Cerebral Cortical Encephalitis in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Cerebral cortical encephalitis (CCE) is a recently described myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) phenotype. In this observational retrospective study, we characterized 19 CCE patients (6.7% of our MOGAD cohort). Headache (n = 15, 79%), seizures (n = 13, 68%), and encephalopathy (n = 12, 63%) were frequent. Magnetic resonance imaging revealed unilateral (n = 12, 63%) or bilateral (n = 7, 37%) cortical T2 hyperintensity and leptomeningeal enhancement (n = 17, 89%). N-Methyl-D-aspartate receptor autoantibodies coexisted in 2 of 15 tested (13%). CCE pathology (n = 2) showed extensive subpial cortical demyelination (n = 2), microglial reactivity (n = 2), and inflammatory infiltrates (perivascular, n = 1; meningeal, n = 1). Most received high-dose steroids (n = 17, 89%), and all improved, but 3 had CCE relapses. This study highlights the CCE spectrum and provides insight into its pathogenesis. ANN NEUROL 2023;93:297-302.

Alterations in Aquaporin-4-IgG Serostatus in 986 Patients: A Laboratory-Based Longitudinal Analysis.

OBJECTIVE: This study was undertaken to investigate factors associated with aquaporin-4 (AQP4)-IgG serostatus change using a large serological database. METHODS: This retrospective study utilizes Mayo Clinic Neuroimmunology Laboratory data from 2007 to 2021. We included all patients with ≥2 AQP4-IgG tests (by cell-based assay). The frequency and clinical factors associated with serostatus change were evaluated. Multivariable logistic regression analysis examined whether age, sex, or initial titer was associated with serostatus change. RESULTS: There were 933 patients who had ≥2 AQP4-IgG tests with an initial positive result. Of those, 830 (89%) remained seropositive and 103 (11%) seroreverted to negative. Median interval to seroreversion was 1.2 years (interquartile range [IQR] = 0.4-3.5). Of those with sustained seropositivity, titers were stable in 92%. Seroreversion was associated with age ≤ 20 years (odds ratio [OR] = 2.25; 95% confidence interval [CI] = 1.09-4.63; p = 0.028) and low initial titer of ≤1:100 (OR = 11.44, 95% CI = 3.17-41.26, p < 0.001), and 5 had clinical attacks despite seroreversion. Among 62 retested after seroreversion, 50% returned to seropositive (median = 224 days, IQR = 160-371). An initial negative AQP4-IgG test occurred in 9,308 patients. Of those, 99% remained seronegative and 53 (0.3%) seroconverted at a median interval of 0.76 years (IQR = 0.37-1.68). INTERPRETATION: AQP4-IgG seropositivity usually persists over time with little change in titer. Seroreversion to negative is uncommon (11%) and associated with lower titers and younger age. Seroreversion was often transient, and attacks occasionally occurred despite prior seroreversion, suggesting it may not reliably reflect disease activity. Seroconversion to positive is rare (<1%), limiting the utility of repeat testing in seronegative patients unless clinical suspicion is high. ANN NEUROL 2023;94:727-735.

Predictors for the development of neurological immune-related adverse events of immune checkpoint inhibitors and impact on mortality.

