|
beyond reason
다발성 경화증을 스스로 완치한 내과의사 테리 휠이 읽은 논문
Gluten sensitivity: from gut to brain
Marios Hadjivassiliou, David S Sanders, Richard A Grünewald, Nicola Woodroofe, Sabrina Boscolo, Daniel Aeschlimann
Gluten sensitivity is a systemic autoimmune disease with diverse manifestations. This disorder is characterised by abnormal immunological responsiveness to ingested gluten in genetically susceptible individuals. Coeliac disease, or gluten-sensitive enteropathy, is only one aspect of a range of possible manifestations of gluten sensitivity. Although neurological manifestations in patients with established coeliac disease have been reported since 1966, it was not until 30 years later that, in some individuals, gluten sensitivity was shown to manifest solely with neurological dysfunction. Furthermore, the concept of extraintestinal presentations without enteropathy has only recently become accepted. In this Personal View, we review the range of neurological manifestations of gluten sensitivity and discuss recent advances in the diagnosis and understanding of the pathophysiological mechanisms underlying neurological dysfunction related to gluten sensitivity.
www.thelancet.com/neurology Vol 9 March 2010
Introduction
Coeliac disease was first described in 100 AD by the Greek doctor Aretaeus,1 who used the term abdominal diathesis. When his extant works were first published in Latin in 1552, the Greek word for abdominal, koiliaki, was transcribed to coeliac. The study of coeliac disease was renewed by Gee2 in 1888. His lecture on the coeliac affection described the disease according to his observations while treating children with the disease. Although clinicians began to recognise and diagnose coeliac disease, its aetiology remained obscure until 1953 when Dicke and colleagues3 reported “the presence in wheat, of a factor having a deleterious effect in cases of celiac disease”. Because gastrointestinal symptoms were dominant in patients with coeliac disease, and enteropathy was seen after enteroscopy and small bowel biopsy, it is not surprising that coeliac disease was thought to be exclusively a disease of the gut.
In 1963–65, Shuster, Marks, and Watson4 observed that dermatitis herpetiformis was a form of gluten-sensitive dermatopathy that shared the same small bowel pathology, but not the gastrointestinal symptoms seen in patients with coeliac disease. This was the first reported evidence that coeliac disease might present with extraintestinal manifestations.
Few case reports of patients with malabsorption or steatorrhoea (also referred to as sprue) and neurological manifestations5–7 were published before the discovery of the aetiology of coeliac disease and the introduction of jejunal biospy, which identified the typical histological features that define coeliac disease.8 Such reports need to be treated with caution as a definite diagnosis of coeliac disease had not been made in patients. When the first comprehensive report of neurological manifestations in the context of histologically confirmed coeliac disease was published in 1966,9 the assumption was that such manifestations were caused by vitamin deficiencies secondary to malabsorption as a result of the enteropathy. The patients were undernourished, with severe weight loss, low albumin, and often multiple vitamin deficiencies. Detailed post-mortem data from the same report, however, showed an inflammatory process that primarily, but not exclusively, affected the cerebellum, and also involved other parts of the CNS and peripheral nervous system. This finding favoured an immune-mediated pathogenesis.
Single and multiple case reports of patients with established coeliac disease who then developed neurological dysfunction continued to be published.10–29 The key findings from these reports were that ataxia (with and without myoclonus) and neuropathy were the most common manifestations; neurological manifest- ations were usually reported in the context of established coeliac disease and were almost always attributed to malabsorption of vitamins; and the effects of dietary restriction were inconsistent. A gluten-free diet did not always alleviate neurological dysfunction, although assessment of the effect of the gluten-free diet was not the main aim of these reports. None of the reports documented any attempts to monitor adherence to the diet with repeat serological testing.
In 1996, 30 years after publication of the first comprehensive case series on neurological manifestations of coeliac disease, we investigated the prevalence of gluten sensitivity in patients who presented with neurological dysfunction of unknown aetiology; most patients had ataxia either with or without neuropathy.30 Presence of antigliadin antibodies (AGA) in these patients was common compared with controls. AGA were the only readily available serological markers of coeliac disease when the study was done (with the exception of R1-type antireticulin antibodies; endomysium antibodies were gradually introduced into clinical practice in the mid- 1990s). On the basis of duodenal biopsy samples, results from this study indicated that the prevalence of coeliac disease in these patients was 16 times higher than the prevalence of coeliac disease in the healthy population. These data rekindled the interest of neurologists in a possible link between gluten sensitivity and certain neurological presentations.
Epidemiology
The prevalence of coeliac disease in the healthy population is at least 1%.31,32 There are no accurate estimates of the prevalence of the neurological manifestations of gluten sensitivity in the general population. A range of 10% to 22.5% for the prevalence of neurological dysfunction among patients with established coeliac disease has been reported,33,34 but is unlikely to be accurate because such numbers are usually derived retrospectivelyfrom gastrointestinal clinics and thus focus exclusively on patients with the classic coeliac disease presentation and also tend to include neurological dysfunctions that might be unrelated to gluten sensitivity (eg, carpal tunnel syndrome, idiopathic Parkinson’s disease).
Moreover, patients are unlikely to have reliably volunteered any neurological symptoms while attending a gastrointestinal clinic, and patients with neurological symptoms are more likely to present to a neurologist than to a gastroenterologist. An analogous situation is seen in patients with undiagnosed gluten sensitivity who have dermatitis herpetiformis, for which few patients will present to gastroenterology clinics as they tend not to have gastrointestinal symptoms, and instead present to a dermatologist with an itchy vesicular rash. Some estimates of prevalence can be made from patients attending the respective specialist clinics, although caution is needed when extrapolating these data as they are inevitably affected by regional referral bias. In dedicated coeliac disease and gluten sensitivity/neurology clinics in Sheffi eld, UK, run by two of the authors (DSS and MH, respectively), 134 patients with coeliac disease presented with neurological dysfunction and were managed in the gluten sensitivity/neurology clinic whereas 462 patients with coeliac disease presented to a gastroenterologist over the same time period. Thus, for every seven patients who present to a gastroenterologist and are then diagnosed with coeliac disease, two patients will present to a neurologist. These numbers exclude patients with neurological manifestations caused by suspected gluten sensitivity but no enteropathy (n=270), patients referred from outside the catchment area served by these clinics, and patients who presented to a gastroenterologist first
before being referred to a neurologist for their symptoms.
Diagnosis of gluten sensitivity presenting with neurological manifestations
Most patients who present with neurological manifestations of gluten sensitivity have no gastrointestinal symptoms. Patients with coeliac disease might not have gastrointestinal symptoms either. Therefore, gluten sensitivity cannot be diagnosed on a clinical basis alone. Several diagnostic tests are now availabe that can help to decide whether patients might have coeliac disease or gluten sensitivity with extraintestinal manifestations with or without enteropathy. Figure 1 is a diagnostic flow chart we recommend to help diagnosis of neurologicaldysfunction related to gluten sensitivity.
Untreated patients typically have circulating antibodies to gliadin and to one or more type of transglutaminase. Except for patients with IgA deficiency, detection of IgG class antibodies has little clinical value for coeliac disease. However, this observation is organ specific and detection of IgG type antibodies could be crucial for extraintestinal manifestations of gluten sensitivity. In patients without overt gastrointestinal involvement, serum antibodies to transglutaminase-2 (TG2) can be absent. Such patients typically have antibodies that primarily react with a different transglutaminase isozyme—TG3 in dermatitis herpetiformis and TG6 in patients with neurological manifestations. Unfortunately, tests for autoantibodies to these latter enzymes are not yet widely available.
Autoantibodies to TG2 in sera samples from patients with gluten senstivity give rise to the characteristic staining pattern on specifi c tissue sections (ie, referred to as reactivity with endomysial [EMA], reticulin [ARA], or jejunal [JEA] antibodies),35 and such tests off er no
additional information to the direct ELISAs now available
for detection of TG2 IgA. Detection of anti bodies to
deamidated gliadin peptides (DGP) is more specifi c for
detection of coeliac disease than are classic AGA assays.36
However, unlike autoantibodies to TG2, anti-DGP
antibodies can be either IgA or IgG class and not all
patients have both. IgG anti-DGP has been reported to
have 100% positive predictive value in adults and should
therefore be included in the analysis.37 At present,
whether these assays are similarly sensitive for detection
of neurological manifestations of gluten sensitivity is not
known. Recent evidence suggests that anti-DGP
antibodies might be present in only 26% of patients with
gluten sensitivity who are negative for TG2 IgA.38 This
fi nding is consistent with our observation of detectable
anti-DGP IgA/IgG in only 25% of patients with ataxia
without enteropathy who test positive for autoantibodies
to one or more transglutaminase isozymes. Table 1
details the prevalence of diff erent types of gluten-related
antibodies in patients with sporadic ataxia and in
patients with gluten ataxia.
