the same

neurologic phenotype. The recognizedneurologic manifestations may includea myelopathy with or without anassociated neuropathy, cognitive im-pairment, optic neuropathy, and par-esthesias without abnormal signs(Healton et al, 1991).

The best-characterized neurologicmanifestation of Cbl deficiency is amyelopathy that has commonly beenreferred to as subacute combined de-generation. The most severely involvedregions are the cervical and upperthoracic posterior columns. Changesare also seen in the lateral columns.Involvement of the anterior columns israre. The neurologic features typicallyinclude a spastic paraparesis, exten-sor plantar response, and impaired

24

FIGURE 1-3 In the stomach, cobalamin (Cbl) bound to food is dissociated from proteins in thepresence of acid and pepsin. The released Cbl binds to R proteins secreted by salivaryglands 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). IFis a Cbl-binding protein secreted by gastric parietal cells. The IF-Cbl complex binds to specific receptorsin the ileal mucosa and is internalized. In addition to the IF-mediated absorption of ingested Cbl, anonspecific absorption of Cbl occurs by passive diffusion at all mucosal sites. This is a relatively inefficientprocess 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 Proc1994;69(2):181–186.

KEY POINTS:

A Nitrous oxide

irreversibly

oxidizes the

cobalt core

of cobalamin

and renders

methylcobalamin

inactive.

A 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.



perception of position and vibration.Symptoms start in the feet and aresymmetric. MRI abnormalities include asignal change in the subcortical whitematter and posterior and lateral col-umns. Neuropsychiatric manifestationsinclude decreased memory, personalitychange, psychosis, and, rarely, delirium(Healton et al, 1991; Lindenbaum et al,1988).

Clinical, electrophysiologic, and path-ologic involvement of the peripheralnervous system has been described.In a recent study, Cbl deficiency wasdetected in 27 of 324 patients with apolyneuropathy (Saperstein et al, 2003).Clues to possible B12 deficiency in apatient with polyneuropathy includeda relatively sudden onset of symptoms,findings suggestive of an associatedmyelopathy, onset of symptoms in thehands, macrocytic red blood cells(RBCs), and the presence of a riskfactor for Cbl deficiency. Autonomicdysfunction with orthostatic hypoten-sion has rarely been described. Elec-trophysiologic abnormalities includenerve conduction studies suggestive ofa sensorimotor axonopathy, and ab-normalities on somatosensory evokedpotentials, visual evoked potentials, andmotor evoked potentials.

It is well known that serum Cbl canbe normal in some patients with Cbldeficiency, and serum methylmalonicacid (MMA) and total homocysteine(Hcy) levels are useful in diagnosingpatients with Cbl deficiency (Carmelet al, 2003; Green and Kinsella, 1995).The sensitivity of the available meta-bolic tests has facilitated the develop-ment of the concept of subclinical Cbldeficiency (Carmel et al, 2003). Thisrefers to biochemical evidence of Cbldeficiency in the absence of hemato-logic or neurologic manifestations.These biochemical findings shouldrespond to Cbl therapy. Its frequencyis estimated to be at least 10 times thatof clinical Cbl deficiency. The incidence

of subclinical Cbl deficiency increaseswith age. It is equally important torecognize that the presence of a lowCbl in association with neurologicmanifestations does not imply causeand effect or indicate the presence ofmetabolic Cbl deficiency. The inci-dence of both cryptogenic polyneu-ropathy and Cbl deficiency increaseswith age, and the latter may be achance occurrence rather than a causeof the neuropathy. The clinical impactof subclinical Cbl deficiency and its ap-propriate management are uncertain.

Investigations. The older microbi-ologic and radioisotopic assays forserum Cbl determination have beenreplaced by immunologically basedchemiluminescence assays. Though awidely used screening test, serum Cblmeasurement has technical and in-terpretive problems and lacks sensi-tivity and specificity for the diagnosisof Cbl deficiency (Carmel et al, 2003).Levels of serum MMA and plasmatotal Hcy are useful as ancillary diag-nostic tests in the diagnosis of Cbldeficiency (Carmel et al, 2003; Greenand Kinsella, 1995). The specificity ofserum MMA is superior to that ofplasma Hcy. Although plasma totalHcy is a very sensitive indicator of Cbldeficiency, its major limitation is itspoor specificity. Table 1-4 indicatescauses other than Cbl deficiency thatcan explain abnormal levels of Cbl,MMA, and Hcy.

A rise in the mean corpuscularvolume may precede development ofanemia. The presence of neutrophilhypersegmentation may be a sensitivemarker for Cbl deficiency and may beseen in the absence of anemia ormacrocytosis.

In order to determine the cause ofCbl deficiency, tests directed at deter-mining the cause of malabsorption areundertaken. Concerns regarding cost,accuracy, and radiation exposure haveled to a significant decrease in the

25

KEY POINT:

A 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.

A 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.


availability of the Schilling test. Anelevated serum gastrin and decreasedpepsinogen I are seen in 80% to 90% ofpatients with PA, but the specificity ofthese tests is limited. Elevated gastrinlevels are a marker for hypochlorhy-dria or achlorhydria, which are invari-ably seen with PA. Anti–intrinsic factorantibodies are more specific but lacksensitivity and are found in approxi-mately 50% to 70% of patients with PA.Parietal cell antibodies are more com-monly seen in PA but lack specificity,particularly in individuals over the ageof 70.

Management. The goals of treat-ment are to reverse the signs andsymptoms of deficiency, replenishbody stores, ascertain the cause of de-

ficiency, and monitor response totherapy. With normal Cbl absorption,oral administration of 3 mg to 5 mg maysuffice. In patients with food-bound Cblmalabsorption due to achlorhydria,50 mg to 100 mg cyano-Cbl given orallyis often adequate. Patients with Cbldeficiency due to achlorhydria-inducedfood-bound Cbl malabsorption shownormal absorption of crystalline B12

but are unable to digest and absorbCbl in food due to achlorhydria. Themore common situation is one of im-paired absorption where parenteraltherapy is required. A short courseof daily or weekly therapy is oftenfollowed by monthly maintenancetherapy (Table 1-3). If the oral doseis large enough, even patients with an

26

TABLE 1-4 Common Causes, Other Than Cobalamin Deficiency, forAbnormal Cobalamin, Methylmalonic Acid, andHomocysteine Levels

Cobalamin Methylmalonic Acid Homocysteine

Decreased by: Increased by: Increased by:

Pregnancy Renal insufficiency Renal insufficiency

Transcobalamin Ideficiency

Volume contraction(possible)

Alcohol abuse

Folate deficiency Bacterial contaminationof gut (possible)

Folate deficiency

Other diseases: HIVinfection, myeloma

Methylmaloniccoenzyme A mutasedeficiency

Vitamin B6 deficiency

Drugs:anticonvulsants,oral contraceptives

Methylmalonicacid–related enzymedefects

Other diseases:hypothyroidism, renaltransplant, leukemia, psoriasis

Increased by: Drugs: isoniazid

Renal failure Inborn errors of homocysteinemetabolism

Liver disease

Myeloproliferativedisorders

Enzyme polymorphisms (eg,methylene tetrahydrofolatereductase)

Adapted from Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine.Hematology Am Soc Hematol Educ Program 2003:62–81. This research was originally published in Blood.Copyright # the American Society of Hematology.

KEY POINT:

A For the diagnosis

of pernicious

anemia,

anti–intrinsic

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.



absorption defect may respond to oralCbl. Inappropriate therapy with folatemay result in partial and transienthematologic improvement but contin-ued neurologic deterioration withdelayed recognition of the Cbl defi-ciency. Patients with B12 deficiency areprone to develop neurologic deteriora-tion following N2O anesthesia. This ispreventable by prophylactic B12 givenweeks before surgery in individualswith a borderline B12 level who areexpected to receive N2O anesthesia. IMB12 should be given to patients withacute N2O poisoning. With chronicexposure, immediate cessation of ex-posure should be ensured.

Response to treatment may relate toextent of involvement and delay instarting treatment (Healton et al,1991). Remission correlates inverselywith the time lapsed between symp-tom onset and therapy initiation. Mostof the symptomatic improvementoccurs during the first 6 months.Response of the hematologic derange-ments is prompt and complete. Retic-ulocyte count begins to rise within 3days and peaks around 7 days. RCBcount begins to rise by 7 days and isfollowed by a decline in mean corpus-cular volume, with normalization by8 weeks. MMA and Hcy levels normal-ize by 10 days. Cbl levels rise afterinjection regardless of the benefit.Hence, MMA and Hcy are more reliableways to monitor response to therapy.In patients with severe B12 deficiency,replacement therapy may be accompa-nied by hypokalemia due to prolifera-tion of bone marrow cells that utilizepotassium. Response of the neurologicmanifestations is more variable andmay be incomplete.

Hydroxo-Cbl has superior retentionand may permit injections every 2 to3 months. Advantages of deliveringCbl by the nasal or sublingual routeare unproven. Oral preparations ofintrinsic factor (IF) are available but

not reliable. Antibodies to IF maynullify its effectiveness in the intestinallumen.

Folic Acid

Folic acid and its metabolites areessential cofactors for DNA synthesis(Figure 1-2). Folate is absorbed bysaturable and unsaturable mechanisms.Nonspecific, unsaturable absorptionpredominates in the ileum. The satu-rable process is specific, occurs in theproximal small intestines, and is medi-ated by the reduced folate carrier. Inthe enterocyte, folate is converted intomethyl-tetrahydrofolate (THF), and acarrier-mediated mechanism exports itinto the bloodstream. Following cellu-lar uptake, folate undergoes polygluta-mation that permits its attachment toenzymes. Daily folate losses may ap-proximate 1% to 2% of body stores.Therefore, a few months of poor nu-trition can result in folate deficiency.Clinically significant depletion of nor-mal folate stores may be seen within 3months, more rapidly with low storesor coexisting alcoholism. Serum folatefalls within 3 weeks after decrease infolate intake or absorption; RBC folatedeclines weeks to months later.

Causes of deficiency. Folate defi-ciency rarely exists in the pure state. Itis often associated with conditions thataffect other nutrients. Hence, attribu-tion of neurologic manifestations tofolate deficiency requires exclusion ofother potential causes. Populations atincreased risk of folate deficiencyinclude alcoholics, premature infants,and adolescents. Increased folate re-quirements are also seen in pregnancy,lactation, and chronic hemolytic ane-mia. Folate deficiency is seen withsmall bowel disorders associated withmalabsorption such as tropical sprue,celiac disease, bacterial overgrowthsyndrome, giardiasis, and inflammatorybowel disease. Folate absorption maybe decreased in conditions associated

27

A Patients with B12

deficiency are

prone to develop

neurologic

deterioration

following nitrous

oxide anesthesia.