BACKGROUND AND PURPOSE: Little is known about risk factors for developing neurological immunological adverse events (neuro-irAEs) from immune checkpoint inhibitors (ICIs). We report the incidence, predictors for development, impact on mortality of neuro-irAEs, and impact of ICIs on pre-existing neurological conditions in a large clinical cohort. METHODS: Patients who received ICIs between January 2011 and December 2018 were identified from a tertiary cancer center registry. Descriptive statistics were used to summarize patient, cancer, and treatment data. Odds ratios from univariable and multivariable logistic regression models were calculated to identify potential predictors for developing a neuro-irAE. Impact of neuro-irAEs on overall survival was estimated by Kaplan-Meier and Cox proportional hazard models. RESULTS: Overall frequency of neurological irAEs was 2.3%. Peripheral nervous system complications were most frequent (53.6%). Melanoma, younger age, prior chemotherapy, prior resection, CTLA-4 ICIs exposure, and combination PD-1 and CTLA-4 ICIs exposure had significantly higher odds for developing a neuro-irAE (p < 0.05) in univariate but not multivariate models. Those with a neuro-irAE were less likely to die at 3 years compared to those without a neuro-irAE (69% vs. 55%, p = 0.004) in univariate but not multivariate model. Flare of pre-existing neurological condition after exposure to ICIs was present (15.4%, 2 of 13 patients) but manageable. One patient was rechallenged with ICIs without recurrent flare. CONCLUSIONS: Neuro-irAEs are not associated with increase in overall mortality. Potential predictors for the development of neuro-irAEs are younger age, melanoma, prior chemotherapy and resection, CTLA-4, or combination ICIs exposure.

Cognitive outcomes in anti-LGI-1 encephalitis.

OBJECTIVE: Cognitive impairment is one of the most common symptoms of anti-leucine rich glioma inactivated 1 (anti-LGI-1) encephalitis, but little is known about the cognitive profile of these patients. This study characterized the cognitive profile of patients with anti-LGI-1 encephalitis and compared patterns of impairment to healthy controls and other patient groups with known temporal lobe/limbic involvement. METHODS: A retrospective analysis of adult patients with anti-LGI-1 encephalitis who underwent neuropsychological assessment was conducted. Performance patterns of anti-LGI-1 patients were compared to patients deemed cognitively healthy (HC), as well as patients with amnestic mild cognitive impairment (aMCI) and temporal lobe epilepsy (TLE). RESULTS: Among 10 anti-LGI encephalitis patients (60% male, median age 67.5 years) who underwent neuropsychological testing (median = 38.5 months from symptom onset), cognitive deficits were common, with 100% of patients showing impairment (≤1.5 SD below mean) on 1+ measures and 80% on 2+ measures. Patients with anti-LGI-1 encephalitis performed worse than controls on measures of basic attention, vigilance, psychomotor speed, complex figure copy, and aspects of learning/memory. Of measures which differed from controls, there were no differences between the anti-LGI-1 and TLE patients, while the anti-LGI-1 patients exhibited higher rates of impairment in basic attention and lower rates of delayed verbal memory impairment compared to the aMCI patients. CONCLUSIONS: Long-term cognitive deficits are common in patients with anti-LGI-1 encephalitis and involve multiple domains. Future research in larger samples is needed to confirm these findings.

Optic chiasm involvement in AQP-4 antibody-positive NMO and MOG antibody-associated disorder.

BACKGROUND: Optic neuritis (ON) is often the presenting symptom in inflammatory central nervous system demyelinating disorders. OBJECTIVE: To compare the frequency and pattern of optic chiasm involvement in patients with aquaporin-4-immunoglobulin G (AQP4-IgG)-associated ON to patients with myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG)-associated ON. METHODS: Retrospective review of all patients evaluated at Mayo Clinic, Stanford University and Ramathibodi Hospital who were found to have: (1) ON, (2) either MOG-IgG or AQP4-IgG by cell-based assay, and (3) magnetic resonance imaging (MRI) at the time of ON. MRI was reviewed for contrast enhancement of the optic chiasm and the pattern of involvement. RESULTS: One hundred and fifty-four patients (74 AQP4-IgG and 80 MOG-IgG) were included. Among patients with AQP4-IgG-ON, 20% had chiasmal involvement, compared with 16% of patients with MOG-IgG-ON (p = 0.66). In patients with chiasmal involvement, longitudinally extensive optic nerve enhancement (from orbit extending to chiasm) was identified in 54% of MOG-IgG-ON patients, compared with 7% of AQP4-IgG-ON patients (p = 0.01). CONCLUSION: Chiasmal involvement of MOG-IgG-ON and AQP4-IgG-ON occur at more similar frequencies than previously reported. Furthermore, MOG-IgG-ON chiasmal involvement is more likely to be part of a longitudinally extensive optic nerve lesion.

