OBJECTIVES:To characterize the magnetic resonance imaging (MRI) lesion dynamics, comorbidities, predictors of relapse, and outcomes in anti-γ-aminobutyric acid type A receptor (GABAAR) encephalitis, and assess the utility of LIM-domain-only-protein 5 (LMO5) antibodies as tumor markers. METHODS:GABAAR antibodies were confirmed by 2 techniques in serum or cerebrospinal fluid. Long-term outcomes were defined as good (modified Rankin scale, mRS = 0-1) or poor (mRS 2-5) at ≥12 months. LMO5 antibodies were assessed by cell-based assays and Western blot. RESULTS:Thirty-three patients were identified (4 children, 29 adults; median age, 5.5 and 60 years; 61% male). Ten patients (10/32, 31%) had concurrent systemic autoimmunity. Adults presented with seizures and cognitive/behavioral symptoms, often with thymoma, gastrointestinal, or other tumors (18/33, 55%), whereas children frequently had seizures and ataxia with cerebellar MRI lesions. Multifocal T2/fluid-attenuated inversion recovery hyperintensities were present at onset in 23 of 31 (74%) or developed later in those with absent or single lesions. Lesions showed dynamic changes, suggesting ongoing inflammation even without clinical correlate. Relapses occurred in 17 of 31 (55%, all adults) and were associated with older age (p = 0.02) and lack of second-line immunotherapy (p = 0.02). Four patients (4/33, 12%) died. After a 32.5-month median follow-up, 9 of 20 (45%) had persistent cognitive deficits, and 6 of 20 (30%) had a poor outcome, which was associated with relapses (p = 0.04). LMO5 antibodies were absent in patients and controls. INTERPRETATION:Anti-GABAAR encephalitis shows age-dependent presentations, most commonly seizures. MRI reveals dynamic changes consistent with an ongoing "clinically silent" inflammation. Relapses and cognitive sequelae are common and associate with not receiving second-line immunotherapy. LMO5 antibodies lack tumor-predictive value. ANN NEUROL 2026;100:139-150.

BACKGROUND:In anti-NMDA receptor (NMDAR) encephalitis, delayed recovery and slow improvement makes it difficult to assess treatment refractoriness, leaving a knowledge gap about prolonged impaired consciousness. We aimed to assess treatment response, long-term outcomes, and their predictors in patients with NMDAR encephalitis and a prolonged vegetative state. METHODS:In this international retrospective cohort study, we included patients with NMDAR encephalitis from Jan 1, 2007 to Sept 30, 2024 who remained in a vegetative state (unresponsive wakefulness) for 9 months or longer in 21 hospitals across Austria, Brazil, Chile, China, Germany, Hong Kong, Japan, the Netherlands, Spain, Switzerland, and the USA. Data on disease presentation and long-term outcomes were collected via medical record review and a structured questionnaire sent to referring physicians. Outcomes were death, ability to follow commands, reaching a modified Rankin Scale (mRS) score of 2, or complete recovery (mRS 0 with return to premorbid activities). Competing risks analysis was used to assess survival and predictors of death, mRS score 2, and recovery. FINDINGS:45 patients were identified (38 female and seven male; median age 22 [IQR 19-31] years). The patients had impaired consciousness a median of 9 days after symptom onset (IQR 5-16). All 45 patients received first-line immunotherapy; 41 (91%) received second-line, and 18 (40%) received third-line immunotherapies. 21 (47%) of 45 patients had ovarian teratomas, which were removed in 20 patients. Median durations were: vegetative state 399 days (IQR 307-698); intensive care unit stay 275 days (189-354); mechanical ventilation 270 days (195-394); and hospitalisation 474 days (349-715). 13 (28%) patients were resuscitated from dysautonomic cardiac arrest. After a median of 5 years (IQR 3-7), 15 (33%) of 45 patients completely recovered (mRS score ≤1 and returned to all previous activities), 13 (29%) substantially improved (mRS score 2), 11 (24%) had mRS score 3-5, and six (13%) died. Five patients began command-following a median of 11 months (IQR 2-21) after last immunotherapy. Estimated cumulative incidence for reaching an mRS score of 2 was 66% at 5 years and 76% at 10 years, and for recovery was 32% at 5 years and 54% at 10 years. Teratomas were associated with a lower probability of reaching mRS score 2 (sub-distribution hazard ratio 0·39 [95% CI 0·18-0·84], p=0·0160), whereas older age (1·10 per year [1·04-1·23], p=0·0052) and higher NMDAR encephalitis 1-Year Functional Status (NEOS)2 score (1·51 [1·12-2·04], p=0·0072) were associated with increased mortality. INTERPRETATION:In people with NMDAR encephalitis and prolonged impairment of consciousness, full or substantial recovery was reached in approximately two-thirds of cases. Consequently, early assessment of treatment response or refractoriness might underestimate delayed improvement, prolonged therapy needs, or spontaneous recovery. Futility decisions should therefore be individualised with multidisciplinary input and based on extended follow-up. FUNDING:Instituto de Salud Carlos III and Fundació La Caixa.

