Handbook of Clinical Neurology, Vol. 120 (3rd series)Neurologic Aspects of Systemic Disease Part IIJose Biller and Jose M. Ferro, Editors© 2014 Elsevier B.V. All rights reserved

Chapter 41

Gluten-related neurologic dysfunction

MARIOS HADJIVASSILIOU1*, ANDREW P. DUKER2, AND DAVID S. SANDERS3

1Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK2Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK3Department of Neurology, University of Cincinnati, Cincinnati, OH, USA

HISTORICAL PERSPECTIVE

Celiac disease (CD) was first described by the Greekdoctor Aretaeus the Cappadocian, in AD 100, only to beforgotten and then rediscovered by Samuel Gee in 1888(Gee, 1888). In a lecture on “the coeliac affection,” Geedescribed the classic pediatric presentation of the disease.Whilst clinicians began to recognize this disease entity, theetiologic agent remained obscure until the observations ofWillem Dicke, a Dutch pediatrician, in 1953 of “the pres-ence in wheat, of a factor having a deleterious effect incases of celiac disease” (Dicke et al., 1953). As gastroin-testinal symptoms (diarrhea, abdominal pain, bloating,weight loss) were dominant in patients with this disease,it was not surprising that CD was thought to be a diseaseof the gut. Indeed the introduction of endoscopy andsmall bowel biopsy in the 1950s confirmed the presenceof an enteropathy (Paulley, 1954).

In 1963 a group of dermatologists made the interest-ing observation that dermatitis herpetiformis (DH), anitchy vesicular rash, was a form of gluten-related derma-topathy sharing the same small bowel pathology, but notthe gastrointestinal symptoms seen in patients with CD(Marks et al., 1966). This was the first evidence of extra-intestinal manifestations.

Only a small number of case reports of patients withCD and neurologic manifestations (Elders, 1925; Reedand Ash, 1927; Woltman and Heck, 1937) were publishedprior to the discovery of the etiologic agent and the intro-duction of small bowel biopsy, demonstrating the typicalhistologic features that define CD. Such reports need tobe treated with caution given that a diagnosis of CD inthose patients was speculative.

The first comprehensive case series of neurologicmanifestations in the context of histologically confirmed

*Correspondence to: Marios Hadjivassiliou, Department of Neurol

2JF, UK. E-mail: m.hadjivassiliou@shefffield.ac.uk

CD was published in 1966 (Cooke and Thomas-Smith,1966). This detailed work described the range of neuro-logic manifestations seen in 16 patients with establishedCD. Of interest was the fact that all patients had gaitataxia and some had severe peripheral neuropathy aswell. The assumption was that such manifestations werenutritional as a result of malabsorption. Indeed all ofthese patients were grossly malnourished and cachectic.Postmortem data from the same report, however, dem-onstrated an inflammatory process primarily affectingthe cerebellum, but also involving other parts of the cen-tral and peripheral nervous systems, a finding that was infavor of an immune-mediated pathogenesis.

Single and multiple case reports of patients withestablished CD who then developed neurologic dysfunc-tion continued to be published (Binder et al., 1967;Bundey, 1967; Morris et al., 1970; Coers et al.,1971; Kepes et al., 1975; Finelli et al., 1980; Kinneyet al., 1982; Ward et al., 1985; Lu et al., 1986;Kristoferitsch and Pointer, 1987; Kaplan et al., 1988;Tison et al., 1989; Collin et al., 1991; Hermaszewskiet al., 1991; Bhatia et al., 1995; Dick et al., 1995;Muller et al., 1996).

The key findings from these reports were as follows:

● Ataxia (with and without myoclonus) and neuropa-

ogy,

thy were the commonest manifestations.

● Neurologic manifestations were usually reported in

the context of established CD and almost alwaysattributed to nutritional deficiencies.

● In those reports where the effect of the dietary

restriction was reported, the results were mixed.None of these reports, however, documented anyattempts tomonitor adherence to the diet with repeatserologic testing.

Royal Hallamshire Hospital, Glossop Road, Sheffield, S10

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Thirty years after the first comprehensive case series onneurologic manifestations of CD saw the publication ofan original study (Hadjivassiliou et al., 1996) approachingthe issue from a neurologic perspective by investigatingthe prevalence of serologic markers of gluten-related dys-function (GRD) in patients presenting with neurologicdysfunction of unknown etiology. The results demon-strated that there was a high prevalence of IgG and/orIgA antigliadin antibodies (AGA) in this group of patientscompared to controls. Based on duodenal biopsies thesame study showed that the prevalence of CD in thisgroup of patients with neurologic dysfunction was 16times higher than the prevalence of CD in the healthy pop-ulation. This study rekindled the interest of neurologists ina possible link between GRD and neurologic disease.

608 M. HADJIVA

Table 41.1

Type of neurologic presentation in gluten sensitivity*

Neurologic presentation No

Total number of patients 500Ataxia (4 patients with myoclonus, 2

with palatal tremor)

233 (93)

Peripheral neuropathy 182 (48)Sensorimotor axonal neuropathy 135

Mononeuropathy multiplex 19Sensory neuronopathy 14Small fiber neuropathy 8

Motor neuropathy 8Encephalopathy 77 (45)Myopathy 18 (10)

Myelopathy 9 (4)Stiff man syndrome 7 (2)Chorea (often with ataxia) 3 (2)Neuromyotonia 1 (1)

Epilepsy and occipital calcifications 1 (0)

*Based on 500 patients with gluten sensitivity, presenting with neuro-

logic dysfunction and seen in the gluten sensitivity/neurology clinic,

Sheffield, UK, from 1994 to 2011. The number of patients from each

group who had enteropathy on biopsy is shown in parentheses. Some

patients had more than one type of neurologic presentation.