Coexisting systemic and organ-specific autoimmunity in MOG-IgG1-associated disorders versus AQP4-IgG+ NMOSD.

Aquaporin-4 (AQP4) neuromyelitis optica spectrum disorder (NMOSD) has been demonstrated to be associated with non-organ and organ-specific autoantibodies (antinuclear antibody, extractable nuclear antibody, double-stranded DNA, muscle acetylcholine receptor antibody) and systemic autoimmune diseases. In this study, we evaluated whether a similar association with non-organ and organ-specifc autoantibodies occurs in patients with MOG-IgG1-associated disorders. We determined that MOG-IgG1 was not strongly associated with these organ and non-organ-specific autoantibodies. Systemic lupus erythematous (SLE) was significantly associated with AQP4-IgG+ NMOSD and not with MOGAD (p = 0.037). These findings suggest differences in co-existing systemic and organ-specific autoimmunity between MOGAD and AQP4-IgG+ NMOSD.

Frequency and characteristics of MRI-negative myelitis associated with MOG autoantibodies.

BACKGROUND: Myelitis accompanied by a negative spinal cord MRI may lead to diagnostic uncertainty. OBJECTIVE AND METHODS: We retrospectively investigated the frequency of negative spinal cord MRI (performed <6 weeks from onset) in Mayo Clinic patients with myelin oligodendrocyte glycoprotein (MOG)-IgG-associated myelitis (2000-2019). RESULTS: The initial spinal cord MRI was negative in 7/73 (10%) patients, despite severe acute disability (median EDSS, 7 (range, 4.5-8)); myelitis symptoms/signs were frequent (paraparesis, neurogenic bladder, sensory level, Lhermitte's phenomenon). Myelitis lesions became overt at follow-up MRI in three patients. CONCLUSIONS: A negative spinal cord MRI should not dissuade from MOG-IgG testing in patients with acute/subacute myelitis.

MOG-IgG1 and co-existence of neuronal autoantibodies.

BACKGROUND: The presence of co-existent neuronal antibodies (neuronal-IgG) in patients with myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG1) is not yet well understood. OBJECTIVES: The aim of this study was to investigate the co-existence of a broad range of neuronal-IgG in MOG-IgG1+ patients. METHODS: MOG-IgG1+ patients were tested for 17 neuronal-IgGs in cerebrospinal fluid (CSF) and serum including NMDA-R-IgG, AMPA-R-IgG, GABAB-R-IgG, LGI1-IgG, CASPR2-IgG, GABAA-R-IgG, GAD65-IgG, mGLUR1-IgG, DPPX-IgG, CRMP5-IgG, amphiphysin-IgG, PCA1,2,Tr, and ANNA1,2,3. Clinical and radiological features of MOG-IgG1+ with NMDA-R-IgG in CSF were compared to a control cohort of MOG-IgG1+ patients without NMDA-R-IgG. RESULTS: A total of 376 MOG-IgG1+ patients underwent testing for neuronal-IgGs. Serum testing for neuronal-IgGs (113 adults, 142 children) identified one child with NMDA-R-IgG (0.7%), one child with CASPR2-IgG (0.7%), one adult with LGI1-IgG (0.9%) and one adult with GABAA-R-IgG (0.9%). CSF testing for neuronal-IgGs (97 adults, 169 children) identified seven children (4%) and seven adults (7%) with NMDA-R-IgG, and one adult with GABAA-R-IgG (1%). The MOG-IgG1+/NMDA-R-IgG+ patients had a median age of 17 (range: 2-39) years. Features associated with MOG-IgG1+/NMDA-R-IgG+ included encephalopathy (p = 0.001), seizures (p = 0.045), and leptomeningeal enhancement (p = 0.045). CONCLUSION: NMDA-R-IgG was the most frequently detected neuronal-IgG to co-exist with MOG-IgG1. MOG-IgG1+/NMDA-R-IgG+ patients most often presented with encephalopathy and seizures. Testing for MOG-IgG1 and NMDA-R-IgG may be warranted in patients with encephalopathy and inflammatory demyelinating syndromes.

