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.  

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. Encephalitis with CNS
hyperexcitability,
prodromal diarrhea
and other GI
symptoms, and weight
loss

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. Lancaster et al., Neurology, 2011; 77:179-89.
Reactivity of intracellular and cell surface neuronal antibodies

5. Anti-IgLON5 disease

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. Video

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. 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. Anti-IgLON5 neuropathological features
Gelpi et al., Acta Neuropathol 2016;132:531-543

11. Anti-IgLON5 disease: 21 patients
Gaig et al., Neurology, in press

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. 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. Anti-NMDA receptor encephalitis
(synaptopathy)
Ann Neurol 2005;58:594-604

15. Video

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. Anti-NMDAR encephalitis: gender and tumor association
in 577 patients
Titulaer et al., Lancet Neurol 2013;12:157-65

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. Triggers of anti-NMDAR encephalitis: tumors and viruses
Dalmau J. Neurology 2016;87:2471-2482
Dalmau et al., Physiol Rev, in press

20. Patient’s antibodies decrease the number of clusters of NMDAR
Dalmau et al. Lancet Neurol 2008;7:1091

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. Planagumà J, et al. Brain 2015; 138:94-109
Effects of patient’s NMDAR antibodies in a mouse model

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. Adapted from Panzer et al., J Neural Transm 2014;121:957-968
Underlying mechanisms in anti-NMDAR encephalitis

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. 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. 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