Serum IgA antibodies represent a surplus from the
gut. Reaction of IgA antibodies with TG2 in the intestinal
mucosa occurs before overt changes in small intestinal
morphology are apparent and at least sometimes before
antibodies are detectable in serum.40 Such anti-TG2 IgA
within the intestinal mucosa also seem to be present in
patients with neurological disorders41 and could
therefore be diagnostically useful. However, the
detection of these deposits in the intestinal mucosa is
not a readily available test and its interpretation requires
experience. In practice, it is best to do serological tests
for both IgA and IgG autoantibodies to TG2 (and, if
available, anti-TG6 and anti-TG3) as well as antibodies
to gliadin and DGPs (fi gure 1).
Limitations of conventional approach for diagnosis
Coeliac disease is characterised by the presence of an enteropathy, a practicable and mostly reliable gold standard of diagnosis. However, an enteropathy is not necessarily
a prerequisite for the diagnosis of gluten sensitivity
with predominantly neurological manifestations. Gluten sensitivity causes a range of changes in the small bowel mucosa—from histologically normal mucosa to fullblown
enteropathy to a pre-lymphomatous state. This
range is categorised by the Marsh classifi cation, which is
currently accepted and used by most centres.42 This variety
of states is a problem when defi ning gluten sensitivity
because diagnosis currently relies on serological tests that
are not 100% specifi c or sensitive. For example, endomysial
antigen and anti-TG2 IgA antibody detection are specifi c
for the presence of enteropathy and are excellent indicators
of coeliac disease; however, these markers are often not
detectable in patients with neurological manifestations,
particularly in the absence of enteropathy. Conversely, IgA
and IgG AGA are not specifi c for coeliac disease (ie, to
indicate presence of enteropathy) and are now being
phased out for diagnosis of coeliac disease as more
reliable tests have become available.
Genetics
Gluten sensitivity is strongly heritable, with about 40% of the genetic load coming from MHC class II association.43 In white populations, more than 90% of patients with coeliac disease carry the HLA DQ2.5 variant (DQA1*05- DQB1*02) and most other patients carry HLA-DQ8 (DQA1*03-DQB1*0302). A few patients with coeliac disease do not belong in either of these groups but carry just one chain of the DQ2 heterodimer, either DQA1*05 (DQ7) or DQB1*02 (DQ2.2), but not both.44 Of the two heterodimers, DQA1*05 on its own confers a low predisposition to coeliac disease. HLA genetic testing is therefore another useful tool to aid diagnosis (figure 1), particularly as, unlike other serological tests, this test is not dependent on an immunological trigger. However, the HLA DQ genotype can be used only as a test of exclusion, as the risk genotype DQ2 is common in white and Asian populations, and many carriers will never develop gluten sensitivity. We have noted an unusually
high frequency of deviation from the MHC class II pattern
typical for coeliac disease in patients with neurological
disease due to gluten sensitivity. DQ8 was substantially
more common in patients in the Sheffi eld neurology
cohort who had no enteropathy (17% [46 of 270]) compared
with patients with coeliac disease presenting to
gastroenterologists (<6% [60 of 1008]).44 Together with the
fi nding of more variability in T-cell epitope specifi city in
patients carrying DQ8 compared with patients carrying
DQ2,45 this observation suggests that there are diff erences
in disease aetiology between patients whose primary
manifestation occurs in the CNS and those whose
primary manifestation aff ects the gastrointestinal system.
Neurological manifestations of gluten sensitivity
The range of neurological manifestations of gluten sensitivity encountered in our specialist clinic over thepast 15 years are listed in table 2.
Gluten ataxia
Cerebellar ataxia is one of the two most common neurological manifestations of gluten sensitivity. We defined gluten ataxia in 1996 as apparently sporadic ataxia with positive serological markers for gluten sensitivity. This definition was based on the serological tests available at the time (AGA). In a series of 500 patients with progressive ataxia evaluated over a period of 13 years in Sheffield, UK, 101 of 215 patients with idiopathic sporadic ataxia had serological evidence of gluten sensitivity.46 The prevalence of gluten ataxia was 20% among all patients with ataxias, 25% among patients with sporadic ataxias, and 45% among patients with idiopathic sporadic ataxias.46,47 By use of the same AGA assay, the prevalence of AGA-positive patients was 10% (7 of 71) in genetically confirmed ataxias, 18% (8 of 45) in familial ataxias (not genetically confirmed), and 12% (149 of 1200) in healthy volunteers. Data from several studies investigating the
occurrence of AGA in ataxias have been published48–56 and
are summarised in table 3. The variations in frequency
might be due to the geographical diff erences in the
prevalence of coeliac disease, referral bias, variability in
the AGA assays used, selection of patients (eg, some
studies categorised patients with cerebellar variant of
multisystem atrophy as idiopathic sporadic ataxia57), small
study size, and absence of controls.
In all these studies, patients with sporadic ataxias had a
high frequency occurrence of AGA antibodies compared
with healthy controls. Gluten ataxia usually presents with
pure cerebellar ataxia or, rarely, ataxia in combination with
myoclonus (see below), palatal tremor,21,58 opsoclonus,59 or
chorea.60 Gluten ataxia usually has an 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.58 All patients have gait ataxia and most have limb
ataxia. Less than 10% of patients with gluten ataxia will
have any gastrointestinal symptoms but a third will have
evidence of enteropathy on biopsy.58 Up to 60% of patients
have neurophysiological evidence of sensorimotor, lengthdependent
axonal neuropathy.58 This neuropathy is usually
mild and does not contribute to the ataxia. Antiendomysium
antibodies are detectable in only 22% of
patients.58 By use of ELISA, anti-TG2 IgA antibodies are
present in up to 38% of patients with gluten ataxia, but
often at lower titres than those seen in patients with coeliac
disease. However, unlike in coeliac disease, IgG class
antibodies to TG2 in patients with gluten ataxia are more
common than IgA (table 1). This fi nding is in line with
data that have provided evidence for intrathecal antibody
production against TG in patients with neurological
diseases.61 The high prevalence of IgG class antibodies to
TG2 and TG6 in these patients is consistent with an
immune response in the CNS. Antibodies against either
TG2 or TG6, or both, can be found in 85% of patients with
ataxia and AGA antibodies.39,62 Some patients also test
positive for anti-TG3 antibodies, although the frequency
of such antibodies is low when compared with patients
with dermatitis herpetiformis, and no patients tested
positive for such antibodies in isolation. Antibodies to
TG2 and TG6 can also be detected in patients with
idiopathic sporadic ataxia who are negative for AGA,
although at much lower frequency compared with patients
with circulating antigliadin antibodies. Whether combined
detection of TG2 and TG6 IgA/IgG can identify all patients
with gluten sensitivity is unclear. However, detection of
anti-DGP antibodies did not identify any additional
patients. The discrepancy between anti-transglutaminase
antibody and AGA detection is in agreement with the
expected rate of false-positive results (about 12%; the
frequency of AGA in the healthy population) and the
sensitivity reported for coeliac disease.63 The HLA type
DQ2 is found in 70% of patients with ataxia who are
positive for AGA (present in 90% of patients with celiac
disease and in 36% of healthy controls); the remaining
30% carry the HLA DQ8 (10%) and HLA DQ1 (20%)
variants. These reported occurrences are in agreement
with the results from serological testing reported in table 1
and are consistent with strict association with the HLA
risk genotype of coeliac disease.
Up to 60% of patients with gluten ataxia have evidence of cerebellar atrophy on MRI. Investigation of the metabolic status of the cerebellum in 15 patients with gluten ataxia and ten controls by use of proton magnetic resonance spectroscopy showed significant differences in mean N-acetyl concentrations at short echo-time and in N-acetyl aspartate to choline ratios at long echo-time between patients with gluten ataxia and healthy controls, suggesting that cerebellar neuronal physiology is abnormal.64 Even in patients without cerebellar atrophy,
proton magnetic resonance spectroscopy of the
cerebellum was abnormal.
The response to treatment with a gluten-free diet
depends on the duration of the ataxia. Loss of Purkinje
cells in the cerebellum, the end result of prolonged gluten exposure in patients with gluten ataxia, is
irreversible and prompt treatment is more likely to
result in improvement or stabilisation of the ataxia.
Although the benefi ts of a gluten-free diet in the
treatment of patients with coeliac disease and dermatitis
herpetiformis have long been established, there are few
studies, mainly case reports, of the eff ect of a glutenfree
diet on the neurological manifestations of gluten
sensitivity.18,22,24,28,29,65–68 Most of these reports mainly
describe patients with established coeliac disease who
then develop neurological symptoms. These studies
suggest variable, but overall favourable, responsiveness
to a gluten-free diet. A small, uncontrolled study
investigated the use of intravenous immuno globulins
in the treatment of four patients with gluten ataxia
without enteropathy.69 All patients improved on the
International Co-operative Ataxia Rating Scale (ICARS).