EPIDEMIOLOGYOF NEUROLOGICMANIFESTATIONS

The prevalence of CD in the healthy population has beenshown to be at least 1% in bothEuropean andNorthAmer-ican studies (Sanders et al., 2003). There are no accuratefigures of the prevalence of the neurologicmanifestationsof gluten sensitivity in the general population. Figures ofbetween 10% and 22.5% have been reported amongstpatients with established CD attending gastrointestinalclinics (Holmes, 1997; Briani et al., 2008). These areunlikely to be accurate because such figures are usuallyretrospective, derived solely from gastrointestinal clinics,concentrating exclusively on patients with classic CD pre-sentation, and often include neurologic dysfunctions thatare unlikely to be gluten related (e.g., carpal tunnel syn-drome, idiopathic Parkinson’s disease, etc.). Some esti-mates of prevalence can be made from patientpopulations attending specialist clinics although cautionmust be exercised in extrapolating these as they are inev-itably affected by referral bias. Data collected from theSheffield dedicated CD and gluten sensitivity/neurologyclinics suggest that for every seven patients presentingto the gastroenterologists who are then diagnosed withCD, there are two patients presenting to the neurologistswho will then be diagnosed as having CD (Hadjivassiliouet al., 2010a). This is likely to be an underestimate becausethis ratio does not take into account those patients withneurologic manifestations due to GRD that do not havean enteropathy (approximately two-thirds of the wholenumber of patients presenting with neurologic dysfunc-tion).Theauthorsbelieve that theprevalenceofneurologicdysfunction even within patients with CD presenting togastroenterologists is likely to be much higher than whathas been published if such patients undergo rigorous neu-rologic workup includingmagnetic resonance (MR) spec-troscopy of the cerebellum. Preliminary work on patientswith CD presenting to gastroenterologists with minor

neurologic complaints demonstrates that up to 80% haveabnormal MR spectroscopy (low NAA/Cr ratios) of thecerebellum (Hadjivassiliou et al., 2011).

LIOU ET AL.

THEDIAGNOSISOFGLUTEN-RELATEDDISEASES

CD is characterized by the presence of an enteropathy, areliable gold standard. It is now accepted, however, thatan enteropathy is not a prerequisite for the diagnosis ofGRD with predominantly neurologic or other extrain-testinal manifestations. Furthermore, the small bowelmucosal changes in the context of GRD represent a spec-trum, from histologically normal mucosa to full-blownenteropathy to a pre-lymphomatous state also referredto as the Marsh classification (Marsh, 1992). Mostpathology departments have now adopted the Marshclassification when reporting the histologic findings ofsmall bowel biopsies. Given that the histology can be nor-mal, a definition of GRD based solely on histologybecomes problematic. Furthermore the diagnosis cur-rently has to rely on serologic tests that are not 100% spe-cific or sensitive. For example, endomysial antibody(EMA) and antitransglutaminase-2 (TG2) IgA antibodydetection are specific for the presence of an enteropathy.However, these markers are frequently not detectable inpatients with neurologic manifestations, particularly inthose who do not have an enteropathy (Table 41.1).

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GRD cannot be diagnosed on clinical grounds alone.The majority of patients presenting with neurologicmanifestations have no gastrointestinal symptoms.Patients with CD can also have no gastrointestinal symp-toms. In patients without overt gastrointestinal involve-ment, serum antibodies to TG2 may be absent. Suchpatients typically have antibodies primarily reacting withdifferent TG isozymes, TG3 in DH and TG6 in patientswith gluten ataxia (Hadjivassiliou et al., 2008a). Reac-tion of such antibodies with TG2 in the intestinal mucosaoccurs prior to overt changes in small intestinal morphol-ogy and sometimes even before the antibodies aredetectable in serum (Korponay-Szabo et al., 2003). Suchantibody deposits seem to be present in patients withneurologic manifestations as well, and may thereforebe diagnostically useful (Hadjivassiliou et al., 2006a).However, this test is not readily available and requiresexperience in its interpretation. In practice, for sus-pected neurologic manifestations of GRD, it is best toperform serologic tests for both IgA and IgG antibodiesto TG2 (and if available anti-TG6 and anti-TG3) as wellas IgG and IgA antibodies to gliadin. Endomysium anti-bodies are very specific for the detection of enteropathy,but they detect the same antigen (transglutaminase 2)and have thus largely been replaced by TG2 antibodytesting. Any differences between the two tests, however,are likely to be related to the different methodologiesused (ELISA for TG2 versus immunofluorescence forthe detection of EMA).

GRD have a strong genetic predisposition whereby�40% of the genetic load comes fromMHC class II asso-ciation (Hunt, 2008). In Caucasian populations more than90%ofCDpatientscarry theHLADQ2,with theremaininghaving the HLA DQ8. A small number of CD patients donot belong into either of these groups but these have beenshowntocarry justonechainof theDQ2heterodimer.HLAgenetic testing is therefore another useful diagnostic tool,particularly as, unlike other serologic tests, it is not depen-dent on an immunologic trigger. However, the HLA DQgenotype can be used only as a test of exclusion as the riskgenotype DQ2 is common in Caucasian andAsian popula-tions and many carriers will never develop GRD.

