We present two patients with partial epilepsy, type-1 diabetes and stiff person syndrome associated with high serum autoantibody levels to glutamate-decarboxylase (anti-GAD). Both patients were or have suffered from additional autoimmune conditions. The presence of stiff person syndrome and elevated anti-GAD levels have to make clinicians look for additional autoimmune conditions including type-1 diabetes. On the other hand, the co-morbidity of partial epilepsy with autoimmune conditions in patients with elevated serum anti-GAD suggests an autoimmune mechanism of partial epilepsy in these cases

Barcs, G.

Folyovich, András

Kamondi, Anita

Soós, Z.

Szűcs, Anna

Winkler, Gábor

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Az alábbi dokumentumot magáncélra töltötték le az eLitMed.hu webportálról. A dokumentum felhasználása a szerzôi jog szabályozása alá esik.Ideggyogy Sz 2014;67(7–8):269–271. 269ESETISMERTETÉSANTI GLUTAMATE-DECARBOXYLASE ANTIBODIES: A LIAISON BETWEEN LOCALISATION RELATED EPILEPSY,STIFF-PERSON SYNDROME AND TYPE-1 DIABETES MELLITUS  Anna SZÛCS1, Gábor BARCS1, Gábor WINKLER2, Zsuzsanna SOÓS2, András FOLYOVICH2, Anna KELEMEN1, Péter VÁRALLYAY1, Anita KAMONDI11National Institute of Neuroscience, Budapest2Szent János Hospital, BudapestANTI-GLUTAMÁT-DEKARBOXILÁZ ANTITESTEK: KAPCSOLAT A LOKALIZÁCIÓFÜGGÔ EPILEPSZIA, A STIFF-PERSON-SZINDRÓMA ÉS AZ 1-ES TÍPUSÚ DIABETES MELLITUS KÖZÖTTSzûcs A, MD; Barcs G, MD; Winkler G, MD; Soós Zs, MD;Folyovich A, MD; Kelemen A, MD; Várallyay P, MD; Kamondi A, MDIdeggyogy Sz 2014;67(7–8):269–271.Két stiff-person-szindrómás, a szérumban emelkedett glu-tamát-dekarboxiláz-antitest (anti-GAD) -szintet hordozóbeteg esetét ismertetjük. Mindketten parciális epilepsziábanés 1-es típusú diabetes mellitusban, valamint továbbiautoimmun betegségekben is szenvedtek. Saját eseteink és az irodalom alapján arra következtetünk,hogy emelkedett szérum-anti-GAD-szinttel járó stiff-person-szindróma esetén további autoimmun betegségek, elsôsor-ban 1-es típusú diabetes keresése indokolt. Másfelôl, a par-ciális epilepszia társulása egyes, emelkedettanti-GAD-szinttel járó kórképekkel arra utal, hogy az ilyenesetekben anti-GAD-függô autoimmun patomechanizmusállhat az epilepszia hátterében is.Kulcsszavak: stiff person, anti-GAD, autoimmun epilepsziaWe present two patients with partial epilepsy, type-1 diabetesand stiff person syndrome associated with high serum auto-antibody levels to glutamate-decarboxylase (anti-GAD). Bothpatients were or have suffered from additional autoimmuneconditions. The presence of stiff person syndrome and elevated anti-GAD levels have to make clinicians look for additionalautoimmune conditions including type-1 diabetes. On theother hand, the co-morbidity of partial epilepsy with autoim-mune conditions in patients with elevated serum anti-GADsuggests an autoimmune mechanism of partial epilepsy inthese cases. Keywords: stiff person’s, anti-GAD, autoimmune epilepsyCorrespondent: Anna SZÛCS MD, National Institute of Neuroscience; H-1145 Budapest, Amerikai út 57. E-mail: szucsan@gmail.comÉrkezett: 2013. augusztus 18. Elfogadva: 2013. november 29.www.elitmed.huGlutamate-decarboxylase (GAD) located withinthe nerve terminals of GABAergic neurons andthe beta-cells of the pancreas, is the rate-limitingenzyme converting glutamate to gamma-hydroxy-butyrate (GABA). Auto-antibodies to GAD (anti-GAD) target the intracellular GAD presented toautoimmune reaction by B lymphocytes and HLAclass II molecules1. Serum anti-GAD is detected in80% of diabetes mellitus type-1 (DM1) patients2, 3 aswell as in late onset isolated cerebellar ataxia;autoimmune poly-endocrine syndrome, cerebellarataxia with poly-endocrine autoimmunity; rheuma-toid arthritis, myasthenia gravis, autoimmunethyreoiditis; and certain para-neoplastic syndromes4. Significantly higher anti-GAD (IgG) levels withdifferent epitope specificity than in DM1 are pres-ent in 60-80% of patients with stiff person’s syn-drome (SPS); a rare condition (prevalence 1/1 000 000) characterized by stiffness and cramps ofstriated muscles, disturbing normal movement5, 6. The classical criteria of SPS are as follows7: – Stiffness, tightness in trunk and proximal limbs, – Prominent lumbar lordosis,– Muscle cramps,szucs_UJ ISZ TUKOR ALAP ANGOL.qxd  2014.07.16.  