The risk of infections for multiple sclerosis and neuromyelitis optica spectrum disorder disease-modifying treatments: Eighth European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop Review. April 2021.

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Most responders opted to cancer screening for 4 years in patients with neuronal surface antibodies (49%) or limbic encephalitis (46%) as opposed to non-limbic seronegative autoimmune encephalitis (36%). Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

Iatrogenic CNS demyelination in the era of modern biologics.

The number of reported cases of iatrogenic demyelination of the central nervous system (CNS) is on the rise. This is, in part, related to the recent expansion in the use of biologics. Review of literature from the past decade suggests that in addition to vaccines, tumor necrosis factor (TNF)-alpha inhibitors and checkpoint inhibitors are the most frequently cited inducers of central inflammation. About one-third of demyelinating cases in the setting of TNF-alpha inhibitors evolve into full-blown multiple sclerosis. In addition to demyelination, checkpoint inhibitors may also cause accelerated paraneoplastic encephalitis and other antibody-mediated conditions. Luckily, the overall prognosis of iatrogenic central inflammation is favorable, with most cases having partial or complete response to steroids and discontinuation of the offending agent. Long-term monitoring and initiation of maintenance immune-modulating therapy may be necessary in some patients. In this article, we provide an updated review of biologic-induced inflammation of the CNS.

Neuromodulation in multiple sclerosis.

Neuromodulation, or the utilization of advanced technology for targeted electrical or chemical neuronal stimulation or inhibition, has been expanding in several neurological subspecialties. In the past decades, immune-modulating therapy has been the main focus of multiple sclerosis (MS) research with little attention to neuromodulation. However, with the recent advances in disease-modifying therapies, it is time to shift the focus of MS research to neuromodulation and restoration of function as with other neurological subspecialties. Preliminary research supports the value of intrathecal baclofen pump and functional electrical stimulation in improving spasticity and motor function in MS patients. Deep brain stimulation can improve MS-related tremor and trigeminal neuralgia. Spinal cord stimulation has been shown to be effective against MS-related pain and bladder dysfunction. Bladder overactivity also responds to sacral neuromodulation and posterior tibial nerve stimulation. Despite limited data in MS, transcranial magnetic stimulation and brain-computer interface are promising neuromodulatory techniques for symptom mitigation and neurorehabilitation of MS patients. In this review, we provide an overview of the available neuromodulatory techniques and the evidence for their use in MS.

Treatment of acute relapses in neuromyelitis optica: Steroids alone versus steroids plus plasma exchange.

BACKGROUND: Although adding plasma exchange (PLEX) to steroids in severe neuromyelitis optica (NMO) attacks is common practice in steroid-resistant cases, the benefit of this strategy has not been previously quantified. OBJECTIVE: The objective of this paper is to compare the efficacy of high-dose intravenous methylprednisolone (IVMP) versus IVMP+PLEX in treatment of acute NMO relapses. METHODS: We conducted a retrospective review of the last 83 NMO admissions to the Johns Hopkins Hospital treated with IVMP alone versus IVMP+PLEX (for steroid-resistant cases). Extended Disability Status Scale (EDSS) score was calculated at baseline, at presentation, at discharge, and on follow-up. RESULTS: Eighteen NMO relapses (16 patients, 87% female, mean age at relapse: 33.9±23.8, median baseline EDSS 2.5) were treated with IVMP alone and 65 relapses (43 patients, 95% female, mean age at relapse: 43.8±15.7, median baseline EDSS 5.75) were treated with IVMP + PLEX. Sixty-five percent of IVMP + PLEX patients achieved an EDSS equal or below their baseline at follow-up while only 35% of the IVMP-only patients achieved their baseline EDSS on follow-up (odds ratio=3.36, 95% CI 1.0657 to 10.6004, p = 0.0386). PLEX was more effective in improving EDSS in patients on preventive immunosuppressive medications at time of relapse. CONCLUSIONS: PLEX+IVMP are more likely to improve EDSS after NMO relapses compared to IVMP alone, especially in patients taking preventive medications.

Socioeconomic Status May Impact Functional Outcome of Deep Brain Stimulation Surgery in Parkinson's Disease.

OBJECTIVES: To investigate the association between socioeconomic status and deep brain stimulation (DBS) outcomes in Parkinson's disease (PD). MATERIALS AND METHODS: We analyzed a cohort of PD patients who underwent DBS from 2007 to 2011, who had Clinical Global Impression Scale-Improvement subscale (CGI-I) scores at approximately one year postsurgery. We also analyzed a subgroup of patients who had pre and postoperative Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II (functional subscale) and European Quality of Life Scale (EQ5D) scores. We performed regression analyses to determine the association between their median household income and their improvement in the MDS-UPDRS Part II, EQ-5D, and CGI-I post-DBS surgery. RESULTS: We analyzed 125 PD patients with CGI-I at one year post-DBS, including a subset of 43 patients who had pre- and post-DBS MDS-UPDRS Part II and EQ5D scores at 6 and 12 months. Median income was not significantly associated with the one-year CGI-I, the six-month MDS-UPDRS II, and the six-month and one-year EQ5D score. However, after adjusting for preoperative MDS-UPDRS II score, for every $10,000 increase in household median income, there was a 2.15-point improvement on the MDS-UPDRS II score after one year (95% confidence interval = -3.63 to -0.66, p = 0.0060). CONCLUSIONS: PD patients with higher household incomes had better functional improvement at one year. However, this did not necessarily translate to better quality of life or overall clinical improvement when compared with PD patients with lower household incomes. The influence of household income on DBS and other advanced therapies for PD will need further investigation.

