Corticospinal tract hyperintensity in patients with LGI1-antibody encephalitis and other central nervous system disorders with neuroglial antibodies.

The frequency of corticospinal tract (CST) T2/FLAIR hyperintensity in disorders with neuroglial antibodies is unclear. Herein, we retrospectively reviewed brain MRIs of 101 LGI1-antibody encephalitis patients, and observed CST hyperintensity in 30/101 (30%). It was mostly bilateral (93%), not associated with upper motor neuron signs/symptoms (7%), and frequently decreased over time (39%). In a systematic review including patients with other neuroglial antibodies, CST hyperintensity was reported in 110 with neuromyelitis optica (94%), myelin oligodendrocyte glycoprotein-associated disease (2%), Ma2-antibody (3%) and GAD65-antibody paraneoplastic neurological syndrome (1%). CST hyperintensity is not an infrequent finding in LGI1-Ab encephalitis and other disorders with neuroglial antibodies.

Predictors and Clinical Characteristics of Relapses in LGI1-Antibody Encephalitis.

BACKGROUND AND OBJECTIVES: Relapses occur in 15%-25% of patients with leucine-rich glioma-inactivated 1 antibody (LGI1-Ab) autoimmune encephalitis and may cause additional disability. In this study, we clinically characterized the relapses and identified factors predicting their occurrence. METHODS: This is a retrospective chart review of patients with LGI1-Ab encephalitis diagnosed at our center between 2005 and 2022. Relapse was defined as worsening of previous or appearance of new symptoms after at least 3 months of clinical stabilization. RESULTS: Among 210 patients, 30 (14%) experienced a total of 33 relapses. The median time to first relapse was 23.9 months (range: 4.9-110.1, interquartile range [IQR]: 17.8). The CSF was inflammatory in 11/25 (44%) relapses, while LGI1-Abs were found in the serum in 16/24 (67%) and in the CSF in 12/26 (46%); brain MRI was abnormal in 16/26 (62%) relapses. Compared with the initial episode, relapses manifested less frequently with 3 or more symptoms (4/30 patients, 13% vs 28/30, 93%; p < 0.001) and had lower maximal modified Rankin scale (mRS) score (median 3, range: 2-5, IQR: 1 vs 3, range: 2-5, IQR: 0; p = 0.001). The median mRS at last follow-up after relapse (2, range: 0-4, IQR: 2) was significantly higher than after the initial episode (1, range: 0-4, IQR: 1; p = 0.005). Relapsing patients did not differ in their initial clinical and diagnostic features from 85 patients without relapse. Nevertheless, residual cognitive dysfunction after the initial episode (hazard ratio:13.8, 95% confidence interval [1.5; 129.5]; p = 0.022) and no administration of corticosteroids at the initial episode (hazard ratio: 4.8, 95% confidence interval [1.1; 21.1]; p = 0.036) were significantly associated with an increased risk of relapse. DISCUSSION: Relapses may occur years after the initial encephalitis episode and are usually milder but cause additional disability. Corticosteroid treatment reduces the risk of future relapses, while patients with residual cognitive dysfunction after the initial episode have an increased relapse risk.

Peripheral nervous system involvement accompanies central nervous system involvement in anti-glial fibrillary acidic protein (GFAP) antibody-related 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.

Anti-LGI1 Encephalitis With Co-occurring IgLON5 Antibodies: Clinical Features and Human Leukocyte Antigen Haplotypes.

