Gluten-related neurologic dysfunction

Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose 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 1 Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK 2

Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK 3

Department of Neurology, University of Cincinnati, Cincinnati, OH, USA

HISTORICAL PERSPECTIVE Celiac disease (CD) was first described by the Greek doctor Aretaeus the Cappadocian, in AD 100, only to be forgotten and then rediscovered by Samuel Gee in 1888 (Gee, 1888). In a lecture on “the coeliac affection,” Gee described the classic pediatric presentation of the disease. Whilst clinicians began to recognize this disease entity, the etiologic agent remained obscure until the observations of Willem Dicke, a Dutch pediatrician, in 1953 of “the presence in wheat, of a factor having a deleterious effect in cases of celiac disease” (Dicke et al., 1953). As gastrointestinal 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 disease of the gut. Indeed the introduction of endoscopy and small bowel biopsy in the 1950s confirmed the presence of an enteropathy (Paulley, 1954). In 1963 a group of dermatologists made the interesting observation that dermatitis herpetiformis (DH), an itchy vesicular rash, was a form of gluten-related dermatopathy sharing the same small bowel pathology, but not the gastrointestinal symptoms seen in patients with CD (Marks et al., 1966). This was the first evidence of extraintestinal manifestations. Only a small number of case reports of patients with CD and neurologic manifestations (Elders, 1925; Reed and Ash, 1927; Woltman and Heck, 1937) were published prior to the discovery of the etiologic agent and the introduction of small bowel biopsy, demonstrating the typical histologic features that define CD. Such reports need to be treated with caution given that a diagnosis of CD in those patients was speculative. The first comprehensive case series of neurologic manifestations in the context of histologically confirmed

CD was published in 1966 (Cooke and Thomas-Smith, 1966). This detailed work described the range of neurologic manifestations seen in 16 patients with established CD. Of interest was the fact that all patients had gait ataxia and some had severe peripheral neuropathy as well. The assumption was that such manifestations were nutritional as a result of malabsorption. Indeed all of these patients were grossly malnourished and cachectic. Postmortem data from the same report, however, demonstrated an inflammatory process primarily affecting the cerebellum, but also involving other parts of the central and peripheral nervous systems, a finding that was in favor of an immune-mediated pathogenesis. Single and multiple case reports of patients with established CD who then developed neurologic dysfunction 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; Kinney et 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; Hermaszewski et al., 1991; Bhatia et al., 1995; Dick et al., 1995; Muller et al., 1996). The key findings from these reports were as follows: ● ●

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Ataxia (with and without myoclonus) and neuropathy were the commonest manifestations. Neurologic manifestations were usually reported in the context of established CD and almost always attributed 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 any attempts to monitor adherence to the diet with repeat serologic testing.

*Correspondence to: Marios Hadjivassiliou, Department of Neurology, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK. E-mail: [email protected]

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Thirty years after the first comprehensive case series on neurologic manifestations of CD saw the publication of an original study (Hadjivassiliou et al., 1996) approaching the issue from a neurologic perspective by investigating the prevalence of serologic markers of gluten-related dysfunction (GRD) in patients presenting with neurologic dysfunction of unknown etiology. The results demonstrated that there was a high prevalence of IgG and/or IgA antigliadin antibodies (AGA) in this group of patients compared to controls. Based on duodenal biopsies the same study showed that the prevalence of CD in this group of patients with neurologic dysfunction was 16 times higher than the prevalence of CD in the healthy population. This study rekindled the interest of neurologists in a possible link between GRD and neurologic disease.

EPIDEMIOLOGY OF NEUROLOGIC MANIFESTATIONS The prevalence of CD in the healthy population has been shown to be at least 1% in both European and North American studies (Sanders et al., 2003). There are no accurate figures of the prevalence of the neurologic manifestations of gluten sensitivity in the general population. Figures of between 10% and 22.5% have been reported amongst patients with established CD attending gastrointestinal clinics (Holmes, 1997; Briani et al., 2008). These are unlikely to be accurate because such figures are usually retrospective, derived solely from gastrointestinal clinics, concentrating exclusively on patients with classic CD presentation, and often include neurologic dysfunctions that are unlikely to be gluten related (e.g., carpal tunnel syndrome, idiopathic Parkinson’s disease, etc.). Some estimates of prevalence can be made from patient populations attending specialist clinics although caution must be exercised in extrapolating these as they are inevitably affected by referral bias. Data collected from the Sheffield dedicated CD and gluten sensitivity/neurology clinics suggest that for every seven patients presenting to the gastroenterologists who are then diagnosed with CD, there are two patients presenting to the neurologists who will then be diagnosed as having CD (Hadjivassiliou et al., 2010a). This is likely to be an underestimate because this ratio does not take into account those patients with neurologic manifestations due to GRD that do not have an enteropathy (approximately two-thirds of the whole number of patients presenting with neurologic dysfunction). The authors believe that the prevalence of neurologic dysfunction even within patients with CD presenting to gastroenterologists is likely to be much higher than what has been published if such patients undergo rigorous neurologic workup including magnetic resonance (MR) spectroscopy of the cerebellum. Preliminary work on patients with CD presenting to gastroenterologists with minor

