Autoimmune and Paraneoplastic Neurological Syndromes Pavel Štourač Department of Neurology University Hospital, Masaryk University Brno, Czech Republic Classical and non-classical paraneoplastic syndromes Classical syndrome Non-classical syndrome Central nervous system Encephalomyelitis Brainstem encephalitis Limbic encephalitis Optic neuritis Subacute cerebellar degeneration Myelitis/necrotizing myelopathy Opsoclonus–myoclonus syndrome Stiff-person syndrome and variants Peripheral nervous system Subacute sensory neuronopathy Distal-symmetric sensorimotor neuropathy Chronic intestinal pseudo-obstruction Polyradiculoneuropathy (acute/chronic) Multiplex mononeuropathy Pure autonomic neuropathies Neuromuscular junction and muscle Lambert–Eaton myasthenic syndrome Myasthenia gravis Dermatomyositis Neuromyotonia JNNP 2004 Well-characterized onconeural antibodies found in paraneoplastic syndromes Antibody Associated syndromes and symptomes Most common tumours Anti-Hu (ANNA-1) Encephalomyelitis, limbic encephalitis, cerebellar degeneration, brain stem encephalitis, multi-segmental myelitis, sensory neuronopathy, sensory motor neuropathy, autonomic neuropathy Lung cancer (85%), mostly SCLC, neuroblastoma, prostate carcinoma Anti-Yo (PCA-1) Paraneoplastic cerebellar degeneration Ovarian, breast cancer Anti-CV2/CRMP5 Encephalomyelitis, polyneuropathy, optic neuritis, limbic encephalitis, choreatic syndromes, cerebellar degeneration SCLS, thymoma Anti-Ta/Ma2 Limbic encephalitis, rhombencephalitis, male>>female Testicular cancer Anti-Ri (ANNA-2) Opsoclonus-myoclonus syndrome, rhombencephalitis, cerebellar degeneration, myelitis, jaw dystonia, laryngospasm Breast, ovarian carcinoma, SCLC Anti-amphiphysin Stiff-person syndrome, limbic encephalitis, , rhombencephalitis, cerebellar degeneration, polyneuropathy Breast cancer, SCLC Anti-recoverin Retinopathy SCLC Anti-Tr (DNER) Paraneoplastic cerebellar degeneration Hodgkin Pathophysiology of paraneoplastic neurological syndromes N Engl J Med 2003; 349:1543-1554 Antibodies against neural surface antigens • Probably pathogenic • Good response to immunotherapy • Do not indicate if syndrome is paraneoplastic Antibody Syndrome % cancer Cancer Type NMDAR Encephalitis 50 Ovarian teratoma AMPAR LE 60 Breast; SCLC GABA(B)R LE 70 SCLC mGluR5 LE 100? Hodgkin CASPR2 Morvan/LE 50/0 Thymoma LGI1 LE 0 GlycineR PERM <1? DPPX Encephalitis 0 GABAaR Encephalitis 0? PERM:progressive encephalomyelitis/rigidity/myoclonus; LE: limbic encephalitis; SCLC: small cell lung cancer Paraneoplastic syndromes of the CNS and relevant wellcharacterized onconeural or neuronal cell-surface antibodies Syndrome Relevant antibodies Subacute cerebellar degeneration 25% Hu, Yo, CV2/CRMP5, Ri, Tr, amphiphysin, VGCC Encephalomyelitis 6% Hu, CV2/CRMP5, amphiphysin Limbic encephalitis 10% Hu, Ma2, GABA(b)-, AMPA-, mGluR5, Opsoclonus-myoclonus syndrome (adults) 2% Ri Retinopathy 1% CV2/CRMP5, recoverin Stiff-person syndrome 1% Amphiphysin, Chorea CV2 Encephalitis NMDAR Recommended tumour screening (Titulaer et al.) Tumour Diagnostics Primary Secondary Tertiary Lung cancer Thoracic CT (80-85%), thoracic MRI FDG-PET or FDG-PET/CT Bronchoscopy/EB-US, possibly needle biopsy and/or mediastinoscopy Thymoma Thoracic CT (75-90%), thoracic MRI FDG-PET or FDG-PET/CT Breast cancer Mammography (80%), ultrasound Breast MRI Ovarian carcinoma Ultrasound (69-90%) + CA-125 Pelvic and abdominal CT FDG-PET Ovarian teratoma Ultrasound (69-90%) MRI (93-98%) Thoracic CT (extra-pelvic teratomas) Testicular cancer Ultrasound (72%) + βHCG, AFP Pelvic/abdominal CT (76%), abdominal MRI Possibly FDG-PET (malignant teratomas) Lymphoma Thoracic/abdominal CT, ultrasound FDG-PET or FDG-PET/CT Skin tumours (Merkel-cell carcinoma) Dermatological examination, biopsy Paraneoplastic cerebellar degeneration - the most common PS syndrome of the CNS • MRI - normal, late phase - cerebellar atrophy • CSF - pleocytosis, oligoclonal IgG bands - 60% • anti - Yo (PCA-1) antibodies (gynaecological malignancy) • anti - Hu (ANNA-1)/VGCC antibodies (SCLC) • CV2/CRMP5 - (SCLC) • anti - Tr antibodies (Hodgkin´s lymphoma) - newly discovered antigen delta notch - like epidermal growth factor related receptor (DNER) • anti - Ri antibodies (breast and lung cancer) + POM • amphiphysin, Zic4, mGluR1,VGCC a) normal cerebellar structure - Purkinje cells, stratum granulare b) PCD - the absence of Purkinje cells and reduced granular layer of cerebellum c) indirect immunofluorescence with positive anti -Yo antibodies a b c New antibodies and paraneoplastic cerebellar degeneration • single cases and small series cases:  anti - protein kinase Cγ/PCD/adenocarcinoma  anti - RhoGTPase - activating protein 26/PCD/ovarian cancer  anti-CARP7/melanoma  idiopathic cerebellitis - associated: – VGKC complex antibodies, GAD, mGluR1 and Homer 3 Anti-GABA(B)receptor antibodies and PNS • antibodies to the GABA(B) receptor GABA(B1) and GABA(B2) receptor subunits - an inhibitory receptor • antibodies against a neuronal cell - surface antigen • limbic encephalitis with seizures; limbic dysfunction (MRI, EEG) • 15 pts suspected from paraneoplastic or immune - mediated encephalitis • 7pts had tumours; 5pts SCLC; 7pts non - neuronal Abs • 9 pts from 10 pts who received immunological or cancer therapy had improved • 50-80% of paraneoplastic origin • Res: treatable condition associated with seizures and SCLC Lancaster E. , Lancet neurol 2010; (9):67-76 GABA (B) receptor www.neurology.org Immunofluorescent analysis of HeLa cells labeling GABA B Receptor 2 with ab181736 at 1/200 (green). Blue: DRAQ5 fluorescent DNA dye. www.abcam.com Anti-NMDA receptor antibodies and PNS • glutamate (inotropic) excitatory receptors: • N-methyl-D-aspartate (NMDA) receptor (4 subunits; two NR1 and two NR2) • (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA receptor) • kainate receptor • metabotropic glutamate receptor (mGluR) coupled with G protein • both glutamate and glycine binds to and open ion channel • paraneoplastic antibodies react with NR1 subunit in NMDAR receptor and downregulate NMDA receptors NMDA receptor http://imgsoup.com www.birmingham.ac.uk NMDAR antibodies determined using commercially available NR1 transfected cells. Fluorescence of the hippocampus (neuropil staining) Anti-NMDA receptor antibodies and PNS • clinical manifestation • cortico-subcortical encephalopathy • psychiatric symptoms; behavioral and cognitive disorders, paranoia, delusions, hallucinations • involuntary movements; orofacial dyskinesias, choreoathetoid dystonia, increased muscle tone • vegetative symptoms; cardiac dysrhytmia,blood pressure instability,hyperhidrosis, dysthermia,sialorhea, ileus ,central hypoventilation • seizures; generalized, focal and also atypical • reduction in consciousness, unconsciousness, arteficial ventilation and ICU Anti-NMDA receptor antibodies and PNS • association with tumours: ≤ 50% mostly ovarian teratomas,endocrine tumour, SCLC • Diagnosis:  EEG slow and epileptic activity (100% pts)  abnormal brain MRI scan (55%)  CSF abnormalities; (100 %) lymphocytic pleocytosis, increased protein concentration and oligoclonal IgG bands • potentially treatable disorder, not always • refractory cases treatment - cyclophosphamide, rituximab Anti-AMPA receptor antibodies and PNS • antibodies against the GluR1/GluR2 subunit of AMPA • clinical manifestations • limbic encephalitis, i.e. amnesia, seizures, psychosis • in 67% (70-75%) paraneoplastic origin - thymoma, lung, breast, ovary • abnormal MRI 85% Bataller et al.,2010; Titulaer et al. 2014 • antibodies against mGluR1 • paraneoplastic cerebellar degeneration (2 pts) Sillevits-Smitt,2000 AMPA receptor http://wiki.bioguider.com Anti-glycine receptor antibodies and PNS • glycine is an inhibitory neurotransmitter in CNS • member of superfamily of inotropic receptors • PERM syndrome - progressive encephalomyelitis, rigidity and myoclonus • cognitive and brainstem disturbance, seizures • lung cancer, thymoma • typically non-paraneoplastic syndrome Glycine receptor http://www.brown.edu