In all these reports, strict adherence to the gluten-free
diet is assumed. The best marker of strict adherence to
a gluten-free diet is serological evidence of elimination
of circulating antibodies related to gluten sensitivity,
although serum antibodies might be present for
6–12 months after the start of the diet. A systematic
study of the eff ect of a gluten-free diet on a cohort of
patients who presented with neurological dysfunction,
with or without an enteropathy, has been published.70
This study also investigated serological confi rmation of
adherence to the diet. 43 patients with gluten ataxia
were enrolled. 26 adhered strictly to the gluten-free diet,
had serological evidence of elimination of antibodies,
and comprised the treatment group. 14 patients refused
the diet and comprised the control group. Treatment and
control groups were matched at baseline for all variables
(age, duration of ataxia). There was no signifi cant
diff erence in the baseline performance for each ataxia
test between the two groups. There was signifi cant
improvement in performance in test scores and in the
subjective global clinical impression scale in the
treatment group when compared with the control group.
The improvement was apparent even after excluding
patients with an enteropathy. A gluten-free diet could
therefore be an eff ective treatment for gluten ataxia.
We are unaware of any published, randomised, placebocontrolled
studies on the subject, perhaps indicating the
practical diffi culties when the intervention is dietary
elimination of gluten and the ethical considerations of
randomising patients with gluten ataxia who have enteropathy.
Gluten neuropathy
Peripheral neuropathy is the other most common manifestation of gluten sensitivity. Up to 23% of patients with established coeliac disease on a gluten-free diet have neurophysiological evidence of a peripheral neuropathy.71 In a large population-based study (84 000 participants) in Sweden that examined the risk of neurological disease in patients with coeliac disease, polyneuropathy was significantly associated with coeliac disease (odds ratio 5.4; 95% CI 3.6–8.2).72 In a UK-based study, 47 of 140 (34%) patients with idiopathic sporadic axonal neuropathy had circulating AGA.73 In an Italian study, a greater proportion of patients with various types of neuropathies were positive for IgA anti-TG2 (68 of 330; 21%) compared with controls (1 of 68; 1.5%; p<0.0001).74 Finally, in a tertiary referral centre in the USA, retrospective evaluation of 400 patients with neuropathy showed the prevalence of coeliac disease to be between 2.5% and 8% (compared with 1% in the healthy population).75
Gluten neuropathy is defined as apparently sporadic idiopathic neuropathy in the absence of an alternative aetiology and in the presence of serological evidence of gluten sensitivity. The most common type is symmetrical sensorimotor axonal peripheral neuropathy, but other types of neuropathies have also been reported (asymmetrical neuropathy,76–78 sensory ganglionopathy,79 small fibre neuropathy,80 and, rarely, pure motor neuropathy73 or autonomic neuropathy81). Gluten neuropathy is a slowly progressive disease with a mean age at onset of 55 years (range 24–77) and a mean duration of neuropathy to diagnosis of gluten sensitivity of 9 years (range 1–33). A third of patients have evidence of enteropathy on biopsy, but the presence or absence of enteropathy does not predetermine the eff ect of a gluten-free diet.82
The few data on pathology available from postmortems and nerve biopsy samples are consistent with an
inflammatory aetiology (perivascular lymphocytic infiltration).73 The evidence of effectiveness of a gluten free diet has mostly been derived from single or multiple case reports, most of which suggest improvement of the neuropathy.22,73,83 Data from a systematic, controlled study of the effect of a gluten-free diet on 35 patients with gluten neuropathy, with close serological monitoring of the adherence to the gluten-free diet, indicated significant improvement in the treatment group compared with the control group after 1 year (p=0.04 for the improvement of sural sensory action potential and p=0.0006 for
improvement of subjective neuropathy symptom score).82
Benefit was defined as improvement of sural sensory action potential, the prespecified primary endpoint, and subjective improvement of the neuropathic symptoms. Subgroup analysis suggested that the capacity for recovery of the peripheral nerves might be reduced when the
neuropathy is severe or that more time might be needed
for such recovery to manifest. As there was a correlation
between disease severity and longer disease duration,
gluten neuropathy could be thought of as a progressive
disease if untreated. This study also reported that
neuropathy improved irrespective of the presence of
enteropathy.
Sensory ganglionopathies can also be a manifestation
of gluten sensitivity and might require immunosuppressive
medication in addition to a strict gluten-free
diet to achieve stabilisation.79
Gluten encephalopathy
In 2001, we reported a series of ten patients with gluten
sensitivity, headache, and CNS white matter
abnormalities, using the term “gluten encephalopathy”
to describe them.84 The headaches are usually episodic
and mimic migraine, can be associated with focal
neurological defi cits, and characteristically resolve with
the introduction of a gluten-free diet. The white matter
abnormalities (fi gure 2) can be diff use or focal and do not
resolve after a gluten-free diet, which simply arrests
progression of these changes. The distribution of white
matter abnormalities is more suggestive of a vascular
rather than a demyelinating aetiology. We believe that
headaches are quite common in patients with newly
diagnosed coeliac disease and thus there is an overrepresentation
of coeliac disease among patients with
migraine-like headaches (4.4% vs 0.4% in the control
population).85 By use of PET brain imaging, data from a
study on regional cerebral perfusion showed that seven
of 11 patients (73%) with coeliac disease who were not on
a gluten-free diet had at least one hypoperfused brain
region as compared with one of 15 healthy controls (7%)
and one of 15 patients (7%) with coeliac disease who were
on a gluten-free diet.86 In another study, 20% of children
with coeliac disease were shown to have white matter
abnormalities.87 A similar prevalence of AGA and TG2
antibodies was found in 86 patients with white matter
lesions in the brain or spinal cord or optic neuritis
compared with controls or patients with multiple
sclerosis.88
Over the past 14 years we have encountered 61 patients
with gluten encephalopathy (including the initial ten
patients reported in the 2001 series). Gluten
encephalopathy does not always occur in isolation and
patients often have additional neurological features such
as ataxia, neuropathy, and cognitive defi cits. A study from
the Mayo Clinic emphasised the substantial cognitive
defi cits encountered in 13 patients with coeliac disease.89
Another study from Finland reported fi ve patients with
coeliac disease with brain atrophy and dementia.26 In a
study from Italy, no higher prevalence of coeliac disease
was found in patients with Alzheimer’s disease compared
with elderly controls,90 perhaps emphasising that patients
with gluten encephalopathy have features that distinguish
them from degenerative dementias (eg, headache,
abnormal MRI, response to gluten-free diet). The
prevalence of enteropathy is greater in patients with
gluten encephalopathy (35 of 61 compared with gluten
ataxia [67 of 184] and gluten neuropathy [46 of 174]), but
the age at onset is similar. The observed improvement of
the headaches and arrest of progression in the MRI brain
abnormalities after a gluten-free diet suggest a causal
link with gluten sensitivity.84,91 Gluten encephalopathy
has a range of clinical presentations, with episodic
headaches responsive to a gluten-free diet at one end
through to severe debilitating headaches associated with
focal neurological defi cits and abnormal white matter on
MRI at the other end.
Other less common manifestations or associations
Epilepsy
Several reports have suggested a link between epilepsy and coeliac disease.92–94 A specific type of focal epilepsy that is associated with occipital calcifications seems to have a strong link with coeliac disease.95–97 This form is common in Italy but rare in other countries, tends to affect young patients (mean age 16 years), and the seizures are resistant to antiepileptic drugs in most patients.97 The prevalence of epilepsy among patients with coeliac disease was 5.5% (9 of 165) according to a 1978 report;92 most patients had temporal lobe epilepsy.
Other studies examining the frequency of coeliac disease among patients with epilepsy93,94 suggest a prevalence of 1.2–2.3%. Larger, recent studies have not confirmed these findings.98 However, most studies treated epilepsy as a homogeneous disorder, which is a weakness in their design. A study of the prevalence of gluten sensitivity in well characterised subgroups ofpatients with epilepsy found a significant association between gluten sensitivity and temporal lobe epilepsy with hippocampal sclerosis (p<0.0002).99 Of interest are some case reports on patients with coeliac disease and epilepsy, whose epileps improved after the introduction of a gluten-free diet.100,101
Myopathy
Myopathy is a rare neurological manifestation of gluten sensitivity. In a Swedish study,102 of 76 patients with suspected polymyositis investigated at a neuromuscular unit, 17 patients had a history of gastrointestinal symptoms with evidence of malabsorption. 14 of these patients fulfilled the diagnostic criteria for polymyositis and, of those, five were diagnosed with coeliac disease. In a more recent study from Spain,103 AGA antibodies were present in 31% of patients with inflammatory myopathies, and there was a higher prevalence of coeliac disease in these patients when compared with healthy controls. The clinical data discussed in this section are based on 18 cases encountered by the authors over the
past 14 years (13 of which have been reported previously104).
