Seizure 21 (2012) 482–485

Case report

Refractory coeliac disease associated with late onset epilepsy, ataxia, tremorand progressive myoclonus with giant cortical evoked potentials—A case reportand review of literature

Saqib Javed a,*, Asimah Safdar c, Allan Forster b, Arul Selvan c, David Chadwick c,Andy Nicholson c, Anu Jacob c

a Salford Royal Hospital, Stott Lane, Salford, M6 8HD, United Kingdomb Aberdeen Royal Infirmary, United Kingdomc The Walton Centre, Lower Lane, Liverpool, L9 7LJ, United Kingdom

A R T I C L E I N F O

Article history:

Received 1 January 2012

Received in revised form 7 April 2012

Accepted 10 April 2012

Keywords:

Coeliac

Myoclonus

Ataxia

Neurological

A B S T R A C T

Population-based screening studies suggest an overall prevalence of coeliac disease in Western

populations of about 1%. A variety of neurological problems have been associated with coeliac disease

occurring in up to 10% of cases of adult coeliac disease. We report an interesting case of a patient with

coeliac disease who subsequently developed neurological symptoms several years later. Furthermore, a

literature review of all cases to date was performed.

� 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Contents lists available at SciVerse ScienceDirect

Seizure

jou r nal h o mep age: w ww.els evier . co m/lo c ate /ys eiz

1. Case summary

A 63-year-old white woman presented with a 12-month historyof progressive tremor, unsteadiness and jerks of limbs. She wasdiagnosed with coeliac disease by biopsy 30 years previously. Thiswas refractory in nature with intermittent diarrhoea and signifi-cant weight loss. She also had late onset complex partial seizuresdiagnosed 4 years previously, pernicious anaemia and osteoarthri-tis. Her medication included low dose steroids, carbamazepine700 mg daily, vitamin B12 and folate. On examination she scored30/30 on MMSE. She had myoclonus, tremor and ataxia. Themyoclonus and tremor were worse in the upper limbs, present atrest, action and on sustained postures and were made worse withactivity. The ataxia was predominantly in the limbs and wasbilateral. She also had peri-oral tremulous movements. Cranialnerves, sensory examination, reflexes and the rest of theneurological examination were normal.

Blood tests showed low albumin and calcium, raised alkalinephosphatase and AST. She had weakly positive ANA (titre 1/40).Vitamin B12, folate, serum lactate, caeruloplasmin were withinnormal limits. Antibodies to ANA and ENA and thyroid peroxidasewere negative. Antiendomysial IgA and antigliadin were negative.

* Corresponding author. Tel.: +44 7779148342.

E-mail address: Shehzada50@doctors.org.uk (S. Javed).

1059-1311/$ – see front matter � 2012 British Epilepsy Association. Published by Else

http://dx.doi.org/10.1016/j.seizure.2012.04.003

Onconeural antibodies including anti-Hu, anti-Yo, anti-Ri, anti-Tr,anti-amphiphysin, and those against voltage gated calcium andpotassium channels were negative. Genetic tests for Huntington’sdisease, mitochondrial disorders (including MELAS mutation 3243,MERRF mutation 8345, NARP mutation 8993 and commonduplications and deletions) were negative. CSF analysis showed4 white cells, with normal protein and glucose. Oligoclonal bandswere present. CT head, CT abdomen and chest X-ray were normal.As she was claustrophobic MRI could not be done after onset oftremor and ataxia. But an MRI done 4 years earlier (when seizuresbegan) showed nonspecific ischemic changes in cerebral hemi-spheres and subtle early vermian and bilateral cerebellarhemispheric atrophy was suspected.

Carotid Doppler and 24 h ECGs were normal. EEG showed rightanterior and mid temporal spike and waves and bilateral slowwaves and sharp waves. Some of these spike waves dischargeswere associated with focal jerks of left arm and leg; there were noperiodic complexes. Tibial somatosensory evoked potentialsshowed giant SEPs (Fig. 1).