Anti-CRMP5/CV2 antibody disease is a rare cause of optic neuritis, therefore the clinical findings, results of neuroimaging, CSF studies and treatment outcomes have been described in case reports or small case series. Here, we performed a systematic review including all published cases of optic neuritis with positive anti-CRMP5/CV2 antibodies. Twenty-four articles comprising 32 patients were included. Median age was 67 years (60-71); 87.1% of patients had clinically symptomatic bilateral optic neuritis, with 64% having a visual acuity worse than 20/200 and ocular pain was uncommon (4.2%). An associated malignancy was identified in 90.6% of cases, most commonly small-cell lung carcinoma (more than 70%) and breast (5%). Optic disc edema occurred in 83.9%, frequently with vitreous (70.8%) and retinal (35%) inflammation. Orbit MRI was normal in 57.1% of cases, but CSF almost universally showed pleocytosis. Overall mortality was 32.1% (9 of 28 patients) at a median follow-up of 9.5 (4-23) months. Absence of tumor response to oncologic treatment was strongly associated with higher mortality (88.9%) and final visual acuity worse than or equal to 20/200 (71.4%), whereas escalation of immunosuppression, such as immunoglobulin, plasmapheresis, and cyclophosphamide, was not associated with improved outcomes. Further investigation into the mechanisms by which CD8+ cytotoxic T-cell recruitment and activation in the pre-laminar optic nerve is essential to develop targeted therapies that can improve visual outcomes.

BACKGROUND AND OBJECTIVES:The aim of this study was to describe the clinical features and long-term outcome of patients with glycine receptor (GlyR) antibody-mediated progressive encephalomyelitis with rigidity and myoclonus (PERM), a disease commonly included under the term of stiff-person spectrum disorders (SPSDs). METHODS:We conducted a retrospective analysis of patients with PERM and GlyR antibodies diagnosed in our laboratory and a systematic literature review (following Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA] 2020 reporting guideline) of previously reported patients with sufficient clinical information and ≥12 months of follow-up. Neurologic disability was measured with the modified Rankin Scale (mRS). Relapses were defined as any event occurring >6 months after the first episode that required immunotherapy. RESULTS:Forty-one patients were identified, 22 from our database and 19 from the literature. The median age was 58 years (IQR: 43-66 years), and 36 (88%) were male and 5 female. The median time from symptom onset to admission was 2 weeks (IQR: 1-4 weeks). Predominant presentations included brainstem symptoms, mainly dysphagia and trismus, in 23 patients (56%); muscle stiffness and myoclonus in 9 (22%); dysesthesias or pruritus in 7 (17%); and cacosmia with dysgeusia in 2 (5%). Five patients (12%) never developed muscle stiffness. The median (range) mRS score at nadir was 5 (3-5). All patients received immunotherapy. Eleven patients died, 8 from complications of PERM. There were 12 relapses in 10 (28%) of 36 patients who lived >6 months. All relapses responded to immunotherapy. The functional status at the last visit, median time 24 months (IQR: 18-72 months), was good (mRS score <3) in 23 (70%) of the 33 patients who did not die from PERM. Age (HR: 1.06; 95% CI 1.01-1.11; p = 0.019) and admission to the intensive care unit (HR: 5.26; 95% CI 1.41-19.57, p = 0.013) were independent predictors of bad outcome (mRS score ≥3). DISCUSSION:GlyR antibody-mediated PERM is a rapidly progressive and severe disease that predominantly affects men and frequently presents with brainstem involvement. Its distinct demographic and clinical features suggest that it should be considered separately from SPSDs, which typically follows a chronic course and is more commonly associated with glutamic acid decarboxylase antibodies.