A 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.

KEY POINTS:

A If the oral

cobalamin dose

is large enough,

even patients

with an

absorption defect

may respond to

oral cobalamin.


with reduced gastric secretions such asgastric surgery (partial gastrectomy)and atrophic gastritis. A number ofdrugs, such as aminopterin, methotrex-ate (amethopterin), pyrimethamine,trimethoprim, and triamterene act asfolate antagonists and produce folatedeficiency by inhibiting dihydrofolatereductase.

Clinical significance. In adultswith acquired folate deficiency, neuro-logic manifestations are rare and mild.The reason for this is unclear sincemethionine synthase requires folate ascosubstrate. The megaloblastic anemiadue to folate deficiency is indistinguish-able from that seen in Cbl deficiency.The occurrence and frequency ofneurologic manifestations of folate de-ficiency have been a matter of debate(Green and Miller, 1999; Reynolds,2002). They are likely less common ascompared with the myeloneuropathyand cognitive symptoms associatedwith Cbl deficiency. The myeloneurop-athy or neuropathy seen in associationwith folate deficiency is indistinguish-able from Cbl deficiency. Folate defi-ciency has been associated withaffective disorders. Congenital errorsof folate metabolism can be relatedeither to defective transport of folatethrough various cells or to defectiveintracellular utilization of folate due tosome enzyme deficiencies. These areoften associated with severe centralneurologic dysfunction.

Metabolic folate deficiency, as sug-gested by elevated plasma total Hcylevels that improve with folate therapy,can be seen in asymptomatic indi-viduals (Green and Miller, 1999). Theincreased Hcy seen with folate defi-ciency has been associated with anincreased risk of cardiovascular andcerebrovascular disease, but the pre-cise significance of this awaits furtherstudies.

Investigations. Serum folate levelsbetween 2.5 mg/L and 5 mg/L may be

indicative of a mildly compromisedfolate status. Erythrocyte folate is morereliable than plasma folate because itslevels are less affected by short-termfluctuations in intake. However, RBCfolate assay is subject to greater varia-tion depending on the method andlaboratory. Reticulocytes have a higherfolate content than mature RBCs. Theirpresence can affect RBC folate levels ascan blood transfusions. Plasma Hcylevels have been shown to be elevatedin many patients with clinically signifi-cant folate deficiency.

Management. In women of child-bearing age with epilepsy, daily folatesupplement of 0.4 mg is recommendedfor prophylaxis against neural tubedefects. With documented folate defi-ciency, higher doses are required. Dailydoses as high as 20 mg may be neces-sary in patients with malabsorption.Acutely ill patients may need parenteraladministration in a dose of 1 mg to5 mg. Coexisting Cbl deficiency shouldbe ruled out before instituting folatetherapy. Reduced folates such as folinicacid (N5-formylTHF) are required onlywhen folate metabolism is impaired bydrugs such as methotrexate or by aninborn error of metabolism. PlasmaHcy is likely the best biochemical toolfor monitoring response to therapy; itdecreases within a few days of institut-ing folate therapy but does not re-spond to inappropriate Cbl therapy.Since folate deficiency is generally seenin association with a broader dietaryinadequacy, the associated comorbid-ities need to be addressed.

Copper

Copper functions as a prostheticgroup in metalloenzymes such ascopper/zinc superoxide dismutase, cy-tochrome c oxidase, and dopamineb-monooxygenase. These enzymeshave a critical role in maintaining thestructure and function of the nervoussystem. Copper absorption occurs

28



primarily in the small intestine. TheMenkes P-type adenosine triphospha-tase (ATPase) (ATP7A) is responsiblefor copper trafficking to the secretorypathway for efflux from enterocytesand other cells. Absorbed copper isbound to albumin and transported viathe portal vein to the liver for uptakeby liver parenchymal cells. Copper isthen released into the plasma, and95% of it is bound to ceruloplasmin.The Wilson P-type ATPase (ATP7B) isresponsible for copper trafficking tothe secretory pathway for ceruloplas-min biosynthesis and for endosomeformation prior to biliary secretion.Excretion of copper into the gastroin-testinal tract is the major pathway thatregulates copper homeostasis andprevents deficiency or toxicity.

Causes of deficiency. Because ofcopper’s ubiquitous distribution andlow daily requirement, acquired dietarycopper deficiency is rare. Excessive zincingestion is a well-recognized cause ofcopper deficiency (Rowin and Lewis,2005). Denture creams, if ingested inexcess, can result in zinc-inducedcopper deficiency. Copper deficiencymay occur in malnourished infants,nephrotic syndrome, and enteropa-thies associated with malabsorption. Itmay be a complication of prolongedtotal parenteral nutrition or enteralfeeding. Copper deficiency followinggastric surgery (for peptic ulcer diseaseor bariatric surgery) is increasinglyrecognized (Kumar et al, 2004a).

Clinical significance. Menkesdisease is the well-known copperdeficiency–related disease in humansand is due to congenital copper defi-ciency. Copper deficiency–associatedmyelopathy is well known in variousanimal species, but only in recentyears have the neurologic manifesta-tions of acquired copper deficiency inhumans been recognized. The mostcommon manifestation is that of amyelopathy or myeloneuropathy that

resembles the subacute combineddegeneration 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 reportedpatients had asymmetric weakness,distal sensory impairment, and elec-trodiagnostic evidence of denervationsuggestive of lower motor neurondisease (Weihl and Lopate, 2006).Hyperzincemia of indeterminate sig-nificance may be present even in theabsence of exogenous zinc ingestion(Kumar, 2006; Kumar et al, 2004b;Prodan et al, 2002). Copper and Cbldeficiency may coexist. Spinal cordMRI in patients with copper deficiencymyelopathy may show increased signalon T2-weighted images, most com-monly in the paramedian cervical cord(Figure 1-4A and 1-4B) (Kumar et al,2006).

The hematologic manifestations ofacquired copper deficiency are wellknown and include anemia, neutrope-nia, and a left shift in granulocytic anderythroid maturation with vacuolatedprecursors, iron-containing plasmacells, and ringed sideroblasts in thebone marrow (Figure 1-4C, 1-4D, and1-4E) (Gregg et al, 2002). The neuro-logic syndrome due to acquired copperdeficiency may be present without thehematologic manifestations.

Investigations. Laboratory indica-tors of copper deficiency include re-duced serum copper or ceruloplasmin,and reduced urinary copper excretion,but these parameters are not sensitiveto marginal copper status. Changesin serum copper usually parallelthe ceruloplasmin concentration. Ce-ruloplasmin is an acute-phase reac-tant, and the rise in ceruloplasminis probably responsible for the increasein serum copper seen in a varietyof conditions such as pregnancy,oral contraceptive use, liver disease,

29

KEY POINTS:

A Excessive zinc

ingestion is a

well-recognized

cause of copper

deficiency.

Copper deficiency

following gastric

surgery is being

increasingly

recognized.

A 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.

A Spinal cord MRI

in patients with

copper deficiency

myelopathy may

show increased

signal on

T2-weighted

images, most

commonly in

the paramedian

cervical cord.


malignancy, hematologic disease, myo-cardial infarction, smoking, diabetes,uremia, and various inflammatory andinfectious diseases.

Treatment. In patients with zinc-induced copper deficiency, discontinu-ing the zinc may suffice. Despite a sus-pected absorption defect, oral coppersupplementation is generally the pre-ferred route of supplementation. Inmost cases, oral administration of 2 mgof elemental copper a day seems tosuffice. A comparable dose of elemen-tal copper IV may be given. At times,prolonged oral therapy may fail toresult in improvement, and parenteraltherapy may be required. Initial paren-teral administration followed by oral

therapy has also been used (Rowin andLewis, 2005). A commonly employedregimen is administration of 6 mg ofelemental copper a day orally for 1week, 4 mg a day for the second week,and 2 mg a day thereafter (Kumar,2006). Alternatively 2 mg of elementalcopper IV may be administered for 5days and periodically thereafter. Re-sponse of the hematologic parameters(including bone marrow findings) isprompt and often complete (Gregg et al,2002; Kumar, 2006; Kumar et al, 2004b).Hematologic recovery may be accom-panied by reticulocytosis. Recovery ofneurologic signs and symptoms seenin association with copper deficiencyis variable. Improvement in neurologic

30

Case 1-2A 54-year-old woman is evaluated for a 2-year history of imbalance anddistal lower limb paresthesias. She had gastric bypass surgery 14 years agofor obesity and since then has been on vitamin B12 replacement. Herneurologic examination is remarkable for a spastic ataxic gait withimpaired perception of position at the toes and decreased perception ofvibration up to the anterior superior iliac spine. Her ankle jerks are absent,knee jerks brisk, and plantar responses extensor. Her nerve conductionstudies show a mild peripheral neuropathy. Somatosensory evokedpotential studies show a central conduction delay that localizes to thecervical cord. Her spine MRI is unremarkable. Laboratory investigationsshow a mild normocytic anemia and neutropenia and normal B12 andMMA levels.

Comment. Her clinical presentation is suggestive of a myeloneuropathy.Vitamin B12 deficiency is a common cause of a myeloneuropathy and iscommonly seen after gastric bypass surgery. B12 supplementation isroutinely recommended. A similar clinical presentation can also result fromcopper deficiency. Hence, it is imperative to look for copper deficiency inpatients with a myeloneuropathy. Both copper and B12 deficiency cancoexist, and a history of gastric surgery is a risk factor for both. In bothconditions neurologic manifestations may be seen in the absence ofhematologic derangement. Copper deficiency can also result from excesszinc ingestion. In some patients with copper-deficiency myelopathy, nocause for copper deficiency is evident. Even in patients with subacutecombined degeneration due to B12 deficiency, deterioration despiteadequate B12 supplementation should prompt a search for copperdeficiency as a likely cause. The spine MRI may be normal or show anincreased signal involving the dorsal column on T2-weighted MRI.Generally, oral copper supplementation improves copper levels. Responseof the hematologic manifestations is prompt and complete, and neurologicdeterioration is prevented.