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

THE DIAGNOSIS OF GLUTEN-RELATED DISEASES CD is characterized by the presence of an enteropathy, a reliable gold standard. It is now accepted, however, that an enteropathy is not a prerequisite for the diagnosis of GRD with predominantly neurologic or other extraintestinal manifestations. Furthermore, the small bowel mucosal changes in the context of GRD represent a spectrum, from histologically normal mucosa to full-blown enteropathy to a pre-lymphomatous state also referred to as the Marsh classification (Marsh, 1992). Most pathology departments have now adopted the Marsh classification when reporting the histologic findings of small bowel biopsies. Given that the histology can be normal, a definition of GRD based solely on histology becomes problematic. Furthermore the diagnosis currently has to rely on serologic tests that are not 100% specific or sensitive. For example, endomysial antibody (EMA) and antitransglutaminase-2 (TG2) IgA antibody detection are specific for the presence of an enteropathy. However, these markers are frequently not detectable in patients with neurologic manifestations, particularly in those who do not have an enteropathy (Table 41.1). Table 41.1 Type of neurologic presentation in gluten sensitivity* Neurologic presentation

No

Total number of patients Ataxia (4 patients with myoclonus, 2 with palatal tremor) Peripheral neuropathy Sensorimotor axonal neuropathy Mononeuropathy multiplex Sensory neuronopathy Small fiber neuropathy Motor neuropathy Encephalopathy Myopathy Myelopathy Stiff man syndrome Chorea (often with ataxia) Neuromyotonia Epilepsy and occipital calcifications

500 233 (93) 182 (48) 135 19 14 8 8 77 (45) 18 (10) 9 (4) 7 (2) 3 (2) 1 (1) 1 (0)

*Based on 500 patients with gluten sensitivity, presenting with neurologic 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.