BACKGROUND AND OBJECTIVES:Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (anti-AMPAR) encephalitis manifests as limbic encephalitis in adults and is often associated with cancer. Although some reports suggest that it may occur in children, the clinical features in this population, as well as the prognostic factors and long-term outcomes in children and adults, are unknown. METHODS:We performed a retrospective, international collaborative study of patients with anti-AMPAR encephalitis. Clinical information was reviewed, together with data from published pediatric patients. Clinical features of children and adults were compared with nonparametric tests. Survival rates (Kaplan-Meier curves) were compared using log-rank tests. Prognostic factors of poor outcome (modified Rankin Scale score >2) were identified using logistic regression models. RESULTS:A total of 115 patients were included, of whom 84 (71 adults, 13 children) had only AMPAR antibodies and 31 (27 adults, 4 children) had additional concurrent neural antibodies. Among patients with AMPAR antibodies alone, tumors were identified in 37 adults (56%) and none of the children (p < 0.0001). Children were more likely than adults to have behavioral/psychiatric symptoms (5/13, 39%, vs 8/71, 11%, p = 0.026) at onset, cerebellar dysfunction (6/13, 46%, vs 7/68, 10% p = 0.005) or movement disorders (5/13, 39%, vs 8/67, 12%, p = 0.032) during the disease course, and extratemporal brain MRI lesions (4/9, 44%, vs 5/44, 11%, p = 0.035). Among 34 patients with prolonged follow-up (>24 months), long-term neurocognitive sequelae were reported in 23 (68%), all adults. Failure to respond to first-line immunotherapy at multivariable analysis predicted a poor outcome (OR 8.0, 95% CI 1.1-59.2, p = 0.043). Among the 31 patients with concurrent neural autoantibodies, 22 (79%) had a tumor; those with high-risk antibodies had lower survival rates (p = 0.008). DISCUSSION:Children and adults with anti-AMPAR encephalitis show distinct clinical-radiologic features. At long-term follow-up, 68% of patients, all adults, have neurologic sequelae, with failure to respond to first-line immunotherapy being associated with worse outcomes.

BACKGROUND AND OBJECTIVES:Anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis is the most common antibody-mediated encephalitis in adults older than 50 years. In addition to antibody effects, cytokines and chemokines drive neuroinflammation in other autoimmune encephalitides. However, their role in anti-LGI1 encephalitis is underexplored. We evaluated cytokine profiles in serum and CSF, correlating them with acute severity and long-term outcome. METHODS:Cytokine/chemokine levels from 57 untreated patients with anti-LGI1 encephalitis were measured in serum and CSF (34 paired samples) with a bead-based multiplex assay and compared with those of patients with noninflammatory neurologic disorders (serum = 24; CSF = 21). Clinical information including degree of severity (modified Rankin Scale, mRS) and 12-month functional outcomes (resume previous activities and work) was assessed. RESULTS:Patients with anti-LGI1 encephalitis exhibited an increased proinflammatory profile in CSF and serum, with elevated levels of IL-1β, IL-1RA, IL-6, IL-8, IL-10, IL-18, IL-35, IP-10, granzyme B, CX3CL1, MIG, TNFα, and SDF1. A higher CSF/serum IL-6 ratio correlated with disease severity at onset (mRS score >2: 1.67 [0.50-7.20] vs 0.39 [0.07-1.22], p = 0.0069). Elevated acute-phase serum IL-35 predicted poorer 12-month outcomes (81.34 vs 9.19 pg/mL in partial vs complete recovery, p = 0.0003). Increased B cell-related markers (IL-21, BAFF, APRIL, CXCL13) in CSF (all p < 0.05) were also observed. DISCUSSION:In this study, we show that the acute-phase IL-6 CSF/serum ratio and serum IL-35 levels in immunotherapy-naive patients with anti-LGI1 encephalitis are associated with disease severity and poor outcomes, respectively, highlighting their potential as biomarkers for risk stratification and therapeutic targeting.