KEY POINT:

A 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.



symptoms is generally absent althoughprogression is typically halted (Kumar,2006; Kumar et al, 2004b). Improve-ment, when present, is slight, oftensubjective, and preferentially involvessensory symptoms.

Vitamin E

The terms vitamin E and a-tocopherolare used interchangeably. Vitamin Eserves as an antioxidant and free radi-cal scavenger. Vitamin E is absorbedfrom the gastrointestinal tract by anonenergy-requiring diffusion mecha-nism that requires bile acids, fatty acids,and monoglycerides for micelle forma-tion. After uptake by enterocytes, allforms of dietary vitamin E are incorpo-rated into chylomicrons. During chylo-micron catabolism in plasma, vitamin Eis transferred to circulating lipopro-teins, which deliver it to tissues. Thechylomicron remnants are taken up bythe liver, which selects the a-tocoph-erol form for secretion into plasma invery low-density lipoproteins. This pro-cess requires the a-tocopherol transferprotein (TTP). Lipolysis of very low-density lipoprotein results in enrich-

ment of circulating lipoproteins withvitamin E, which is delivered to pe-ripheral tissue. The majority of vita-min E in the human body is localized inthe adipose tissue. Analysis of adiposetissue a-tocopherol content provides auseful estimate of long-term vitamin Eintake. Most ingested vitamin E iseliminated by the fecal route.

Causes of deficiency. Vitamin Eabsorption requires biliary and pancre-atic secretions. Hence vitamin E defi-ciency is seen with chronic cholestasisand pancreatic insufficiency. Vitamin Edeficiency is also seen with otherconditions associated with malabsorp-tion such as celiac disease, Crohndisease, cystic fibrosis, blind loopsyndrome, bacterial overgrowth, andextensive small bowel resection. Vita-min E supplementation in total paren-teral nutrition may be inadequate tomaintain vitamin E stores.

Vitamin E deficiency may alsoresult from genetic defects in a-TTP(ataxia with vitamin E deficiency[AVED]), in apolipoprotein B (ho-mozygous hypobetalipoproteinemia),or in the microsomal triglyceride trans-fer protein (abetalipoproteinemia or

31

FIGURE 1-4 Sagittal (A) and axial (B) T2-weighted MRIs in a patient with copper deficiencyshowing increased signal in the paramedian aspect of the dorsal cervicalcord. Bone marrow study (C, D, and E) in a patient with copper deficiency

myelopathy showing vacuolated myeloid precursors (C). Iron staining (D and E) showsiron-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):78–83. Reprinted with permission from Springer Science andBusiness Media. Panels C and D reproduced with permission from Kumar N. Copper deficiency myelopathy(human swayback). Mayo Clin Proc 2006;81(10):1371–1384. Panel E from Kumar N. Nutritional neuropathies.Neurol Clin 2007;25(1):209–255. Copyright # 2007. Reprinted with permission from Elsevier.

KEY POINT:

A Vitamin E

deficiency may

result from

genetic defects

in a-TTP (ataxia

with vitamin E

deficiency), in

apolipoprotein B

(homozygous

hypobetalipo-

proteinemia), or

in the microsomal

triglyceride

transfer protein

(abetalipo-

proteinemia or

Bassen-Kornzweig

disease).


Bassen-Kornzweig disease). An additionalcause is defect in chylomicron synthe-sis and secretion (chylomicron reten-tion disease). AVED is an autosomalrecessive disorder in which isolatedvitamin E deficiency occurs withoutgeneralized fat malabsorption or gas-trointestinal disease. The defect lies inimpaired incorporation of vitamin Einto hepatic lipoproteins for tissuedelivery. Mutations in the a-TTP geneon chromosome 8q13 are responsible(Cavalier et al, 1998). Patients withhypobetalipoproteinemia or abetalipo-proteinemia have impaired secretion ofchylomicrons or other apolipoproteinB (ApoB)-containing lipoproteins, spe-cifically very low-density lipoproteinsand low-density lipoproteins. Patientswith homozygous hypobetalipoprotei-nemia have a defect in the ApoB gene,and ApoB-containing lipoproteins se-creted into the circulation turn overrapidly. Patients with abetalipoprotei-nemia have a genetic defect in themicrosomal triglyceride transfer pro-tein that prevents normal lipidation ofApoB, and the secretion of ApoB-containing lipoproteins is nonexistent.In chylomicron retention disease, im-paired assembly and secretion of chy-lomicrons and chylomicron retentionin the intestinal mucosa are present.

Clinical significance. The neu-rologic manifestations of vitamin Edeficiency include a spinocerebellar syn-drome with variable peripheral nerveinvolvement (Sokol, 1988). The pheno-type is similar to that of Friedreich ataxia.The clinical features include cerebellarataxia, hyporeflexia, and proprioceptiveand vibratory loss, and in some patientsan extensor plantar response. Ophthal-moplegia, ptosis, and pigmentary reti-nopathy have been reported. An asso-ciated myopathy may be present. Theneuropathy associated with vitamin Edeficiency preferentially involves centrallydirected fibers of large myelinated neu-rons. It is rare for vitamin E deficiency

to present as an isolated neuropathy.Somatosensory evoked potential stud-ies may show evidence of central delay,and nerve conduction studies mayshow evidence of an axonal neuropathy.With retinal pigmentary degeneration,abnormal electroretinograms may beseen. Spinal MRI in patients with vitaminE deficiency–related myeloneuropathymay show increased signal in the cervicalcord dorsal column (Vorgerd et al,1996). In children with cholestatic liverdisease, neurologic abnormalities ap-pear as early as the second year oflife. In AVED, hypolipoproteinemia,and abetalipoproteinemia, neurologicmanifestations start by the first orsecond decade. Development of neu-rologic symptoms in adults with ac-quired fat malabsorption syndromestakes decades. In Bassen-Kornzweigdisease, abetalipoproteinemia is associ-ated with low vitamins A and E, retinitispigmentosa, ataxia, areflexia, acantho-cytes, and steatorrhea.

Investigations. Serum vitamin Elevels are dependent on the concen-trations of serum lipids, cholesterol,and very low-density lipoprotein. Hy-perlipidemia or hypolipidemia canindependently increase or decreaseserum vitamin E without reflectingsimilar alterations in tissue levels ofthe vitamin (Sokol et al, 1984). Effec-tive serum a-tocopherol concentra-tions are calculated by dividing theserum a-tocopherol by the sum ofserum cholesterol and triglycerides. Se-rum a-tocopherol concentrations maybe in the normal range in patients witha-tocopherol deficiency due to chole-static liver disease, a disorder that isalso associated with high lipid levels. Inpatients with neurologic manifestationsdue to vitamin E deficiency, the serumvitamin E levels are frequently unde-tectable. Additional markers of fatmalabsorption such as increased stoolfat and decreased serum carotenelevels may be present. Vitamin E

32

KEY POINT:

A 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.



determination in adipose tissue hasalso been used.

Management. In AVED, oral sup-plementation with vitamin E in a doseof 600 IU twice daily raises plasma con-centration levels to normal. In patientswith cholestasis and malabsorption,larger oral doses or IM administrationmay be required. An empiric approachis to start with a lower dose, increase itgradually, and, based on the clinicaland laboratory response, consider ahigher dose or parenteral formulation.Doses of a-tocopheryl acetate rangingfrom 200 mg per day to 2 g per dayhave been used.

Thiamine

The terms vitamin B1 and thiamine areused interchangeably. Following cellu-lar uptake, thiamine is phosphorylatedinto thiamine diphosphate, the meta-bolically active form that is involved inseveral enzyme systems in the metabo-lism of carbohydrates and branched-chain amino acids. Thiamine deficiencyresults in reduced synthesis of high-energy phosphates and lactate accu-mulation. After gastrointestinal uptake,thiamine is transported by portal bloodto the liver. Because of its short half-lifeand absence of significant storageamounts, a continuous dietary supplyof thiamine is necessary. A thiamine-deficient diet may result in manifesta-tions of thiamine deficiency in 2 to 3weeks. Prolonged cooking of food,baking of bread, and pasteurization ofmilk are all potential causes of thia-mine loss.

Causes of deficiency. Thiaminedeficiency may be seen with persistentvomiting, anorexia nervosa, dieting,malnutrition, severe gastrointestinal orliver disease, gastrointestinal surgeryincluding bariatric surgery, and AIDS(Reuler et al, 1985). Thiamine defi-ciency in alcoholism results from in-adequate dietary intake, reducedgastrointestinal absorption, reduced

liver thiamine stores, and impairedphosphorylation of thiamine to thia-mine diphosphate. Thiamine require-ment is dependent on the body’smetabolic rate, with the requirementbeing the greatest during periods ofhigh metabolic demand or high glu-cose intake. Symptoms of thiaminedeficiency may be seen in high-riskpatients during periods of vigorousexercise and high carbohydrate intake,as with IV glucose administration andrefeeding. In patients with a marginalnutritional status, increased metabolicdemand, as is seen in hyperthyroidism,malignancy, and systemic infections,may precipitate symptoms. Pregnantand lactating women have increasedthiamine requirements, and infant beri-beri may be seen in infants who arebreast-fed by thiamine-deficient asymp-tomatic mothers. Maternal thiaminedeficiency may result from eating astaple diet of polished rice with foodscontaining thiaminase or antithiaminecompounds.

Clinical significance. The best-characterized human neurologic dis-orders related to thiamine deficiencyare beriberi, Wernicke encephalopathy(WE), and Korsakoff syndrome (KS)(Reuler et al, 1985). The three forms ofberiberi are dry beriberi, wet beriberi,and infantile beriberi. Dry beriberi ischaracterized by a sensorimotor, distal,axonal peripheral neuropathy oftenassociated with calf cramps, muscletenderness, and burning feet. Auto-nomic neuropathy may be present. Arapid progression of the neuropathymay mimic Guillain-Barre syndrome.Pedal edema may be seen due tocoexisting wet beriberi. Wet beriberi isassociated with a high-output conges-tive heart failure with peripheral neu-ropathy. ‘‘Shoshin’’ beriberi is thename given to a fulminant form thatpresents with tachycardia and circula-tory collapse. Infantile beriberi is seenbetween 2 and 6 months of age and

33

KEY POINTS:

A Thiamine

deficiency may

be seen with

persistent

vomiting, anorexia

nervosa, dieting,

malnutrition,

severe

gastrointestinal

or liver disease,

gastrointestinal

surgery including

bariatric surgery,

and AIDS.

