Neuromuscular and sensory disturbances in patients with
well treated coeliac disease
L Luostarinen, S-L Himanen, M Luostarinen, P Collin, T Pirttilä
J Neurol Neurosurg Psychiatry 2003;74:490–494
Objectives: A body of evidence shows that coeliac disease is associated with protean manifestations
outside the intestine, and neurological disorders are well recognised. However, it remains obscure
whether there are signs of clinical or subclinical nervous system involvement even in patients adopting
an adequate gluten free diet. The aim of this study was to assess in a controlled study whether patients
with treated coeliac disease carry an increased risk for neuropathy and characterise the type of possi-
Methods: Electroneuromyographic findings and vibration, thermal, and tactile thresholds of 26
patients with coeliac disease and 23 patients with reflux disease were analysed.
Results: Six (23.1 %) coeliac disease patients and one (4.3 %) reflux disease patient showed findings
of chronic axonal neuropathy in quantitative needle EMG. In addition, two coeliac disease patients
showed findings suggestive for myopathy. There were no significant differences in warm, cold, or
vibration thresholds between the groups but means of heat pain thresholds and tactile thresholds were
significantly higher in coeliac patients than in controls.
Conclusion: An increased occurrence of axonal neuropathy was observed in well treated coeliac dis-
ease. This further indicates that neurological manifestations occur even in patients without overt
susceptible people, possibly affecting 1:300–1:100 of the
population. The most common symptoms are diarrhoea,
weight loss, and malabsorption, which recover with a gluten
free diet. Coeliac disease may remain silent, but it can lead to
various non-gastrointestinal complications such as osteoporo-
sis, infertility, or lymphoma. Gluten free diet is beneficial in
preventing these complications, and the risk seems to be alto-
gether low in treated patients. The diagnosis is established by
the finding of small bowel villous atrophy and clinical or his-
tological remission on gluten free diet.1Untreated coeliac dis-
ease may present with various neurological manifestations
such as cerebellar ataxia, epilepsy, or brain atrophy.2–6
Association between peripheral neuropathy and coeliac
disease has been described,7–9and recently,Hadjivassiliou with
his colleagues reported nine patients in whom neuromuscular
disorder was a presenting feature of coeliac disease.9Diabetes
and alcohol misuse are the most common causes of peripheral
neuropathy in developed countries. Other well established
causes of neuropathy include hereditary, metabolic, toxic,
infectious,inflammatory,ischaemic,and paraneoplastic disor-
ders. However, despite extensive evaluation, the aetiology
remains unknown in up to 20% of patients with neuropathy
even in very specialised neurological units.10 11
The role of gluten free diet has remained unknown in
modifying symptoms and findings of neuropathy in coeliac
disease.Gluten free diet may reverse or at least slow down the
progression of peripheral neuropathy and on the other hand,
transgressions in gluten free diet may exacerbate neurological
disorders in coeliac disease. In one case report the symptoms
disappeared after introducing gluten free diet.8
The aim of this cross sectional study was to assess whether
even patients with a well treated coeliac disease carry an
increased risk of neuropathy.
oeliac disease is an inflammatory condition of the small
intestine characterised by villous atrophy and crypt
hyperplasia induced by dietary gluten in genetically
The study was carried out at the Department of Neurology in
Tampere University Hospital. The study group comprised 26
patients with coeliac disease. The diagnosis of coeliac disease
had been established according to current criteria of European
Society for Paediatric Gastroenterology and Nutrition12at the
department of Medicine in Tampere University Hospital. All
coeliac disease patients were maintaining gluten free diet
since the establishment of the diagnosis for a median of three
years (range 2–28). They were in clinical and histological
remission—that is, they had no small bowel mucosal atrophy
anymore. Control biopsies were no older than three years
before neurophysiological studies and the strictness of gluten
free diet was assessed by interview.Twenty three patients with
gastro-oesophageal reflux disease served as controls; coeliac
disease was excluded by histological examination of small
bowel mucosa while these patients were evaluated for surgical
treatment for gastro-oesophageal reflux disease (table 1).
The study protocol was approved by the ethical committee
of Tampere University Hospital,and written informed consent
was obtained from all patients.
Neurophysiological examinations included the measures of
the function of both motor fibres and sensory large fibres and
small myelinated and unmyelinated fibres.