OBJECTIVES:To report the association of zinc finger and SCAN domain containing 1 antibodies (ZSCAN1-abs) with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome in patients without tumor. METHODS:Patients with symptoms compatible with ROHHAD syndrome but without an associated tumor were selected from our database. Serum and CSF samples were examined for the presence of ZSCAN1-abs by an in-house cell-based assay. In addition, samples from 149 patients with several inflammatory and noninflammatory disorders and 50 healthy participants served as controls. RESULTS:Thirteen patients with ROHHAD syndrome were identified. Of these, we had paired serum/CSF samples from 6 patients and only serum from the other 7. Five of 6 patients (83.3%) with paired serum/CSF (4 children, 1 adult) had ZSCAN-abs only in CSF and 1 had antibodies in serum and CSF. ZSCAN1-abs were not detected in the remaining 7 patients with ROHHAD with only serum available or in any of the 199 control samples. DISCUSSION:Patients with ROHHAD syndrome should be investigated for the presence of ZSCAN1-abs in CSF. The antibodies do not necessarily predict the presence of a tumor. The detection of ZSCAN1-abs in an adult patient suggests that this condition also occurs beyond the pediatric age.

OBJECTIVES:To assess the daily function of children with anti-N-methyl-d-aspartate receptor encephalitis (NMDARe) after a minimal follow-up of 5 years.METHODS:Patients 18 years and younger by the time of disease onset, whose serum and CSF were studied in our center between 2013 and 2017, were included in the study. Patients' daily life function was assessed by their physicians using a 15-domain question format (Liverpool Outcome Score).RESULTS:Of 76 patients, 8 (11%) died and 68 were followed for a mean of 7.1 years (SD 1.5 years, range: 5.0-10.1). Three outcome patterns were identified: full recovery (50; 73%); behavioral and school/working deficits (12; 18%); and multidomain deficits (6; 9%) involving self-care ability, behavioral-cognitive impairment, and seizures. Younger age of disease onset was significantly associated with multidomain deficits (OR 1.6, 95% CI 1.02-2.4, p = 0.04), particularly in children younger than 6 years, among whom 8 of 23 (35%) remained sociofamiliar dependent.DISCUSSION:After a minimal follow-up of 5 years, most children with NMDARe had substantial or full functional recovery, but approximately one-fifth remained with behavioral and school/working deficits. The younger the patient at disease onset, the more probable it was to remain with multidomain deficits and dependent on sociofamiliar support.

The encounter of disorders associated with antibodies to neuronal enzymes caused a paradigm shift in understanding the CNS autoimmunity.The autoimmune disorders targeting the 65kDa isoform of glutamic acid decarboxylase (GAD65) not only comprehends type 1 diabetes mellitus (T1DM), but also rather rare neurological disorders, including stiff-person syndrome (SPS), cerebellar ataxia, limbic encephalitis, and epilepsy.The patients with these autoimmune neurological disorders usually present with T1DM and suggests the presence of GAD65 antibodies.This is suggestive of autoimmune mechanisms for the development and worsening of these disorders.For better prognosis, its advanced screening and swift treatment are essential.Mesenchymal stem cells (MSCs) can be a promising salvage to these autoimmune disorders as they have proven hypoimmunogenic and immunomodulatory properties along with excellent regenerative ability.These self-renewing progenitor cells can differentiate into numerous cell types under explicit conditions, which includes neurons and pancreatic beta cells.MSCs annul the proinflammatory response in autoimmune disorders, may be through paracrine secretions, and hence, can help managing the hurricane of disturbed immunity.We present a link between the mechanisms driving autoimmune neurological diseases and T1DM in this review, based on the existence of GAD65 antibodies and an MSC-mediated solution for their treatment.