THE SPECTRUMOFGLUTEN-RELATEDNEUROLOGICMANIFESTATIONS

Gluten ataxia

Gluten ataxia (GA) was originally defined as otherwiseidiopathic sporadic ataxia with positive AGA(Hadjivassiliou et al., 2003a). This original definitionwas based on the serologic tests available at the time.In a series of 853 patients with progressive ataxia evalu-ated over a period of 15 years in Sheffield, UK, therewere 152 patients out of 681 with sporadic ataxia who

GLUTEN-RELATED NEU

had serologic evidence of GRD. Therefore gluten ataxiahad a prevalence of 22% amongst sporadic ataxias but ashigh as 45% amongst idiopathic sporadic ataxias. Usingthe same AGA assay the prevalence of positive AGA ingenetically confirmed ataxias was 8/82 (10%), in familialataxias (not genetically confirmed) 8/49 (16%), and inhealthy volunteers 149/1200 (12%). A number of studieslooking at the prevalence of antigliadin antibodies inataxias have been published: The original publicationby the authors (Hadjivassiliou et al., 2003a) reportedthe incidence of IgG and/or IgA AGA in a large cohortof 224 patients seen in Sheffield, UK,with idiopathic andhereditary ataxia. Antibodies were present in 41% ofpatients with sporadic ataxia (54/132), compared to12% (149/1200) of normal controls from the same popu-lation. Positive antibodies were also found in 14% ofpatients with familial ataxia (8/59) and 15% of patientswith clinically probable multiple system atrophy(MSA)-C (5/33). Among AGA-positive individuals withsporadic ataxia, evidence of celiac disease was presentin 24% (12/51) of those patients who underwent duodenalbiopsy. In this same study, a separate group of patientsfrom a second center in London with sporadic ataxiashowed positive antibodies in 32% (14/44). Another study(B€urk et al., 2001a) found positive antibodies in 11.5%(12/104) of patients with idiopathic ataxia and negativegenetic testing, compared to 5% of 600 blood donorsfrom the same country. An Italian study (Pellecchiaet al., 1999a) confirmed a higher incidence of positiveantigliadin antibodies and celiac disease on intestinalbiopsy in idiopathic ataxia (3/24, 12.5%) compared topatients with known hereditary ataxia (0/23, 0%). Furtherconfirmatory studies with smaller numbers fromFinland, Japan, and France have also been published(Luostarinen et al., 2001; Anheim et al., 2006; Iharaet al., 2006). However, other studies have not shownas clear a distinction in antibody prevalence between idi-opathic and other causes of ataxia. Abele et al. (2002)found positive antibodies in 15% (10/65) of patients withidiopathic ataxia compared to 9% (3/32) of patients withMSA and 7% (1/15) with genetic ataxia. In a separatestudy, Abele et al. (2003) found no statistically signifi-cant difference between the prevalence of positive IgGand/or IgA AGA in sporadic ataxia (19% of 32 patients),recessive ataxia (8% of 24 patients), dominant ataxia(15% of 39 patients), and controls (8% of 73 patients).Analyzing IgG and IgA subtypes separately also didnot show significant differences between groups.Bushara et al. (2001) noted similar rates of positiveIgG and/or IgA AGA in sporadic ataxia (27%, 7/26)and autosomal dominant ataxia (37%, 9/24). Someauthors believe the elevated incidence of AGA in hered-itary ataxia may be driven in part by spinocerebellarataxia type 2 (SCA2). In one study, 23% of SCA2

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Fig. 41.1. Severe cerebellar atrophy on axial MR imaging in a

40-year-old woman with a 10 year history of progressive

ataxia diagnosed eventually with gluten sensitivity. She

remains stable on a gluten-free diet but the ataxia is still present

as a result of permanent damage to the cerebellum.

SSILIOU ET AL.

patients had positive AGA, significantly higher com-pared to 9% of controls (Almaguer-Mederos et al.,2008). The variations in prevalence may relate to geo-graphical differences in the prevalence of CD, referralbias, variability in theAGA assays used, patient selection(some studies included as idiopathic sporadic ataxiapatients with cerebellar variant of multisystem atrophy(Combarros et al., 2000)), the small number of patientsstudied, and no controls. The common theme in most ofthese studies is the consistently high prevalence of AGAantibodies in sporadic ataxias when compared to healthycontrols.

GA usually presents with pure cerebellar ataxia orrarely ataxia in combination with myoclonus, palataltremor (Hadjivassiliou et al., 2008b), opsoclonus(Deconinck et al., 2006), or rarely, chorea (Pereiraet al., 2004). GA is usually of insidious onset with ameanage at onset of 53 years. Rarely the ataxia can be rapidlyprogressive mimicking paraneoplastic cerebellar degen-eration. Gaze-evoked nystagmus and other ocular signsof cerebellar dysfunction are seen in up to 80% of cases.All patients have gait ataxia and the majority have limbataxia. Less than 10% of patients with GA will have anygastrointestinal symptoms but a third will have evidenceof enteropathy on biopsy. Up to 60% of patients haveneurophysiologic evidence of sensorimotor, length-dependent axonal neuropathy. This is usually mild anddoes not contribute to the ataxia. Anti-TG2 IgA anti-bodies are present in up to 38% of patients, but oftenat lower titers than those seen in patients with CD. How-ever, unlike CD, IgG class antibodies to TG2 are morefrequent than IgA. Antibodies against TG2 and TG6combined can be found in 85% of patients with ataxiawho are positive for AGA antibodies (Hadjivassiliouet al., 2009). Some patients also test positive foranti-TG3 antibodies although the prevalence of suchantibodies in patients with gluten ataxia is low whencompared to DH. It is unclear at present whether com-bined detection of TG2 and TG6 IgA/IgG without theuse of antigliadin antibodies identifies all patients withgluten ataxia.