Prediction of on-treatment disability worsening in RRMS with the MAGNIMS score.

BACKGROUND: The magnetic resonance imaging in multiple sclerosis (MAGNIMS) score combines relapses and magnetic resonance imaging (MRI) lesions to predict disability outcomes in relapsing-remitting multiple sclerosis (RRMS) treated with interferon-ß. OBJECTIVE: To validate the MAGNIMS score and extend to other disease-modifying therapies (DMTs). To examine the prognostic value of gadolinium contrast-enhancing (Gd+) lesions. METHODS: This RRMS MSBase cohort study (n = 2293) used a Cox model to examine the prognostic value of relapses, MRI activity and the MAGNIMS score for disability worsening during treatment with interferon-ß and three other DMTs. RESULTS: Three new T2 lesions (hazard ratio (HR) = 1.60, p = 0.028) or two relapses (HR = 2.24, p = 0.002) on interferon-ß (for 12 months) were predictive of disability worsening over 4 years. MAGNIMS score = 2 (1 relapse and ⩾3 T2 lesions or ⩾2 relapses) was associated with a greater risk of disability worsening on interferon-ß (HR = 2.0, p = 0.001). In pooled cohort of four DMTs, similar associations were seen (MAGNIMS score = 2: HR = 1.72, p = 0.001). Secondary analyses demonstrated that the addition of Gd+ to the MAGNIMS did not materially improve its prediction of disability worsening. CONCLUSION: We have validated the MAGNIMS score in RRMS and extended its application to three other DMTs: 1 relapse and ⩾3 T2 lesions or ⩾2 relapses predicted worsening of disability. Contrast-enhancing lesions did not substantially improve the prognostic score.

SMART syndrome: retrospective review of a rare delayed complication of radiation.

BACKGROUND: SMART (stroke-like migraine attacks after radiation therapy) is a rare, delayed complication of brain radiation. In this study, we wanted to review the spectrum of symptoms, neuroradiological findings, autoimmune status, and outcomes in SMART syndrome patients. METHODS: We conducted a retrospective cohort study of all consecutive adult patients (≥18 years) diagnosed with SMART syndrome at Mayo Clinic, Rochester between January 1995 and December 2018. RESULTS: We identified 25 unique patients with SMART syndrome and a total of 31 episodes and 15 (60%) patients were male. The median age at onset was 46 (interquartile range [IQR] 43-55) years and the median latency of onset after the initial radiation was 21.6 (IQR 14.4-28.2) years. Magnetic resonance imaging (MRI) showed gyral edema and enhancement in all cases with the temporal (25, 80.6%) and parietal (23, 74.2%) lobes being the most commonly affected. The median follow-up of the patients in our cohort was 10 (IQR 6-32) weeks. On univariate analysis, factors associated with an increased risk of recurrent SMART episodes were female gender (odds ratio [OR] 8.1, 95% confidence interval [95% CI] 1.1-52.6, p = 0.019) and absence of electrographic seizure discharges during initial symptoms (OR 7.4, 95% CI 1.1-45.9, p = 0.032). We could not identify an autoimmune etiology. Longer duration of symptoms (>10 weeks) correlated with an older age (p = 0.049), temporal lobe involvement (p < 0.001), and diffusion restriction (p = 0.043). CONCLUSIONS: SMART is a syndrome with characteristic imaging findings and clinical features. Incomplete recovery by 10 weeks occurred in one-third of individuals and was associated with older age, temporal lobe involvement, and restricted diffusion on MRI.

Brainstem and cerebellar involvement in MOG-IgG-associated disorder versus aquaporin-4-IgG and MS.