GLUTEN-RELATED NEUROLOGIC DYSFUNCTION 609 GRD cannot be diagnosed on clinical grounds alone. had serologic evidence of GRD. Therefore gluten ataxia The majority of patients presenting with neurologic had a prevalence of 22% amongst sporadic ataxias but as manifestations have no gastrointestinal symptoms. high as 45% amongst idiopathic sporadic ataxias. Using Patients with CD can also have no gastrointestinal sympthe same AGA assay the prevalence of positive AGA in toms. In patients without overt gastrointestinal involvegenetically confirmed ataxias was 8/82 (10%), in familial ment, serum antibodies to TG2 may be absent. Such ataxias (not genetically confirmed) 8/49 (16%), and in patients typically have antibodies primarily reacting with healthy volunteers 149/1200 (12%). A number of studies different TG isozymes, TG3 in DH and TG6 in patients looking at the prevalence of antigliadin antibodies in with gluten ataxia (Hadjivassiliou et al., 2008a). Reacataxias have been published: The original publication tion of such antibodies with TG2 in the intestinal mucosa by the authors (Hadjivassiliou et al., 2003a) reported occurs prior to overt changes in small intestinal morpholthe incidence of IgG and/or IgA AGA in a large cohort ogy and sometimes even before the antibodies are of 224 patients seen in Sheffield, UK, with idiopathic and detectable in serum (Korponay-Szabo´ et al., 2003). Such hereditary ataxia. Antibodies were present in 41% of antibody deposits seem to be present in patients with patients with sporadic ataxia (54/132), compared to neurologic manifestations as well, and may therefore 12% (149/1200) of normal controls from the same popube diagnostically useful (Hadjivassiliou et al., 2006a). lation. Positive antibodies were also found in 14% of However, this test is not readily available and requires patients with familial ataxia (8/59) and 15% of patients experience in its interpretation. In practice, for suswith clinically probable multiple system atrophy pected neurologic manifestations of GRD, it is best to (MSA)-C (5/33). Among AGA-positive individuals with perform serologic tests for both IgA and IgG antibodies sporadic ataxia, evidence of celiac disease was present to TG2 (and if available anti-TG6 and anti-TG3) as well in 24% (12/51) of those patients who underwent duodenal as IgG and IgA antibodies to gliadin. Endomysium antibiopsy. In this same study, a separate group of patients bodies are very specific for the detection of enteropathy, from a second center in London with sporadic ataxia but they detect the same antigen (transglutaminase 2) showed positive antibodies in 32% (14/44). Another study and have thus largely been replaced by TG2 antibody (B€ urk et al., 2001a) found positive antibodies in 11.5% testing. Any differences between the two tests, however, (12/104) of patients with idiopathic ataxia and negative are likely to be related to the different methodologies genetic testing, compared to 5% of 600 blood donors used (ELISA for TG2 versus immunofluorescence for from the same country. An Italian study (Pellecchia the detection of EMA). et al., 1999a) confirmed a higher incidence of positive GRD have a strong genetic predisposition whereby antigliadin antibodies and celiac disease on intestinal
40% of the genetic load comes from MHC class II assobiopsy in idiopathic ataxia (3/24, 12.5%) compared to ciation (Hunt, 2008). In Caucasian populations more than patients with known hereditary ataxia (0/23, 0%). Further 90% of CD patients carry the HLA DQ2, with the remaining confirmatory studies with smaller numbers from having the HLA DQ8. A small number of CD patients do Finland, Japan, and France have also been published not belong into either of these groups but these have been (Luostarinen et al., 2001; Anheim et al., 2006; Ihara shown to carry just one chain of the DQ2 heterodimer. HLA et al., 2006). However, other studies have not shown genetic testing is therefore another useful diagnostic tool, as clear a distinction in antibody prevalence between idiparticularly as, unlike other serologic tests, it is not depenopathic and other causes of ataxia. Abele et al. (2002) dent on an immunologic trigger. However, the HLA DQ found positive antibodies in 15% (10/65) of patients with genotype can be used only as a test of exclusion as the risk idiopathic ataxia compared to 9% (3/32) of patients with genotype DQ2 is common in Caucasian and Asian populaMSA and 7% (1/15) with genetic ataxia. In a separate tions and many carriers will never develop GRD. study, Abele et al. (2003) found no statistically significant difference between the prevalence of positive IgG THE SPECTRUM OF GLUTEN-RELATED and/or IgA AGA in sporadic ataxia (19% of 32 patients), NEUROLOGIC MANIFESTATIONS recessive ataxia (8% of 24 patients), dominant ataxia (15% of 39 patients), and controls (8% of 73 patients). Gluten ataxia Analyzing IgG and IgA subtypes separately also did Gluten ataxia (GA) was originally defined as otherwise not show significant differences between groups. idiopathic sporadic ataxia with positive AGA Bushara et al. (2001) noted similar rates of positive (Hadjivassiliou et al., 2003a). This original definition IgG and/or IgA AGA in sporadic ataxia (27%, 7/26) was based on the serologic tests available at the time. and autosomal dominant ataxia (37%, 9/24). Some In a series of 853 patients with progressive ataxia evaluauthors believe the elevated incidence of AGA in heredated over a period of 15 years in Sheffield, UK, there itary ataxia may be driven in part by spinocerebellar were 152 patients out of 681 with sporadic ataxia who ataxia type 2 (SCA2). In one study, 23% of SCA2

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patients had positive AGA, significantly higher compared to 9% of controls (Almaguer-Mederos et al., 2008). The variations in prevalence may relate to geographical differences in the prevalence of CD, referral bias, variability in the AGA assays used, patient selection (some studies included as idiopathic sporadic ataxia patients with cerebellar variant of multisystem atrophy (Combarros et al., 2000)), the small number of patients studied, and no controls. The common theme in most of these studies is the consistently high prevalence of AGA antibodies in sporadic ataxias when compared to healthy controls. GA usually presents with pure cerebellar ataxia or rarely ataxia in combination with myoclonus, palatal tremor (Hadjivassiliou et al., 2008b), opsoclonus (Deconinck et al., 2006), or rarely, chorea (Pereira et al., 2004). GA is usually of insidious onset with a mean age at onset of 53 years. Rarely the ataxia can be rapidly progressive mimicking paraneoplastic cerebellar degeneration. Gaze-evoked nystagmus and other ocular signs of cerebellar dysfunction are seen in up to 80% of cases. All patients have gait ataxia and the majority have limb ataxia. Less than 10% of patients with GA will have any gastrointestinal symptoms but a third will have evidence of enteropathy on biopsy. Up to 60% of patients have neurophysiologic evidence of sensorimotor, lengthdependent axonal neuropathy. This is usually mild and does not contribute to the ataxia. Anti-TG2 IgA antibodies are present in up to 38% of patients, but often at lower titers than those seen in patients with CD. However, unlike CD, IgG class antibodies to TG2 are more frequent than IgA. Antibodies against TG2 and TG6 combined can be found in 85% of patients with ataxia who are positive for AGA antibodies (Hadjivassiliou et al., 2009). Some patients also test positive for anti-TG3 antibodies although the prevalence of such antibodies in patients with gluten ataxia is low when compared to DH. It is unclear at present whether combined detection of TG2 and TG6 IgA/IgG without the use of antigliadin antibodies identifies all patients with gluten ataxia. Up to 60% of patients with gluten ataxia have evidence of cerebellar atrophy on MR imaging (Fig. 41.1). Investigation of the metabolic status of the cerebellum in 15 patients with gluten ataxia and 10 controls using proton MR spectroscopy demonstrated significant differences in mean N-acetylaspartate/creatine levels between patients with GA and healthy controls, suggesting that cerebellar neuronal physiology in these patients is abnormal (Wilkinson et al., 2005). Even in those patients without cerebellar atrophy, proton MR spectroscopy of the cerebellum was abnormal. There is emerging evidence that MR spectroscopy is often abnormal in patients with newly diagnosed CD with minimal or

