NEUROGASTROENTEROLOGY Neeraj Kumar ABSTRACT The interrelationship between neurology and the gastrointestinal system is discussed in this chapter, which is divided into four sections: (1) neurologic manifestations of diseases that typically involve the gastrointestinal tract but may involve the nervous system in association with or independent of gastrointestinal involvement (celiac disease, Whipple disease, and inflammatory bowel disease); (2) neurologic manifestations related to deficiency of key nutrients, such as vitamin B 12 , folate, copper, vitamin E, thiamine, and others; (3) nervous system disorders including cerebrovascular disease, extrapyramidal and spinal cord disorders, and disorders of the peripheral and autonomic nervous system that are associated with gastrointestinal manifestations such as dysphagia, gastroparesis, and constipation; and (4) the increasingly important topic of neurologic complications related to gastric surgery. The interested reader is directed to four recent reviews on neurogastroenterology for additional information (Kumar, 2007; Murray and Ross, 2004; Perkin and Murray-Lyon, 1998; Skeen, 2002). Continuum Lifelong Learning Neurol 2008;14(1):13–52. NEUROLOGIC MANIFESTATIONS OF SPECIFIC GASTROINTESTINAL DISORDERS Celiac Disease Celiac disease is an immune-mediated enteropathy triggered by the ingestion of gluten-containing grains in genet- ically susceptible individuals (Craig et al, 2007; Farrell and Kelly, 2002; Rostom et al, 2006). It is characterized by mucosal inflammation and resul- tant malabsorption. Celiac disease can present with intestinal or extraintesti- nal symptoms (like the skin rash of dermatitis herpetiformis) or may even be detected in asymptomatic individ- uals. The diagnostic guidelines for celiac disease have required the pres- ence of characteristic lesions on small bowel biopsy and demonstration of clinical improvement following elimi- nation of gluten from the diet. Recent population-based studies suggest that subclinical celiac disease may be much more common than previously recog- nized (Fasano et al, 2003). With aware- ness of a high disease prevalence has come the recognition of a broad spec- trum of clinical presentations. Neurologic complications may occur in 10% of patients with well-established celiac disease. In earlier reports, neu- rologic manifestations associated with celiac disease were attributed to spe- cific nutrient deficiencies (iron, folate, calcium and vitamin D, vitamin A, vitamin E, copper, pyridoxine, vitamin K, and vitamin B 12 ). More recently the focus has been on immunologic mechanisms. Severe malabsorption is generally rare in patients with a neuro- logic presentation. Documentation of patients with neurologic manifestations and elevated autoantibodies associated with celiac disease (primarily antiglia- din), often without gastrointestinal manifestations, has led to the sugges- tion that gluten sensitivity (as opposed to celiac disease) can cause neurologic manifestations without gastrointestinal symptoms or small bowel biopsy changes (Hadjivassiliou et al, 2002b). In some of these cases, neurologic 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.
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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).
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.
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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
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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.
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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.
"NEUROGASTROENTEROLOGY
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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.
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.
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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)
(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)
(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.
"NEUROGASTROENTEROLOGY
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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.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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.
"NEUROGASTROENTEROLOGY
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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.
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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.
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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.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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.
"NEUROGASTROENTEROLOGY
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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.
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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
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.
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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.
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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
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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.
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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.
"NEUROGASTROENTEROLOGY
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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).
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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.
"NEUROGASTROENTEROLOGY
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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.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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.
"NEUROGASTROENTEROLOGY
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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.
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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.
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.
"NEUROGASTROENTEROLOGY
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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.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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.
"NEUROGASTROENTEROLOGY
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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.
"NEUROGASTROENTEROLOGY
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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.
"NEUROGASTROENTEROLOGY
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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.
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.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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.
"NEUROGASTROENTEROLOGY
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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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The study suggests than gluten sensitivity may be etiologically linked to asubstantial number of idiopathic axonal neuropathies. In this manuscript theauthors describe clinical features of gluten neuropathy in 100 patients.
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Review article that discusses the role of folic acid and neurologic disorders, includinga change in thinking over the past 3 decades.
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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.
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A summary of the physiology and biochemistry of cobalamin deficiency.
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