OBJECTIVES: Autoimmune encephalitis (AE) with antibodies against LGI1 and IgLON5 are clinically distinctive but share some particularities such as a strong association with specific human leukocyte antigen (HLA) class II alleles. METHODS: We clinically describe a patient with double positivity for LGI1 and IgLON5 antibodies. In addition, we conducted specific immunodepletion with the patient's serum and HLA typing and investigated the presence of serum IgLON5 antibodies in a cohort of 23 anti-LGI1 patients carrying the HLA predisposing for anti-IgLON5 encephalitis. RESULTS: A 70-year-old woman with a history of lymphoepithelial thymoma presented with subacute cognitive impairment and seizures. Investigations included MRI and EEG showing medial temporal involvement, increased CSF protein content, and polysomnography with REM and non-REM motor activity, along with obstructive apnea. Neural antibody testing revealed both LGI1 and IgLON5 antibodies in serum and CSF, and serum immunodepletion ruled out cross-reactivity. The patient carried DRB1*07:01 and DQA1*01:01∼DQB1*05:01, but no other IgLON5-positive case was identified in a cohort of anti-LGI1 patients carrying DQA1*01∼DQB1*05. Nearly full therapeutic response was obtained after intensified immunosuppressive treatment. DISCUSSION: We present a case of anti-LGI1 encephalitis with concomitant IgLON5 antibodies. Co-occurring IgLON5 antibodies in anti-LGI1 encephalitis are exceptional, but may appear in genetically predisposed individuals.

Glial Fibrillary Acidic Protein Autoimmunity: A French Cohort Study.

BACKGROUND AND OBJECTIVES: To report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies. METHODS: We retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers. RESULTS: We identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies. DISCUSSION: GFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.

Central nervous system complications associated with immune checkpoint inhibitors.

OBJECTIVE: To describe the spectrum and outcome of central nervous system complications associated with immune checkpoint inhibitors (CNS-ICI). METHODS: Patients with CNS-ICI were identified and their characteristics compared with ICI-related peripheral neuropathy (PN-ICI). RESULTS: We identified 19 patients with CNS-ICI. The patients were receiving nivolumab (n=8), pembrolizumab (n=6), a combination of ipilimumab-nivolumab (n=3), ipilimumab-durvalumab (n=1), or atezolizumab (n=1). Underlying malignancies included non-small-cell lung cancer (n=8), melanoma (n=3), and other less common tumours (n=8). Neurological phenotypes were limbic encephalitis (n=8), meningoencephalitis (n=4) and cerebellitis (n=4). Two patients developed isolated confusion and one parkinsonism. Associated autoantibodies included onconeural (Ma2, n=7; Hu, n=1), astrocytic (glial fibrillar acidic protein, n=2) and neuronal surface (contactin-associated protein-like 2, n=1) specificities. ICIs were withheld and corticosteroid treatment was given in all cases. Five patients received intravenous immunoglobulin, two rituximab, one plasmapheresis and one infliximab. Overall, six patients died. Readministration of ICI was attempted in three patients, without further relapses. Non-small-cell lung cancer was significantly more frequent in patients with CNS-ICI (p<0.01), while melanoma and ipilimumab treatment were more common in PN-ICI (p<0.01 and p=0.01). Conversely, CNS-ICI cases were more frequently antibody-positive than PN-ICI (p<0.01) and showed a strong trend towards poorer outcome (p=0.053). CONCLUSION: Three main clinical phenotypes characterise CNS complications of ICIs, each with distinct immunological background, disease course and response to treatment. Other clinical manifestations (including parkinsonism and steroid-responsive confusion) are also possible. Underlying cancers, antibody prevalence and outcome appear different from those of patients with PN-ICI.

Malignant tumors in autoimmune encephalitis with anti-NMDA receptor antibodies.

OBJECTIVE: The aim of this study was to describe specificities of patients with NMDA receptor antibody (NMDAR-Ab) encephalitis associated with a malignant tumor. METHODS: Retrospective observational study of 252 patients with NMDAR-Ab encephalitis of the French Paraneoplastic Neurological Syndrome Reference Center. Patients were classified in three groups: (1) non-malignant ovarian teratomas, (2) malignant ovarian teratomas (immature), and (3) other malignant tumors. RESULTS: Sixty patients (23.8%) had an associated tumor and 15 (6%) were malignant. No particular neurological symptom was observed in these patients. Ovarian teratomas were the most frequent (51 cases) with 6 of them immature (11.8% of teratomas). Nine patients (3.6%) developed other malignant tumors (3 small cell lung carcinomas, 1 uterine adenocarcinoma, 1 prostate adenocarcinoma, 1 Hodgkin lymphoma, 1 pineal dysgerminoma, 1 neuroblastoma and 1 pancreatic neuroendocrine tumor). Among patients with a cancer other than teratoma, 6/9 were elderly patients (median age 65 years, representing 30% of elderly patients with such encephalitis) compared to a median age of 26 years in adult patients included herein. The clinical course was similar in the three groups, other than a higher death rate among patients with malignant tumors (86 versus 2%; p < 0.001) mainly due to tumor progression (5/7 deaths). CONCLUSION: Immature ovarian teratomas represent 11.8% of all teratomas in patients with NDMAR-Ab encephalitis. The other malignant tumors are mainly observed in elderly patients. The presence of a malignant tumor does not impact the neurological presentation but is directly associated with a higher risk of death.