OBJECTIVE: To determine the frequency and characteristics of brainstem or cerebellar involvement in myelin-oligodendrocyte-glycoprotein-antibody-associated-disorder (MOGAD) versus aquaporin-4-IgG-seropositive-neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD) and multiple sclerosis (MS). METHODS: In this observational study, we retrospectively identified 185 Mayo Clinic MOGAD patients with: (1) characteristic MOGAD phenotype, (2) MOG-IgG seropositivity by live cell-based assay and (3) MRI lesion(s) of brainstem, cerebellum or both. We compared the symptomatic attacks to AQP4-IgG-NMOSD (n=30) and MS (n=30). RESULTS: Brainstem or cerebellar involvement occurred in 62/185 (34%) MOGAD patients of which 39/62 (63%) were symptomatic. Ataxia (45%) and diplopia (26%) were common manifestations. The median age in years (range) in MOGAD of 24 (2-65) was younger than MS at 36 (16-65; p=0.046) and AQP4-IgG-NMOSD at 45 (6-72; p=0.006). Isolated attacks involving the brainstem, cerebellum or both were less frequent in MOGAD (9/39 (23%)) than MS (22/30 (73%); p<0.001) but not significantly different from AQP4-IgG-NMOSD (14/30 (47%); p=0.07). Diffuse middle cerebellar peduncle MRI-lesions favoured MOGAD (17/37 (46%)) over MS (3/30 (10%); p=0.001) and AQP4-IgG-NMOSD (3/30 (10%); p=0.001). Diffuse medulla, pons or midbrain MRI lesions occasionally occurred in MOGAD and AQP4-IgG-NMOSD but never in MS. Cerebrospinal fluid (CSF) oligoclonal bands were rare in MOGAD (5/30 (17%)) and AQP4-IgG-NMOSD (2/22 (9%); p=0.68) but common in MS (18/22 (82%); p<0.001). Disability at nadir or recovery did not differ between the groups. CONCLUSION: Involvement of the brainstem, cerebellum or both is common in MOGAD but usually occurs as a component of a multifocal central nervous system attack rather than in isolation. We identified clinical, CSF and MRI attributes that can help discriminate MOGAD from AQP4-IgG-NMOSD and MS.

Autoimmune glial fibrillary acidic protein astrocytopathy.

PURPOSE OF REVIEW: To describe a recently characterized autoimmune, inflammatory central nervous system (CNS) disorder known as autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. RECENT FINDINGS: Affected patients present with symptoms of one or more of meningitis (headache and neck ache), encephalitis (delirium, tremor, seizures, or psychiatric symptoms), and myelitis (sensory symptoms and weakness). Optic disc papillitis (blurred vision) is common. CNS inflammation is evident in characteristic T1 postgadolinium enhancement of GFAP-enriched CNS regions, and lymphocytic cerebrospinal fluid (CSF) white cell count elevation. CSF is more reliable than serum for GFAP-immunoglobulin G (IgG) testing. Ovarian teratoma commonly coexists, particularly among patients with accompanying N-methyl-D-aspartate receptor or aquaporin-4 autoimmunity. Parainfectious autoimmunity is suspected in some other patients, though the culprit organism is rarely verified. Pathophysiologic relevance of T cells is underscored by neuropathology and cases of dysregulated T-cell function (HIV or checkpoint inhibitor cancer therapy). Corticosteroid-responsiveness is a hallmark of the disease. Relapses occur in approximately 20% of patients, necessitating transition to a steroid-sparing drug. Reported outcomes vary, though in the authors' experience, early and sustained intervention usually portends recovery. SUMMARY: Autoimmune GFAP astrocytopathy is a treatable autoimmune CNS disease diagnosable by GFAP-IgG testing in CSF. This disease presents opportunities to explore novel mechanisms of CNS autoimmunity and inflammation.

Review of the Longitudinal Management of Autoimmune Encephalitis, Potential Biomarkers, and Novel Therapeutics.