A The best-

characterized

human neurologic

disorders related

to thiamine

deficiency are

beriberi, Wernicke

encephalopathy,

and Korsakoff

syndrome.


may present with the cardiac, aphonic,or pseudomeningitic forms.

The clinical features of WE include asubacute onset of ocular motor distur-bance, gait ataxia, and confusion. Thisclassic triad is infrequently present.Involvement of the hypothalamic andbrainstem autonomic pathways may beassociated with hypothermia and or-thostatic hypotension. Skin changes,tongue redness, features of liver dis-ease, and truncal ataxia may be pres-ent. Over 80% of patients may have anassociated peripheral neuropathy. Typi-cal MRI findings include increased T2or proton density or diffusion-weightedimaging signal around the third ventri-cle, periaqueductal midbrain, dorsome-dial thalami, and mamillary bodies(Doherty et al, 2002) (Figure 1-5). Inthe early stages contrast enhancementmay be seen. Rarely, symmetric corticalinvolvement may occur. The signalabnormalities resolve with treatment,but shrunken mamillary bodies maypersist as sequelae. The frequency ofWE in various autopsy studies is far inexcess of what would be expected fromclinical studies (Reuler et al, 1985).

In some autopsy-confirmed cases ofWE, the only clinical manifestation hasbeen psychomotor retardation. Suddendeath may occur and is related tohemorrhagic brainstem lesions. KS isan amnestic-confabulatory syndromethat follows WE and emerges as ocularmanifestations and encephalopathy sub-side. Rarely, KS may be present withoutWE or may be present at the time ofdiagnosis of WE. Neuropathologic find-ings in WE include symmetric lesions ofthe periventricular regions of the thala-mus and hypothalamus, mammillarybodies, nuclei at the level of the thirdand fourth ventricle, and superiorcerebellar vermis.

Investigations. Urinary thiamine ex-cretion and serum thiamine levels maybe decreased but do not accuratelyreflect tissue concentrations and arenot reliable indicators of thiaminestatus. The preferred tests are theerythrocyte transketolase activation as-say or measurement of thiamine di-phosphate in RBC hemolysates usinghigh-performance liquid chromatogra-phy. The erythrocyte transketolaseactivation assay is an assay of functional

34

FIGURE 1-5 Brain MRI (fluid-attenuated inversion recovery) in a patient with Wernickeencephalopathy 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 encephalopathyshowing increased signal involving the medial thalamus and hypothalamus that wasassociated with a reduced apparent diffusion coefficient. The signal change was less apparenton T2-weighted imaging.

Reprinted with permission from Doherty MJ, Watson NF, Uchino K, et al. Diffusion abnormalities in patients withWernicke encephalopathy. Neurology 2002;58(4):655–657. Copyright # 2002, AAN Enterprises, Inc.

KEY POINTS:

A 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.

A Typical MRI

findings in

Wernicke

encephalopathy

include increased

T2 or proton

density or

diffusion-

weighted imaging

signal around

the third ventricle,

periaqueductal

midbrain,

dorsomedial

thalami, and

mamillary bodies.

A Korsakoff

syndrome is

an amnestic-

confabulatory

syndrome that

follows Wernicke

encephalopathy

and emerges

as ocular

manifestations

and

encephalopathy

subside.



status and is based on measurement oftransketolase activity in hemolysates ofRBCs in the absence of (and in thepresence of) added excess cofactor(thiamine diphosphate). Since theselaboratory abnormalities normalizequickly, a blood sample should bedrawn before initiation of treatment.

Management. IV glucose infusionin patients with thiamine deficiencymay consume the available thiamineand precipitate an acute WE. At-riskpatients should receive parenteral thia-mine prior to administration of glu-cose or parenteral nutrition. Patientssuspected of having beriberi or WEshould promptly receive parenteralthiamine. The recommended dose ofthiamine in beriberi is 100 mg IVfollowed by 100 mg IM daily for 5 daysand permanent oral maintenance. Theparenteral form is used when doubtexists about adequate gastrointestinalabsorption. In wet beriberi, a rapidimprovement is seen with clearing ofsymptoms within 24 hours. Improve-ment in motor and sensory symptomstakes weeks or months. Patients withWE may need higher doses of thia-mine. Response in WE is variable.Apathy and lethargy improve over daysor weeks. Even with thiamine treat-ment the mortality is 10% to 20%. Asthe global confusional state recedes,some patients are left with a KS.Ophthalmoplegia improves rapidly, buta fine horizontal nystagmus may per-sist. Improvement in gait ataxia andmemory is variable and often delayed.

Vitamin A

Vitamin A refers to retinol. The termretinoids refers to vitamin A derivativessuch as retinal (vitamin A aldehyde),retinoic acid (vitamin A acid), and thecarotenoids. Vitamin A is essential forvisual function. It influences growth andtissue differentiation and is required formaintenance of epithelial cell integrity.In the intestinal mucosa, retinol is

esterified to retinyl palmitate, which isincorporated into chylomicrons andtransported into the general circulation.Vitamin A is stored in the liver in theform of retinyl palmitate and releasedfrom the liver by hydrolysis.

Causes of deficiency. Nutritionaldeficiency is seen when the diet con-sists of rice and wheat (grains lackingbeta-carotene). Dietary deficiency maybe seen in alcoholics, older adults, andindividuals who are poor. Vitamin Adeficiency is seen in conditions associ-ated with fat malabsorption such asceliac disease, pancreatitis, and chole-static liver disease.

Clinical significance. Vitamin Adeficiency causes night blindness anddryness and keratinization of the cor-nea and conjunctiva. White, foamyspots on the conjunctiva due tosloughed cells may be seen (Bitotspots). Other manifestations includeimpaired sense of taste, follicular hy-perkeratosis of the skin, and keratiniza-tion of the respiratory, gastrointestinal,and urinary tracts. Excess ingestion ofcarotenes causes yellow skin pigmenta-tion. Excess vitamin A ingestion causesdry skin, cheilitis, brittle nails, alopecia,petechiae, painful joints, anorexia, fa-tigue, nausea, diarrhea, and hepatotox-icity. Neurologic manifestations includeheadache, insomnia, irritability, papille-dema, and pseudotumor cerebri.

Investigations. Normal vitamin Alevels range from 30 mg/dL to 65 mg/dL.Levels of less than 10 mg/dL are clearlylow and over 100 mg/dL clearly high.

Management. Prophylactically treat-ing high-risk infants and children withlarge oral doses of vitamin A preventsdevelopment of a deficient state. In thesetting of malabsorption, oral vitamin Asupplementation is undertaken to nor-malize plasma levels.

Niacin

Niacin in humans is an end product oftryptophan metabolism. It is converted

35

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.

A 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.


into nicotinamide adenine dinucleotide(NAD) and its reduced form (NADphosphate), coenzymes important incarbohydrate metabolism. Niacin andits amide are absorbed through theintestinal mucosa by simple diffusion.Niacin and nicotinamide are metabo-lized by separate pathways. Complexedand free niacin are taken up by tissue,and niacin is retained by metabolictrapping to NAD.

Causes of deficiency. Pellagra, thecondition caused by niacin deficiency, israre in developed countries. Niacindeficiency is predominantly seen inpopulations dependent on corn as theprimary carbohydrate source. Cornlacks niacin and tryptophan. Nonen-demic pellagra may rarely be seen withalcoholism and malabsorption. Pellagramay also be seen in the carcinoid syn-drome in which tryptophan is con-verted to serotonin instead of beingused in niacin synthesis. Biotransforma-tion of tryptophan to nicotinic acidrequires several vitamins and mineralssuch as B2, B6, iron, and copper. Dietsdeficient in these nutrients can predis-pose to pellagra. Isoniazid (INH)depletes B6 and can trigger pellagra.Excess of neutral amino acids, such asleucine, in the diet can compete withtryptophan for uptake and predisposeto niacin deficiency by impairing itssynthesis from tryptophan. Hartnupsyndrome is an autosomal recessivedisorder characterized by impaired syn-thesis of niacin from tryptophan andresults in pellagralike symptoms. Nico-tinamide deficiency has also beendescribed in some disorders of the ali-mentary tract. Bacterial colonization ofthe small intestines can lead to conver-sion of dietary tryptophan to indoles.Reversible nicotinamide-deficiency en-cephalopathy has been described in apatient with jejunal diverticulosis.

Clinical significance. Pellagraaffects the gastrointestinal tract, skin,and nervous system. Skin changes in-

clude a reddish-brown hyperkeratoticrash, which has a predilection for theface, chest, and dorsum of the handsand feet. Gastrointestinal manifesta-tions include anorexia, abdominal pain,diarrhea, and stomatitis. Reported neu-rologic manifestations include a confu-sional state, which may progress tocoma, spasticity, and myoclonus. Un-explained progressive encephalopathyin alcoholics that is not responsive tothiamine should raise the possibility ofpellagra (Serdaru et al, 1988). Theperipheral neuropathy seen in pellagrais indistinguishable from the peripheralneuropathy seen with thiamine defi-ciency. Nonendemic pellagra tends tolack dermatitis and has features similarto those of alcoholic pellagra (Serdaruet al, 1988).

Investigations. The most reliableand sensitive measures of niacin statusare urinary excretion of the methylatedmetabolitesN1-methyl-nicotinamide andits 2-pyridone derivative (N1-methyl-2-pyridone-5-carboxamide). No sensitiveand specific blood measures of nia-cin status exist. It has been suggestedthat measures of erythrocyte NAD andplasma metabolites may serve as mark-ers of niacin status.

Management. Oral nicotinic acid ina dose of 50 mg 3 times a day orparenteral doses of 25 mg 3 times a dayare used for treatment of symptomaticpatients. Nicotinamide has comparabletherapeutic efficacy in pellagra. Ad-vanced stages of pellagra can be curedwith IM nicotinamide given in doses of50 mg to 100 mg 3 times a day for 3 to4 days, followed by similar quantitiesorally.

Vitamin B6

The term pyridoxine is generally usedsynonymously with vitamin B6. Pyri-doxal and pyridoxamine are two othernaturally occurring compounds thathave comparable biological activity. All

36

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.



three compounds are readily convertedto pyridoxal phosphate, which servesas a coenzyme in many reactionsinvolved in the metabolism of aminoacids, lipids, nucleic acid, one-carbonunits, and in the pathways of gluco-neogenesis and neurotransmitter andheme biosynthesis. Meat, fish, eggs,soybeans, nuts, and dairy products arerich in vitamin B6. Starchy vegetables,noncitrus fruits, and whole grain cerealproducts are additional sources.