Up to 60% of patients with gluten ataxia have evi-dence of cerebellar atrophy on MR imaging (Fig. 41.1).Investigation of the metabolic status of the cerebellumin 15 patients with gluten ataxia and 10 controls usingproton MR spectroscopy demonstrated significant dif-ferences in mean N-acetylaspartate/creatine levelsbetween patients with GA and healthy controls, suggest-ing that cerebellar neuronal physiology in these patientsis abnormal (Wilkinson et al., 2005). Even in thosepatients without cerebellar atrophy, proton MR spec-troscopy of the cerebellum was abnormal. There isemerging evidence thatMR spectroscopy is often abnor-mal in patients with newly diagnosed CDwithminimal or

610 M. HADJIVA

no neurologic complaints and that such abnormalitiesimprove with the introduction of a gluten-free diet.The clinical improvement manifests after 1 year on thediet but continues for at least 2 years. The response totreatment with a gluten-free diet depends on the dura-tion of the ataxia prior to the diagnosis of GRD. Lossof Purkinje cells in the cerebellum, the end result of pro-longed gluten exposure in patients with GA, is irrevers-ible, and prompt treatment is more likely to result inimprovement or stabilization of the ataxia. Whilst thebenefits of a gluten-free diet in the treatment of patientswith CD and DH have long been established, there arevery few studies, mainly case reports, of the effect ofa gluten-free diet on the neurologic manifestations.Most of these reports primarily concern patients withestablished CD who then develop neurologic symptoms(Beversdorf et al., 1996; Hahn et al., 1998; Pellecchiaet al., 1999). These studies suggest variable but overallfavorable responsiveness to a gluten-free diet. A small,uncontrolled study looked at the use of intravenousimmunoglobulins in the treatment of four patients with

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GAwithout enteropathy (B€urk et al., 2001b; Sander et al.,2003). All patients improved. In all of these reports,strict adherence to the gluten-free diet was assumedand no serologic evidence was provided. The best markerof strict adherence to a gluten-free diet is serologic evi-dence of elimination of circulating GRD-related anti-bodies. Only one systematic study of the effect of agluten-free diet on a cohort of patients presenting withataxia, with orwithout an enteropathy, has been published(Hadjivassiliou et al., 2003b). This study also reportedserologic evidence of elimination of the antigliadin anti-bodies as a confirmation of strict adherence to the diet.A total of 43 patients with gluten ataxia were enrolled.Of these, 26 adhered strictly to the gluten-free diet, hadserologic evidence of elimination of antibodies, and com-prised the treatment group; 14 patients refused the dietand comprised the control group and 3 patients wereexcluded as despite the diet their antibodies were still pos-itive. Patient and control groups were matched at baselinefor all variables (age, duration of ataxia, etc.). There wasno significant difference in the baseline performance foreach ataxia test between the two groups. Therewas signif-icant improvement in performance in test scores and inthe subjective global clinical impression scale in the treat-ment group when compared to the control group. Theimprovement was apparent even after excluding patientswith an enteropathy. The study concluded that gluten-freediet can be an effective treatment for GA.

There are no published randomized, placebo-controlled studies on the subject, perhaps reflectingthe difficulties associated with such a study when theintervention is dietary elimination of gluten and the eth-ical considerations of randomizing patients withGAwhohave enteropathy. The current recommendation is thatpatients presenting with progressive cerebellar ataxiashould be screened for gluten sensitivity using antigliadinIgG and IgA, anti-TG2 antibodies and if available anti-TG6 antibodies. Patients positive for any of these anti-bodies with no alternative cause for their ataxia shouldbe offered a strict gluten-free diet with regular follow-up to ensure that the antibodies are eliminated (usuallytakes 6–12 months). Stabilization or even improvementof the ataxia at 1 year would be a strong indicator thatthe patient suffers from gluten ataxia. The commonestreason for lack of response is lack of compliance withthe diet. If patients on strict gluten-free diet continue toprogress, with or without elimination of antibodies, theuse of immunosuppressive medication (mycophenolate)should be considered. Such cases are rare.

GLUTEN-RELATED NEU

Gluten neuropathy

Up to 23% of patients with established CD on gluten-freediet have neurophysiologic evidence of a

peripheral neuropathy (Luostarinen et al., 2003). A largepopulation-based studyofover 84000 subjects in Swedenexamined the risk of neurologic disease in patients withCDandfound thatpolyneuropathyhadasignificant asso-ciation with CD (Ludvigsson et al., 2007). In our ownUK-based study, 34%ofpatientswith idiopathic sporadicsensorimotor axonal neuropathy were found to havecirculating AGA (Hadjivassiliou et al., 2006b). Usinganti-TG2 antibody detection an Italian study also showeda significantly number of patients (21%) with peripheralneuropathy to be positive (Mata et al., 2006). Finally, in atertiary referral centre in theUS, retrospective evaluationof patientswith neuropathy showed the prevalence ofCDto be between 2.5% and 8% as compared to 1% in thehealthy population (Chin et al., 2003).