Purpose of Review: Increasing awareness and earlier diagnosis of autoimmune encephalitis (AE) have led to a greater number of patients being cared for longitudinally by neurologists. Although many neurologists are now familiar with the general approach to diagnosis and acute immunosuppression, this review aims to provide neurologists with guidance related to management beyond the acute phase of disease, including long-term immunosuppression, monitoring, potential biomarkers of disease activity, outcome measures, and symptom management. Recent Findings: Observational studies in AE have demonstrated that early diagnosis and treatment is associated with improved neurologic outcomes, particularly in AE with antibodies targeting neuronal cell surface/synaptic proteins. The literature regarding long-term management is evolving. In addition to traditional immunosuppressive approaches, there is emerging use of novel immunosuppressive therapies (ISTs) in case series, and several randomized controlled trials are planned. Novel biomarkers of disease activity and methods to measure outcomes and response to treatment are being explored. Furthermore, it is increasingly recognized that many individuals have chronic symptoms affecting quality of life including seizures, cognitive impairment, fatigue, sleep disorders, and mood disorders, and there are emerging data supporting the use of patient centered outcome measures and multidisciplinary symptom-based care. Summary: This review aims to summarize recent literature and offer a practical approach to long-term management of adult patients with AE through a multidisciplinary approach. We summarize current knowledge on ISTs, potential biomarkers of disease activity, outcome measures, and long-term sequelae. Further research is needed to answer questions regarding optimal IST, biomarker validity, and sequelae of disease.

Neuropsychological Testing in Autoimmune Encephalitis: A Scoping Review.

BACKGROUND AND OBJECTIVES: Identifying optimal methods for evaluation and monitoring of cognitive outcomes in AE is important for clinical care and research. This scoping review aimed to evaluate neuropsychological tests (NPT) that are most frequently impaired in AE cohorts to provide recommendations for a standardized NPT battery for AE outcome. METHODS: PubMed search for studies examining NPT in patients with AE was conducted on June 9, 2023. Studies were screened for inclusion/exclusion criteria as follows: at least 1 NPT, individual NPT test scores with comparison with healthy controls or normative data and neural-IgG status, total sample size ≥5, and English manuscript available. RESULTS: The search yielded 5,393 studies, of which 3,359 were screened, 107 were full text reviewed, and 32 met inclusion/exclusion criteria, anti-NMDA-R (k = 18), anti-LGI1 (k = 10), anti-GABAB-R (k = 2), anti-GAD-65 (k = 4), and anti-CASPR2 (k = 3). The cognitive domains most frequently impaired were visual and verbal episodic memory, attention/working memory, processing speed, and aspects of executive functions. DISCUSSION: Given the dearth of literature examining NPT in AE in combination with small sample sizes and methodological differences, more research in this area is needed. However, we provide recommendations for a test battery to be used in future studies, with the aim of standardizing research in this area. Based on the available literature, we recommend the use of comprehensive NPT batteries, spanning all cognitive domains. The highest yield measures may include the tests of (1) visual and verbal learning/memory, (2) basic and sustained attention, (3) processing speed, and (4) executive functions.

Progressive Encephalomyelopathy in an Older Man: A Case Report From the National Multiple Sclerosis Society Case Conference Proceedings.

We present a case of subacute onset progressive encephalomyelopathy in a 77-year-old man with symmetric lateral column signal abnormalities on spinal MRI. We discuss the differential and presumptive final diagnosis along with a review of the postulated disease immunopathogenesis.

Longitudinal Disability, Cognitive Impairment, and Mood Symptoms in Patients With Anti-NMDA Receptor Encephalitis.