Electroneuromyography (ENMG) was carried out using a
Keypoint (Dantec, Skovlunde, Denmark) ENMG device. As a
rule, the ENMG was performed to the left extremities. In
addition,the right extremities were examined in patients with
predominantly right sided symptoms. Concentric needle elec-
tromyography (EMG) was performed on one distal (m tibialis
anterior) and one proximal (m biceps brachii) muscle. The
EMG was considered abnormal if fibrillation or positive sharp
waves, or both were present in more than one location within
Abbreviations: ENMG, electroneuromyography; EMG,
electromyography; MUP, motor unit potential
See end of article for
Dr L Luostarinen,
Department of Neurology,
Keskussairaalankatu 7, FIN
-15850 Lahti, Finland;
Received 26 July 2002
Accepted in revised form
21 December 2002
the muscle. In addition, the muscles were studied quantita-
tively by the multi-mup analysis method.13The number of
outliers14were noticed as well as the mean amplitude and
duration of the motor unit potentials (MUPs), which were
manufacturer.15The results were considered abnormal if the
number of outliers exceeded three, or the mean values were
outside the normal range (>2.5 SD). Nerve conduction stud-
ies were carried out in motor nerves (left median, ulnar, and
peroneal nerves) and sensory nerves (left median, ulnar,
radial,and sural nerves).All studies were performed with sur-
face electrodes using standard techniques16 17with the excep-
tion of the median and ulnar digital nerves, which were
measured antidromically. The hands and feet were warmed at
least up to 30°C before all conduction velocity measurements.
values providedby the
The left peroneal motor conduction measurements, the left
sural and radial sensory measurements, and F waves of all
motor nerves were utilised. The results were compared with
reference values provided by the manufacturer standardised
for age and height. The conduction velocities were considered
abnormal if they were slower than 2.5 SD from the calculated
Vibration thresholds were measured from carpal and tarsal
areas using the method of limits (Vibrameter,Somedic,Stock-
holm, Sweden). In addition, vibration thresholds from the
index fingers and big toes were studied by the Bio-
Thesiometer (Bio Medical Instrument, Newbury, OH, USA).
Thermal thresholds (heat, cold, and heat pain thresholds)
were assessed by a skilled technician by Somedic Thermotest
equipment (Somedic) as previously described.18Tactile thresh-
olds were assessed with Semmes-Weinstein monofilaments19
in dermatomes L3 and S1.
Data were expressed as means with standard deviations or
frequencies as indicated. Confidence intervals (95%) and con-
tingency table with χ2test and Mann-Whitney U test were
used for statistical comparisons when appropriate.
Nine coeliac disease patients and 11 patients with reflux dis-
ease complained of numbness and paraestesias distally in the
Number of patients (male/female)
Mean age (range) (y)
Time from diagnosis: mean (range) (y)
Time from diagnosis: median (y)
Predisposing factor to neuropathy
51 (22–77) 50 (18–73)
Clinical data and neurophysiological findings in seven patients with neuropathy
Time from diagnosis (y)
Possible predisposing factor
Clinical/subclinical neuropathy clinical
Motor nerve conduction
Median nerve (elbow–wrist)
Ulnar nerve (elbow–wrist)
Peroneal nerve (knee–ankle)
Sensory nerve conduction
Median nerve (wrist–digit 2)
Ulnar nerve (wrist–digit 5)
Sural nerve (calf–ankle)
m tibialis anterior
mean amplitude (SD)
duration of MUPs (SD)
Number of outliers
m biceps brachii
mean amplitude (SD)
duration of MUPs (SD)
Number of outliers
Heat pain threshold (°C)
Tactile threshold ( as10log of force, mg compressing skin)
Coeliac disease Coeliac disease Coeliac disease Coeliac disease Coeliac disease Coeliac disease Reflux disease
male female femalefemale
70 5677 65
clinical subclinical subclinical
Graves’ disease alcohol
All conduction measurements were within normal limits. A, high amplitude of MUPs; D, long duration of MUPs. *Abnormal value.
Neuromuscular and sensory disturbances and coeliac disease491
extremities.Objective clinical signs of polyneuropathy (absent
tendon reflexes and diminished sensory findings) were found
in three coeliac disease patients. Seven (27%) coeliac disease
patients and five (22%) control patients had a possible predis-
posing factor to neuropathy (table 1); the difference was not
statistically significant. Altogether four patients suffered from
alcoholism,one had operated breast cancer,two had medically
treated hypothyroidism, and two had treated Graves’ disease,
one suffered from inactive ankylosing spondylitis and two had
treated rheumatoid arthritis. No patients had previous
diagnosis of diabetes, vitamin deficiency, or malnutrition.