Gluten neuropathy is defined as otherwise idiopathicsporadic neuropathy with serologic evidence of GRD.The commonest types are symmetric sensorimotor axonalperipheral neuropathy and sensory ganglionopathy(Hadjivassiliou et al., 2010b). Other types of neuropathieshave also been reported including asymmetric neuropathy(Kelkar et al., 1996; Hadjivassiliou et al., 1997; Chin et al.,2006), small fiber neuropathy (Brannagan et al., 2005),and rarely, pure motor neuropathy (Hadjivassiliouet al., 1997) or autonomic neuropathy (Gibbons andFreeman, 2005). Gluten neuropathy is a slowly progres-sive disease with a mean age at onset of the neuropathyof 55 years (range 24–77 years) and a mean duration of9 years (range 1–33 years). A third of the patients will haveevidence of enteropathy on biopsy but the presence orabsence of an enteropathy does not predetermine theeffect of a gluten-free diet (Hadjivassiliou et al., 2006b).

Limited pathologic data available from postmortemsand nerve biopsies are consistent with an inflammatoryetiology (perivascular lymphocytic infiltration). The evi-dence of effectiveness of gluten-free diet has largelybeen derived from single or multiple case reports mostof which suggest improvement of the neuropathy. Theonly systematic, controlled study of the effect of agluten-free diet on 35 patients with gluten neuropathy,with close serologic monitoring of the adherence tothe gluten-free diet, found significant improvement inthe treated compared with the control group after 1 yearon the diet (Hadjivassiliou et al., 2006b). The improve-ment took the form of an increase in the sural sensoryaction potential, the predefined primary endpoint, andsubjective improvement of the neuropathic symptoms.Subgroup analysis suggested that the capacity forrecovery of the peripheral nerves may be less when theneuropathy is severe or that more time may be neededfor such recovery tomanifest. As there was a correlationbetween disease severity and longer duration, glutenneuropathy may be considered a progressive disease ifuntreated. In the context of sensory ganglionopathy

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GRD has been shown to be as common a cause asSj€ogren’s syndrome. Dorsal root ganglia demonstrateevidence of inflammatory infiltrates. The disease pro-gresses slowly if untreated. Strict adherence to agluten-free diet may result in stabilization or evenimprovement of the neuropathy irrespective of the pres-ence of enteropathy (Hadjivassiliou et al., 2010b).

612 M. HADJIVA

Gluten encephalopathy (headache andwhite matter abnormalities)

Headache is a common feature in patients with GRD. In2001 we reported a series of 10 patients with GRD andheadache who in addition had CNS white matter abnor-malities onMRI scan suggesting the term “gluten enceph-alopathy” to describe them (Hadjivassiliou et al., 2001).The headaches are usually episodic, similar to migraines,may be associated with focal neurologic deficits, andcharacteristically resolve with the introduction of agluten-free diet. The white matter abnormalities can bediffuse or focal and donot resolve following a gluten-freediet, which simply arrests progression of these changes(Fig. 41.2). Their distribution is more suggestive of a vas-cular rather than demyelinating etiology. Multiple sclero-sis does not seem to be associated with GRD on the basis

Fig. 41.2. Marked diffuse white matter abnormalities on MR

imaging in a 55-year-old man with celiac disease presenting

with headaches and mild ataxia. There was complete resolu-

tion of the headaches following the introduction of a gluten-

free diet. Neurologically he remains stable.

of numerous studies (Pengiran Tengah et al., 2004;Hadjivassiliou et al., 2005; Borhani Haghighi et al,2007; Nicoletti et al, 2008).

In patients with migraine there is an over-representation of CD with a prevalence of 4.4% versus0.4% in the control population (Gabrielli et al., 2003).Using positron emission tomography (PET) brain imag-ing, a study on regional cerebral perfusion demonstratedthat 73% of patients with CD not on a gluten-free diet,had at least one hypoperfused brain region as comparedto 7% in healthy controls and in patients with CD on agluten-free diet (Addolorato et al., 2004). Another studyinvestigated the prevalence of white matter abnormali-ties in children with CD and found that 20% of patientshad such abnormalities (Kieslich et al., 2001).

Over the last 14 years we have encountered 70 patientswith gluten encephalopathy, a figure that includes theinitial 10 patients reported in the 2001 series. Glutenencephalopathy does not always occur in isolation andsuch patients will often have additional neurologicfeatures such as ataxia, neuropathy, and cognitivedeficits. A study from the Mayo Clinic emphasizedthe significant cognitive deficits encountered in 13 suchpatients (Hu et al., 2006). In comparison to gluten ataxiaand gluten neuropathy there is a higher prevalence ofenteropathy in patients with gluten encephalopathy(40/70), but the age at onset is the same. The observedimprovement of the headaches and arrest of progressionin the MRI brain abnormalities, suggest a causal linkwith gluten ingestion. Gluten encephalopathy representsa spectrum of clinical presentations, from episodic head-aches responsive to a gluten-free diet at one end tosevere debilitating headaches associated with focalneurologic deficits and abnormal white matter on MRIat the other.