Many medications were tried over the subsequent 2 years tocontrol the myoclonus but were poorly tolerated. Sodiumvalproate caused encephalopathy; clobazam was associated withdrowsiness, lamotrigine with rash and zonisamide caused confu-sion. Levetiracetam was well tolerated however this did notcontrol the myoclonus effectively. She was seen by gastroenter-ologists and in attempts to control the coeliac disease the

vier Ltd. All rights reserved.

Fig. 1. Tibial somatosensory evoked potentials showed giant SEPs.

S. Javed et al. / Seizure 21 (2012) 482–485 483

prednisone dose was increased to 60 mg once daily on alternatedays, along with azathioprine 100 mg daily. Over the next 2 years,she developed progressive cognitive problems along with deterio-ration in mobility and disabling myoclonus requiring 24-h care.She died following a cardio-respiratory arrest at home 6 years afterthe onset of neurologic symptoms and 33 years after the diagnosisof coeliac disease.

2. Discussion

We believe that the patient had refractory coeliac disease whichis linked to her progressive neurological condition. Thoughcausality is still not proven, several strands of evidence (immuno-logical, histological and treatment response) support this conceptincluding several similar reports.

Coeliac disease, gluten ataxia and dermatitis herepetiformis arethe three gluten related autoimmune disorders.1 Coeliac disease ischaracterized by malabsorption, structural abnormalities of smallbowel mucosa such as villous atrophy, crypt hyperplasia andinflammation, and intolerance to gluten protein. In 1966, Cookeand Smith reported 16 patients with neurological complications ofcoeliac disease.2 A variety of neurological problems have beenassociated with coeliac disease occurring in up to 10% of cases ofadult coeliac disease.3 These include peripheral neuropathy,myelopathy, encephalopathy and cerebellar ataxia.2,3 In 1980the first case of progressive myoclonic ataxia syndrome and coeliacdisease was reported.3 At first this was thought to be a chanceassociation as coeliac disease is common in the Caucasianpopulation affecting 1 in 100 people.4 However, further caseswere reported and they are summarized below. A literature searchfor cases with progressive myoclonus and ataxia associated withcoeliac disease was performed through medline with search terms

‘coeliac’ and ‘myoclonus’ and ‘ataxia’ identifying 15 cases in total(Table 1).

Our patient too had a characteristic phenotype dominated byaction myoclonus and ataxia. As in some of the previous cases,electrophysiological assessment revealed a cortical origin for themyoclonus. Our patient had a biopsy diagnosis of coeliac disease,but antiendomysial and antigliadin antibody were negative. Fourprevious cases have also been antibody negative. The prevalence ofseronegative coeliac disease is 6.4–9.1% of all diagnosed cases.15

These patients tend to be older and have more severe disease.16

Ataxia can also occur in the absence of coeliac disease. Glutenataxia was originally defined as otherwise idiopathic sporadicataxia with positive serological markers for gluten sensitization.17

It is an auto-immune disease where damage to the cerebellumleads to ataxia. Recent studies have shown patients with glutenataxia have deposits of anti-tissue transglutamase (anti-TTG)antibodies on brain vessels supporting the hypothesis that anti-TTG antibodies may affect the functioning of the blood–brainbarrier.

Neurological disorders are only part of the wide spectrum ofimmunological conditions associated with coeliac. In one study 63out of 314 patients (20%) with coeliac disease were found to haveadditional immunological disorders.18 Autoimmune disease ingeneral occurs more frequently in patients with coeliac diseasecompared with the normal population. These include autoimmunethyroid disease, type 1 diabetes mellitus, autoimmune liverdiseases and inflammatory bowel disease. Prevalence of coeliacdisease was noted to be 1–19% in patients with type 1 diabetesmellitus, 2–5% in autoimmune thyroid disorders and 3–7% inprimary biliary cirrhosis in prospective studies.19

Some reports have demonstrated an improvement in neuro-logical complications with a gluten free diet. Hadjivassilou et al.

