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The identification of circulating autoantibodies against neuronal receptors in neuropsychiatric disorders has fostered new conceptual and clinical frameworks. However, detection reliability, putative presence in different diseases and in health have raised questions about potential pathogenic mechanism mediated by autoantibodies. Using a combination of single molecule-based imaging approaches, we here ascertain the presence of circulating autoantibodies against glutamate NMDA receptor (NMDAR-Ab) in about 20% of psychotic patients diagnosed with schizophrenia and very few healthy subjects. NMDAR-Ab from patients and healthy subjects do not compete for binding on native receptor. Strikingly, NMDAR-Ab from patients, but not from healthy subjects, specifically alter the surface dynamics and nanoscale organization of synaptic NMDAR and its anchoring partner the EphrinB2 receptor in heterologous cells, cultured neurons and in mouse brain. Functionally, only patients’ NMDAR-Ab prevent long-term potentiation at glutamatergic synapses, while leaving NMDAR-mediated calcium influx intact. We unveil that NMDAR-Ab from psychotic patients alter NMDAR synaptic transmission, supporting a pathogenically relevant role. Autoantibodies are found in neuropsychiatric conditions but without clear cellular mechanism and disease relevance. This study shows higher prevalence of autoantibodies against NMDAR receptors in schizophrenia patients, and patient-associated antibody can alter synaptic receptor trafficking and plasticity.

Objective To assess the long-term outcomes of patients with temporal lobe epilepsy and CSF anti-glutamate decarboxylase antibodies (GAD65-Abs). Methods We retrospectively analyzed the clinical records of 35 patients with temporal lobe epilepsy and CSF GAD65-Abs, collected from January 1993 to December 2016 and assessed cognitive impairment and seizure activity at last visit. Cognitive impairment was considered significant if impacting on daily life activities. Immunohistochemistry on rat brain slices and ELISA were used for antibody detection and titration. Results Median age was 30 years (range 2–63), 32/35 (91%) patients were female, and median follow-up was 68 months (range 7–232). At presentation, 20 patients had isolated temporal lobe epilepsy and 15 patients had other limbic symptoms, including anterograde amnesia ( n  = 10) and behavioral disturbances ( n  = 5). Progressive clinical deterioration over follow-up was reported in 28/35 patients (80%), including gradual increase of memory impairment ( n  = 25), and apparition of behavioral disturbances ( n  = 4) or mood disorders ( n  = 18). At last follow-up, 24/35 (69%) patients had cognitive disturbances with an impact on patient’s daily life activities, and 28/35 (80%) still had active seizures. Conclusion Most patients with temporal lobe epilepsy and CSF GAD65-Abs develop a chronic disease with progressive cognitive impairment and refractory epilepsy regardless of the presence of additional limbic symptoms at onset.

Abstract Rationale Encephalitis caused by anti–N-methyl-d-aspartate receptor (NMDAR) antibodies is the leading cause of immune-mediated encephalitis. There are limited data on intensive care unit (ICU) management of these patients. Objectives To identify prognostic factors of good neurologic outcome in patients admitted to an ICU with anti-NMDAR encephalitis. Methods This was an observational multicenter study of all consecutive adult patients diagnosed with anti-NMDAR encephalitis at the French National Reference Centre, admitted to an ICU between 2008 and 2014. The primary outcome was a good neurologic outcome at 6 months after ICU admission, defined by a modified Rankin Scale score of 0–2. Measurements and Main Results Seventy-seven patients were included from 52 ICUs. First-line immunotherapy consisted of steroids (n = 61/74; 82%), intravenous immunoglobulins (n = 71/74; 96%), and plasmapheresis (n = 17/74; 23%). Forty-five (61%) patients received second-line immunotherapy (cyclophosphamide, rituximab, or both). At 6 months, 57% of patients had a good neurologic outcome. Independent factors of good neurologic outcome were early (≤8 d after ICU admission) immunotherapy (odds ratio, 16.16; 95% confidence interval, 3.32–78.64; for combined first-line immunotherapy with steroids and intravenous immunoglobulins vs. late immunotherapy), and a low white blood cell count on the first cerebrospinal examination (odds ratio, 9.83 for <5 vs. >50 cells/mm3; 95% confidence interval, 1.07–90.65). Presence of nonneurologic organ failures at ICU admission and occurrence of status epilepticus during ICU stay were not associated with neurologic outcome. Conclusions The prognosis of adult patients with anti-NMDAR encephalitis requiring intensive care is good, especially when immunotherapy is initiated early, advocating for prompt diagnosis and early aggressive treatment.

Paraneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes caused by an auto-immune response against neuronal antigens (Ags) expressed by tumor cells. However, the mechanisms responsible for such immune tolerance breakdown are unknown. We characterized 26 ovarian carcinomas associated with Yo-PCD for their tumor immune contexture and genetic status of the 2 onconeural Yo-Ags, CDR2 and CDR2L . Yo-PCD tumors differed from the 116 control tumors by more abundant T and B cells infiltration occasionally organized in tertiary lymphoid structures harboring CDR2L protein deposits. Immune cells are mainly in the vicinity of apoptotic tumor cells, revealing tumor immune attack. Moreover, contrary to un-selected ovarian carcinomas, 65% of our Yo-PCD tumors presented at least one somatic mutation in Yo-Ags, with a predominance of missense mutations. Recurrent gains of the CDR2L gene with tumor protein overexpression were also present in 59% of Yo-PCD patients. Overall, each Yo-PCD ovarian carcinomas carried at least one genetic alteration of Yo-Ags. These data demonstrate an association between massive infiltration of Yo-PCD tumors by activated immune effector cells and recurrent gains and/or mutations in autoantigen-encoding genes, suggesting that genetic alterations in tumor cells trigger immune tolerance breakdown and initiation of the auto-immune disease.

Background Glial fibrillary acidic protein (GFAP) is expressed by astrocytes in the central nervous system (CNS), but also by immature and regenerative Schwann cells in the peripheral nervous system (PNS). GFAP antibodies (GFAP-Abs) in cerebrospinal fluid (CSF) have been mainly described in patients with meningoencephalomyelitis. We aimed to study PNS symptoms in patients with CSF GFAP-Abs. Methods We retrospectively included all patients tested positive for GFAP-Abs in the CSF by immunohistochemistry and confirmed by cell-based assay expressing human GFAPα since 2017, from two French reference centers. Results In a cohort of 103 CSF GFAP-Abs patients, 25 (24%) presented with PNS involvement. Among them, the median age at onset was 48 years and 14/25 (56%) were female. Abnormal electroneuromyography was observed in 11/25 patients (44%), including eight isolated radiculopathies, one radiculopathy associated with polyneuropathy, one radiculopathy associated with sensory neuronopathy, and one demyelinating polyradiculoneuropathy. Cranial nerve involvement was observed in 18/25 patients (72%). All patients except one had an associated CNS involvement. The first manifestation of the disease concerned the PNS in three patients. First-line immunotherapy was administered to 18/24 patients (75%). The last follow-up modified Rankin Scale was ≤ 2 in 19/23 patients (83%). Patients with PNS involvement had significantly more bladder dysfunction than patients with isolated CNS involvement (68 vs 40.3%, p  = 0.031). Conclusions PNS involvement in GFAP-Abs autoimmunity is heterogeneous but not rare and is mostly represented by acute or subacute cranial nerve injury and/or lower limb radiculopathy. Rarely, PNS involvement can be the first manifestation revealing the disease.