Enteropathy was identified in duodenal biopsy samples in ten of these patients. The mean age at onset of myopathic symptoms was 54 years. Ten patients had
predominantly proximal weakness, fi ve patients had
both proximal and distal weakness, and three 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
concentration ranged from normal (25–190 IU/L) to
4380 IU/L at presentation. Infl ammatory myopathy was
the most common fi nding on neuropathological
examination. Six patients received immunosuppressive
treatment in addition to starting a gluten-free diet,
whereas the other patients were on a gluten-free diet
only. Most of the patients who did not receive immunosuppressive
treatment had clinical improvement of the
myopathy with the gluten-free diet, suggesting that the
myopathy was aetiologically linked to the gluten
sensitivity. One patient developed a profound myopathy
after inadvertently eating rye fl our while on a gluten-free
diet. He made a full recovery by re-establishing a strict
gluten-free diet.
Myelopathy
Clinical evidence of a myelopathy in the absence of vitamin and other deficiencies (particularly copper) can be a rare manifestation of coeliac disease. This myelopathy is usually associated with normal imaging of the spinal cord. However, there have been reports of patients with neuromyelitis optica (Devic’s disease) and gluten sensitivity who have antibodies to aquaporin-4.105,106 These patients had abnormal MRI of the spinal cord, but the diagnosis of coeliac disease was only made at the time of their neurological presentation. Whether this is merely
an association based on the same genetic susceptibility
remains to be determined. There are few data on the
eff ect of a gluten-free diet in such patients. Neuromyelitis
optica and coeliac disease share the same HLA genetic susceptibility.
Multiple sclerosis
There is no evidence of an increase in prevalence of gluten sensitivity in patients with relapsing-remitting or secondary-progressive multiple sclerosis.107,108 Cases of gradually progressive neurological disease and gluten sensitivity associated with white matter lesions, both in the brain and in the spinal cord, indistinguishable fromthose seen in patients with multiple sclerosis, have been
described.108,109 Such patients might also have evidence of peripheral nerve involvement, which is not seen in primary-progressive multiple sclerosis.
Stiff -man syndrome
Stiff -man syndrome is a rare autoimmune disease characterised by stiffness and positivity for anti-glutamic acid decarboxylase (GAD) antibodies. This syndrome has a strong association with other autoimmune disease(eg, insulin-dependent diabetes mellitus and hypothyroidism). We have found a high prevalence of glutensensitivity in patients with this disorder,110 more so than that expected from an association of two autoimmune diseases. The effect of a gluten-free diet on stiff ness and
anti-GAD titre is being studied.
Myoclonic ataxia
Myoclonic ataxia is a rare manifestation of gluten sensitivity first described in 1986.19 The myoclonus is of cortical origin but the pathology is primarily cerebellar.28In a series of patients with neurological manifestations of gluten sensitivity, fi ve of six patients with myoclonic
ataxia had evidence of enteropathy on biopsy. Despite a
strict gluten-free diet, the condition of two patients
progressed. Both patients were treated with
mycophenolate, which resulted in stabilisation. In the
remaining patients, the ataxia responded to the glutenfree
diet but the myoclonus persisted.
Pathophysiology of neural damage
Neurological deficits are immune mediated. Current evidence suggests that neurological manifestations
are immune mediated. Vitamin and trace element
defi ciencies rarely play a part, particularly as most patients
with neurological manifestations have no enteropathy and
are thus not prone to malabsorption and vitamin
defi ciencies. Post-mortem examination from patients with
gluten ataxia showed patchy loss of Purkinje cells
throughout the cerebellar cortex, a common finding in
many end-stage diseases of the cerebellum (fi gure 3D).9,111
However, additional fi ndings supporting an immunemediated
pathogenesis include diff use infi ltration mainly
of Tlymphocytes within the cerebellar white matter as well
as marked perivascular cuffi ng with infl ammatory cells
(fi gure 3A). The peripheral nervous system also showed
sparse lymphocytic infi ltrates with perivascular cuffi ng in
sural nerve biopsy samples of patients with gluten
neuropathy73 and in dorsal root ganglia in patients with
sensory neuronopathy and patients with myopathy caused
by gluten sensitivity.79 Similar fi ndings have been described
in patients with established coeliac disease who then
developed neurological dysfunction.9
Some experimental clues to pathogenesis
Evidence suggests there might be antibody cross-reactivity
between antigenic epitopes on Purkinje cells and gluten
proteins. Serum from patients with gluten ataxia and
from patients with coeliac disease without neurological
symptoms showed cross-reactivity with epitopes on
Purkinje cells of both human and rat cerebellum.112 Such
reactivity can also be seen with polyclonal AGA, and the
reactivity can be eliminated by absorption with crude
gliadin. When using sera from patients with gluten ataxia,
there is evidence of additional antibodies targeting
Purkinje cell epitopes, because elimination of AGA alone
is not suffi cient to remove such reactivity. Additional
antibodies might be causing this reactivity, such as
antibodies against one or more transglutaminase
isozymes (see below). Furthermore, shared epitopes
between TG2 and DGPs could provide a link between
these seemingly unrelated immunological targets.113 In
the case of gluten neuropathy there is evidence of antibody
cross-reactivity with the neuronal protein synapsin I.114
Additionally, gliadin can bind to GM1 ganglioside.115
Ganglioside antibodies are associated with autoimmune
peripheral neuropathies. Finally, sera from patients with
coeliac disease and neurological manifestations also
evoke a mitochondrial-dependent apoptosis in vitro,116
suggesting that neurotoxic antibodies might be present.
However, the nature of these antibodies and their role in
in vivo neurotoxicity remains to be shown.
The role of transglutaminases
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.117 However, in some instances, TG2 can
react with water in preference over an amine, leading to
the deamidation of glutamine residues.118,119 Gluten
proteins, the immunological trigger of gluten sensitivity,
are glutamine-rich donor substrates amenable to
deamidation. TG2 contributes to disease development in
at least two ways: fi rst, by deamidating gluten peptides and
thereby increasing their affi nity for HLA-DQ2/DQ8, which
potentiates the T-cell response,120,121 and, second, by
haptenisation of self-antigens through crosslinking with
gliadins.122 This latter activity has been implicated in
autoantibody development (fi gure 4). Activation of TG2
and deamidation of gluten peptides seems to be central to
disease development and is now well understood at a
molecular level. However, events leading to the formation
of the characteristic autoantibodies to TG2 are still unclear.
Evidence suggests that unusually stable thioester complexes
of the enzyme with the substrate peptides might have a
role.122 Questions also remain as to the contribution of
these autoantibodies to organ-specifi c defi cits. Anti-TG2
antibodies are deposited in the small bowel mucosa of
patients with gluten sensitivity, even in the absence of
enteropathy.126 Furthermore, such deposits have been
found in extraintestinal sites, such as muscle and liver.126
Widespread deposition of transglutaminase antibodies has
also been found around blood vessels of the brain in
patients with gluten ataxia.41 The deposition was most
pronounced in the cerebellum, pons, and medulla. This
fi nding suggests that these autoantibodies could have a
role in the pathogenesis of all the manifestations seen in
gluten sensitivity. However, whether these antibodies are
derived from the circulation, or whether their production is mediated within target organs after stimulation of gutprimed
gliadin-reactive CD4+ T cells, is unclear. Such recirculating
T cells have been postulated to be central to
intrathecal immune responses.127
Is the diversity of manifestations due to the type of
transglutaminase targeted by the immune response?
Variations in the specifi city of antibodies produced in
individual patients (eg, selectivity for a particular TG2
conformation128 or cross-reactivity between diff erent
transglutaminase isozymes) could explain the wide range
of manifestations of coeliac disease. However, recent
evidence suggests more fundamental diff erences between
patients with diff erent manifestations. While TG2 is the
autoantigen in coeliac disease,129 the epidermal TG3 seems
to be the predominant autoantigen in dermatitis
herpetiformis.130 More recently, antibodies against TG6, a
transglutaminase primarily expressed in the brain, were
found in patients with gluten ataxia.39 In gluten ataxia and
dermatitis herpetiformis, IgA deposits (containing TG6
and TG3, respectively) seem to accumulate in the periphery
of vessels in which the respective antigens are absent in
healthy individuals (fi gure 3C).39,130 This observation could
indicate either that the deposits originate from immune
complexes formed elsewhere and accumulate as a
consequence of enhanced vascular leaking, or that TG6 or
TG3 are derived from perivascular infi ltrating infl ammatory
cells preceding deposit formation. Perivascular cuffi ng
with lymphocytes is a common fi nding in brain tissue
from patients with gluten ataxia, but is also seen in
peripheral nerve and muscle in patients with gluten
neuropathy or myopathy.73 Furthermore, in most sera
reactive to more than one transglutaminase isozyme,
distinct antibody populations cause such reactivity, rather
than this reactivity being a result of antibody cross-reactivity
with diff erent transglutaminase isozymes.39 This fi nding
makes shared epitopes less likely to be the cause of
immune responses to other TGs and suggests that
transglutaminase isozymes other than TG2 might be the
primary antigen in certain patients (fi gure 4). Both TG6
and TG3 can deamidate gluten peptides and generate
major T-cell epitopes, although there are some diff erences
in sequence specifi city of the enzymes.131
Evidence supporting a role for autoantibodies in the
neurological manifestations
IgA deposition in blood vessels of the brain and the
pathological fi nding of perivascular cuffi ng with
infl ammatory cells might indicate that vasculature-centred
infl ammation (driven by perivascular macrophages/
dendritic cells in the choroid plexus or the subarachnoid
space) could compromise the blood–brain barrier; this
could expose the CNS to pathogenic antibodies and
therefore trigger nervous system involvement (fi gure 3).