OBJECTIVES:Pathogenic variants in presenilin 1 (PSEN1) are related to early-onset Alzheimer disease (AD) and may occur as de novo variants. In comparison with sporadic forms, it can present with psychiatric manifestations, seizures, myoclonus, and focal presentation. Because PSEN1 can occur in young patients who lack a family history of neurologic disorders and because these symptoms are also frequent in autoimmune encephalitis (AE), diagnosis may be overlooked. Our aim was to demonstrate the challenge in diagnosing young patients with neurodegenerative diseases that simulate AE. METHODS:We describe a case of a young patient with insidious progressive dementia, myoclonus, seizures, and aphasia, with no family history of dementia, along with signs suggestive of neuroinflammation on brain MRI and CSF examination. RESULTS:She was initially misdiagnosed as having AE. Further investigation was performed, leading to the discovery of a novel and de novo pathogenic variant in PSEN1. DISCUSSION:This case demonstrates the importance of considering PSEN1 in young patients with insidious progressive dementia with atypical clinical and neuroimaging features, even in patients without a family history of neurologic disorders. Not adhering to published criteria of possible and probable AE and overinterpretation of subtle inflammatory findings in CSF and MRI contribute to misdiagnosis.

ABSTRACT Autoimmune encephalitis (AE) comprises a group of diseases mediated by antibodies against neuronal cell surface or synaptic antigens, such as ion channels or neurotransmitter receptors. New clinical syndromes and their associated antibodies were and are still being characterized over the last two decades. The fact that their main clinical features are interdisciplinary, - encompassing neuropsychiatric symptoms, cognitive dysfunction, epileptic seizures, movement and sleep disorders - has led to a surge of interest in this field. Some of these diseases present with a well-defined syndrome, being recognizable on clinical grounds. Correct diagnosis is important since AE are potentially treatable diseases, despite their severity. On the other hand, an increasing number of neuronal antibodies being described casts doubt upon the way we should utilize antibody testing and interpret results. In this article we review, summarize and update the current knowledge on antibody mediated encephalitis.

BACKGROUND AND OBJECTIVES:Anti-IgLON5 disease is a recently described neurologic disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are underreported. We describe the frequency and types of movement disorders in a series of consecutive patients with this disease.METHODS:In this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by 3 experts in movement disorders.RESULTS:Seventy-two patients were included. In 41 (57%), the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least 1 movement disorder with a median of 3 per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients [72%]), chorea (24 [33%]), bradykinesia (20 [28%]), dystonia (19 [26%]), abnormal body postures or rigidity (18 [25%]), and tremor (15 [21%]). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients [32%]) including dystonia (13), myorhythmia (6), chorea (4), or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31 (43%) patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only 7 (13%) cases.DISCUSSION:Movement disorders are a frequent and leading cause of initial neurologic consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.

Meningoencephalitis following yellow fever vaccination is considered a viral neuroinvasive disease. We describe three patients with typical autoimmune encephalitis syndromes that developed 1?27 days following yellow fever vaccination. Anti-N-methyl-D-aspartate-r antibodies were identified in the CSF and serum of two patients and the other case was associated with anti-neurexin-3 antibodies. One case was confirmed as vaccine-associated neurotropic disease due to reactive CSF yellow fever IgM, which suggested an infectious-autoimmune overlap mechanism. Two aditional cases of Anti-N-methyl-D-aspartate-r encephalitis were identified in the literature review. Antibody-positive autoimmune encephalitis should be included in the differential diagnosis of neurologic adverse events following yellow fever vaccination.

A 41-year-old man was admitted to the neurology ward due to progressive vertigo and unsteadiness for the previous 2 months. Neurologic examination was remarkable for a global cerebellar syndrome. Investigation with brain MRI led to the hypothesis of a histiocytosis due to infiltrative lesions of the pons, cerebellar peduncles, and pituitary. Therefore, investigation progressed with chest/abdomen/pelvis CT, bone scintigraphy, and a tibial biopsy that confirmed the diagnosis of Erdheim-Chester disease (figures 1 and 2, video).