LES ATAXIES CEREBELLEUSES AUTOIMMUNES

PR J. HONNORAT

DES NEUROLOGIE Clermont-Ferrand Mars 2012

NEURO-ONCOLOGIE HOPITAL NEUROLOGIQUE

LYON, FRANCE

LES ATAXIES CEREBELLEUSES SPORADIQUES

-  Génétiques récessives (Freidreich, AOA, mitochondries…) - Dégénératives idiopathiques (MSA…) - Tumorales - vasculaires - infectieuses (VZV, CMV, EBV, Herpes, Prions, HIV, LEMP) - Toxiques (alcool, Phénytoines, Lithium, Cytarabine, Mercure,

Toluène, Plomb, CO, Bromure, Thallium...) -  métaboliques (carences vitaminiques : E, B1, Folique, A ;

Hypothyroidie ; dégénérescence Hépato-cérébrale ) -  Auto-immunes (SEP, LED, Wegener, Behcet, maladie coeliaque,

paranéoplasiques, autres auto-Ac…) -  Autres (Hémosidérose marginée du névraxe ; Hyperthermie maligne) - inconnues +++

CAUSES MULTIPLES :

AUTOIMMUNE HYPOTHESIS IN PARANEOPLASTIC NEUROLOGICAL SYNDROMES

CSF : pleocytosis elevated protein levels increased IgG concentration oligoclonal bands

Brain : T lymphocytes infiltration

Anti-neuronal autoantibodies : - specificity 100 % - sensitivity 50 % - determine: tumor types neurological signs

specificity 99 % ; sensitivity 50 % ; intra-cellular antigens

Giometto et al, Arch Neurol, 2010;67:330-335

PNS with onconeural antibodies are rare Only 979 patients with definite PNS collected

By the PNS Euronetwork consortium between 2000 and 2008 (11 countries, 22 centers)

979 patients with definite PNS collected By the PNS Euronetwork consortium between 2000 and 2008

Giometto et al, Arch Neurol, 2010;67:330-335

Cerebellar ataxia and sensory neuronopathy are the most frequent PNS

Caractéristiques des patients présentant une ataxie cérébelleuse dans la base de données PNS-Euronetwork 2000-2008

Anti-YO ICC on rat cerebellum WB on Purkinje cells

- -

62

34

Tumoral expression : yes

Peterson et al, Neurology 1992;42:1931-1937. Rojas et al, Neurology 2000;55:713-715.

Anti-Yo

Associated tumours : - Breast - Ovary

Neurological disorders : - subacute cerebellar ataxia

Median age : 61 years (98 % female)

Evolution : - median survival : 100 months (breast cancer) 22 months (gynecologic cancer)

- Cancer was cause of death in 52 % of patients

PARANEOPLASTIC NEUROLOGICAL SYNDROMES

Miss M…, 63 years old, subacute cerebellar ataxia for 1 month, anti-Yo antibodies, ovarian carcinoma.

PARANEOPLASTIC NEUROLOGICAL SYNDROMES

Miss M…, 67 years old, subacute cerebellar ataxia for 1 month, anti-Yo antibodies, ovarian carcinoma for 1 year.

Anti-CV2 / Anti-CRMP 5

Associated tumours : - Thoracic : 83 % ° SCLC 58 % ; Thymoma 15 % - Extrathoracic : 17 %(Prostate, uterus sarcoma…)

Neurological disorders : - neuropathy : 74 % - cerebellar ataxia : 61 % - optic neuropathy : 17 % - chorea : 10 %

Median survival : - 52 months Can be associated with anti-Hu

Honnorat et al, J Neurol Neurosurg Psy 1996;61:270-278 Rogemond et Honnorat, Clin Rev All Immunol 2000;19:48-57. Honnorat et al, J Neurol Neurosurg Psy 2009;80:412-416

Median age : 61,5 years (male 72 %)

Mr P…, 55 years old, subacute cerebellar ataxia (1 month) anti-CV2 antibodies, SCLC (found 23 months after neurological signs)

Anti-CV2

Pathophysiology of PNS with onconeural antibodies is unclear Example of anti-Yo antibodies

Miss M…, 63 years old subacute cerebellar ataxia for 1 month, anti-Yo antibodies, ovarian carcinoma.

Auto-antibodies

Yo selectively expressed by Purkinje cells

Selective loss of Purkinje cells No animal model

Albert et al, Ann Neurol, 2000;47:9-17

Cellular immunity seems to play a major role

T8 cells (arrows) around neuron

Intra-cellular antigen. Antibody access ???

New concepts in auto-immune encephalitis

° OLD CONCEPT :

Paraneoplastic Anti-Hu Anti-CV2 Anti-Ma2 Anti-NMDAR Anti-neuropile

Non paraneoplastic Anti-VGKC Anti-VGCC But 20 to 60% of cancer

° NEW CONCEPT :

Intra-cellular antigens Anti-Hu Anti-CV2 Anti-Ma2…. Markers, no direct role

Membrane antigens Anti-NMDA-R Anti-VGKC Anti-AMPAr Anti-GABABr Anti-neuropile… Markers and direct role

All of them paraneoplastic or not

Graus et al, J Neuroimmunol 1997;74:55-61!Graus et al, Neurology 2003;!