TG2 is expressed by smooth muscle and endothelial cells
in non-infl amed brain, and is an abundant component of
the blood–brain barrier; autoantibody binding could
initiate an infl ammatory response. Anti-TG2 antibodies
could act together with other autoantibodies (eg, AGA)
to cause selective neuronal degeneration. Neuronal
degeneration might also be a consequence of the
repertoire of anti-transglutaminase antibodies (ie, it
occurs in patients with antibodies reactive to a neuronal
transglutaminase). IgG class antibodies are present in
only 60% of patients with coeliac disease, whereas the
occurrence was 90% in patients with gluten ataxia who
were positive for anti-transglutaminase.39 This shift from
IgA to IgG might refl ect the target organ involved
(cerebellum rather than small bowel).
The development and deposition of antibodies could be
coincidental rather than pathogenic. One method of
showing the pathological eff ect of an antibody is the
passive transfer of the disease through antibody injection
into a naive animal. Although there is experimental
evidence for only a few antibody-mediated diseases, IgG
fractions of patients with anti-GAD ataxia and stiff person
syndrome have been shown to compromise motor
function and impair learning in rodents, an eff ect
possibly ascribed to antibodies against GAD and
amphiphysin.132 A common problem in such studies is to
be able to show whether these specifi c antibodies or other
autoantibodies in the IgG fraction of patient sera are the
ones that cause neuronal damage. In a mouse model,
sera from patients with gluten ataxia, as well as clonal
monovalent anti-transglutaminase immunoglobulins
obtained by phage display, caused ataxia when injected intraventricularly.133 The fact that not only immunoglobulin
fractions but also monospecifi c single-chain
variable fragments mediate functional defi cits 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-transglutaminase immunoglobulins (derived
from patients) compromise neuronal function in selected
areas of the brain once exposed to the CNS, and suggest
that this eff ect involves a mode of action that is independent
of the immune system. However, whether this event leads
to excitotoxicity of distinct neuronal cell populations
remains to be shown. Nevertheless, the observed
functional defi cits are consistent with the selective loss of
Purkinje cells in patients with ataxia and with a unique
pattern of reactivity of gluten ataxia sera towards Purkinje
cells when applied to brain sections. Although these data
implicate anti-transglutaminase antibodies in ataxia,
they do not explain the range of distinct neurological
defi cits currently ascribed to gluten sensitivity, nor why
only a small proportion of patients with circulating antitrans
glutaminase antibodies are aff ected.
TG2, TG3, and TG6 share genetic and substantial structural similarities (phylogenetic tree of TG family is shown on the left123) and have some overlap in substrate specifi city, particularly in relation to pathogenic gluten epitopes. TG2 is the autoantigen in coeliac disease and TG3 the autoantigen in dermatitis herpetiformis. TG6 is primarily expressed in the CNS and antibodies against TG6 have been detected in sera from patients with gluten ataxia. A primary immune response targeting diff erent transglutaminase isozymes might therefore explain the diverse manifestations. This is consistent with the current concept of events leading to autoantibody production and implicates the shared activity of these enzymes rather than their sequence similarity in induction of antibody production. Autocatalytic crosslinking activity of transglutaminase can result in the formation of a transglutaminase–gliadin complex. Such isopeptide bond-linked complexes, as well as potentially stable enzymegliadin peptide thioester complexes, are recognised by surface immunoglobulin of transglutaminase-specifi c B cells and are endocytosed. These B cells will then not only present peptides derived from transglutaminase but
also from transglutaminase linked to gliadin. CD4+ T cells predominantly recognise several deamidated gliadin
peptides, presented by HLA DQ2, DQ8 molecules on the cell surface of antigen-presenting cells. Such T cells can
provide help to transglutaminase-specifi c B cells and therefore trigger expansion and antibody production.124,125 In
the case of coeliac disease, these events occur in the gut. In dermatitis herpetiformis and in neurological
manifestations, the location of these reactions is not apparent because respective enzymes are normally extremely
sparse or absent in the gut. TCR=T-cell receptor.TG=transglutaminase. *As shown in figure 3.
Conclusions and future directions
Gluten sensitivity is a common disease that can manifest
in diverse ways. As screening for gluten sensitivity has
become a reality in clinical practice, and as more details
of the individual genetic background that leads to aberrant
immune responses are being revealed,43 emphasis is
likely to shift towards the early identifi cation of patients
who are specifi cally at risk of severe, and sometimes
permanent, complications (eg, T-cell lymphoma, liver
failure, neurological defi cits). New diagnostic tools are
becoming available (eg, detection of antibodies against
TG6), which will enable identifi cation of, for example,
patients with neurological manifestations. At baseline, up
to 40% of patients who present to gastroenterologists and
who are then diagnosed with coeliac disease also have
antibodies against TG6 in addition to antibodies against
TG2.39 This subgroup of patients with classic coeliac
disease presentation might be susceptible to the
development of neurological dysfunction if they continue
to consume gluten, although this association remains to
be shown in longitudinal studies of large patient cohorts.
The presence of gastrointestinal symptoms, however,
gives this group a major potential advantage: patients
who present with gastrointestinal symptoms are more
likely to be diagnosed with coeliac disease, and therefore
to receive treatment, than are patients who present with
only extraintestinal manifestations. To improve diagnosis
rates, the perception of physicians that gluten sensitivity
is solely a disease of the gut must be changed. The
discovery of better markers of the extraintestinal
manifestations could be a good starting point in the
attempt to alter this conventional but outdated thinking.
Removal of the immunological trigger (gluten) must be
the basis of treatment of all manifestations and should be recommended to all patients once the diagnosis is properly
made. Alternative approaches to treatment are being
developed and have reached clinical trial stage.134 Such
approaches principally target uptake of toxic gluten
peptides by enhancing their enzymatic breakdown, by
sequestering gluten proteins, or by restoring epithelial
barrier function. Other approaches aim to prevent
activation of gluten-specifi c CD4+ T cells by inhibiting
transglutaminase and preventing deamidation or by
blocking binding of gluten peptides to HLA DQ2/DQ8.
Modulation of the immune system might also be possible
in the future (via anticytokine therapy or vaccination to
gluten epitopes). Such intervention is not without risks
and therefore requires absolute certainty in the diagnosis. It remains to be seen whether the CNS pathology
associated with gluten sensitivity is the result of access of
circulating antibodies that react with brain antigens after
compromise of the blood–brain barrier or whether it
relates to a specifi c T-cell subset that is involved in
immune surveillance of the brain.135 Naive T cells
activated by gluten-presenting antigen-presenting cells
in mesenteric lymph nodes or Peyer’s patches recirculate
to the target organ via the eff erent lymph or thoracic duct
and the systemic circulation. Gut-homing T cells can also
enter the CNS and might be reactivated by resident
macrophages present within the subarachnoid space.
Reactivation of these antigen-specifi c T cells leads to
cytokine-mediated activation of the endothelium and
subsequent perivascular T-cell accumulation, consistent
with that shown in fi gure 3. However, why gluten
presentation should specifi cally occur at a site distant to
the digestive system (CNS, skin) is unclear. Despite
recent insights from the genome-wide association study
for coeliac disease,43,136 which further highlighted the predominant
linkage of the disease to immune regulation,
much of the genetic predisposition remains unknown.
Some of these additional unknown factors could add an
organ-specifi c bias to the immune response.
Future studies should now focus on the extraintestinal
manifestations of gluten sensitivity as they could provide
more clues and ultimately hold the key to fully
understanding the pathogenesis of gluten sensitivity.
Contributors
MH oversaw the paper and produced the fi rst draft, did the literature
search, and composed fi gure 2. DA and MH selected and composed the
remaining fi gures and made major alterations to the initial draft. DSS,
RAG, NW, and SB contributed comments and edited the paper.
Confl icts of interest
We have no conflicts of interest.
Acknowledgments
Most of the work done by the authors would not have been possible
without the fi nancial support, in the form of research grants, by the
following charitable organisations: Ataxia UK, Bardhan Research and
Education Trust, Sheffi eld Hospitals Charitable Trust, and Ryder-Briggs
Memorial Fund for the Advancement of Neurological Science.
References
1 Aretaeus. Liber IV. Celiac diathesis. In: Corpus Medicorum
Graecorum. Berlin: Akademie-Verlag GmbH, 1956: 74.
2 Gee S. On the coeliac aff ection. St Bartholomews Hosp Rep 1888;
24: 17–20.