15:09  Page 269Az alábbi dokumentumot magáncélra töltötték le az eLitMed.hu webportálról. A dokumentum felhasználása a szerzôi jog szabályozása alá esik.– Parallel muscle activity of antagonistic musclessimultaneously; in at least one axial muscle (theEMG may be normal), – No brainstem-, basal ganglia-, or moto-neuronsigns; normal sensory, autonomic and cognitivefunctions,– Female preponderance,– Association with other autoimmune diseases,– Pulmonary/breast cancer in 15%.Besides anti-GAD, additional auto-antibodies arefound in SPS8: tyrogastric antibodies, islet-cell anti-bodies, auto antibodies against GABA-ergic neu-rons, 125/130 kd protein, amphiphysin and ge -phyrin, GABA A receptor-associated protein. Ten percent of SPS patients have epilepsy andanti-GAD (IgG) was detected in seven out of 51(13%) pharmaco-resistant partial epilepsy patientsagainst none of 49 with generalized epilepsy9. We present two female patients sharing SPS, par-tial epilepsy and DM1; both suffering also in addi-tional autoimmune conditions. We want to callattention to this multi-organ co-morbidity and toraise the possibility of anti-GAD related autoim-mune aetiology in some epilepsies.Case studiesPATIENT 1A 51-year-old female had brain concussion at age19. At age 29 complex partial and generalizedtonic-clonic seizures started with right temporalinterictal spikes seen on her EEG. Subcortical whitematter lesions were detected on the MRI brain-scanof the patient; no hippocampal sclerosis was seen.No seizure freedom could be reached by adequatelyselected and therapeutic dose antiepileptic drugs. At age 39 DM1 was diagnosed. At age 45 sacro-ileitis was diagnosed and sero-negative spondy-larthritis was suspected. At age 46, stiffness in the lumbar spine and limbmuscles as well as painful cramps in the thighdeveloped. Electromyography at age 49 showedsimultaneous motor activity in the antagonist mus-cles of the thigh, which could be suspended byintravenous diazepam. The diagnosis of SPS wassupported by high anti-GAD titre in her serum[103.24 U/ml (reference <20)]. After unsuccessfultreatment with Pregabaline and improvement onDiazepam; five sessions of plasma aphaeresis wereinstituted resulting in significant improvement ofher stiffness. One month later she has becomeseizure free for six months on unchanged antiepi -leptic medication.PATIENT 2A 69-year-old female had partial epilepsy from age20, treated with phenytoin and carbamazepine. Shehad generalized tonic-clonic seizures and left tem-poral lobe spikes on her EEG. After antiepileptictreatment lasting for 15 years, she has becomeseizure-free, so the antiepileptic medications couldbe discontinued. Her DM-1 started at age 40. At age 58 stiff lower limbs and trunk developedwith hyper-lordotic posture and painful cramps inleg-muscles. She was unable to bend and had opisto-tonus when lying on her back. Minimal effort causedtachycardia. The whole-spine MRI scan was normal,the MRI brain-scan revealed cerebellar atrophy.Electromyography (without parallel agonist-antago-nist muscle testing) was normal, but there was typi-cal clinical presentation for SPS: the small lady couldbe pushed into the MRI-tube supported at her lowback only; not bending at all. Her serum anti-GAD(IgG) was 5100U/ml (reference<20) supporting thediagnosis of SPS. Treat ment with clonazepam andbaclofen