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.

no neurologic complaints and that such abnormalities improve with the introduction of a gluten-free diet. The clinical improvement manifests after 1 year on the diet but continues for at least 2 years. The response to treatment with a gluten-free diet depends on the duration of the ataxia prior to the diagnosis of GRD. Loss of Purkinje cells in the cerebellum, the end result of prolonged gluten exposure in patients with GA, is irreversible, and prompt treatment is more likely to result in improvement or stabilization of the ataxia. Whilst the benefits of a gluten-free diet in the treatment of patients with CD and DH have long been established, there are very few studies, mainly case reports, of the effect of a gluten-free diet on the neurologic manifestations. Most of these reports primarily concern patients with established CD who then develop neurologic symptoms (Beversdorf et al., 1996; Hahn et al., 1998; Pellecchia et al., 1999). These studies suggest variable but overall favorable responsiveness to a gluten-free diet. A small, uncontrolled study looked at the use of intravenous immunoglobulins in the treatment of four patients with

GLUTEN-RELATED NEUROLOGIC DYSFUNCTION 611 GA without enteropathy (B€ urk et al., 2001b; Sander et al., peripheral neuropathy (Luostarinen et al., 2003). A large 2003). All patients improved. In all of these reports, population-based study of over 84 000 subjects in Sweden strict adherence to the gluten-free diet was assumed examined the risk of neurologic disease in patients with and no serologic evidence was provided. The best marker CD and found that polyneuropathy had a significant assoof strict adherence to a gluten-free diet is serologic eviciation with CD (Ludvigsson et al., 2007). In our own dence of elimination of circulating GRD-related antiUK-based study, 34% of patients with idiopathic sporadic bodies. Only one systematic study of the effect of a sensorimotor axonal neuropathy were found to have gluten-free diet on a cohort of patients presenting with circulating AGA (Hadjivassiliou et al., 2006b). Using ataxia, with or without an enteropathy, has been published anti-TG2 antibody detection an Italian study also showed (Hadjivassiliou et al., 2003b). This study also reported a significantly number of patients (21%) with peripheral serologic evidence of elimination of the antigliadin antineuropathy to be positive (Mata et al., 2006). Finally, in a bodies as a confirmation of strict adherence to the diet. tertiary referral centre in the US, retrospective evaluation A total of 43 patients with gluten ataxia were enrolled. of patients with neuropathy showed the prevalence of CD Of these, 26 adhered strictly to the gluten-free diet, had to be between 2.5% and 8% as compared to 1% in the serologic evidence of elimination of antibodies, and comhealthy population (Chin et al., 2003). prised the treatment group; 14 patients refused the diet Gluten neuropathy is defined as otherwise idiopathic and comprised the control group and 3 patients were sporadic neuropathy with serologic evidence of GRD. excluded as despite the diet their antibodies were still posThe commonest types are symmetric sensorimotor axonal itive. Patient and control groups were matched at baseline peripheral neuropathy and sensory ganglionopathy for all variables (age, duration of ataxia, etc.). There was (Hadjivassiliou et al., 2010b). Other types of neuropathies no significant difference in the baseline performance for have also been reported including asymmetric neuropathy each ataxia test between the two groups. There was signif(Kelkar et al., 1996; Hadjivassiliou et al., 1997; Chin et al., icant improvement in performance in test scores and in 2006), small fiber neuropathy (Brannagan et al., 2005), the subjective global clinical impression scale in the treatand rarely, pure motor neuropathy (Hadjivassiliou ment group when compared to the control group. The et al., 1997) or autonomic neuropathy (Gibbons and improvement was apparent even after excluding patients Freeman, 2005). Gluten neuropathy is a slowly progreswith an enteropathy. The study concluded that gluten-free sive disease with a mean age at onset of the neuropathy diet can be an effective treatment for GA. of 55 years (range 24–77 years) and a mean duration of There are no published randomized, placebo9 years (range 1–33 years). A third of the patients will have controlled studies on the subject, perhaps reflecting evidence of enteropathy on biopsy but the presence or the difficulties associated with such a study when the absence of an enteropathy does not predetermine the intervention is dietary elimination of gluten and the etheffect of a gluten-free diet (Hadjivassiliou et al., 2006b). ical considerations of randomizing patients with GA who Limited pathologic data available from postmortems have enteropathy. The current recommendation is that and nerve biopsies are consistent with an inflammatory patients presenting with progressive cerebellar ataxia etiology (perivascular lymphocytic infiltration). The evishould be screened for gluten sensitivity using antigliadin dence of effectiveness of gluten-free diet has largely IgG and IgA, anti-TG2 antibodies and if available antibeen derived from single or multiple case reports most TG6 antibodies. Patients positive for any of these antiof which suggest improvement of the neuropathy. The bodies with no alternative cause for their ataxia should only systematic, controlled study of the effect of a be offered a strict gluten-free diet with regular followgluten-free diet on 35 patients with gluten neuropathy, up to ensure that the antibodies are eliminated (usually with close serologic monitoring of the adherence to takes 6–12 months). Stabilization or even improvement the gluten-free diet, found significant improvement in of the ataxia at 1 year would be a strong indicator that the treated compared with the control group after 1 year the patient suffers from gluten ataxia. The commonest on the diet (Hadjivassiliou et al., 2006b). The improvereason for lack of response is lack of compliance with ment took the form of an increase in the sural sensory the diet. If patients on strict gluten-free diet continue to action potential, the predefined primary endpoint, and progress, with or without elimination of antibodies, the subjective improvement of the neuropathic symptoms. use of immunosuppressive medication (mycophenolate) Subgroup analysis suggested that the capacity for should be considered. Such cases are rare. recovery of the peripheral nerves may be less when the neuropathy is severe or that more time may be needed for such recovery to manifest. As there was a correlation Gluten neuropathy between disease severity and longer duration, gluten Up to 23% of patients with established CD on gluten-free neuropathy may be considered a progressive disease if diet have neurophysiologic evidence of a untreated. In the context of sensory ganglionopathy