3 Dicke WK, Weijers HA, Van De Kamer JH. Coeliac disease. II. The
presence in wheat of a factor having a deleterious eff ect in cases of
coeliac disease. Acta Paediatrica 1953; 42: 34–42.
4 Marks J, Shuster S, Watson AJ. Small bowel changes in dermatitis
herpetiformis. Lancet 1966; 1280–82.
5 Elders C. Tropical sprue and pernicious anaemia, aetiology and
treatment. Lancet 1925; 1: 75–77.
6 Reed AC, Ash JE. Atypical sprue. Arch Intern Med 1927; 40: 786–99.
7 Woltman HW, Heck FJ. Funicular degeneration of the spinal cord
without pernicious anemia. Arch Intern Med 1937; 60: 272–300.
8 Paulley JW. Observations on the aetiology of idiopathic steatorrhoea,
jejunal and lymph node biopsies. BMJ 1954; 2: 1318–21.
9 Cooke WT, Thomas-Smith W. Neurological disorders associated
with adult coeliac disease. Brain 1966; 89: 683–722.
10 Binder H, Solitaire G, Spiro H. Neuromuscular disease in patients
with steatorrhoea. Gut 1967; 8: 605–11.
11 Bundey S. Adult celiac disease and neuropathy. Lancet 1967;
1: 851–52.
12 Morris JS, Ajdukiewicz AB, Read AE. Neurological disorders and
adult celiac disease. Gut 1970; 11: 549–54.
13 Coers C, Telerman-Toppet N, Cremer M. Regressive vacuolar
myopathy in steatorrhea. Arch Neurol 1971; 24: 217–27.
14 Kepes JJ, Chou SM, Price LW. Progressive multifocal
leukoencephalopathy with 10-year survival in a patient with
nontropical sprue. Neurology 1975; 25: 1006–12.
15 Finelli P, McEntee W, Ambler M, Kestenbaum D. Adult celiac
disease presenting as cerebellar syndrome. Neurology 1980;
30: 245–49.
16 Harding AE, Muller DP, Thomas PK, Willison HJ. Spinocerebellar
degeneration secondary to chronic intestinal malabsorption:
a vitamin E defi ciency syndrome. Ann Neurol 1982; 12: 419–24.
17 Kinney HC, Burger PC, Hurwitz BJ, Hijmans JC, Grant JP.
Degeneration of the central nervous system associated with celiac
disease. J Neurol Sci 1982; 53: 9–22.
18 Ward ME, Murphy JT, Greenberg GR. Celiac disease and
spinocerebellar degeneration with normal vitamin E status.
Neurology 1985; 35: 1199–201.
19 Lu CS, Thompson PD, Quinn NP, Parkes JD, Marsden CD.
Ramsay Hunt syndrome and coeliac disease: a new association.
Mov Disord 1986; 1: 209–19.
20 Kristoferitsch W, Pointer H. Progressive cerebellar syndrome in
adult coeliac disease. J Neurol 1987; 234: 116–18.
21 Brucke T, Kollegger H, Schmidbauer M, Muller C, Podreka I,
Deecke L. Adult celiac disease and brain stem encephalitis.
J Neurol Neurosurg Psychiatry 1988; 51: 456–57.
22 Kaplan JG, Pack D, Horoupian D, DeSouza T, Brin M,
Scaumburg H. Distal axonopathy associated with chronic gluten
enteropathy: a treatable disorder. Neurology 1988; 38: 642–45.
23 Tison F, Arne P, Henry P. Myoclonus and adult celiac disease.
J Neurol 1989; 236: 307–08.
24 Mauro A, Orsi L, Mortara P, Costa P, Schiff er D. Cerebellar
syndrome in adult celiac disease with vitamin E defi ciency.
Acta Neurol Scand 1991; 84: 167–70.
25 Hermaszewski RA, Rigby S, Dalgleish AG. Coeliac disease presenting
with cerebellar degeneration. Postgrad Med J 1991; 67: 1023–24.
26 Collin P, Pirttila T, Nurmikko T, Somer H, Erila T, Keyrainen O. Celiac
disease, brain atrophy and dementia. Neurology 1991; 41: 372–75.
27 Dick DJ, Abraham D, Falkous G, Hishon S. Cerebellar ataxia in
coeliac disease—no evidence of a humoral aetiology. Postgrad Med J
1995; 71: 186.
28 Bhatia KP, Brown P, Gregory R, et al. Progressive myoclonic ataxia
associated with celiac disease. Brain 1995; 18: 1087–93.
29 Muller AF, Donnelly MT, Smith CML, Grundman MJ,
Holmes GKT, Toghill PJ. Neurological complications of coeliac
disease—a rare but continuing problem. Am J Gastroenterol 1996;
91: 1430–35.
30 Hadjivassiliou M, Gibson A, Davies-Jones GAB, Lobo A,
Stephenson TJ, Milford-Ward A. Is cryptic gluten sensitivity an
important cause of neurological illness? Lancet 1996; 347: 369–71.
31 Sanders DS, Patel D, Stephenson TJ, et al. A primary care crosssectional
study of undiagnosed adult celiac disease.
Eur J Gastroenterol Hepatol 2003; 15: 407–13.
32 West J, Logan RFA, Hill PG, et al. Seroprevalence, correlates, and
characteristics of undetected celiac disease in England. Gut 2003;
52: 960–65.
33 Holmes GKT. Neurological and psychiatric complications in coeliac
disease. In: Gobbi G, Anderman F, Naccarato S, Banchini G, eds.
Epilepsy and other neurological disorders in coeliac disease.
London: John Libbey, 1997: 251–64.
34 Briani C, Zara G, Alaedini A, et al. Neurological complications of
coeliac disease and autoimmune mechanisms: a prospective study.
J Neuroimmunol 2008; 195: 171–75.
35 Korponay-Szabo IR, Laurila K, Szondy Z, et al. Missing endomysial
and reticulin binding of celiac antibodies in transglutaminase 2
knockout tissues. Gut 2003; 52: 199–204.
36 Rashhtak S, Ettore MW, Homburger HA, Murray JA.
Comparative usefulness of deamidated gliadin antibodies in the
diagnosis of celiac disease. Clin Gastroenterol Hepatol 2008;
6: 426–32.
37 Niveloni S, Sugai E, Cabanne A, et al. Antibodies against synthetic
deamidated gliadin peptides as predictors of coeliac disease:
prospective assessment in an adult population with a high pretest
probability of disease. Clin Chem 2007; 53: 2186–92.
38 Sugai E, Hwang HJ, Vasquez H, et al. New serology assays can
detect gluten sensitivity among enteropathy patients seronegative
for anti-tissue transglutaminase. Clin Chem 2009; published online
Dec 18. DOI:10.1373/clinchem.2009.129668.
39 Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS,
Woodroofe N, Aeschlimann D. Autoantibodies in gluten ataxia
recognise a novel neuronal transglutaminase. Ann Neurol 2008;
64: 332–43.
40 Koskinen O, Collin P, Lindfors K, Laurila K, Maki M, Kaukinen K.
Usefulness of small-bowel mucosa transglutaminase-2 specifi c
autoantibody deposits in the diagnosis and follow-up of celiac
disease. J Clin Gastroenterol 2009; published online Sept 23.
DOI:10.1097/MCG.0b013e3181b64557.
41 Hadjivassiliou M, M.ki M, Sanders DS, et al. Autoantibody
targeting of brain and intestinal transglutaminase in gluten ataxia.
Neurology 2006; 66: 373–77.
42 Marsh M. Gluten, Major histocompatibility complex and the small
intestine. Gastroenterology 1992; 102: 330–54.
43 Hunt KA. Newly identifi ed genetic risk variants for coeliac disease
related immune response. Nat Genet 2008; 40: 395–402.
44 Karell K, Louka AS, Moodie SJ, et al. HLA types in CD patients not
carrying the DQA 1 05-DQB1 02 (DQ2) heterodimer: results from the
European Genetics Cluster on CD. Hum Immunol 2003; 64: 469–77.
45 Henderson KN, Tye-Din JA, Reid HH, et al. A structural and
immunological basis for the role of human leukocyte antigen DQ8
in celiac disease. Immunity 2007; 27: 23–34.
46 Hadjivassiliou M. Immune mediated acquired ataxias. In:
Subrahmony SH, Durr A, eds. Ataxia disorders 1: clinical neurology
series, 3rd edn. Elsevier (in press).
47 Hadjivassiliou M, Boscolo S, Tongiorgi E, et al. Cerebellar ataxia as
a possible organ specifi c autoimmune disease. Mov Disord 2008;
23: 1370–77.
48 Hadjivassiliou M, Grünewald RA, Sharrack B, et al. Gluten ataxia in
perspective: epidemiology, genetic susceptibility and clinical
characteristics. Brain 2003; 126: 685–91.