decreased her muscle-stiffness, she wasunable to walk without them. Intravenous adminis-tration of Methyl pred nisolon 1000 mg/day for aweek did not help. Her mobility worsened over theyears, her cerebellar ataxia also progressed till shebecame wheelchair-bound. Because of her diarrhoea and weight loss, bowelbiopsy has been carried out; and positive anti-gliadin antibodies were found in her serum, celiacdisease was diagnosed at age 64. DiscussionThe diagnosis of SPS was supported by the clinicalpresentation and high serum anti-GAD antibodytitres in both patients; no CSF testing was per-formed. EMG evidence was present only in patient1. The autoimmune mechanism of both SPS andepilepsy of patient 1 is supported by her improve-ment of muscle stiffness as well as becomingseizure free; in response to plasma exchange thera-py. The steroid treatment of patient 2 proved to beinsufficient. The apparently distant combination of SPS, DM1and partial epilepsy was described by Solimena andcolleagues back in 198810 and was reported later11.Although we haven’t performed full autoimmunescreening in our patients, their laboratory check-upbased on their specific syndrome revealed addition-al autoimmune conditions e.g. sacro-ileitis (Patient1); celiac disease and progressive cerebellar ataxia(Patient 2). 270 Szûcs: Anti glutamate-decarboxylase antibodiesszucs_UJ ISZ TUKOR ALAP ANGOL.qxd  2014.07.16.  15:09  Page 270Az alábbi dokumentumot magáncélra töltötték le az eLitMed.hu webportálról. A dokumentum felhasználása a szerzôi jog szabályozása alá esik.Celiac disease shares the demographic featuresof SPS. Serum antigliadin antibodies (diagnostic forceliac disease) are found in 30-40% of sporadiccerebellar ataxia patients12. Because celiac diseasemay manifest as “gluten ataxia” and causeseizures13; the epilepsy and cerebellar ataxia ofpatient 2 could be related both to her celiac diseaseand her high serum anti-GAD level.Both SPS and epileptic seizures respond toGABAergic agonists as benzodiazepines, sodiumvalproate, baclofen and vigabatrin. There aredecreased cortical GABA levels in both condi-tions14–16 as evidenced by MR spectroscopy, sug-gesting an aetiological role of low GABA-relatedcortical inhibition17– 19. It has been recently shown that GAD-67 is expres-sed in hippocampal mossy fibers of temporal lobeepilepsy patients20 offering a clue why partial epilep-sy unlike generalized epilepsy is associated to GADautoimmunity; and intrathecal anti-GAD synthesishas been found in 77% of pharmaco-resistant tempo-ral lobe epilepsy patients with elevated serum anti-GAD11. Low cortical GABA may be due todecreased glutamate-GABA conversion; as a resultof anti-GAD autoimmunity. The beneficial effect ofcorticosteroids, intravenous immu noglobulin andplasma-aphaeresis in SPS support this hypothesis,and the role of autoimmunity in epilepsy is support-ed by the intra-thecal presence of anti-GAD antibod-ies found in status epilepticus patients21. The combination of different autoimmune condi-tions in our patients suggests that the diagnosis ofSPS and high anti-GAD level in the serum have tomake clinicians seek for co-morbid autoimmuneconditions and keep in mind the risk (up to 10%) ofthe co-occurrence of epilepsy in these patients.ACKNOWLEDGEMENTThe study was supported by the Hungarian BrainResearch ProgramIdeggyogy Sz 2014;67(7–8):269–271. 271REFERENCES1. Qu HQ, Polychronakos C. The effect of the MHC locus onautoantibodies in type 1 diabetes. J Med Genet 2010;46:469-71.2. Baekkeskov S, Aanstoot H-J, Christgau S, Reetz A,Solimena M, Cascalho M, et al. 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Anti glutamate-decarboxylase antibodies: A liaison between localisation related epilepsy, stiff-person syndrome and type-1 diabetes mellitus

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