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GRD has been shown to be as common a cause as Sj€ogren’s syndrome. Dorsal root ganglia demonstrate evidence of inflammatory infiltrates. The disease progresses slowly if untreated. Strict adherence to a gluten-free diet may result in stabilization or even improvement of the neuropathy irrespective of the presence of enteropathy (Hadjivassiliou et al., 2010b).

Gluten encephalopathy (headache and white matter abnormalities) Headache is a common feature in patients with GRD. In 2001 we reported a series of 10 patients with GRD and headache who in addition had CNS white matter abnormalities on MRI scan suggesting the term “gluten encephalopathy” to describe them (Hadjivassiliou et al., 2001). The headaches are usually episodic, similar to migraines, may be associated with focal neurologic deficits, and characteristically resolve with the introduction of a gluten-free diet. The white matter abnormalities can be diffuse or focal and do not resolve following a gluten-free diet, which simply arrests progression of these changes (Fig. 41.2). Their distribution is more suggestive of a vascular rather than demyelinating etiology. Multiple sclerosis does not seem to be associated with GRD on the basis

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 overrepresentation of CD with a prevalence of 4.4% versus 0.4% in the control population (Gabrielli et al., 2003). Using positron emission tomography (PET) brain imaging, a study on regional cerebral perfusion demonstrated that 73% of patients with CD not on a gluten-free diet, had at least one hypoperfused brain region as compared to 7% in healthy controls and in patients with CD on a gluten-free diet (Addolorato et al., 2004). Another study investigated the prevalence of white matter abnormalities in children with CD and found that 20% of patients had such abnormalities (Kieslich et al., 2001). Over the last 14 years we have encountered 70 patients with gluten encephalopathy, a figure that includes the initial 10 patients reported in the 2001 series. Gluten encephalopathy does not always occur in isolation and such patients will often have additional neurologic features such as ataxia, neuropathy, and cognitive deficits. A study from the Mayo Clinic emphasized the significant cognitive deficits encountered in 13 such patients (Hu et al., 2006). In comparison to gluten ataxia and gluten neuropathy there is a higher prevalence of enteropathy in patients with gluten encephalopathy (40/70), but the age at onset is the same. The observed improvement of the headaches and arrest of progression in the MRI brain abnormalities, suggest a causal link with gluten ingestion. Gluten encephalopathy represents a spectrum of clinical presentations, from episodic headaches responsive to a gluten-free diet at one end to severe debilitating headaches associated with focal neurologic deficits and abnormal white matter on MRI at the other.

Myoclonic ataxia

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 resolution of the headaches following the introduction of a glutenfree diet. Neurologically he remains stable.