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Myoclonic ataxia

This form of ataxia is much less common in comparisonto gluten ataxia. It was first described in 1986 (Lu et al.,1986). It has been shown that the myoclonus is of corticalorigin despite the presence of cerebellar atrophy (Bhatiaet al., 1995). Somemyoclonus can be seen in a number ofsuch patients but it is not usually troublesome. In ourseries of patients (over 500) with neurologic manifesta-tions of GRD we have encountered four patients withwhat appears to be focal disabling myoclonus. Allpatients had evidence of enteropathy on biopsy. Intwo patients, despite a strict gluten-free diet, their con-dition progressed. Both have been treated withmycophe-nolate resulting in some stabilization. In the remainingpatients the ataxia responded to the gluten-free dietbut the myoclonus persists. In some of these patientsthe apparent focal myoclonus resembles epilepsia

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partialis continua in neurophysiologic terms. The appar-ent refractoriness of this neurologic manifestation ismirrored by evidence of ongoing enteropathy despite astrict adherence to the gluten-free diet. The treatmentof such patients remains problematic but the limited evi-dence from these small series suggests that mycopheno-late may be a useful therapeutic intervention for thosepatients who appear to progress neurologically despitestrict gluten-free diet.

GLUTEN-RELATED NEU

Epilepsy

A number of reports have suggested a link between epi-lepsy and CD (Chapman et al., 1978; Fois et al., 1994;Cronin et al., 1998). There is a particular type of focalepilepsy associated with occipital calcifications thatappears to have a strong link with CD (Gobbi et al.,1992). This entity is common in Italy but rare in othercountries (Fig. 41.3). It tends to affect young patients(mean age 16 years) and in the majority the seizuresare resistant to antiepileptic drugs. The pathogenesisof the cerebral calcifications remains unclear. Anautopsy study showed the depositions consisted of bothcalcium and silica, and microscopically were found inthree main types: psammoma-like bodies without anyidentifiable relationship to cells, vessels, or other struc-tures; small granular deposition along small vessels; and

Fig. 41.3. CT head scan on a 52-year-old patient with epilepsy

and gluten sensitivity demonstrating occipital calcifications.

This condition is rare outside Italy and it primarily affects

children. This patient presented with loss of consciousness

ataxia and cognitive decline.

focal scanty areas of calcium within neurons (Toti et al.,1996). As most of the reported cases are from Italy,Spain, and Argentina, it has been hypothesized thatthe syndrome of celiac disease, epilepsy, and cerebralcalcifications is “a genetic, non-inherited, ethnicallyand geographically restricted syndrome associated withenvironmental factors” (Gobbi, 2005).

Whilst studies examining theprevalenceofCDamongstpatients with epilepsy have suggested a prevalence of 1.2–2.3%, largermore recent studies failed todemonstrate suchan increased prevalence (Ranua et al., 2005). However,most studies on the subject suffer from the samemethodo-logic problemof treating epilepsy as a homogeneous disor-der. The only study that attempted to look at the prevalenceof GRD in well characterized subgroups of patients withepilepsy found a significant association between AGAand temporal lobe epilepsy with hippocampal sclerosis(Paltola et al., 2009). Of interest are some case reportson patients with CD and epilepsy whose epilepsy improvesfollowing the introduction of gluten-free diet (Mavroudiet al., 2005; Harper et al., 2007).

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Myopathy

This is a relatively rare neurologic manifestation ofGRD, first described by Henriksson et al. (1982).This study from Sweden reported that out of 76 patientswith suspected polymyositis investigated at a neuromus-cular unit, 17 had a history of gastrointestinal symptomswith evidence of malabsorption. Fourteen of these ful-filled the diagnostic criteria for polymyositis and ofthose, five were diagnosedwith CD.Amore recent studyfrom Spain (Selva-O’Callaghan et al., 2007) demon-strated the prevalence of AGA antibodies amongstpatients with inflammatory myopathies to be 31%. Thiswas accompanied by a higher prevalence of CD withinthe same population when compared to healthy controls.

The clinical data from our series of patients are basedon 18 cases encountered over the last 14 years, 13 ofwhich have been reported previously (Hadjivassiliouet al., 2007). Enteropathy was identified following duo-denal biopsy in 10 of these patients. The mean age atonset of the myopathic symptoms was 54 years. Tenpatients had predominantly proximal weakness, fivepatients had both proximal and distal weakness, and fourpatients had primarily distal weakness. Two patients hadataxia and neuropathy, and one patient had just neurop-athy in addition to the myopathy. Serum creatine kinase(CK) level ranged from normal (25–190 IU/L) to4380 IU/L at presentation. Inflammatory myopathywas the most common finding on neuropathologicexamination (Fig. 41.4). Six patients received immuno-suppressive treatment in addition to starting a gluten-free diet whereas the others went on a gluten-free diet

Fig. 41.5. Spinal cord atrophy on MR imaging of the thoracic

cord of a 55-year-old man with celiac disease and sensory

ataxia. Whilst the patient had celiac disease for many years,

he never adhered to the diet strictly and went on to develop

neurologic manifestations.

Fig. 41.4. Muscle biopsy demonstrating focal inflammatory

infiltration in a 60-year-old man with celiac disease who

became profoundly weak after inadvertently eating a cake

made out of rye flour. His weakness was profound and neces-

sitated admission. He made a full recovery just with reintro-

duction of a strict gluten-free diet.