Causes of deficiency. Vitamin B6

deficiency is seen with B6 antagonistssuch as INH, cycloserine, hydralazine,and penicillamine. Individuals at risk ofdeveloping vitamin B6 deficiency in-clude chronic alcoholics, pregnant andlactating women, and older adults.Plasma pyridoxal phosphate levels arereduced in celiac disease, inflammatorybowel disease, and renal disease.

Clinical significance. Dietary defi-ciency of pyridoxine or congenitaldependency on pyridoxine may mani-fest as infantile seizures. In infants,pyridoxine deficiency may manifest asirritability and increased startle re-sponse. Adults are much more tolerantof pyridoxine deficiency. Vitamin B6

deficiency, usually related to INH use,can result in a painful, axonal, sensori-motor, peripheral neuropathy. INH-associated neuropathy is dose related.Up to 50% of slow acetylators maydevelop a peripheral neuropathy whentreated with INH. Chronic vitamin B6

deficiency results in a microcytic hypo-chromic anemia. A form of sidero-blastic anemia can be treated withpyridoxine supplementation. Chronicvitamin B6–deficient patients may de-velop secondary hyperoxaluria and,thus, are at higher risk for nephroli-thiasis. As with other B vitamin defi-ciencies, glossitis, stomatitis, cheilosis,and dermatitis may be seen. Excessconsumption of B6 has been associatedwith a pure sensory peripheral neu-ropathy or ganglionopathy character-

ized by sensory ataxia, areflexia,impaired cutaneous and deep sensa-tions, and positive Romberg sign(Schaumburg et al, 1983). The risk ofdeveloping the neuropathy decreasesat doses less than 100 mg/d.

Investigations. B6 status can beassessed by measuring its levels in theblood or urine. The most commonlyused measure is plasma pyridoxalphosphate. Urinary excretion of itsmajor metabolite, 4-pyridoxic acid, isan additional marker. Functional indi-cators of B6 status are based onpyridoxal phosphate–dependent reac-tions and include the tryptophan andmethionine load tests.

Management. INH-induced neu-ropathy is reversible by drug discontin-uation or B6 supplementation. VitaminB6 may be supplemented in a dose of50 mg/d to 100 mg/d to preventdevelopment of the neuropathy. Theneuropathy due to vitamin B6 toxicitymay reverse once the supplementationis withdrawn. Patients with congenitaldependency on pyridoxine developsymptoms despite a normal dietarysupplementation of pyridoxine. Highdoses of vitamin B6 are required, andeven after years, seizures reappearwithin days of vitamin B6 withdrawal.

Vitamin D

Vitamin D exists in two forms: vitaminD2 (ergocalciferol, produced by plants)and vitamin D3 (cholecalciferol, de-rived from 7-dehydrocholesterol whenexposed to ultraviolet light in the skin).Vitamin D functions more like ahormone than a vitamin. It acts intra-cellularly at high affinity nuclear recep-tors, which, when stimulated, altergene transcription. Receptors in smallbowel enterocytes enhance calciumand phosphorus absorption, and bonereceptors stimulate mineralization ofnewly formed bone. Sun-stimulatedskin synthesis can provide 100% of

37

KEY POINT:

A Vitamin B6

deficiency,

usually related

to isoniazid use,

can result in a

painful, axonal,

sensorimotor,

peripheral

neuropathy.

Excess

consumption of

vitamin B6 has

been associated

with a pure

sensory peripheral

neuropathy or

ganglionopathy.


the daily requirement from 7-dehydro-cholesterol in the absence of oralintake. In the presence of bile salts,orally ingested vitamin D is packagedinto micelles and absorbed passively inthe small intestine. It is then bound tolipoproteins and transported in chylo-microns to the liver via the lymphaticsystem. In the liver it is hydroxylatedto 25-hydroxy vitamin D. Further hy-droxylation occurs in the kidney to 1,25-dihydroxy vitamin D, the activeform. Vitamin D hydroxylation is in-creased by parathormone. With repletestores, 25-hydroxy vitamin D is hydrox-ylated to 24, 25-dihydroxy vitamin Dand excreted in the bile (and urine).Vitamin D hydroxylation is decreasedin severe liver and kidney disease.Routine supplementation of foodssuch as dairy products makes dietarydeficiency rare.

Causes of deficiency. Inadequatesun exposure may cause vitamin Ddeficiency in chronically ill, institution-alized, or housebound individuals. Mal-absorption, as seen in celiac disease,Crohn disease, cholestatic liver disease,and extensive small bowel resection,may cause vitamin D deficiency. Vita-min D deficiency has also beenreported following gastric bypass andpartial gastrectomy. Pancreatic diseaserarely leads to vitamin D deficiency.Advanced liver or kidney disease candecrease the active form of vitamin D.The antiepileptic drugs phenobarbitaland phenytoin inhibit vitamin D hy-droxylation in the liver and inhibitcalcium absorption in the intestines.

Clinical significance. Vitamin Ddeficiency results in defective mineral-ization of newly formed bone andhypocalcemia with secondary hyper-parathyroidism, which further impairsnormal bone mineralization. Thiscauses rickets in children and osteo-malacia in adults. Vitamin D deficiencycan cause a proximal myopathy, whichoften exists in association with osteo-

malacia, pathologic fractures, and bonepain (Russell, 1994). The pelvic andthigh musculature are involved morethan the arms. A waddling gait may bepresent. Severe hypocalcemia mayresult in tetany and be associated withhypomagnesemia. Vitamin D deficiencyhas been reported to cause cutaneoushyperalgesia that is resistant to anti-depressants and opiates but respondsto vitamin D repletion (Gloth et al,1991).

Investigations. Vitamin D deficiencymay be accompanied by decreasedserum calcium and increased parathor-mone levels. Since 25-hydroxy vitaminD is hydroxylated to the active form,the level of 1, 25-dihydroxy vitamin Dmay be normal while its immediateprecursor may be very low. Kidney dis-ease may result in low 1, 25-dihydroxyvitamin D and normal 25-hydroxyvitamin D. Other laboratory abnor-malities may include raised alkalinephosphatase of bone origin, hypocal-cemia, hypophosphatemia, raised par-athormone, reduced urinary calciumexcretion, and raised urinary hydroxy-proline. Radiologic changes of ricketsor osteopenia may be present.

Management. Vitamin D can begiven orally as vitamin D2 or vitaminD3. A dose of 400 IU of vitamin D perday is adequate to prevent deficiencyin individuals with minimal sun expo-sure. With clinical deficiency 50,000 IUweekly may be required. Larger oraldoses or parenteral administrationmay be required in the presence ofmalabsorption. Associated secondaryhyperparathyroidism can cause hy-percalcemia, hypercalciuria, and neph-rolithiasis. These conditions can beprevented by ensuring that calciumrepletion is adequate and thus avoidingparathyroid stimulation. An inappropri-ately high phosphate level suggestssecondary hyperparathyroidism. Labo-ratory monitoring is required withdoses of 50,000 IU 3 times a week.

38

KEY POINT:

A Vitamin D

deficiency can

cause a proximal

myopathy that

often exists in

association with

osteomalacia,

pathologic

fractures, and

bone pain. The

pelvic and thigh

musculature are

involved more

than the arms. A

waddling gait

may be present.



Toxicity includes hypercalcemia, hyper-calciuria, and renal failure. Serum andurine calcium and serum 25-hydroxyvitamin D should be monitored, andwhen urinary calcium excretion ex-ceeds 100 mg/24 h, the vitamin D doseshould be reduced. With liver dysfunc-tion 25-hydroxy vitamin D (calciferol)can be used.

NEUROLOGIC COMPLICATIONSOF GASTRIC SURGERY

Bariatric surgery, which is increasinglyperformed because of the obesity epi-demic, may result in neurologic compli-cations related to nutrient deficiencies.Earlier surgical treatments for obesityincluded malabsorptive procedures,such as the jejunocolic shunt andjejunoileal bypass. These were aban-doned because of severe metabolicderangements and associated malnutri-tion. Gastric restriction proceduresused have included gastric partitioning,gastroplasty, and vertical banded gastro-plasty. However, the weight loss afterthese procedures has not been foundto be sustained, either because thesurgical technique was not durable orbecause patients developed maladap-tive eating behaviors that circumventedthe restriction. Gastric bypass proce-dures result in weight loss by a morephysiologic mechanism. They restrictthe volume ingested, cause partialmalabsorption of fat, and induce adumping syndrome with a high carbo-hydrate meal, thus leading to sustainedweight loss. The Roux-en-Y gastricbypass is often the procedure of choiceand is often done laparoscopically.Recently, a laparoscopically placed ad-justable gastric band has gained popu-larity. This procedure differs frompreviously performed restrictive proce-dures in that the band adjusts inresponse to rate of weight loss andabsence of an enterotomy or perma-nent change to the anatomy. Additionalprocedures that result in greater

degrees of maldigestion and malab-sorption combined with partial gastricresection have been advocated for thetreatment of patients with ‘‘super’’ obe-sity (body mass index over 50 kg/m2).These include distal gastric bypass,biliopancreatic diversion with duodenalswitch modification, partial biliopancre-atic bypass, and very, very long limbRoux-en-Y gastric bypass.

Nature of Deficiencies

Vitamin B12 deficiency is the most com-mon nutritional deficiency noted afterbariatric surgery. It may result frominadequate intake, impaired hydrolysisof B12 from dietary protein, or abnor-mal IF and B12 interaction. Vitamin B12

replacement is now routine followingbariatric surgery. B1 deficiency follow-ing bariatric surgery is due to intracta-ble vomiting, rapid weight loss, andinadequate vitamin repletion. Asso-ciated neurologic complications dueto B1 deficiency, such as WE andperipheral neuropathy, may be seenas early as 6 weeks after gastric surgery.Also recognized are other vitamindeficiencies such as folate and vitaminD. The most commonly identifiedmineral deficiency following bariatricsurgery is iron and may be seen innearly half the patients. The occur-rence of aches and pains 1 year afterbypass surgery has been called ‘‘bypassbone disease’’ and is thought to be dueto bone demineralization from im-paired calcium absorption, often withconcurrent vitamin D deficiency. Otheridentified mineral deficiencies includecopper and potassium.