This form of ataxia is much less common in comparison to gluten ataxia. It was first described in 1986 (Lu et al., 1986). It has been shown that the myoclonus is of cortical origin despite the presence of cerebellar atrophy (Bhatia et al., 1995). Some myoclonus can be seen in a number of such patients but it is not usually troublesome. In our series of patients (over 500) with neurologic manifestations of GRD we have encountered four patients with what appears to be focal disabling myoclonus. All patients had evidence of enteropathy on biopsy. In two patients, despite a strict gluten-free diet, their condition progressed. Both have been treated with mycophenolate resulting in some stabilization. In the remaining patients the ataxia responded to the gluten-free diet but the myoclonus persists. In some of these patients the apparent focal myoclonus resembles epilepsia

GLUTEN-RELATED NEUROLOGIC DYSFUNCTION partialis continua in neurophysiologic terms. The apparent refractoriness of this neurologic manifestation is mirrored by evidence of ongoing enteropathy despite a strict adherence to the gluten-free diet. The treatment of such patients remains problematic but the limited evidence from these small series suggests that mycophenolate may be a useful therapeutic intervention for those patients who appear to progress neurologically despite strict gluten-free diet.

Epilepsy A number of reports have suggested a link between epilepsy and CD (Chapman et al., 1978; Fois et al., 1994; Cronin et al., 1998). There is a particular type of focal epilepsy associated with occipital calcifications that appears to have a strong link with CD (Gobbi et al., 1992). This entity is common in Italy but rare in other countries (Fig. 41.3). It tends to affect young patients (mean age 16 years) and in the majority the seizures are resistant to antiepileptic drugs. The pathogenesis of the cerebral calcifications remains unclear. An autopsy study showed the depositions consisted of both calcium and silica, and microscopically were found in three main types: psammoma-like bodies without any identifiable relationship to cells, vessels, or other structures; 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.

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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 that the syndrome of celiac disease, epilepsy, and cerebral calcifications is “a genetic, non-inherited, ethnically and geographically restricted syndrome associated with environmental factors” (Gobbi, 2005). Whilst studies examining the prevalence of CD amongst patients with epilepsy have suggested a prevalence of 1.2– 2.3%, larger more recent studies failed to demonstrate such an increased prevalence (Ranua et al., 2005). However, most studies on the subject suffer from the same methodologic problem of treating epilepsy as a homogeneous disorder. The only study that attempted to look at the prevalence of GRD in well characterized subgroups of patients with epilepsy found a significant association between AGA and temporal lobe epilepsy with hippocampal sclerosis (Paltola et al., 2009). Of interest are some case reports on patients with CD and epilepsy whose epilepsy improves following the introduction of gluten-free diet (Mavroudi et al., 2005; Harper et al., 2007).

Myopathy This is a relatively rare neurologic manifestation of GRD, first described by Henriksson et al. (1982). This study from Sweden reported that out of 76 patients with suspected polymyositis investigated at a neuromuscular unit, 17 had a history of gastrointestinal symptoms with evidence of malabsorption. Fourteen of these fulfilled the diagnostic criteria for polymyositis and of those, five were diagnosed with CD. A more recent study from Spain (Selva-O’Callaghan et al., 2007) demonstrated the prevalence of AGA antibodies amongst patients with inflammatory myopathies to be 31%. This was accompanied by a higher prevalence of CD within the same population when compared to healthy controls. The clinical data from our series of patients are based on 18 cases encountered over the last 14 years, 13 of which have been reported previously (Hadjivassiliou et al., 2007). Enteropathy was identified following duodenal biopsy in 10 of these patients. The mean age at onset of the myopathic symptoms was 54 years. Ten patients had predominantly proximal weakness, five patients had both proximal and distal weakness, and four patients had primarily distal weakness. Two patients had ataxia and neuropathy, and one patient had just neuropathy in addition to the myopathy. Serum creatine kinase (CK) level ranged from normal (25–190 IU/L) to 4380 IU/L at presentation. Inflammatory myopathy was the most common finding on neuropathologic examination (Fig. 41.4). Six patients received immunosuppressive treatment in addition to starting a glutenfree diet whereas the others went on a gluten-free diet

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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 necessitated admission. He made a full recovery just with reintroduction of a strict gluten-free diet.

only. In the majority of those patients who did not receive immunosuppressive treatment there was clinical improvement of the myopathy with gluten-free diet, suggesting that the myopathy was etiologically linked to the GRD. One patient developed a profound myopathy after inadvertently eating rye flour. He made a full recovery by re-establishing a strict gluten-free diet. Two patients had histologic evidence of inclusion body myositis. It is interesting to note that inclusion body myositis shares the same HLA genetic predisposition with CD.

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.