Anti-Tr

38 years old. November 11th 2003 diagnosis of Hodgkin lymphoma November 13th 2003 dysarthria November 14th 2003 gait ataxia, Tr antibodies positive November 24th 2003 beddriden, onset of chemotherapy October 2004, alive, cerebellar ataxia, cancer remission, Tr negative

Anti-mGluR1 4 cas décrits depuis 2000

Doute sur origine paranéoplasique ; Hodgkin ?? Effet direct de l’IgG sur le récepteur (Sillevis-Smitt et al, N Engl J Med 2000)

Marignier et al, Arch Neurol 2010

GLUTAMATE

GABA

GAD

Neurotransmetteur inhibiteur

Neurotransmetteur excitateur

GAD = Glutamate Acide Décarboxylase enzyme

Anti-GAD et ataxies cérébelleuses

ANTI-GAD ANTIBODIES AND NEUROLOGICAL DISORDERS

but three specific syndromes have been described :

- Stiff-person syndrome

- Late onset cerebellar ataxia

- epilepsia and encephalitis

This association seems to be very rare

- axial muscles and proximal limbs - most patients respond to GABAergic drugs - 90 % are associated with anti-GAD - 30 % develop IDDM - 40 % have at least one auto-immune disease

(thyroiditis, myasthenia gravis, pernicious anemia….)

-  10 % develop generalized epilepsia

-  Few paraneoplastic cases with amphiphysin antibodies

Anti-GAD et ataxies cérébelleuses

Between 1995 and 1999 : 6 new cases have been published

- Giometto et al, J Neurol Sci 1996;143:57-59.

- Saiz et al, Neurology 1997;49:1026-1030.

- Abele et al, Neurology 1999;52:857-859.

- Ishida et al, Ann Neurol 1999;46:263-267.

European study :

- 5 centers : Lyon - 9000 tested sera Barcelona St Etienne Padova Oxford

- 36 anti-GAD sera - 22 Stiff-person syndrome - 14 cerebellar ataxia

1 = monoclonal anti-GAD65 antibody 2 à 15 = patients sera with cerebellar ataxia (dilution 1/20 000 à 1/5000) 16-17 = control patients

Patients ’ clinical presentation :

- 13 female / 1 male - median age : 55 years (20 to 74 years) - insidious and progressive signs 93% - truncal ataxia +++ (100%) Rankin score > 2 (71%) - limb ataxia + (85%) - Nystagmus 85% ; Dysarthria 64 % - Stiff-limb syndrome (2 cases) - Myasthenia gravis (1 case) - Neuropathy (1 case)

CSF and MRI studies :

CSF : - 4 patients : normal - 100% normal protein levels - High level IgG Index : 3 cases - oligoclonal Bands : 71%

IRM : - Cerebellar atrophy (50%) - Brainstem atrophy (0%)

Family and patients histories :

Family : - Cerebellar ataxia (0%) - Auto-immune diseases (43%)

patients : - particular IDDM (71%) median age : 47 years (28-66) - auto-immune thyroiditis (57%) - pernicious anemia (2 cases) - Psoriasis (1 cases) - Coeliac disease (1 cases) - Malignant Thymoma (2 cases) - other organ specific autoantibodies (79%)

74 years old woman, progressive ataxia for three years

Female patient, 74 years old, with progressive cerebellar ataxia, anti-GAD antibodies and periodic alternating nystagmus

Without treatment 15 days with Baclofen 15 mg/d

- Frequence of family and personal histories of auto-immune diseases - CSF synthesis of anti-GAD antibodies (6 cases /7) - IgG oligoclonal bands in the CSF - Particular MHC II : DR3 in 71 % (versus 11% in controls) - relationship with stiff-person syndrome

° Similar type and titers of anti-GAD antibodies ° 2 patients with stiff-person syndrome

Anti-GAD antibodies of patients with cerebellar ataxia produce, in vitro, selective suppression of GABAergic transmission

(Ishida et al, Ann Neurol 1999;46:263-267) (Mitoma et al, J Neurol Sci 2000;175:40-44)

(Takenoshita et al, J Neurol Neurosurg Psychiatr 2001;70:386-389)

Manto et al, Ann Neurol, 2007

- anti-GAD can be used as diagnostic and prognostic markers

- association : anti-GAD and stiff-person syndromes subtype of cerebellar ataxia

Is now well established

- understanding of GAD immunity could help us to develop specific treatments

- As IDDM is frequent anti-GAD can lead to misdiagnosis In case of atypical neurological syndromes

Autres autoanticorps associés aux ataxies

Anti-Gliadine (Gluten Ataxia - Sheffield) Anti-CASPR2 (Angela Vincent – Oxford)

CONCLUSIONS :

-  Les ataxies auto-immunes sont en cours de description, Mais elles sont manifestement rares

-  Formes paranéoplasiques clairement auto-immunes, mais mécanisme inconnu…

-  Formes avec anti-GAD, effet direct de l’IgG suspectée. Diagnostic sur un faisceau d’arguments

-  Anti-Gliadine et anti-CASPR2 doivent être précisés