Types and Frequency ofNeurologic Complications

Neurologic complications after gastrec-tomy for ulcer disease or bariatricsurgery have been well recognized,but frequently the cause is not deter-mined (Abarbanel et al, 1987; Juhasz-Pocsine et al, 2007; Koffman et al, 2006;

39

KEY POINTS:

A Vitamin B1

deficiency

following bariatric

surgery is due to

intractable

vomiting, rapid

weight loss, and

inadequate

vitamin repletion.

Associated

neurologic

complications due

to B1 deficiency,

such as Wernicke

encephalopathy

and peripheral

neuropathy, may

be seen as early

as 6 weeks after

gastric surgery.

A Vitamin B12

deficiency is the

most common

nutritional

deficiency noted

after bariatric

surgery. B12

replacement is

now routinely

given following

bariatric surgery.


Thaisetthawatkul et al, 2004). Neuro-logic complications may be noted in5% to 16% of patients undergoing sur-gery for obesity (Abarbanel et al, 1987;Thaisetthawatkul et al, 2004). Specificvitamin and mineral deficiencies havebeen identified following bariatric sur-gery. Central and peripheral neurologiccomplications are often multifactorialin etiology.

A recent review of reported cases ofneurologic complications of bariatricsurgery identified 96 patients (Koffmanet al, 2006). A peripheral neuropathywas identified in 60 and encepha-lopathy in 30 patients. Among thepatients with peripheral neuropathy,40 had a polyneuropathy and 18 hada mononeuropathy. Lumbar plexopa-thy or radiculopathy were rare, andeach was seen in only one case. Of thepolyneuropathy cases, 40 were attrib-uted to thiamine deficiency. Wernicke-Korsakoff syndrome or WE was identi-fied in 27 cases, optic nerve involve-ment in 8, a myelopathy in 2, andprimary muscle disease in 7. In a con-trolled retrospective study of periph-eral neuropathy after bariatric surgery,peripheral neuropathy was noted todevelop in 71 of 435 patients: sensory-predominant polyneuropathy in 27,mononeuropathy in 39, and radicu-loplexopathy in 5 (Thaisetthawatkulet al, 2004). A recent series of 26patients with bariatric surgery–relatedneurologic complications identified adelayed-onset posterolateral myelopa-thy, often related to B12 or copperdeficiency, as the commonest compli-cation (Juhasz-Pocsine et al, 2007). Inthis series, encephalopathy and poly-radiculoneuropathy were acute andearly complications.

Risk Factors for NeurologicComplications

Risk factors for neurologic complica-tions include rate and absolute amount

of weight loss, prolonged gastrointes-tinal symptoms, failure to attend anutritional clinic after bariatric sur-gery, less vitamin and mineral supple-mentation, reduced serum albuminand transferrin, postoperative surgicalcomplications requiring hospitaliza-tion, and having jejunoileal bypass(Thaisetthawatkul et al, 2004). In aseries of 23 patients with neurologiccomplications associated with bar-iatric surgery, protracted vomiting wasnoted in all affected patients (Abarbanelet al, 1987).

Management

Prevention, diagnosis, and treatmentof these disorders are necessary partsof lifelong care after bariatric surgery.Long-term follow up with dietary coun-seling is important. All bariatric sur-gery patients should have 6-monthfollow-up laboratory studies that in-clude complete blood count, serumiron, iron-binding capacity, B12, cal-cium, and alkaline phosphatase. It isunclear which patients may developcopper deficiency after gastric surgeryand whether routine screening andsupplementation should be consid-ered. Oral supplementation containingthe recommended daily allowance formicronutrients can prevent abnormalblood indicators of most vitamins andminerals but are insufficient to main-tain normal plasma B12 levels in ap-proximately 30% of gastric bypasspatients. Multivitamin with mineralsupplements may not prevent devel-opment of iron deficiency or subse-quent anemia. Indefinite use of thefollowing daily supplements has beensuggested (Crowley et al, 1984): amultivitamin-mineral combination con-taining B12, folic acid, vitamin D, andiron; an additional iron tablet, prefera-bly with vitamin C; an additional B12

tablet of 50 mg to 100 mg; a calciumsupplement equivalent to 1 g of ele-mental calcium.

40

KEY POINTS:

A Neurologic

complications

may be noted

in 5% to 16%

of patients

undergoing

surgery for

obesity. Specific

vitamin and

mineral

deficiencies have

been identified

following bariatric

surgery. Central

and peripheral

neurologic

complications

are often

multifactorial

in etiology.

A A recent series of

26 patients

with bariatric

surgery–related

neurologic

complications

identified a

delayed-onset

posterolateral

myelopathy,

often related to

B12 or copper

deficiency, to

be the

commonest

complication.



GASTROINTESTINALDYSFUNCTION INNEUROLOGIC DISORDERS

The enteric nervous system providesthe gut with a neural apparatus capableof modulating intestinal function(Bharucha et al, 1993; Camilleri andBharucha, 1996). Its activity is modu-lated by input from the CNS providedby autonomic nerves (sympathetic andparasympathetic). Shared morphologiccharacteristics between the entericnervous system and the CNS makeboth vulnerable to similar afflictions. Itis, therefore, common for patients withneurologic disease to have gastrointes-tinal dysfunction.

A neurogenic cause for dysphagiamay be suggested by the presence ofdrooling, nasal regurgitation, and epi-sodes of choking or coughing duringswallowing. Neurogenic dysphagia mayresult from involvement of the corticalareas concerned with swallowing, theirefferent pathways, brainstem nuclei,lower cranial nerves, neuromuscularjunction, or the striated muscle. Inmost patients the neurologic cause fordysphagia is quite evident. Rarely,dysphagia may be the presenting man-ifestation of the underlying neurologicdisorder. A videofluoroscopy can clarifythe etiology, quantify the severity, dem-onstrate aspiration, and provide sug-gestions for compensatory maneuvers.Motor dysfunction resulting in delayedgastric emptying is commonly seen inautonomic neuropathies such as thatassociated with diabetes mellitus.Symptoms may be limited to vaguepostprandial abdominal discomfort orinclude recurrent postprandial emesiswith malnutrition. In such cases gastricoutlet obstruction needs to be ex-cluded. Scintigraphic gastric emptyingstudies may help confirm the diagnosis.Chronic intestinal pseudo-obstructionrefers to symptoms suggestive of intes-tinal obstruction in the absence of amechanical cause. This syndrome may

result from degeneration of the gutsmooth muscle, dysfunction of themyenteric plexus, or neurologic dis-eases extrinsic to the gut (Table 1-5).Motility studies may differentiate myo-pathic and neuropathic processes andexclude mechanical obstruction. Neu-rologic disorders that impair mobilityare often associated with constipation.Lack of rectal sensation with impairedurge to defecate may also contribute toconstipation in certain neurologic dis-orders. These patients may be evalu-ated with colon transit studies or

41

KEY POINTS:

A Risk factors for

neurologic

complications

following bariatric

surgery include

rate and absolute

amount of weight

loss, prolonged

gastrointestinal

symptoms, not

attending a

nutritional clinic

after bariatric

surgery, and

postoperative

surgical

complications

requiring

hospitalization.

A A neurogenic

cause for

dysphagia may

be suggested by

the presence of

drooling, nasal

regurgitation,

and episodes

of choking or

coughing during

swallowing.

TABLE 1-5 CommonNeurologicCauses of ChronicIntestinal Pseudo-Obstruction

" Neuropathic

Parkinson disease

Brainstem tumor

Multiple sclerosis

Spinal cord transection

Chaga disease

Diabetes mellitus

Porphyria

Lead poisoning

Drugs

Tricyclic antidepressants

Narcotics

" Myopathic

Myotonic and otherdystrophies

" Neuropathic or Myopathic

Infiltrative disorders

Progressive systemic sclerosis

Amyloidosis

Adapted with permission from Camilleri M,Bharucha AE. Gastrointestinal dysfunction inneurologic disease. Semin Neurol 1996;16(3):203–216.


radioscintigraphy. Neurologic damageto the pelvic nerves with denervationof pelvic floor musculature and dener-vation of the external anal sphincteris associated with fecal incontinence.The combination of incontinence andimpaired rectal sensation suggests apudendal neuropathy. Sympatheticdenervation causes weakness of theinternal anal sphincter and manifestsas nocturnal incontinence. Stress in-continence suggests loss of externalanal sphincter control and results frompudendal nerve or S2-4 lesions. Ano-rectal manometry, defecating proctog-raphy, and external anal sphincter EMGmay be required in selected cases.

Gastrointestinal manifestations ofneurologic disorders are discussedbelow according to site of neurologicinvolvement.

Disorders Affecting the Cortexand Brainstem

Dysphagia, often transient, may beseen in up to 50% of patients after astroke. It is more commonly seen instrokes involving the brainstem, butmay also be seen with bilateral or evenunilateral cerebral hemispheric infarc-tions. A lateralization of swallowingfunction in the cortex may accountfor the latter. Episodes of nausea,vomiting, abdominal pain, or hungermay occur as a seizure or seizure aura.Migraine is often associated with nau-sea, vomiting, and, at times, abdominalpain. Tumors involving the anterome-dial frontal lobe may be associated withdisturbances of micturition and, lessoften, defecation. Tumors involving themedullary vomiting center or thechemoreceptor trigger zone in the areapostrema may be associated withvomiting. Impaired gastrointestinal mo-tility may also be seen with brainstemtumors. Traumatic brain injury can beassociated with dysphagia, delayedgastric emptying, and stress ulcers withgastrointestinal hemorrhage. Progres-

sive bulbar palsy is also associatedwith dysphagia. In Chiari I malforma-tion, tonsillar herniation may resultin lower cranial nerve traction anddysphagia.