BACKGROUND AND OBJECTIVES: Longitudinal outcomes in anti-NMDA receptor encephalitis (anti-NMDARe) are still not fully understood and may not be adequately captured with the modified Rankin Scale (mRS), often the sole reported outcome. We aim to characterize longitudinal outcomes in anti-NMDARe using multiple outcome measures. METHODS: This single-center, retrospective, observational study examined outcome measures (mRS and Clinical Assessment Scale in Autoimmune Encephalitis [CASE]) in adults with NMDA receptor-IgG in CSF at short- and long-term follow-ups using linear and logistic regression modeling. Patients with evaluations for cognitive impairment (Montreal Cognitive Assessment/Mini-Mental State Examination), depression (Patient Health Questionnaire-9), and anxiety (General Anxiety Disorder-7) >6 months from symptom onset were correlated with final CASE scores. RESULTS: Thirty-eight patients (76% female, median disease onset age = 28 years, range = 1-75 years) were included. The majority received first-line immunosuppressants (97%) at a median of 3.9 weeks (interquartile range [IQR] = 2.1-9.7) from symptom onset and 68% received second-line therapies. At baseline, median/mean mRS and CASE were 4 (IQR = 3-5) and 12.9 (SD = 7.2), respectively. At short-term follow-up (median = 10 weeks, IQR = 6-17), factors associated with higher CASE and mRS included dysautonomia, coma/lethargy, seizures/status epilepticus, and intensive care unit admission (p < 0.05). At long-term follow-up (median = 70 weeks, IQR = 51-174), median/mean mRS and CASE were 2 (IQR = 1-3) and 4.4 (SD = 4.2), respectively. Only weakness at symptom onset predicted higher mRS scores (odds ratio = 5.6, 95% confidence interval 1.02-30.9, p = 0.047). Despite both mRS and CASE improving from baseline (p < 0.001), only 9 patients (31%) returned to their premorbid function. Among patients with cognitive and mood evaluations >6 months from onset, moderate-severe cognitive impairment (42%), depression (28%), and anxiety (30%) were frequent. Cognitive and depression measures were associated with final CASE subscores (including memory, language, weakness, and psychiatric). DISCUSSION: Multiple clinical factors influenced short-term outcomes, but only onset weakness influenced long-term mRS, highlighting that mRS is predominantly affected by global motor function. Although mRS and CASE improved over time for most patients, these outcome measures did not capture the full extent of long-term functional impairment in terms of mood, cognition, and the ability to return to premorbid function. This emphasizes the need for increased utilization of more nuanced cognitive and mood outcome measures.

Predicting disability and mortality in CV2/CRMP5-IgG associated paraneoplastic neurologic disorders.

BACKGROUND: We aimed to investigate the prognostic factors associated with clinical outcomes in CV2/Collapsin response-mediator protein 5 (CRMP5)-IgG paraneoplastic neurologic disorders (PND). METHODS: This is a retrospective study of patients with CV2/CRMP5-IgG PND evaluated between 2002-2022. We examined the association of clinical variables (including age, clinical phenotype [autoimmune encephalopathy, myelopathy, polyneuropathy/radiculopathy, MG, cerebellar ataxia, chorea, optic neuropathy], cancer) with three clinical outcomes (wheelchair dependence, modified Rankin Scale [mRS], mortality) using univariate logistic regression and Cox proportional hazards modeling. Kaplan-Meier estimates were used to determine the probability of survival. RESULTS: Twenty-seven patients (56% female) with CV2/CRMP5-IgG PND were identified with a median follow-up of 54 months (IQR = 11-102). An underlying tumor was identified in 15 patients (56%) including small cell lung cancer (SCLC) (8, [53%]), thymoma (4, [27%]), and other histologies (3, [20%]). At last follow-up, 10 patients (37%) needed a wheelchair for mobility and this outcome was associated with myelopathy (HR = 7.57, 95% CI = 1.87-30.64, P = 0.005). Moderate-severe mRS = 3-5 was associated with CNS involvement (encephalopathy, myelopathy, or cerebellar ataxia) (OR = 7.00, 95% CI = 1.18-41.36, P = 0.032). The probability of survival 4 years after symptom onset was 66%. Among cancer subtypes, SCLC (HR = 18.18, 95% CI = 3.55-93.04, P < 0.001) was significantly associated with mortality, while thymoma was not. INTERPRETATION: In this retrospective longitudinal study of CV2/CRMP5-IgG PND, patients with CNS involvement, particularly myelopathy, had higher probability of disability. SCLC was the main determinant of survival in this population.