49 Pellecchia MT, Scala R, Filla A, De Michele G, Ciacci C, Barone P.
Idiopathic cerebellar ataxia associated with celiac disease: lack of
distinctive neurological features. J Neurol Neurosurg Psychiatry 1999;
66: 32–35.
50 Bürk K, B.sch S, Müller CA, et al. Sporadic cerebellar ataxia
associated with gluten sensitivity. Brain 2001; 124: 1013–19.
51 Bushara KO, Goebel SU, Shill H, Goldfarb LG, Hallett M. Gluten
sensitivity in sporadic and hereditary ataxia. Ann Neurol 2001;
49: 540–43.
52 Abele M, Bürk K, Sch.ls L, et al. The aetiology of sporadic adultonset
ataxia. Brain 2002; 125: 961–68.
53 Luostarinen LK, Collin PO, Paraaho MJ, Maki MJ, Pirttila TA.
Coeliac disease in patients with cerebellar ataxia of unknown origin.
Ann Med 2001; 33: 445–49.
54 Abele M, Schols L, Schwartz S, Klockgether T. Prevalence of
antigliadin antibodies in ataxia patients. Neurology 2003; 60: 1674–75.
55 Ihara M, Makino F, Sawada H, et al. Gluten sensitivity in Japanese
patients with adult-onset cerebellar ataxia. Intern Med 2006; 45: 135–40.
56 Anheim M, Degos B, Echaniz-Laguna A, Fleury M, Grucker M,
Tranchant C. Ataxia associated with gluten sensitivity, myth or
reality? Rev Neurol 2006; 162: 214–21.
57 Combarros O, Infante J, Lopez-Hoyos M, et al. Celiac disease and
idiopathic cerebellar ataxia. Neurology 2000; 54: 2346.
58 Hadjivassiliou M, Sanders DS, Woodroofe N, Williamson C,
Grunewald RA. Gluten ataxia. Cerebellum 2008; 7: 494–98.
59 Deconinck N, Scaillon M, Segers V, Groswasser JJ, Dan B.
Opsoclonus-myoclonus associated with celiac disease.
Pediatr Neurol 2006; 34: 312–14.
60 Pereira AC, Edwards MJ, Buttery PC, et al. Choreic syndrome and
coeliac disease: a hitherto unrecognised association. Mov Disord
2004; 19: 478–82.
61 Schrodl D, Kahlenberg F, Peter-Zimmer K, et al. Intrathecal
synthesis of autoantibodies against tissue transglutaminase.
J Autoimmun 2004; 22: 335–40.
62 Hadjivassiliou M, Aeschlimann P, Sanders DS, et al. Antibodies
against TG6 as the only serological marker of gluten ataxia.
Proceedings of the 13th International Coeliac Disease Symposium.
Amsterdam; April 6–8, 2009. 09.1.
63 Kaukinen, K, Collin, P, Laurila, K et al. Resurrection of gliadin
antibodies in celiac disease. Deamidated gliadin peptide antibody
test provides additional diagnostic benefi t. Scand J Gastroenterol
2007; 42: 1428–33.
64 Wilkinson ID, Hadjivassiliou M, Dickson JM, et al. Cerebellar
abnormalities on proton MR spectroscopy in gluten ataxia.
J Neurol Neurosurg Psychiatry 2005; 76: 1011–13.
65 Pellecchia MT, Scala R, Perretti A, et al. Cerebellar ataxia associated
with subclinical celiac disease responding to gluten-free diet.
Neurology 1999; 53: 1606–07.
66 Sander HW, Magda P, Chin RL, et al. Cerebellar ataxia and celiac
disease. Lancet 2003; 362: 1548.
67 Beversdorf D, Moses P, Reeves A, Dunn J. A man with weight loss,
ataxia, and confusion for 3 months. Lancet 1996; 347: 448.
68 Hahn JS, Sum JM, Bass D, Crowley RC, Horoupian DS. Celiac
disease presenting as gait disturbance and ataxia in infancy.
J Child Neurol 1998; 13: 351–53.
69 Bürk K, Melms A, Schulz JB, Dichgans J. Eff ectiveness of
intravenous immunoglobulin therapy in cerebellar ataxia associated
with gluten sensitivity. Ann Neurol 2001; 50: 827–28.
70 Hadjivassiliou M, Davies-Jones GAB, Sanders DS, Grünewald RAG.
Dietary treatment of gluten ataxia. J Neurol Neurosurg Psychiatry
2003; 74: 1221–24.
71 Luostarinen L, Himanen SL, Luostarinen M, Collin P, Pirttila T.
Neuromuscular and sensory disturbances in patients with well
treated celiac disease. J Neurol Neurosurg Psychiatry 2003; 74: 490–94.
72 Ludvigsson JF, Olsson T, Ekbom A, Montgomery SM. A
population based study of celiac disease, neurodegenerative and
neuroinfl ammatory diseases. Aliment Pharmacol Ther 2007;
25: 1317–27.
73 Hadjivassiliou M, Grunewald RA, Kandler RH, et al. Neuropathy
associated with gluten sensitivity. J Neurol Neurosurg Psychiatry
2006; 77: 1262–66.
74 Mata S, Renzi D, Pinto F, Calabro A. Anti-tissue transglutaminase
IgA antibodies in peripheral neuropathy and motor neuronopathy.
Acta Neurol Scand 2006; 114: 54–58.
75 Chin RL, Sander HW, Brannagan TH, et al. Celiac neuropathy.
Neurology 2003; 60: 1581–85.
76 Kelkar P, Ross M, Murray J. Mononeuropathy multiplex associated
with celiac disease. Muscle Nerve 1996; 19: 234–36.
77 Hadjivassiliou M, Chattopadhyay AK, Davies-Jones GAB, Gibson A,
Grunewald RA, Lobo AJ. Neuromuscular disorder as a presenting
feature of celiac disease. J Neurol Neurosurg Psychiatry 1997; 63: 770–75.
78 Chin RL, Tseng VG, Green PHR, Sander HW, Brannagan TH,
Latov N. Multifocal axonal polyneuropathy in celiac disease.
Neurology 2006; 66: 1923–25.
79 Rao DG, Hadjivassiliou M. Sensory neuronopathy due to gluten
sensitivity. Ann Indian Acad Neurol 2007; 10 (suppl 2): 16.
80 Brannagan TH, Hays AP, Chin SS, et al. Small-fi ber neuropathy/
neuronopathy associated with celiac disease: skin biopsy fi ndings.
Arch Neurol 2005; 62: 1574–78.
81 Gibbons CH, Freeman R. Autonomic neuropathy and celiac
disease. J Neurol Neurosurg Psychiatry 2005; 76: 579–81.
82 Hadjivassiliou M, Kandler RH, Chattopadhyay AK, et al. Dietary
treatment of gluten neuropathy. Muscle Nerve 2006; 34: 762–66.
83 Luostarinen L, Pirttila T, Collin P. Coeliac disease presenting with
neurological disorders. Eur Neurol 1999; 42: 132–35.
84 Hadjivassiliou M, Grünewald RAG, Lawden M, Davies-Jones GAB,
Powell T, Smith CML. Headache and CNS white matter abnormalities
associated with gluten sensitivity. Neurology 2001; 56: 385–88.
85 Gabrielli M, Cremonini F, Fiore G, et al. Association between
migraine and celiac disease: results from a preliminary casecontrol
and therapeutic study. Am J Gastroenterol 2003; 98: 625–29.
86 Addolorato G, Di Giuda D, De Rossi G, et al. Regional cerebral
hypoperfusion in patients with celiac disease. Am J Med 2004;
116: 312–17.
87 Kieslich M, Errazuriz G, Rosselt HG, Moeller-Hartmann W,
Zanell BH. Brain white matter lesions in celiac disease: a prospective
study in diet treated patients. Paediatrics 2001; 108: E21.
88 Paul F, Pfueller CF, Wuerfel JT, et al. Celiac antibodies in the
diagnostic workup of white matter lesions. Neurology 2008; 71: 223–25.
89 Hu WT, Murray JA, Greenway MC, Parisi JE, Josephs KA. Cognitive
impairment and celiac disease. Arch Neurol 2006; 63: 1440–46.
90 Frisoni GB, Carabellese N, Longhi M, et al. Is celiac disease associated
with Alzheimer’s disease. Acta Neurol Scand 1997; 95: 147–51.
91 Serratrice J, Disdier P, De Roux C, Christides C, Weiller PJ.
Migraine and celiac disease. Headache 1998; 38: 627–28.
92 Chapman RWG, Laidlow JM, Colin-Jones D, Eade OE, Smith CL.
Increased prevalence of epilepsy in coeliac disease. BMJ 1978;
2: 250–51
93 Fois A, Vascotto M, Di Bartolo RM, Di Marco V. Celiac disease and
epilepsy in pediatric patients. Childs Nerv Syst 1994; 10: 450–54.
94 Cronin CC, Jackson LM, Feighery C, et al. Coeliac disease and
epilepsy. Q JM 1998; 91: 303–08.