Altogether six (23.1%, three with clinically symptomatic and
three asymptomatic neuropathy) coeliac disease patients and
one (4.3%) reflux disease patient revealed findings of chronic
axonal motor neuropathy in quantitative EMG with increased
amplitude or duration of the MUPs. The findings were more
prominent in distal than proximal muscles in five of six coeliac
disease patients.None of the subjects had fibrillations or posi-
tive sharp waves in EMG. The clinical data and results of
patients with neuropathy are summarised in table 2. All con-
duction velocities and amplitudes of the action potentials as
well as F latencies were within reference values in each coeliac
and control patient.In neuropathy patients sensory and motor
action potential amplitudes tended to be lower. Thus three
coeliac disease patients had clinically symptomatic and three
had subclinical, mainly distal chronic axonal neuropathy,
whereas only one control patient had subclinical axonal neu-
ropathy. Reasons of subjective numbness and paraestesias in
the rest of the patients remained unclear.Two of the six coeliac
patients with neuropathy had a predisposing factor for
neuropathy (table 2). Four (21.1%) of 19 coeliac disease
patients without predisposing factor compared with one
(5.6%) out 18 controls had neuropathy findings (p=0.3).
Two coeliac disease patients (7.7%) showed reduced ampli-
tudes and duration of MUPs in quantitative EMG. Muscle
biopsy was not performed because the patients did not show
clinical signs of myopathy.
Quantitative somatosensory findings
Heat pain and tactile thresholds in both upper and lower
extremities were significantly higher in patients with coeliac
disease than in control subjects. There were no significant dif-
ferences in warm, cold, or vibration thresholds between the
groups (table 3). When patients with neuropathy were
excluded, mean values of tactile thresholds in both upper and
lower extremities and heat pain thresholds in lower extremity
were significantly higher in patients with coeliac disease than
in control subjects (table 4). All patients with neuropathy
finding in ENMG,that is six with coeliac disease and one with
reflux disease had higher means of somatosensory thresholds
than patients without neuropathy. We could not demonstrate
any patient with pure small fibre neuropathy.
Our study is the largest comparative study assessing the
frequency and features of neuromuscular disorders associated
with coeliac disease. We showed that even well treated
patients with coeliac disease carry an increased risk of
neuropathy, to be seen in one fourth (23%) of patients. Even
more, 31%, showed abnormalities in neurophysiological stud-
ies compared with 4.3% in controls. Although most manifes-
tations were subclinical,coeliac disease can be considered as a
Quantitative sensory thresholds in patients with coeliac disease and reflux
Coeliac disease patients
n=26 mean (SD)
Reflux disease patients
n=23 mean (SD)p
Warm threshold (°C)
Cold threshold (°C)
Heat pain threshold (°C)
(deviation from mean)
Tactile threshold ( as10log of force, mg, compressing skin)
All values are within normal limits.
findings in ENMG
Quantitative heat pain and tactile thresholds; patients without neuropathy
Coeliac disease patients
n=20 mean (SD)
Reflux disease patients
n=22 mean (SD)p
Heat pain threshold (°C)
Tactile threshold (as10log of force, mg, compressing skin)
All values are within normal limits.
492 Luostarinen, Himanen, Luostarinen, et al
risk condition for neuromuscular disorders. In fact, neu-
ropathy in coeliac disease is as common in coeliac disease as in
diseases commonly thought to be risk factors for neuropathy.
By comparison, in scleroderma, the frequency of neuropathy
has been reported to be 34%,clinical neuropathy in 15.6%,and
subclinical in 18.8%.20In patients with newly diagnosed non-
insulin dependent diabetes 8.3% had definite or probable
polyneuropathy compared with 2.1% among the control
subjects;a frequency comparable to our control group.21Seven
patients in the coeliac group and five in the control group had
a predisposing factor for neuropathy, of these two coeliac
patients had neuropathy (table 2). We cannot exclude that
these predisposing conditions might be aetiological factors for
neuropathy.However,when people without known predispos-
ing factors for neuropathy were excluded, the frequency of
neuropathy was higher (21.1%) in coeliac disease patients
than in controls (5.6%). Even though the difference was not
statistically significant, the finding suggests that coeliac
disease itself may carry an increased risk of neuropathy. On
the other hand it may also be that coeliac disease may aggra-
vate neuropathy when there already exists some underlying
risk for this complication.
Most studies of neurological complications of coeliac
disease have emphasised central nervous system involvement.