Myelopathy Clinical evidence of a myelopathy in the absence of vitamin and other deficiencies (particularly copper) can be a rare manifestation of CD (Fig. 41.5). It is usually associated with normal imaging of the spinal cord. However, there have been some recent reports of patients with neuromyelitis optica (Devic’s disease) and GRD who have antibodies to aquaporin-4 (Jacob et al., 2005; Jarius et al., 2008). Such patients clearly had abnormal MRI of the spinal cord but the diagnosis of CD was only made at the time of their neurologic presentation. Neuromyelitis optica and CD share the same HLA genetic susceptibility (HLA DQ2). There are very limited data on the effect of the diet on the likelihood of relapse of the disease, particularly given the fact that most patients with Devic’s disease end up on long-term immunosuppressive medication.

positivity for anti-GAD or anti-amphiphysin antibodies. It has a strong association with other autoimmune diseases (e.g., insulin-dependent diabetes mellitus (IDDM), hypothyroidism, etc.). We have found a high prevalence of gluten-related antibodies in patients with this condition over and above that expected from an association of two autoimmune diseases. The relapsing remitting nature of the condition makes a study of any responsiveness to gluten-free diet difficult. There is, however, evidence of reduction of the anti-GAD antibody titer following the introduction of a gluten-free diet suggesting that the diet may be beneficial in treating the condition (Hadjivassiliou et al., 2010c). This finding also supports the concept of prevention of autoimmunity in patients with GRD if the gluten-free diet is introduced early enough.

Stiff man syndrome

PATHOGENESIS

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

Current evidence suggests that neurologic manifestations are immune mediated. Postmortem examination

GLUTEN-RELATED NEUROLOGIC DYSFUNCTION from patients with gluten ataxia demonstrate patchy loss of Purkinje cells throughout the cerebellar cortex, a nonspecific finding in many cerebellar disorders. However, additional findings supporting an immune-mediated pathogenesis include diffuse infiltration mainly of T lymphocytes within the cerebellar white matter as well as marked perivascular cuffing with inflammatory cells (Hadjivassiliou et al., 1998). The peripheral nervous system also shows sparse lymphocytic infiltrates with perivascular cuffing being observed in sural nerve biopsy of patients with gluten neuropathy (Hadjivassiliou et al., 2006a), in dorsal root ganglia in patients with sensory neuronopathy (Hadjivassiliou et al., 2010a) and in patients with gluten myopathy due to GRD (Hadjivassiliou et al., 2007). There is evidence to suggest that there is antibody cross-reactivity between antigenic epitopes on Purkinje cells and gluten proteins. Serum from patients with GA and from patients with CD but no neurologic symptoms, display cross-reactivity with epitopes on Purkinje cells of both human and rat cerebellum (Hadjivassiliou et al., 2002). This reactivity can also be seen using polyclonal AGA and the reactivity eliminated by absorption with crude gliadin. When using sera from patients with GA there is evidence of additional antibodies targeting Purkinje cell epitopes since elimination of AGA alone is

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.

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not sufficient to eliminate such reactivity (Fig. 41.6). There is some evidence that additional antibodies that may be causing such reactivity, including antibodies against one or more transglutaminase isoenzymes. TG2 belongs to a family of enzymes that covalently crosslink or modify proteins by formation of an isopeptide bond between a peptide-bound glutamine residue and a primary amine. However, in some instances TG2 may react with water in preference over an amine leading to the deamidation of glutamine residues. Gluten proteins (from wheat, barley, and rye), the immunologic trigger of GRD, are glutamine-rich donor substrates amenable to deamidation. Activation of TG2 and deamidation of gluten peptides appears to be central to disease development and is now well understood at a molecular level. However, events leading to the formation of autoantibodies against TG2 are still unclear. Questions also remain as to the contribution of these autoantibodies to organ-specific deficits. Anti-TG2 antibodies have been shown to be deposited in the small bowel mucosa of patients with GRD even in the absence of enteropathy. Furthermore such deposits have been found in extraintestinal sites, such as muscle and liver (Korponay-Szabo´ et al., 2004). Widespread deposition of transglutaminase antibodies has also been found around brain vessels in GA (Hadjivassiliou et al., 2006a). The deposition was most pronounced in the cerebellum, pons, and medulla. This finding suggests that such autoantibodies could play a role in the pathogenesis of the whole spectrum of manifestations seen in GRD. However, it is not clear whether these antibodies are derived from the circulation or if their production is mediated within target organs after stimulation of gutprimed gliadin-reactive CD4þ T cells. Variations in the specificity of antibodies produced in individual patients could explain the wide spectrum of manifestations. Whilst TG2 has been shown to be the autoantigen in CD (Dietrich et al., 1997), the epidermal transglutaminase TG3 has been shown to be the autoantigen in DH (Sa´rdy et al., 2002). More recently, antibodies against TG6, a primarily brain expressed transglutaminase, have been shown to be present in patients with GA (Hadjivassiliou et al., 2008a). In GA and DH, IgA deposits of TG6 and TG3 respectively seem to accumulate in the periphery of blood vessels. This could indicate that either the deposits originate from immune complexes formed elsewhere, and are accumulating as a consequence of enhanced vascular leaking, or that TG6/TG3 are derived from perivascular infiltrating inflammatory cells preceding deposit formation. Indeed perivascular cuffing with lymphocytes is a common finding in brain tissue from patients with GA but is also seen in peripheral nerve and muscle in patients with gluten neuropathy or myopathy. In most sera reactive