To describe autoantibodies (Abs) against tripartite motif-containing (TRIM) protein 9 and 67 in two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma. Abs were characterized using immunohistochemistry, Western blotting, cultures of murine cortical, and hippocampal neurons, immunoprecipitation, mass spectrometry, knockout mice for Trim9 and 67, and cell-based assay. Control samples included sera from 63 patients with small cell lung cancer without any paraneoplastic neurological syndrome, 36 patients with lung adenocarcinoma and PNS, CSF from 100 patients with autoimmune encephalitis, and CSF from 165 patients with neurodegenerative diseases. We found Abs targeting TRIM9 and TRIM67 at high concentration in the serum and the cerebrospinal fluid (CSF) of a 78-year-old woman and a 65-year-old man. Both developed subacute severe cerebellar ataxia. Brain magnetic resonance imaging found no abnormality and no cerebellar atrophy. Both had CSF inflammation with mild pleiocytosis and a few oligoclonal bands. We identified a pulmonary adenocarcinoma, confirming the paraneoplastic neurological syndrome in both patients. They received immunomodulatory and cancer treatments without improvement of cerebellar ataxia, even though both were in remission of their cancer (for more than 10 years in one patient). Anti-TRIM9 and anti-TRIM67 Abs were specific to these two patients. All control serum and CSF samples tested were negative for anti-TRIM9 and 67. Anti-TRIM9 and anti-TRIM67 Abs appeared to be specific biomarkers of PCD and should be added to the panel of antigens tested when this is suspected.

BackgroundPatients with leucine-rich glioma-inactivated 1 antibody (LGI1-Ab) encephalitis are typically elderly men that often carry human leucocyte antigen (HLA)-DRB1*07:01 (≈90%). Herein, we aimed to investigate whether patients with atypical demographic profiles or not carrying DRB1*07:01 have distinct clinical manifestations and outcome.MethodsRetrospective chart review of LGI1-Ab patients diagnosed at the French Reference Centre and three other European centres.ResultsAmong 238 patients included, median age at onset was 66 years (IQR: 60–73), 65% were male, 89% carried DRB1*07:01 and 10% DRB1*04:02, another known secondary HLA association. We identified three age groups (young, typical, old) based on percentiles of age distribution. Young (≤51 years) patients were less commonly male (35%, p=0.004), while faciobrachial dystonic seizures (FBDS; 65%, p=0.047) and hyponatraemia (64%, p=0.046) were more frequent in old (≥79 years) patients. Old patients experienced poor outcome (modified Rankin Scale [mRS] >2 at last follow-up) more frequently (64%, p<0.001). There were no significant differences between males and females. DRB1*07:01 non-carriers were younger (p=0.005) and less frequently male (47%, p=0.044), while non-carriers of both DRB1*07:01 and DRB1*04:02 experienced poor outcome more commonly (64%, p=0.005). Older age (adjusted OR: 1.08, 95% CI [1.02 to 1.14], p=0.008), higher mRS at nadir (4.22 [2.46–7.24], p<0.001) and DRB1*07:01 non-carrier status (8.39 [1.88–37.44], p=0.005) were independently associated with poor outcome. Moreover, older age (1.08 [1.04–1.11], p<0.001), FBDS (2.20 [1.17–4.13], p=0.014) and hyponatraemia (2.30 [1.22–4.34], p=0.010) were associated with severe encephalitis (mRS >3 at nadir).ConclusionsAge appears to be the main driver of clinical presentation, severity and outcome in LGI1-Ab encephalitis. Remarkably, DRB1*07:01 non-carriers are younger, more commonly female and experience poorer prognosis, reflecting a distinct pathophysiology.