Association of neuropathy or myopathy with coeliac disease
has been described infrequently over time. Holmes22has ana-
lysed neurological manifestations in a community based coe-
neuropathy was 0.5% and for myopathy 1.3%. In all cases,
myopathy was a result of osteomalacia, which is nowadays
very uncommon in coeliac disease and responded to treatment
with vitamin D and gluten free diet. There are no previous
controlled studies with neurophysiological measurements
concerning the frequency of neuropathy in association with
coeliac disease.Kaplan et al8described a middle aged man with
15 year history of coeliac disease who developed a large fibre
axonopathy affecting mainly sensory fibres. Sural nerve
biopsy demonstrated Wallerian degeneration and findings
indicating degeneration and regeneration of nerve fibres. One
recent study showed inflammatory cell infiltrates in the nerve
rootsof the spinalcord
polyneuropathy.23The largest series until now was reported by
Hadjivassiliou et al.9They described six patients with axonal
sensorimotor polyneuropathy (of whom two presented with a
pure motor neuropathy), one patient with mononeuropathy
multiplex and one patient with Guillan-Barre type acute
polyneuropathy affected by coeliac disease. Sensory deficits
were more pronounced than motor findings in six patients
with axonal polyneuropathy. Our results verify that polyneu-
ropathy associated with coeliac disease is axonal type and
affects both motor and sensory fibres. We also showed for the
first time that patients with coeliac disease showed higher
heat pain and touch thresholds than controls.This finding still
existed when patients with neuropathy diagnosis were
excluded from analysis. Increase of heat pain and touch
thresholds in coeliac patients compared with controls provide
further evidence that peripheral nerve fibres, even small
unmyelinated fibres, are affected in coeliac patients.
Even though all our patients were adopting gluten free diet
and coeliac disease was in good remission, they still had an
increased risk of clinical or subclinical neuropathy. Earlier,
patients with coeliac disease were often malnourished and
suffered from severe malabsorption of nutrients. Only the
most severe cases were detected, and manifest neurological
complications occurred in as many as 36% of patients.24Influ-
ence of gluten free diet in the alleviation of the neuropathy is
poorly understood. However, polyneuropathy has been re-
ported to resolve after gluten withdrawal in coeliac disease.8
All patients with neuropathy findings were 54 years or older
and there may have been long diagnostic delay before
introducing gluten free diet. It is therefore not excluded that
gluten free diet may have prevented the development of
of our patients on a gluten free diet had still signs of
neuropathy, alternative mechanisms, apart from gluten, may
be involved in the development of neuropathy.
One possibility for the occurrence of neurological complica-
tions in coeliac disease is an immune reaction against a shared
epitope expressed in small intestine and peripheral nerve or
muscle. Coeliac disease is an inflammatory disorder induced
by dietary gluten. Immunological and genetic factors contrib-
ute to the pathogenesis of the disease.The genetic susceptibil-
ity locus is in the MHC region, and the disease is associated
with the HLA-DQ alleles DQA1*0501 and DQB1*0201. A
recent study by Hadjivassiliou et al4has shown the high
HLA-DQ 2 association with sporadic ataxia attributable to
gluten sensitivity and subsequently confirmed by Burk et al.25
It is probable that immunological factors contribute to the
development of neuropathy in coeliac disease.
In conclusion, coeliac patients have an increased frequency
of chronic axonal neuropathy, even when adhering to a long
term strict gluten free diet. Early detection of coeliac disease
might prevent the development of manifest neuropathy. The
relation between gluten containing diet and the occurrence of
neuropathy is a subject for further studies.Until that,it is rea-
sonable to assume that a strict diet is warranted to prevent
manifest neuropathy and follow up of dietary compliance
would be indicated.
L Luostarinen, Departments of Neurology, Tampere University Hospital
and Medical School, University of Tampere, and Päijät-Häme Central
Hospital, Lahti, Finland
S-L Himanen, Department of Clinical Neurophysiology, Tampere
University Hospital and Medical School
M Luostarinen, Department of Surgery, Tampere University Hospital and
Medical School, University of Tampere, and Päijät-Häme Central Hospital
P Collin, Department of Internal Medicine, Tampere University Hospital
and Medical School
T Pirttilä, Departments of Neurology, University of Tampere, University of
Kuopio and Kuopio University Hospital, Kuopio, Finland
Funding: this work was supported by a grant from the Medical Research
Fund of Tampere University Hospital.
Competing interests: none declared.
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494 Luostarinen, Himanen, Luostarinen, et al