614 M. HADJIVASSILIOU ET AL.

only. In the majority of those patients who did notreceive immunosuppressive treatment there was clinicalimprovement of themyopathywith gluten-free diet, sug-gesting that the myopathy was etiologically linked to theGRD. One patient developed a profoundmyopathy afterinadvertently eating rye flour. He made a full recoveryby re-establishing a strict gluten-free diet. Two patientshad histologic evidence of inclusion body myositis. It isinteresting to note that inclusion body myositis sharesthe same HLA genetic predisposition with CD.

Myelopathy

Clinical evidence of amyelopathy in the absence of vitaminand other deficiencies (particularly copper) can be a raremanifestation ofCD (Fig. 41.5). It is usually associatedwithnormal imaging of the spinal cord. However, there havebeen some recent reports of patients with neuromyelitisoptica (Devic’s disease) and GRD who have antibodies toaquaporin-4 (Jacob et al., 2005; Jarius et al., 2008). Suchpatients clearly had abnormal MRI of the spinal cord butthe diagnosis ofCDwas onlymade at the time of their neu-rologic presentation. Neuromyelitis optica and CD sharethe same HLA genetic susceptibility (HLA DQ2). Thereare very limited data on the effect of the diet on the likeli-hood of relapse of the disease, particularly given the factthatmost patientswithDevic’s disease endupon long-termimmunosuppressive medication.

Stiff man syndrome

Stiff man syndrome (SMS) is a rare autoimmune diseasecharacterized by axial stiffness, painful spasms, and

positivity for anti-GAD or anti-amphiphysin antibodies.It has a strong association with other autoimmune dis-eases (e.g., insulin-dependent diabetes mellitus (IDDM),hypothyroidism, etc.). We have found a high prevalenceof gluten-related antibodies in patients with this conditionover and above that expected from an association of twoautoimmune diseases. The relapsing remitting nature ofthe condition makes a study of any responsiveness togluten-free diet difficult. There is, however, evidence ofreduction of the anti-GAD antibody titer following theintroduction of a gluten-free diet suggesting that the dietmay be beneficial in treating the condition (Hadjivassiliouet al., 2010c). This finding also supports the concept ofprevention of autoimmunity in patients with GRD if thegluten-free diet is introduced early enough.

PATHOGENESIS

Current evidence suggests that neurologic manifesta-tions are immune mediated. Postmortem examination

RO

from patients with gluten ataxia demonstrate patchy lossof Purkinje cells throughout the cerebellar cortex, a non-specific finding in many cerebellar disorders. However,additional findings supporting an immune-mediatedpathogenesis include diffuse infiltration mainly of Tlymphocytes within the cerebellar white matter as wellas marked perivascular cuffing with inflammatory cells(Hadjivassiliou et al., 1998). The peripheral nervous sys-tem also shows sparse lymphocytic infiltrates with peri-vascular cuffing being observed in sural nerve biopsy ofpatients with gluten neuropathy (Hadjivassiliou et al.,2006a), in dorsal root ganglia in patients with sensoryneuronopathy (Hadjivassiliou et al., 2010a) and in patientswith gluten myopathy due to GRD (Hadjivassiliou et al.,2007). There is evidence to suggest that there is antibodycross-reactivity between antigenic epitopes on Purkinjecells and gluten proteins. Serum from patients with GAand from patients with CD but no neurologic symptoms,display cross-reactivity with epitopes on Purkinje cells ofboth human and rat cerebellum (Hadjivassiliou et al.,2002). This reactivity can also be seen using polyclonalAGA and the reactivity eliminated by absorption withcrude gliadin. When using sera from patients with GAthere is evidence of additional antibodies targeting Pur-kinje cell epitopes since elimination of AGA alone is

GLUTEN-RELATED NEU

Fig. 41.6. Duodenal biopsy from a patient presenting with

progressive ataxia and positive antigliadin antibodies. The

biopsy demonstrates the triad of crypt hyperplasia, villous

atrophy, and increase in the intraepithelial lymphocytes. Only

a third of patients with gluten ataxia will have enteropathy.

not sufficient to eliminate such reactivity (Fig. 41.6). Thereis some evidence that additional antibodies that may becausing such reactivity, including antibodies against oneor more transglutaminase isoenzymes.

TG2 belongs to a family of enzymes that covalentlycrosslink or modify proteins by formation of an isopep-tide bond between a peptide-bound glutamine residueand a primary amine. However, in some instances TG2may react with water in preference over an amine lead-ing to the deamidation of glutamine residues. Glutenproteins (from wheat, barley, and rye), the immunologictrigger of GRD, are glutamine-rich donor substratesamenable to deamidation. Activation of TG2 and deami-dation of gluten peptides appears to be central to diseasedevelopment and is now well understood at a molecularlevel. However, events leading to the formation of auto-antibodies against TG2 are still unclear. Questions alsoremain as to the contribution of these autoantibodiesto organ-specific deficits. Anti-TG2 antibodies havebeen shown to be deposited in the small bowelmucosa of patients with GRD even in the absence ofenteropathy. Furthermore such deposits have beenfound in extraintestinal sites, such as muscle and liver(Korponay-Szabo et al., 2004). Widespread depositionof transglutaminase antibodies has also been foundaround brain vessels in GA (Hadjivassiliou et al.,2006a). The deposition was most pronounced in the cer-ebellum, pons, and medulla. This finding suggests thatsuch autoantibodies could play a role in the pathogenesisof the whole spectrum of manifestations seen in GRD.However, it is not clear whether these antibodies arederived from the circulation or if their production ismediated within target organs after stimulation of gut-primed gliadin-reactive CD4þ T cells.