Characteristics in limbic encephalitis with anti-adenylate kinase 5 autoantibodies.

OBJECTIVE: To report 10 patients with limbic encephalitis (LE) and adenylate kinase 5 autoantibodies (AK5-Abs). METHODS: We conducted a retrospective study in a cohort of 50 patients with LE with uncharacterized autoantibodies and identified a specific target using immunohistochemistry, Western blotting, immunoprecipitation, mass spectrometry, and cell-based assay. RESULTS: AK5 (a known autoantigen of LE) was identified as the target of antibodies in the CSFs and sera of 10 patients with LE (median age 64 years; range 57-80), which was characterized by subacute anterograde amnesia without seizure and sometimes preceded by a prodromal phase of asthenia or mood disturbances. Anterograde amnesia can be isolated, but some patients also complained of prosopagnosia, paroxysmal anxiety, or abnormal behavior. No associated cancer was observed. All 10 patients had bilateral hippocampal hypersignal on a brain MRI. CSF analysis generally showed a mild pleiocytosis with elevated immunoglobulin G index and oligoclonal bands, as well as high levels of tau protein with normal concentration of Aß42 and phospho-tau, suggesting a process of neuronal death. Except for one patient, clinical response to immunotherapy was unfavorable, with persistence of severe anterograde amnesia. Two patients evolved to severe cognitive decline. Hippocampal atrophy was observed on control brain MRI. Using in vitro tests on hippocampal neurons, we did not identify clues suggesting a direct pathogenic role of AK5-Abs. CONCLUSIONS: AK5-Abs should be systematically considered in aged patients with subacute anterograde amnesia. Recognition of this disorder is important to develop new treatment strategies to prevent irreversible limbic damage.

Anti-NMDA-R encephalitis: Should we consider extreme delta brush as electrical status epilepticus?

Seizures are common clinical manifestations in anti-N-methyl-d-aspartate receptor (anti-NMDA-R) encephalitis, among other neurological and psychiatric symptoms. During the course of the disease, some specific EEG patterns have been described: generalized rhythmic delta activity (GRDA) and extreme delta brush (EDB). In comatose patients, the association of these EEG abnormalities with subtle motor manifestations can suggest ongoing non-convulsive status epilepticus (NCSE). We report the case of a 28-year-old woman admitted for a clinical presentation typical of anti-NMDA-R encephalitis, which was confirmed by CSF analysis. She was rapidly intubated because of severe dysautonomia and disturbed consciousness. Clinical examination revealed subtle paroxysmal and intermittent myoclonic and tonic movements, correlated on video-EEG with GRDA and/or EDB. NCSE was then suspected, but electroclinical manifestations persisted despite many anti-epileptic drugs combinations, or reappeared when barbiturate anesthesia was decreased. In order to confirm or dismiss the diagnosis, intracranial pressure (ICP) and surface video-EEG monitoring were performed simultaneously and revealed no ICP increase, thus being strongly against a diagnosis of seizures. Sedation was progressively weaned, and clinical condition as well as EEG appearance progressively improved. Literature review revealed 11 similar cases, including 2 with focal NCSE. Of the nine other cases, NCSE diagnosis was finally excluded in 5 cases. NCSE diagnosis in association with anti-NMDA-R encephalitis is sometimes very difficult and its occurrence might be overestimated. Video-EEG is highly recommended and more invasive techniques may sometimes be necessary.