Anti-VGKC antibodies and PNS • voltage gated potassium channels complexes: • LGI1 = leucine-rich glioma inactivated 1 (70% of VGKC) • CASPR 2 = conctactin associated protein 2 (20% of VGKC) • Contactin 2 (10% of VGKC) • Cell based assay for detection of LGI1, CASPR 2, Contactin 2 • Radioimmunoassay for VGKC complex antibodies Anti-VGKC antibodies reacting with hippocampal tissue (A) and superficial (membrane) structures of neuron (B) Antibodies against LGI1 and PNS • antibodies against LGI1 leucine rich glioma inactivated 1 • clinical manifestation: limbic encephalitis, amnesia, epileptic seizures, psychiatric manifestations, faciobrachial dystonic seizures, myoclonus, dysautonomia • paraneoplastic origin: thymoma, thyroid gland cancer, SCLC ovarian teratoma, kidney cell carcinoma paraneoplastic origin rare 0-10 % http://en-journal.org Antibodies against CASPR2 and PNS • CASPR2 - contactin- associated protein 2 • clinical manifestation: limbic encephalitis, Morvan syndrome, neuromyotonia, confusion, memory disorders, dysautonomia and neuronal hyperexcitability • paraneoplastic origin 0-35 % • associated tumours: thymoma, endometrial cancer www.abcam.com Transfected cells and tissue substrate IIFT: Autoimmune Encephalitis Mosaic 1 NMDAR CASPR2 AMPAR1 LGI1 AMPAR2 GABA(B)R Limbic encephalitis • classified as „new classical paraneoplastic syndrome“ • clinical pattern: epileptic seizures, short - term memory deficit, behavioral and psychiatric disturbances • minor involvement of other areas of nervous system • associated with onconeural antibodies: Hu, Ma2, CV2/CRMP5, Ri, amphiphysin • associated with neuronal cell surface antibodies: NMDAR, LGI1, CASPR2, GABA(B)R, AMPAR, mGluR5, GlyR • associated tumours: lung cancer, SCLC, breast and ovarian cancer, testicular cancer, lymphoma, thymomas Limbic encephalitis • Hodgkin lymphoma and limbic encephalitis (Ophelia syndrome) • treatment outcome more favorable with synaptic and cellsurface antibodies • treatment outcome worse in syndromes with onconeural antibodies Case Report • The patient (male) presented at age 48 with diplopia, nystagmus, dysphagia,nausea and vertigo of subacute course in May 1998. Cerebellar symptoms and mild paresis of the left arm developed some weeks later reaching the plateau phase. Anti-Hu antibodies were repeatedly positive by immunoblot and indirect immunofluorescence • Repeated MR scan showed mild atrophia of vermis cerebellum and repeated PET (positron emission tomography) did not revealed any tumour for 22 years , now • The patient´s mobility is very limited and most of time patient is wheelchairbound • Antibody positive (anti-Hu) patient with brainstem encephalitis/cerebellar syndrome of possible paraneoplastic origin keeps alive the hypothesis that the tumour could be discovered later beyond the 5 years arbitrary period • Alternatively the tumour was removed by immune response. The persistent neurological deficit is probably a scar caused by an immune system attack during the oncogenesis Case Report Immunoblot anti-Hu positive patient is on the position No.10 Indirect immunofluorescence of antiHu antibodies in plexus myentericus of mouse tissue Treatment of paraneoplastic neurological syndromes Tumour therapy • elimination of tumour tissue is beneficial i.e. recovery or stabilization • longer survival (PCD) • NMDAR encephalitis (teratoma) lesser risk of relapse • treatment according to the current oncological guidelines • no specific guidelines for PNS • tumour therapy initiate as soon as possible Treatment of paraneoplastic neurological syndromes Immunotherapy • syndromes with onconeural antibodies - low level evidence for efficacy • no clear consensus about the type of immunosupression: 1.line: steroids, plasmapheresis, IVIG, immunoadsorption 2.line: cyclophosphamide, azathioprine, methotrexate,cyclosporin A, tacrolimus, mycophenolate mofetile • NMDAR encephalitis (LGI1, CASPR2,GABA(b),AMPAR) 1.line: steroids, IVIG and plasmapheresis 2.line: cyclophosphamide, rituximab or both