ObjectiveTo report the clinical features and long-term outcome of 22 newly diagnosed paraneoplastic patients with GABAB receptor antibodies (GABABR-Abs).MethodsRetrospective clinical study of CSF-confirmed cases of GABABR-Abs encephalitis.ResultsWe identified 22 patients (4 female) with GABABR-Abs, with a median age of 64 years (range 55–85). All were paraneoplastic: 20 small-cell lung cancer, one malignant thymoma, and one uncharacterized lung mass. The most frequent first symptom was the isolated recurrent seizures without cognitive inter-ictal impairment in 17 patients (77%). In the other, three presented the first behavioral disorders and two presented de novo status epilepticus (SE). After a median delay of 10 days (range 1–30), the recurrent seizures’ phase was followed by an encephalitic phase characterized by confusion in 100% of cases and SE in 81% (n = 17), with 53% (n = 9) non-convulsive SE. Dysautonomic episodes were frequent (36%, n = 8, bradycardia and central apnea) and killed three patients. CSF study was abnormal in 95% of the cases (n = 21). At the encephalitic phase, MRI showed a temporal FLAIR hypersignal in 73% (n = 16) of the cases. First-line immunotherapy was initiated after a median delay of 26 days (range 6–65) from disease onset, and a partial response was observed in 10 out of 20 patients (50%). There was no complete response. Two years after onset, a massive anterograde amnesia affected all still alive patients. Nine patients died from cancer progression (median survival: 1.2 years).ConclusionParaneoplastic GABABR-Abs encephalitis is characterized by a stereotype presentation with an epilepsy phase before an encephalitic phase with dysautonomia. The functional prognosis is poor.

The primary cause of neurological syndromes with antibodies against glutamic acid decarboxylase 65 (GAD65-Ab) is unknown, but genetic predisposition may exist as it is suggested by the co-occurrence in patients and their relatives of other organ-specific autoimmune diseases, notably type 1 diabetes mellitus (T1DM), and by the reports of a few familial cases. We analyzed the human leukocyte antigen (HLA) in 32 unrelated patients and compared them to an ethnically matched sample of 137 healthy controls. Four-digit resolution HLA alleles were imputed from available Genome Wide Association data, and full HLA next-generation sequencing-based typing was also performed. HLA DQA1*05:01–DQB1*02:01–DRB1*03:01 was the most frequent class II haplotype in patients (13/32, 41%). DQB1*02:01 was the only allele found to be significantly more common in patients than in controls (20/137, 15%, corrected p  = 0.03, OR 3.96, 95% CI [1.54–10.09]). There was also a trend towards more frequent DQA1*05:01 among patients compared to controls (22/137, 16%; corrected p  = 0.05, OR 3.54, 95% CI [1.40–8.91]) and towards a protective effect of DQB1*03:01 (2/32, 6% in patients vs. 42/137, 31% in control group; corrected p  = 0.05, OR 0.15, 95% CI [0.02–0.65]). There was no significant demographic or clinical difference between DQ2 and non-DQ2 carriers ( p  > 0.05). Taken together, these findings suggest a primary DQ effect on GAD65-Ab neurological diseases, partially shared with other systemic organ-specific autoimmune diseases such as T1DM. However, it is likely that other non-HLA loci are involved in the genetic predisposition of GAD65-Ab neurological syndromes.

Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response to a peripheral cancer. Patients with small cell lung carcinoma or malignant thymoma can develop an autoimmune response against the CV2/collapsin response mediator protein 5 (CRMP5) antigen, with approximately 80% of these patients experiencing painful neuropathies. Here we investigate the mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related pain and find that patient-derived CV2/CRMP5-Abs bind to their target on rat dorsal root ganglia (DRG) and superficial laminae of the spinal cord, to induce DRG neuron hyperexcitability and mechanical hypersensitivity. These effects from patient-derived Abs are recapitulated in rats immunized with a DNA vaccine for CRMP5, in which therapeutic treatment with anti-CD20 depleting B cells ameliorates autoimmunity and neuropathy. Our data thus reveal a mechanism of neuropathic pain in patients with paraneoplastic neurological syndromes and implicates CV2/CRMP5-Abs as a potential target for treating paraneoplastic neurological syndromes. Lung and thymoma cancer patients often suffer from autoimmunity and related painful neuropathies. Here the authors show that patient-derived anti-CRMP5 autoantibody binds to rat dorsal root ganglia to cause pain, that immunizing rats with CRMP5 recapitulates these phenotypes, and that depleting rat B cells with anti-CD20 ameliorates related symptoms.