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with more than one TG isoenzyme, distinct antibody populations are responsible for such reactivity rather than this being a result of cross-reactivity with different TG isozymes. This makes shared epitopes less likely to be the cause for immune responses to other TGs and points to the possibility that TG isozymes other than TG2 can be the primary antigen in GRD. IgA deposition in brain vessels and the pathologic finding of perivascular cuffing with inflammatory cells, may indicate that vasculature-centered inflammation may compromise the blood–brain barrier, allowing exposure of the CNS to pathogenic antibodies, and therefore be the trigger of nervous system involvement. Indeed, TG2 is expressed by smooth muscle and endothelial cells in noninflamed brain, is an abundant component of the blood–brain barrier and autoantibody binding could initiate an inflammatory response. Anti-TG2 and other autoantibodies (e.g., AGA) may directly cause selective neuronal degeneration. It is possible that neuronal degeneration is a consequence of the anti-TG antibody spectrum, i.e., occurs in those patients with antibodies reactive with a neuronal TG. IgG class antibodies have been shown to be present in only 60% of CD patients whereas in GA patients positive for anti-TG, the prevalence was 90%. This shift from IgA to IgG may reflect the target organ involved (central nervous system rather than the small bowel). It could be argued that development and deposition of antibodies is an epiphenomenon rather than being pathogenic. One method to demonstrate the pathologic effect of an antibody is the passive transfer of the disease through antibody injection into a naı¨ve animal. While such experimental evidence exists for only very few antibody-mediated diseases, IgG fractions of patients with anti-GAD ataxia and stiff man syndrome have been shown to compromise motor function and impair learning in rodents, an effect possibly ascribed to antibodies against GAD (Manto et al., 2007). A common problem in such studies is to be able to demonstrate whether it is these specific antibodies or other autoantibodies in the IgG-fraction of patient sera that cause neuronal damage. Using a mouse model we have recently shown that serum from GA patients, as well as clonal monovalent anti-TG immunoglobulins derived using phage display, cause ataxia when injected intraventricularly in mice (Boscolo et al., 2010). The fact that not only Ig fractions but also monospecific scFvs mediate functional deficits shows that there is no requirement for complement activation or for the engagement of Fc receptors on Fc receptor-bearing cells in the brain. These data therefore provide evidence that anti-TG immunoglobulins (derived from patients) compromise neuronal function in selected areas of the brain once exposed to the CNS and suggest that this involves an immune system

independent mode of action. While these data implicate anti-TG antibodies in ataxia they do not explain the spectrum of distinct neurologic deficits currently ascribed to gluten sensitivity, nor why only a fraction of patients with circulating anti-TG antibodies are affected.

CONCLUSIONS GRD include immune-mediated diseases triggered by ingestion of gluten proteins. While celiac disease has been the most comprehensively studied of all GRD, dermatitis herpetiformis and neurologic manifestations are the commonest extraintestinal manifestations. To fully understand the immunologic insults resulting from gluten ingestion, the emphasis should perhaps shift toward the study of extraintestinal manifestations. In addition there is a need for the early identification of those patients that are specifically at risk of irreversible complications (e.g., gluten ataxia). To that effect, new diagnostic tools are now becoming available (e.g., antibodies against TG6) which may make a more reliable identification of those patients with neurologic manifestations a reality. Up to 40% of patients presenting to the gastroenterologist who are ultimately diagnosed with CD also have antibodies against TG6 in addition to antibodies against TG2. This subgroup of patients with classic CD presentation may well be the ones susceptible to the development of neurologic dysfunction if they continue to consume gluten, although this remains to be shown in longitudinal studies. The presence of gastrointestinal symptoms, however, offers a major potential advantage to this group, as it substantially increases their chances of being diagnosed with, and treated for, CD, whereas the diagnosis of those patients presenting purely with extraintestinal manifestations may be more difficult. The only way that this can be improved upon is by changing the perception of physicians that glutenrelated diseases are solely diseases of the gut.

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