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Jdalmau@clinic.ub.es
Josep.dalmau@uphs.upenn.edu
Josep Dalmau, MD, PhD
ICREA Research Professor at IDIBAPS, University of ...
Encephalitis with CNS
hyperexcitability,
prodromal diarrhea
and other GI
symptoms, and weight
loss
Antigen Syndrome and main features Tumor
NMDAR Anti-NMDAR encephalitis 40-50 % women (thymoma)
AMPAR Limbic encephalitis, ...
Lancaster et al., Neurology, 2011; 77:179-89.
Reactivity of intracellular and cell surface neuronal antibodies
Anti-IgLON5 disease
REM sleep behavior disorder
Autoimmune
encephalitis
Neurodegenerative
diseases
Synucleinopathies
(Parkinson’s disease,
dem...
Video
HLA genotyping: DRB1*1001 and DQB1*0501 (in normal population 1.6% and 14.4%)
Sabater et al., Lancet Neurol 2014;13:575-58...
Neuronal loss and tau deposits seen only in neurons
• Hypothalamus
• Tegmentum of the brainstem
- Laterodorsal tegmental a...
Anti-IgLON5 neuropathological features
Gelpi et al., Acta Neuropathol 2016;132:531-543
Anti-IgLON5 disease: 21 patients
Gaig et al., Neurology, in press
- Neurofascins *
- Contactins *
• N-Cadherins
• Integrins
• Selectins
• Immunoglobulin superfamily
- Neural CAMs
- Syn-CAM...
1. IgLON5 antibodies identify a novel neurological syndrome associated with
prominent sleep dysfunction.
4. Pathological e...
Anti-NMDA receptor encephalitis
(synaptopathy)
Ann Neurol 2005;58:594-604
Video
High
dose
antagonist
Medium
dose
antagonist
5-24 months
Time
MentalStatus
baseline
coma
Viral-like
prodrome
~1 week
Stage ...
Anti-NMDAR encephalitis: gender and tumor association
in 577 patients
Titulaer et al., Lancet Neurol 2013;12:157-65
Follow-up (months)
Relapse(%)
0 6 12 18 24
0
5
10
15
20
25
no treatment
1st line treatment (steroids, IVIg, plasma exchang...
Triggers of anti-NMDAR encephalitis: tumors and viruses
Dalmau J. Neurology 2016;87:2471-2482
Dalmau et al., Physiol Rev, ...
Patient’s antibodies decrease the number of clusters of NMDAR
Dalmau et al. Lancet Neurol 2008;7:1091
Hughes et al., J Neurosci 2010;30:5866-5875 Mikasova et al., Brain 2012;135:1606-1621
Patients’ antibodies crosslink and i...
Planagumà J, et al. Brain 2015; 138:94-109
Effects of patient’s NMDAR antibodies in a mouse model
Antibody binding to brain
1 2
Patients’ antibodies specifically decrease synaptic NMDARs
1
2
Planagumà J, et al. Brain 201...
Adapted from Panzer et al., J Neural Transm 2014;121:957-968
Underlying mechanisms in anti-NMDAR encephalitis
Psychosis: hallucinations, delusions,
memory, cognitive deficits
Antibody-mediated reduction of NMDAR
from synapses
Models...
Summary
• Antibody-mediated encephalopathies exemplify a new category
of diseases mediated by antibodies to relevant neuro...
Funding:
- NIH (NINDS, NIMH)
- ICREA – IDIBAPS
- ISCIII, FIS Spanish Ministry Health
- ISCIII, PIE
- ISCIII, CIBERER
- CEL...
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74th ICREA Colloquium "Autoimmunity meets neurodegeneration: different pathways for similar brain dysfunctions" by Josep Dalmau

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Studies during the last 10 years have revealed a new category of brain diseases in which crucial neuronal receptors are attacked by autoantibodies. As a result of this attack there is a reduction of the target synaptic proteins leading to alterations in synaptic transmission. The clinical manifestations vary according to the receptor involved, and may resemble many of the symptoms caused by neurodegenerative diseases in which specific receptors are involved, including among others Parkinson, epilepsy, chronically progressive sleep disease, or schizophrenia.  