Disorders Affecting theBasal Ganglia

Patients with Parkinson disease (PD)may have drooling, defects in tonguemovements, delayed swallowing reflex,aspiration, reduced pharyngeal peri-stalsis, gastroesophageal reflux, andgastrointestinal hypomotility with de-layed gastric emptying and constipation(Edwards et al, 1992). A paradoxicalcontraction of the striated sphinctermuscles during defecation, called anis-mus, may occur and is considered a fo-cal dystonia. Involvement of the dorsalmotor nucleus of the vagus in PD mightproduce gastrointestinal dysfunction.The presence of Lewy bodies in themyenteric plexus of both the esopha-gus and colon suggests that the PDprocess may also affect the entericnervous system and contribute togastrointestinal dysfunction through aperipheral mechanism (Edwards et al,1992). Lewy bodies have also beenfound in the dorsal group of thenucleus intermediolateralis of the thirdsacral segment of the spinal cord.Levodopa administration may help byimproving swallowing. Intraparotid in-jections of botulinum toxin may allevi-ate parkinsonian drooling. In additionto the gastrointestinal abnormalitiesseen in PD, patients with multiplesystem atrophy are also prone to de-velop postprandial hypotension (Mathias,1996). This is due to vasodilatation inthe splanchnic circulation that is notcounterbalanced by compensatory car-diovascular changes because of sympa-thetic dysfunction. Anal sphincter EMGstudies have delineated a characteristicpattern of denervation and reinnerva-tion, but the reliability of this abnormal-ity has been questioned. Dysphagia is

42

KEY POINTS:

A Dysphagia, often

transient, may be

seen in up to

50% of patients

after a stroke. It is

more commonly

seen in strokes

involving the

brainstem but

may also be seen

with bilateral or

even unilateral

cerebral

hemispheric

infarctions. A

lateralization

of swallowing

function in the

cortex may

account for

the latter.

A Patients with

Parkinson disease

may have

drooling,

defects in tongue

movements,

delayed

swallowing

reflex, aspiration,

reduced

pharyngeal

peristalsis,

gastroesophageal

reflux, and

gastrointestinal

hypomotility

with delayed

gastric emptying

and constipation.



almost invariably present in advancedprogressive supranuclear palsy and maybe accompanied by drooling and aspira-tion. Eating difficulties may be com-pounded by difficulty with inferior gazeand by neck extension. Dysphagia is alsoseen in Huntington disease and Wilsondisease. Dysphagia in spasmodic torticol-lis is largely due to head and neckposture.

Disorders Affecting theSpinal Cord

Parasympathetic innervation of thedescending colon, rectum, and anus isfrom the sacral parasympathetic cen-ters in the spinal cord and is thereforeaffected in cord lesions at all levels.Sympathetic supply to the gastrointes-tinal tract is from T5-L3 and is affectedin cervical and upper thoracic lesions.During the stage of spinal shockfollowing spinal cord injury, slowingof colonic motility with ileus occurs(Pfeiffer, 2004). Patients with neurolog-ic sequelae secondary to spinal cordinjury may develop esophageal dys-motility and reflux, delayed gastricemptying, decreased bowel movementfrequency with a vague abdominalbloating, and postprandial distention.Lesions of the cauda equina or conusare associated with fecal incontinence.With higher cord lesions, the externalanal sphincter becomes spastic, andloss of conscious sphincter controlwith anorectal dyssynergy results. Im-paired sensations secondary to thespinal cord injury may cause delayedrecognition of acute abdominal emer-gencies such as intestinal obstructionand peritonitis. Autonomic dysreflexiamay be the manifestation of acuteabdominal pathology and is character-ized by hypertension, pallor, sweating,and piloerection. It is seen with cervicaland upper thoracic cord injuries,reflects loss of cerebral inhibitory inputon thoracolumbar outflow, and is dueto massive sympathetic overactivity

triggered by noxious stimuli belowthe level of a lesion.

CNS Disorders Associated WithMultiple Sites of Involvement

Dysphagia and esophageal dysmotilityin patients with multiple sclerosis maybe due to disease in the brainstem.Gastroparesis, constipation, and de-layed colon transit time may be seen.During attempted defecation, patientsmay experience paradoxical contrac-tion or failure of relaxation of thepuborectalis muscle. Dysmotility ofthe gut is due to impaired supraspinaland spinal control of sacral parasympa-thetic supply to the colon. In ALS,damage to corticobulbar pathways andcranial nerve motor nuclei in thebrainstem cause impairment of lingual,pharyngeal, and esophageal function.

Disorders Involving thePeripheral Nerves, Muscles,and Neuromuscular Junction

Prominent bulbar involvement may beseen in Guillain-Barre syndrome. Weak-ness of masticatory and pharyngealmuscles with chewing and swallow-ing difficulties are commonly seen inmyasthenia gravis. Seronegative myas-thenics with positive anti-MuSK anti-bodies have prominent faciobulbarweakness. Dysphagia may be seen insome congenital myopathies and maybe the presenting manifestation ofoculopharyngeal muscular dystrophy.Dysphagia is also seen in inflammatorymuscle disease, thyrotoxic myopathy,and, rarely, in inclusion body myositis.In these disorders facial and masticatorymuscles are spared. In addition tostriated muscle involvement, disorderssuch as myotonic dystrophy, Duchennemuscular dystrophy, and mitochondrialmyopathy can be associated withsmooth muscle involvement. An asso-ciated neurogenic component withimpaired innervation and motility of

43

KEY POINT:

A Autonomic

dysreflexia

may be the

manifestation of

acute abdominal

pathology and is

characterized by

hypertension,

pallor, sweating,

and piloerection.

It is due to

massive

sympathetic

overactivity

triggered by

noxious stimuli

below the level

of a lesion.


striated and smooth muscle can beseen in myotonic dystrophy and certainmitochondrial myopathies. Myotonicdystrophy may be associated withdysphagia, delayed gastric emptying,diarrhea, abdominal cramps, or radio-logic evidence of megacolon. Dystro-phin is abundant in striated and smoothmuscle, and gastrointestinal complaintsincluding masticatory disturbance, dys-phagia, esophageal dysmotility, delayedgastric emptying, and gastric dilationare common in Duchenne musculardystrophy. Patients with Kearns-Sayresyndrome may have progressive in-volvement of pharyngeal and esopha-geal muscle with resulting dysphagia.Obligatory gastrointestinal involvementis seen in the mitochondrial disorder,mitochondrial neurogastrointestinal en-cephalomyopathy (MNGIE).

Disorders Affecting theEnteric Plexus

Achalasia is characterized by failure ofrelaxation of the lower esophagealsphincter with absence of peristalsis inthe esophageal body. Loss of ganglioncells and destruction of the myentericplexus, including loss of inhibitorynerves containing vasoactive intestinalpeptide, somatostatin, and nitric oxide,are key features. The distal bowelaganglionosis in Hirschsprung diseaseresults from incomplete migration ofneurenteric ganglion cells from theneural crest to the most distal part ofthe gut. Hirschsprung disease presentssoon after birth and is associated withconstipation and gaseous distention.There is a narrowed distal bowelsegment characterized by loss of para-sympathetic ganglion cells from theintramural plexus.

Disorders Affecting theAutonomic Nervous System

Motility disturbance is the common-est gastrointestinal manifestation of

autonomic nervous system disordersaffecting the gastrointestinal tract. Gas-trointestinal manifestations may bethe presenting or only manifestationof autonomic neuropathies. Gastro-intestinal manifestations of autonomicneuropathies can include abdominalpain, paralytic ileus, intestinal pseudo-obstruction, gastroparesis with earlysatiety and bloating, nausea, vomiting,constipation, or diarrhea (Low, 2004).Accompanying evidence of sympatheticdysfunction (orthostatic hypotension,anhidrosis) or parasympathetic failure(dry eyes and mouth, constipation,blurred vision, urinary retention) maybe present. A small fiber neuropathywith distal impairment of pain andtemperature may be seen. Patients withidiopathic orthostatic hypotension andidiopathic autonomic neuropathy mayhave gastrointestinal dysmotility.

Many acute- and subacute-onset au-tonomic neuropathies are immune me-diated. A limited form of autonomicneuropathy involving the gastrointes-tinal tract may occur (autoimmune gas-trointestinal dysmotility) (Pasha et al,2006). Autonomic neuropathies withgastrointestinal involvement may oc-cur as a paraneoplastic manifestationwith detection of antibodies suchas ANNA-1 or anti-Hu and CRMP-5(Lennon et al, 1991, Lucchinetti et al,1998). Autoantibodies to ganglionicacetylcholine receptors have beenidentified in patients with autoimmuneautonomic neuropathies (also calledautoimmune autonomic ganglionopa-thies) (Vernino et al, 2000). In somepatients, these antibodies may be as-sociated with gastrointestinal dysmotil-ity. Substantial autonomic involvementis seen in Guillain-Barre syndrome. Se-lective cholinergic dysfunction is seenin acute cholinergic neuropathy. Gas-trointestinal dysfunction may also beseen in other conditions included in thedifferential diagnosis of acute auto-nomic neuropathies such as botulism,

44

KEY POINTS:

A Many acute- and

subacute-onset

autonomic

neuropathies are

immune

mediated. A

limited form of

autonomic

neuropathy

involving the

gastrointestinal

tract may occur

(autoimmune

gastrointestinal

dysmotility).

These autonomic

neuropathies

may occur as a

paraneoplastic

manifestation

with detection

of antibodies

such as ANNA-1

or anti-Hu and

CRMP-5.

A Autoantibodies

to ganglionic

acetylcholine

receptors have

been identified

in patients with

autoimmune

autonomic

neuropathies

(also called

autoimmune

autonomic

ganglionopathies).

In some patients

these antibodies

may be

associated with

gastrointestinal

dysmotility.



porphyria, and autonomic neuropa-thies due to drugs like vincristine andvacor.

Diabetic autonomic neuropathy maybe associated with gastroparesis, con-stipation, fecal incontinence, or diar-rhea. Autonomic dysfunction may bethe cause of diarrhea in patients withHIV infection. Chagas disease is causedby Trypanosmoma cruzi. ChronicChagas disease develops years afterprimary infection and commonlyaffects the heart and gastrointestinalsystem. Patients may complain ofdysphagia and constipation and have

a chronic cholinergic megaesophagus,megaduodenum, and megacolon. Insporadic systemic amyloid neuropathyor familial amyloidotic polyneuro-pathy, infiltration of the myentericand submucosal plexus may causediarrhea or constipation. Amyloid infil-tration of the lower esophagus maycause dysphagia. Autonomic impair-ment is less common in amyloidosisassociated with multiple myeloma.Gastrointestinal symptoms are alsoseen in familial dysautonomia (Riley-Day syndrome, hereditary sensory andautonomic neuropathy type III).

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" Koffman BM, Greenfield LJ, Ali II, Pirzada NA. Neurologic complicationsafter surgery for obesity. Muscle Nerve 2006;33(2):166–176.

A comprehensive review of neurologic complications after bariatric surgery.

" Kumar N. Copper deficiency myelopathy (human swayback).Mayo Clin Proc 2006;81(10):1371–1384.