Table 1A summary of cases from the literature with progressive myoclonus and ataxia associated with coeliac disease.

Case

number

Author Age and

gender

Neurological features Antigliadin

antibodies

Time to onset of neurologi-

cal symptoms from onset

of gastrointestinal symp-

toms (years)

Response of

coeliac disease

to treatment

Electrophysiology

1 Bhatia et al. (1995)5 68F Action and stimulus sensitive

myoclonus, sensory neuropathy,

upper limb ataxia.

Negative 7 Good Cortical reflex myoclonus

2 Bhatia et al. (1995)5 44M Action and stimulus sensitive

myoclonus, gait and limb ataxia

Negative 19 Good Cortical reflex and action

myoclonus

3 Bhatia et al. (1995)5 52M Action myoclonus, seizures and

mild ataxia

Negative 25 Good Cortical reflex myoclonus

4 Bhatia et al. (1995)5 66M Action myoclonus, frequent

seizures, cerebellar ataxia

Negative 10 Good Multifocal polyspike

and slow waves

5 Finelli et al. (1980)3 56M Palatal myoclonus, cerebellar

ataxia, internuclear

opthalmoplegia

Not done 0 Nil Not done

6 Kinney et al. (1982)6 56M Diffuse myoclonus, ataxia,

dementia

Not stated 1 Nil Not done

7 Lu et al. (1986)7 42M Action myoclonus limbs,

seizures, ataxia

Not stated Neurological symptoms

preceded GI symptoms by

1 year

Good Cortical reflex and action

myoclonus

8 Lu et al. (1986)7 54F Action myoclonus of limbs,

seizures, ataxia

Not stated Neurological symptoms

preceded GI symptoms

by 5 years

Not reported No cortical correlates

9 Brucke et al. (1988)8 45M Arm, tongue and palatal

myoclonus, Ataxia

Positive 0 Not reported Not done

10 Tison et al. (1989)9 56F Arm, neck, face stimulus

sensitive + palatal myoclonus,

cerebellar ataxia

Positive 0 Good Cortical reflex myoclonus

11 Hanagasi et al. (2000)10 31F Gait ataxia stimulus-induced

myoclonus, abnormalities of eye

movement

Positive Neurological symptoms

preceded GI symptoms

by 5 years

Not reported Normal

12 Chinnery (1997)11 20F Stimulus sensitive and action

myoclonus.

Positive No GI symptoms. Diagnosis

of coeliac made 12 years

after neurological symptoms

Poor Not done

13 Fung (2000)12 48F Unilateral limb tremor, dystonia,

myoclonus and ataxia

Positive 46 Not reported Cortical action myoclonus

14 Mumford (1996)13 44M Myoclonic ataxia, seizures Not stated 0 Poor Focal cortical myoclonus

15 Sallem (2009)14 46F Generalised seizures, myoclonus

and ataxia

Positive Not stated Poor Generalised polyspike

wave complexes

S. Javed et al. / Seizure 21 (2012) 482–485484

studied 43 patients with ataxia caused by gluten sensitivity. After 1year there was a significant improvement in ataxia in patientstreated with a gluten-free diet compared to the control group. Thediet associated improvement was apparent irrespective of thepresence of an enteropathy.20 Unfortunately, our patient did notimprove with a gluten free diet. Immunosuppressant drugs havebeen tried but with inconclusive evidence.18 Our patient was onprednisolone and azathioprine with no improvement in herneurological function.

In conclusion, we report a case of progressive neurologicaldisorder in association with coeliac disease. We feel that thepossibility of a gluten related disorder needs to be explored whenunexplained neurological symptoms such as seizures, tremor,ataxia or myoclonus occur. In our case the epilepsy developed 26years, and myoclonus and ataxia 29 years after the diagnosis ofcoeliac disease. Despite the lack of response to treatment, ourpatient and her family were grateful for an explanation for hercondition.

Conflict of interest statement

Nothing to declare.

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