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74th ICREA Colloquium "Autoimmunity meets neurodegeneration: different pathways for similar brain dysfunctions" by Josep Dalmau

  1. 1. Jdalmau@clinic.ub.es Josep.dalmau@uphs.upenn.edu Josep Dalmau, MD, PhD ICREA Research Professor at IDIBAPS, University of Barcelona, Spain Adjunct Professor Neurology, University of Pennsylvania, Philadelphia, USA “Autoimmunity meets neurodegeneration: different pathways for similar brain dysfunctions”
  2. 2. Encephalitis with CNS hyperexcitability, prodromal diarrhea and other GI symptoms, and weight loss
  3. 3. Antigen Syndrome and main features Tumor NMDAR Anti-NMDAR encephalitis 40-50 % women (thymoma) AMPAR Limbic encephalitis, psychosis 70 % lung, breast, thymoma GABAbR Limbic encephalitis with prominent seizures 50 % SCLC LGI1 Limbic encephalitis, myoclonus, hyponatremia <5 % thymoma Caspr2 Encephalitis, neuromyotonia, Morvan 50 % with Morvan DPPX (Kv4.2) CNS hyperexcitability, GI symptoms - GABAaR Status epilepticus, refractory seizures Thymoma Neurexin 3a Encephalitis with seizures and dyskinesias - mGluR5 Ophelia syndrome Hodgkin’s lymphoma GlyR Stiff-person syndrome, hyperekplexia, PERM 5 % thymoma, lymphoma Amphiphysin Stiff-person, encephalitis >90% breast, lung cancer Dopamine (D2) R Basal ganglia encephalitis, Sydenham’s chorea - mGluR1 Cerebellitis (+/- Hodgkin’s Disease) Hodgkin’s lymphoma DNER (Tr) Cerebellitis (+/- Hodgkin’s Disease) Hodgkin’s lymphoma VGCC Cerebellar degeneration >90% SCLC “IgLON5” “NREM and RBD with sleep-breathing dysfunction - Disorders of synaptic/cell surface autoimmunity
  4. 4. Lancaster et al., Neurology, 2011; 77:179-89. Reactivity of intracellular and cell surface neuronal antibodies
  5. 5. Anti-IgLON5 disease
  6. 6. REM sleep behavior disorder Autoimmune encephalitis Neurodegenerative diseases Synucleinopathies (Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy) Agrypnia excitata Limbic encephalitis (antibodies against Lgi1) Morvan’s syndrome (antibodies against Caspr2) Fatal familial insomnia Sleep disorders Parasomnia
  7. 7. Video
  8. 8. HLA genotyping: DRB1*1001 and DQB1*0501 (in normal population 1.6% and 14.4%) Sabater et al., Lancet Neurol 2014;13:575-586 Anti-IgLON5 antibodies
  9. 9. Neuronal loss and tau deposits seen only in neurons • Hypothalamus • Tegmentum of the brainstem - Laterodorsal tegmental area - Periaqueductal grey matter - Pedunculopontine nucleus - Magnocellular nuclei - Nucleus ambiguus No other abnormal protein deposits (e.g beta-amyloid or alpha-synuclein) No inflammatory infiltrates Anti-IgLON5 neuropathological features Sabater et al., Lancet Neurol 2014;13:575-586 Gelpi et al., Acta Neuropathol 2016;132:531-543
  10. 10. Anti-IgLON5 neuropathological features Gelpi et al., Acta Neuropathol 2016;132:531-543
  11. 11. Anti-IgLON5 disease: 21 patients Gaig et al., Neurology, in press
  12. 12. - Neurofascins * - Contactins * • N-Cadherins • Integrins • Selectins • Immunoglobulin superfamily - Neural CAMs - Syn-CAMs - L1 CAMs (neurofascins) - MAGs - Contactins - IgLONs - Nectins Immunoglobulin-like domains GPI anchorage Neuronal membrane IgLON5 *CAMs associated with autoantibodes and autoimmunity * * * Neuronal surface cell adhesion molecules (CAMs)
  13. 13. 1. IgLON5 antibodies identify a novel neurological syndrome associated with prominent sleep dysfunction. 4. Pathological examinations suggest a novel neuronal tauopathy with predominant brainstem and hypothalamic involvement. 2. The sleep disorder is characterized by a distinctive non-REM sleep dysfunction with simple and finalistic behaviors, REM sleep behavior disorder, and stridor with obstructive sleep apnea. 3. Associated symptoms include gait dysequilibrium, chorea, and brainstem dysfunction. 5. The full clinical range of this syndrome and whether the underlying pathophysiology is degenerative or autoimmune remains to be clarified. Summary, IgLON 5 Disease