A review article on copper deficiency myelopathy, which includes descriptionsof 25 cases seen at the Mayo Clinic.

" Kumar N. Nutritional neuropathies. Neurol Clin 2007;25(1):209–255.

A recent review of specific nutrient deficiencies and related neurologic manifestations.

" Kumar N, Ahlskog JE, Gross JB Jr. Acquired hypocupremia after gastricsurgery. Clin Gastroenterol Hepatol 2004a;2(12):1074–1079.

A report of four patients with copper deficiency myelopathy. In two patients priorgastric surgery was the likely cause of copper deficiency, and in the other twoa primary copper transport defect was the likely cause.

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" Kumar N, Ahlskog JE, Klein CJ, Port JD. Imaging features of copperdeficiency myelopathy: a study of 25 cases. Neuroradiology2006;48(2):78–83.

A detailed report on the neuroimaging findings in 25 patients with copperdeficiency myelopathy. The most common abnormality is increased T2 signalinvolving the dorsal midline cervical and thoracic cord.

" Kumar N, Gross JB Jr, Ahlskog JE. Copper deficiency myelopathyproduces a clinical picture like subacute combined degeneration.Neurology 2004b;63(1):33–39.

A description of 13 patients with copper deficiency myelopathy. The reportpoints out the similarities with the subacute combined degeneration seen withvitamin B12 deficiency.

" Lennon VA, Sas DF, Busk MF, et al. Enteric neuronal autoantibodies inpseudoobstruction with small-cell lung carcinoma. Gastroenterology1991;100(1):137–142.

A discussion of gastrointestinal dysmotility as a paraneoplastic syndrome and therole of serologic testing.

" Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorderscaused by cobalamin deficiency in the absence of anemia or macrocytosis.N Engl J Med 1988;318(26):1720–1728.

A study of 40 patients with neuropsychiatric disorders caused by cobalamindeficiency in the absence of hematologic manifestations.

" Lossos A, River Y, Eliakim A, Steiner I. Neurologic aspects of inflammatorybowel disease. Neurology 1995;45(3 pt 1):416–421.

A retrospective review of neurologic manifestations in 19 patients with inflammatorybowel disease. Also includes a literature review of neurologic manifestationsin patients with inflammatory bowel disease.

" Louis ED, Lynch T, Kaufmann P, et al. Diagnostic guidelines in centralnervous system Whipple’s disease. Ann Neurol 1996;40(4):561–568.

A review of reported cases of CNS Whipple disease (81 from the literature and threenew) that describes the frequencies of abnormalities on neurologic examination,CSF studies, neuroimaging, and intestinal biopsy studies. Guidelines for diagnosisof CNS Whipple disease are also proposed.

" Low PA. The autonomic neuropathies. In: Quigley EMM, Pfeiffer RF, eds.Neuro-gastroenterology. Philadelphia: Butterworth Heinemann,2004:83–100.

A review of autonomic neuropathies and gastrointestinal dysfunction.

" Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologicprofiles of patients seropositive for type 1 antineuronal nuclearautoantibodies. Neurology 1998;50(3):652–657.

A study of the neurologic manifestations in patients with antineuronal nuclearantibody type 1, including a discussion of the fact that some patients can haveonly gastrointestinal manifestations.

" Marth T, Raoult D. Whipple’s disease. Lancet 2003;361(9353):239–246.

A review of Whipple disease.

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" Mathias CJ. Gastrointestinal dysfunction in multiple system atrophy.Semin Neurol 1996;16(3):251–258.

A review of gastrointestinal dysfunction in multiple system atrophy.

" Matthews BR, Jones LK, Saad DA, et al. Cerebellar ataxia and centralnervous system Whipple disease. Arch Neurol 2005;62(4):618–620.

A report of 11 patients with CNS Whipple disease, which suggests that cerebellarataxia is a common feature of the disease.

" Messori A, Di Bella P, Polonara G, et al. An unusual spinal presentationof Whipple disease. AJNR Am J Neuroradiol 2001;22(5):173:1004–1008.

Report of a patient with a spinal presentation of Whipple disease and a discussionof the neuroimaging findings.

" Murray JA, Ross MA. Malabsorption and neurological disease.In: Quigley EMM, Pfeiffer RF, eds. Neuro-gastroenterology. Philadelphia:Butterworth Heinemann, 2004:203–254.

A recent review of malabsorption and neurologic disease.

" Pasha SF, Lunsford TN, Lennon VA. Autoimmune gastrointestinaldysmotility treated successfully with pyridostigmine. Gastroenterology2006;131(5):1592–1596.

Report of a patient with gastroparesis and neuronal acetylcholine esteraseantibodies who responded to pyridostigmine. The concept of autoimmunegastrointestinal dysmotility as a limited form of autoimmune (paraneoplastic)autonomic neuropathy is discussed.

" Perkin GD, Murray-Lyon I. Neurology and the gastrointestinal system.J Neurol Neurosurg Psychiatry 1998;65(3):291–300.

A review of gastrointestinal disorders due to neurologic disease, disorders of gastricand intestinal motility, primary disorders of gut function or absorption, celiacdisease, inflammatory bowel disease, and Whipple disease.

" Pfeiffer RF. Gastrointestinal dysfunction in spinal cord disease.In: Quigley EMM, Pfeiffer RF, eds. Neuro-gastroenterology.Philadelphia: Butterworth Heinemann, 2004:101–112.

A review of gastrointestinal dysfunction in spinal cord disease.

" Prodan CI, Holland NR, Wisdom PJ, et al. CNS demyelinationassociated with copper deficiency and hyperzincemia. Neurology2002;59(9):1453–1456.

A report of two patients with idiopathic hypocupremia and hyperzincemia andCNS demyelination.

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A prospective case-control study of over 100 patients, which addresses the clinicaland epidemiologic features of the association between Campylobacter jejuniinfection and Guillain-Barre syndrome or Miller Fisher syndrome.

" Reuler JB, Girard DE, Cooney TG. Current concepts. Wernicke’sencephalopathy. N Engl J Med 1985;312(16):1035–1039.

A review article on Wernicke encephalopathy.

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" Reynolds EH. Benefits and risks of folic acid to the nervous system.J Neurol Neurosurg Psychiatry 2002;72(5):567–571.

Review article that discusses the role of folic acid and neurologic disorders, includinga change in thinking over the past 3 decades.

" Rostom A, Murray JA, Kagnoff MF. American GastroenterologicalAssociation (AGA) Institute technical review on the diagnosis andmanagement of celiac disease. Gastroenterology 2006;131(6):1981–2002.

An American Gastroenterological Association Institute technical review of celiacdisease that addresses celiac disease epidemiology, detection by serologic testing,diagnosis by biopsy, treatment, and outcome.

" Rowin J, Lewis SL. Copper deficiency myeloneuropathy and pancytopeniasecondary to overuse of zinc supplementation. J Neurol NeurosurgPsychiatry 2005;76(5):750–751.

An illustrative case of copper deficiency myeloneuropathy and pancytopenia secondaryto excess use of zinc supplementation.

" Russell JA. Osteomalacic myopathy. Muscle Nerve 1994;17(6):578–580.

Report of a patient with a reversible, painful myopathy associated with vitamin Ddeficiency.

" Saperstein DS, Wolfe GI, Gronseth GS, et al. Challenges in theidentification of cobalamin-deficiency polyneuropathy. Arch Neurol2003;60(9):1296–1301.

A study of the clinical and laboratory features in 27 patients with acobalamin-deficiency neuropathy.

" Schaumburg H, Kaplan J, Windebank A, et al. Sensory neuropathy frompyridoxine abuse. A new megavitamin syndrome. N Engl J Med1983;309(8):445–448.

A report of seven adults with ataxia and sensory neuropathy or neuronopathysecondary to pyridoxine abuse.

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A retrospective analysis of 22 cases of alcoholic pellagra encephalopathy. Alcoholicswith encephalopathy may receive thiamine and pyridoxine without niacin, andthis may trigger an encephalopathy due to niacin deficiency.

" Skeen MB. Neurologic manifestations of gastrointestinal disease.Neurol Clin 2002;20(1):195–225.

A comprehensive review of neurologic manifestations of gastrointestinal disease,including a detailed discussion of neurologic consequences of deficiency states.

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A review article on vitamin E deficiency and neurologic disease.

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" Sokol RJ, Heubi JE, Iannaccone ST, et al. Vitamin E deficiency with normalserum vitamin E concentrations in children with chronic cholestasis.N Engl J Med 1984;310(19):1209–1212.

A study suggesting that the ratio of serum vitamin E to total serum lipids is the mostreliable biochemical index of vitamin E status during chronic childhood cholestasis.

" Tefferi A, Pruthi RK. The biochemical basis of cobalamin deficiency.Mayo Clin Proc 1994;69(2):181–186.

A summary of the physiology and biochemistry of cobalamin deficiency.

" Thaisetthawatkul P, Collazo-Clavell ML, Sarr MG, et al. A controlledstudy of peripheral neuropathy after bariatric surgery. Neurology2004;63(8):1462–1470.

A controlled study of peripheral neuropathy after bariatric surgery, which showed that16% of 435 patients who had bariatric surgery developed peripheral neuropathy.

" Vernino S, Low PA, Fealey RD, et al. Autoantibodies to ganglionicacetylcholine receptors in autoimmune autonomic neuropathies.N Engl J Med 2000;343(12):847–855.

Reports on the presence of antibodies that bind to or block ganglionic acetylcholinereceptors in patients with various forms of autoimmune autonomic neuropathy,including some with prominent gastrointestinal symptoms.

" von Herbay A, Ditton HJ, Schuhmacher F, Maiwald M. Whipple’s disease:staging and monitoring by cytology and polymerase chain reactionanalysis of cerebrospinal fluid. Gastroenterology 1997;113(2):434–441.

A study that addresses the role of PCR analysis of CSF in patients with Whipple disease.

" Vorgerd M, Tegenthoff M, Kuhne D, Malin JP. Spinal MRI inprogressive myeloneuropathy associated with vitamin E deficiency.Neuroradiology 1996;38(suppl 1):111–113.

Report of a patient with a myeloneuropathy due to vitamin E deficiency and a signalchange in the posterior column on a spine MRI.

" Weihl CC, Lopate G. Motor neuron disease associated with copperdeficiency. Muscle Nerve 2006;34(6):789–793.

A report of three patients with asymmetric weakness, distal sensory impairment,and electrodiagnostic evidence of lower motor neuron disease.

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