Variations in the specificity of antibodies produced inindividual patients could explain the wide spectrum ofmanifestations. Whilst TG2 has been shown to be theautoantigen in CD (Dietrich et al., 1997), the epidermaltransglutaminase TG3 has been shown to be the autoan-tigen in DH (Sardy et al., 2002). More recently, anti-bodies against TG6, a primarily brain expressedtransglutaminase, have been shown to be present inpatients with GA (Hadjivassiliou et al., 2008a). In GAandDH, IgA deposits of TG6 and TG3 respectively seemto accumulate in the periphery of blood vessels. Thiscould indicate that either the deposits originate fromimmune complexes formed elsewhere, and are accumu-lating as a consequence of enhanced vascular leaking, orthat TG6/TG3 are derived from perivascular infiltratinginflammatory cells preceding deposit formation. Indeedperivascular cuffing with lymphocytes is a commonfinding in brain tissue from patients with GA but isalso seen in peripheral nerve and muscle in patients withgluten neuropathy or myopathy. In most sera reactive

LOGIC DYSFUNCTION 615

SSI

with more than one TG isoenzyme, distinct antibodypopulations are responsible for such reactivity ratherthan this being a result of cross-reactivity with differentTG isozymes. Thismakes shared epitopes less likely to bethe cause for immune responses to other TGs and pointsto the possibility that TG isozymes other than TG2 can bethe primary antigen in GRD.

IgA deposition in brain vessels and the pathologicfinding of perivascular cuffing with inflammatory cells,may indicate that vasculature-centered inflammationmay compromise the blood–brain barrier, allowing expo-sure of the CNS to pathogenic antibodies, and thereforebe the trigger of nervous system involvement. Indeed,TG2 is expressed by smooth muscle and endothelial cellsin noninflamed brain, is an abundant component of theblood–brain barrier and autoantibody binding could ini-tiate an inflammatory response. Anti-TG2 and otherautoantibodies (e.g., AGA) may directly cause selectiveneuronal degeneration. It is possible that neuronaldegeneration is a consequence of the anti-TG antibodyspectrum, i.e., occurs in those patients with antibodiesreactive with a neuronal TG. IgG class antibodies havebeen shown to be present in only 60% of CD patientswhereas in GA patients positive for anti-TG, the preva-lence was 90%. This shift from IgA to IgG may reflectthe target organ involved (central nervous system ratherthan the small bowel).

It could be argued that development and depositionof antibodies is an epiphenomenon rather than beingpathogenic. One method to demonstrate the pathologiceffect of an antibody is the passive transfer of the dis-ease through antibody injection into a naıve animal.While such experimental evidence exists for only veryfew antibody-mediated diseases, IgG fractions ofpatients with anti-GAD ataxia and stiff man syndromehave been shown to compromise motor function andimpair learning in rodents, an effect possibly ascribedto antibodies against GAD (Manto et al., 2007). A com-mon problem in such studies is to be able to demonstratewhether it is these specific antibodies or other autoanti-bodies in the IgG-fraction of patient sera that cause neu-ronal damage. Using a mouse model we have recentlyshown that serum from GA patients, as well as clonalmonovalent anti-TG immunoglobulins derived usingphage display, cause ataxia when injected intraventricu-larly in mice (Boscolo et al., 2010). The fact that not onlyIg fractions but also monospecific scFvs mediate func-tional deficits shows that there is no requirement forcomplement activation or for the engagement of Fcreceptors on Fc receptor-bearing cells in the brain. Thesedata therefore provide evidence that anti-TG immuno-globulins (derived from patients) compromise neuronalfunction in selected areas of the brain once exposed tothe CNS and suggest that this involves an immune system

616 M. HADJIVA

independent mode of action. While these data implicateanti-TG antibodies in ataxia they do not explain the spec-trum of distinct neurologic deficits currently ascribed togluten sensitivity, nor why only a fraction of patients withcirculating anti-TG antibodies are affected.

CONCLUSIONS

GRD include immune-mediated diseases triggered byingestion of gluten proteins. While celiac disease hasbeen the most comprehensively studied of all GRD, der-matitis herpetiformis and neurologic manifestations arethe commonest extraintestinal manifestations. To fullyunderstand the immunologic insults resulting from glu-ten ingestion, the emphasis should perhaps shift towardthe study of extraintestinal manifestations. In additionthere is a need for the early identification of thosepatients that are specifically at risk of irreversible com-plications (e.g., gluten ataxia). To that effect, new diag-nostic tools are now becoming available (e.g., antibodiesagainst TG6) which maymake a more reliable identifica-tion of those patients with neurologic manifestations areality. Up to 40% of patients presenting to the gastroen-terologist who are ultimately diagnosed with CD alsohave antibodies against TG6 in addition to antibodiesagainst TG2. This subgroup of patients with classicCD presentation may well be the ones susceptible tothe development of neurologic dysfunction if they con-tinue to consume gluten, although this remains to beshown in longitudinal studies. The presence of gastroin-testinal symptoms, however, offers a major potentialadvantage to this group, as it substantially increasestheir chances of being diagnosed with, and treated for,CD, whereas the diagnosis of those patients presentingpurely with extraintestinal manifestations may be moredifficult. The only way that this can be improved upon isby changing the perception of physicians that gluten-related diseases are solely diseases of the gut.

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