  14. 14. Anti-NMDA receptor encephalitis (synaptopathy) Ann Neurol 2005;58:594-604
  15. 15. Video
  16. 16. High dose antagonist Medium dose antagonist 5-24 months Time MentalStatus baseline coma Viral-like prodrome ~1 week Stage of intensive support care: abnormal movements (dyskinesias), dissociative reactions, catatonia, coma, autonomic dysregulation, hypoventilationweeks-months 1-4 weeks Prolonged recovery/deficits: executive dysfunction, impulsivity, disinhibition, memory deficit Psychiatric manifestations: Psychosis, agitation, hallucinations, mania, pressured speech, reduced verbal output, insomnia, memory deficit, (often seizures) Kayser & Dalmau. Curr Psychiatry Rev 2011;7:189-193 Psychosis Low dose antagonist Symptoms and course of anti-NMDAR encephalitis
  17. 17. Anti-NMDAR encephalitis: gender and tumor association in 577 patients Titulaer et al., Lancet Neurol 2013;12:157-65
  18. 18. Follow-up (months) Relapse(%) 0 6 12 18 24 0 5 10 15 20 25 no treatment 1st line treatment (steroids, IVIg, plasma exchange) 2st line treatment (rituximab, cyclophosphamide) Titulaer et al., Lancet Neurol 2013;12:157-65 Anti-NMDAR encephalitis: Outcome and relapses
  19. 19. Triggers of anti-NMDAR encephalitis: tumors and viruses Dalmau J. Neurology 2016;87:2471-2482 Dalmau et al., Physiol Rev, in press
  20. 20. Patient’s antibodies decrease the number of clusters of NMDAR Dalmau et al. Lancet Neurol 2008;7:1091
  21. 21. Hughes et al., J Neurosci 2010;30:5866-5875 Mikasova et al., Brain 2012;135:1606-1621 Patients’ antibodies crosslink and internalize NMDARs
  22. 22. Planagumà J, et al. Brain 2015; 138:94-109 Effects of patient’s NMDAR antibodies in a mouse model
  23. 23. Antibody binding to brain 1 2 Patients’ antibodies specifically decrease synaptic NMDARs 1 2 Planagumà J, et al. Brain 2015; 138:94-109 Patients’ antibodies alter memory and behavior
  24. 24. Adapted from Panzer et al., J Neural Transm 2014;121:957-968 Underlying mechanisms in anti-NMDAR encephalitis
  25. 25. Psychosis: hallucinations, delusions, memory, cognitive deficits Antibody-mediated reduction of NMDAR from synapses Models of pharmacologic or genetic decrease or ablation of NMDAR NMDA hypofunction theory of schizophrenia
  26. 26. Summary • Antibody-mediated encephalopathies exemplify a new category of diseases mediated by antibodies to relevant neuronal cell surface or synaptic proteins. • Their discovery is changing paradigms in the diagnostic and treatment approach to many neurological and psychiatric disorders. • Provide models to better understand how autoimmunity to specific synaptic receptors alter memory, behavior, and cognition.
  27. 27. Funding: - NIH (NINDS, NIMH) - ICREA – IDIBAPS - ISCIII, FIS Spanish Ministry Health - ISCIII, PIE - ISCIII, CIBERER - CELLEX Foundation Hospital Clinic-IDIBAPS (University of Barcelona) • J Planagumà, T Armangué, M Petit, F Mannara, E Martinez, L Sabater, H Ariño, E Aguilar, MR Rosenfeld, F Graus • P Jercog, J de la Rocha, A Compte • C Gaig, A Iranzo, J Santamaria • E Gelpi, R Höftberger Pompeu Fabra University (Barcelona) R Maldonado ICFO (Barcelona) M Lakadamyali Erasmus MC (The Netherlans) M. Titulaer Jena University (Germany) Christian Geis NIH (USA) Irene Cortese, Avindra Nath University of Barcelona

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