95 Gobbi G, Bouquet F, Greco L, et al. Coeliac disease, epilepsy and
cerebral calcifi cations. Lancet 1992; 340: 439–43.
96 Magaudda A, Dalla Bernardina B, De Marco P, et al. Bilateral
occipital calcifi cation, epilepsy and celiac disease: clinical and
neuroimaging features of a new syndrome.
J Neurol Neurosurg Psychiatry 1993; 56: 885–89.
97 Toti P, Balestri P, Cano M, et al. Celiac disease with cerebral
calcium and silica deposits: X-ray spectroscopic fi ndings, an autopsy
study. Neurology 1996; 46: 1088–92.
98 Ranua J, Luoma K, Auvinen A, et al. Celiac disease-related
antibodies in an epilepsy cohort and matched reference population.
Epilepsy Behav 2005; 6: 388–92.
99 Paltola M, Kaukinen K, Dastidar P, et al. Hippocampal sclerosis in
refractory temporal lobe epilepsy is associated with gluten
sensitivity. J Neurol Neurosurg Psychiatry 2009; 80: 626–30.
100 Mavroudi A, Karatza E, Papastavrou T, Panteliadis C, Spiroglou K.
Succesful treatment of epilepsy and celiac disease with a gluten-free
diet. Pediatr Neurol 2005; 33: 292–95.
101 Harper E, Moses H, Lagrange A. Occult celiac disease presenting as
epilepsy and MRI changes that responded to gluten-free diet.
Neurology 2007; 68: 533.
102 Henriksson KG, Hallert C, Norrby K, Walan A. Polymyositis and
adult celiac disease. Acta Neurol Scand 1982; 65: 301–19.
103 Selva-O’Callaghan A, Casellas F, De Torres I, Palou E,
Grau-Junyent JM, Villardell-Tarres M. Celiac disease and antibodies
associated with celiac disease in patients with infl ammatory
myopathy. Muscle Nerve 2007; 35: 49–54.
104 Hadjivassiliou M, Chattopadhyay AK, Grünewald RA, et al. Myopathy
associated with gluten sensitivity. Muscle Nerve 2007; 35: 443–50.
105 Jacob S, Zarei M, Kenton A, Allroggen H. Gluten sensitivity and
neuromyelitis optica: two case reports. J Neurol Neurosurg Psychiatry
2005; 76: 1028–30.
106 Jarius S, Jacob S, Waters P, Jacob A, Littleton E, Vincent A.
Neuromyelitis optica in patients with gluten sensitivity associated with
antibodies to aquaporin-4. J Neurol Neurosurg Psychiatry 2008; 79: 1084.
107 Haghighi AB, Ansari N, Mokhtari M, Geramizadeh B,
Lankarani KB. Multiple sclerosis and gluten sensitivity.
Clin Neurol Neurosurg 2007; 109: 651–53.
108 Hadjivassiliou M, Sanders DS, Grunewald RA. Multiple sclerosis
and occult gluten sensitivity. Neurology 2004; 62: 2326–27.
109 Pengiran-Tengah C, Lock R, Unsworth DJ, Wills A. Multiple
sclerosis and occult gluten sensitivity. Neurology 2004; 62: 2326–27.
110 Hadjivassiliou M, Williamson CA, Grunewald RA, et al. Glutamic
acid decarboxylase as a target antigen in gluten sensitivity: the link to
neurological manifestations? J Neurol Neurosurg Psychiatry Proceedings
of the Association of British Neurologists Meeting 2005; 76: 150–58.
111 Hadjivassiliou M, Grunewald RA, Chattopadhyay AK, et al. Clinical,
radiological, neurophysiological and neuropathological
characteristics of gluten ataxia. Lancet 1998; 352: 1582–85.
112 Hadjivassiliou M, Boscolo S, Davies-Jones GAB, et al. The humoral
response in the pathogenesis of gluten ataxia. Neurology 2002;
58: 1221–26.
113 Korponay-Szab. IR, Vecsei Z, Kir.ly R, et al. Deamidated gliadin
peptides form epitopes that transglutaminase antibodies recognize.
J Pediatr Gastroenterol Nutr 2008; 46: 253–61.
114 Alaedini A, Okamoto H, Briani C, et al. Immune cross-reactivity in
coeliac disease: antigliadin antibodies bind to neuronal symapsin I.
J Immunol 2007; 178: 6590–95.
115 Alaedini A, Latov N. Transglutaminase-independent binding of
gliadin to intestinal brush border membrane and GM1 ganglioside.
J Neuroimmunol 2006; 177: 167–72.
116 Cervio E, Volta U, Verri M, et al. Sera from patients with celiac
disease and neurologic disorders evoke a mitochondrial-dependent
apoptosis in vitro. Gastroenterol 2007; 133: 195–206.
117 Aeschlimann D, Thomazy V. Protein crosslinking in assembly and
remodelling of extracellular matrices: the role of transglutaminases.
Connect Tissue Res 2000; 41: 1–27.
118 Boros S, Ahrman E, Wunderink L, et al. Site-specifi c transamidation
and deamidation of the small heat-shock protein Hsp20 by tissue
transglutaminase. Proteins 2006; 62: 1044–52.
119 Stamnaes J, Fleckenstein B, Sollid L. The propensity for
deamidation and transamidation of peptides by transglutaminase 2
is dependent on substrate affi nity and reaction conditions.
Biochim Biophys Acta 2008; 1784: 1804–11.
120 Molberg O, McAdam SN, K.rner R, et al. Tissue transglutaminase
selectively modifi es gliadin peptides that are recognized by gutderived
T cells in celiac disease. Nat Med 1998; 4: 713–17.
121 Van de Wal Y, Kooy Y, van Veelen P, et al. Selective deamidation by
tissue transglutaminase strongly enhances gliadin-specifi c T cell
reactivity. J Immunol 1998; 161: 1585–88.
122 Fleckenstein B, Qiao SW, Larsen MR, Jung G, Roepstorff P,
Sollid LM. Molecular characterization of covalent complexes
between tissue transglutaminase and gliadin peptides. J Biol Chem
2004; 279: 17607–16.
123 Grenard P, Bates MK, Aeschlimann D. Evolution of
transglutaminase genes: identifi cation of a transglutaminase gene
cluster on human chromosome 15q15. J Biol Chem 2001;
276: 33066–78.
124 Molberg O, Sollid LM. A gut feeling for joint infl ammation—
using coeliac disease to understand rheumatoid arthritis.
TRENDS Immunol 2006; 27: 188–94.
125 Vinuesa CG, Tangye SG, Moser B, Mackay CR. Follicular B helper
T cells in antibody responses and autoimmunity. Nat Rev Immunol
2005; 5: 853–65.
126 Korponay-Szab. IR, Halttunen T, Szalai Z, et al. In vivo targeting of
intestinal and extraintestinal transglutaminase 2 by coeliac
autoantibodies. Gut 2004; 53: 641–48.
127 Kivisa KP, Tucky B, Wei T, et al. Human cerebrospinal fl uid
contains CD4 memory cells expressing gut or skin-specifi c
traffi cking determinants: relevance for immunotherapy.
BMC Immunol 2006; 7: 14.
128 Pinkas DM, Strop P, Brunger AT, Khosla, C. Transglutaminase 2
undergoes a large conformational change upon activation.
PLoS Biol 2007; 5: e327.
129 Dietrich W, Ehnis T, Bauer M, et al. Identifi cation of tissue
transglutaminase as the autoantigen of celiac disease. Nat Med
1997; 3: 797–801.
130 S.rdy M, K.rp.ti S, Merkl B, Paulsson M, Smyth N. Epidermal
transglutaminase (TGase3) is the autoantigen of dermatitis
herpetiformis. J Exp Med 2002; 195: 747–57.
131 Stamnaes J, Dorum S, Fleckenstein B, Aeschlimann D, Sollid LM.
Gliadin T-cell epitope targeting by TG3 and TG6: implications for
gluten ataxia and dermatitis herpetiformis.
Proceedings of the 13th International Symposium on Coeliac
Disease, Amsterdam, 2009; P-163: 148.
132 Manto MU, Laute MA, Aguera M, Rogemond V, Pandolfo M,
Honnorat J. Eff ects of anti-glutamic acid decarboxylase antibodies
associated with neurological diseases. Ann Neurol 2007; 61: 544–51.
133 Boscolo S, Sarich A, Lorenzon A, et al. Gluten ataxia: passive
transfer in a mouse model. Ann NY Acad Sci 2007; 1107: 319–28.
134 Sollid LM, Lundin KEA. Diagnosis and treatment of celiac disease.
Mucosal Immunol 2009; 2: 3–7.
135 Goverman J. Autoimmune T cell responses in the central nervous
system. Nat Rev Immunol 2009; 9: 393–407.
136 van Heel DA, Franke L, Hunt KA, et al. A genome-wide association
study for celiac disease identifi es risk variants in the region
harbouring IL2 and IL21. Nat Genet 2007; 39: 827–29.
|