Utility of the 2023 international MOGAD panel proposed criteria in clinical practice: An institutional cohort.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently defined demyelinating disorder with a rapidly evolving clinical spectrum. Recently, consensus criteria have been proposed (Banwell et al., 2023) to help with disease diagnosis. However, validation of the proposed criteria in real-life MOGAD patients is lacking. In this study, we applied the proposed criteria to an institutional cohort of MOG antibody-positive patients. METHODS: A retrospective study was conducted at a tertiary neuroimmunology clinic from 2018 to 2023. Patients who had at least one core clinical feature of MOGAD and positive serum MOG antibody by cell-based assay were included. Demographics and clinical data were recorded and analyzed. Cases were divided into definite MOGAD, questionable MOGAD, and false-positive MOG antibody as determined by the treating neuroimmunology and/or neuro-ophthalmology specialists prior to applying the new MOGAD criteria by an independent investigator. We then calculated the sensitivity, specificity, positive predictive value, and negative predictive value of the new criteria compared to the treating physicians' assessment. RESULTS: A total of 27 patients were included of which, 19 (70.4%) were female, the average age of the sample was 44 +/- 15 years. High titer MOG antibody (≥ 1:100) was found in 11 patients (40.7%); low titer (< 1: 100) in 13 (48.1%), and unreported titer in 3 patients. As determined by expert opinion; 18 (66.7%) were identified as definitive MOGAD, 6 (22.2%) as false-positive MOG antibody, and 3 (11.1%) as questionable MOGAD. All 18 patients identified by clinicians as definite MOGAD met the new 2023 criteria. Of the 9 patients with questionable MOGAD or false-positive MOG antibody, four patients met the 2023 MOGAD criteria. Those four patients had the following final diagnoses: CNS vasculitis, primary progressive MS with activity and progression, pseudotumor cerebri, and bevacizumab-induced anterior ischemic optic neuropathy in the setting of paraneoplastic retinopathy. Compared to clinician assessment, applying the 2023 MOGAD criteria to our institutional cohort yielded a sensitivity of 100%, a specificity of 55.5%, a positive predictive value of 81.5% and a negative predictive value of 100%. CONCLUSION: These findings suggest that the 2023 MOGAD criteria are highly sensitive for detection of definite MOGAD but has modest specificity. A number of MOGAD mimickers can resemble the core clinical events of MOGAD and share similar supportive clinical and MRI features. Clinicians should practice caution when evaluating patients with low titer MOG antibody even if they meet the additional supportive features proposed by the 2023 criteria. Further studies are needed to evaluate the 2023 criteria in larger cohorts and in the pediatric population.

Pathological findings in autoimmune encephalitis autopsy specimens from cases of suspected prion disease.

OBJECTIVE: The underlying pathology of autoimmune encephalitis is not well characterized due to the limited opportunities to study tissue specimens. Autopsy specimens available at prion surveillance centers from patients with suspected Creutzfeldt-Jakob disease offer a unique opportunity to study the pathology of autoimmune encephalitis. Our objective was to describe pathological findings of autoimmune encephalitis specimens submitted to the U.S. National Prion Disease Pathology Surveillance Center. METHODS: Pathology reports were obtained from the National Prion Center. Specimens negative for prion disease were screened for inflammatory pathology and those suggestive of autoimmune encephalitis were analyzed. Cases identified on autopsy were compared to institutional cases with fatal seronegative autoimmune encephalitis and available brain biopsy. RESULTS: Between 1998 and 2022, 7934 specimens were evaluated of which 2998 (38%) were negative for prion protein. Querying the database for alternative diagnoses of encephalitis/encephalopathy yielded 43 cases that were screened by an experienced neuropathologist yielding 14 (0.5%) cases consistent with autoimmune encephalitis. Most specimens showed diffuse inflammation involving the limbic system (86%), basal ganglia (86%), cortex (71%), diencephalon (71%), and in some cases the brainstem (43%) and cerebellum (43%). Lymphocytic inflammatory infiltrate was predominantly perivascular with parenchymal extension in 64%. Microglial activation/nodules were seen in 64% of cases. Neuronal loss was present only in 50%. Pathological findings were identical to biopsy specimens from our institutional cohort. DISCUSSION: Seronegative AE may have consistent pathology with diffuse or multifocal perivascular inflammation and microglial activation. Half the patients do not have neuronal loss suggesting a potential for neurological recovery. These findings are preliminary and require further confirmation.

Characterization of neurological morbidity associated with thyroid antibodies: Hashimoto's encephalopathy and beyond.

BACKGROUND: Hashimoto's Encephalopathy (HE) manifests with various neurologic symptoms associated with elevated thyroglobulin (TG) and/or thyroperoxidase (TPO) antibodies. Some patients with thyroid antibodies exhibit neurological presentations not consistent with HE. This study aims to characterize the spectrum of neurological morbidity in patients with thyroid antibodies. METHODS: We reviewed all patients tested for TG or TPO antibodies from 2010 to 2019. Patients tested for thyroid antibodies as part of a neurological workup for new symptoms were classified into the following categories: patients meeting full criteria for HE, patients with other neuroimmunological disorders, patients with unexplained neurological symptoms not fully meeting HE criteria, and patients with incidental non neuroimmunological disorders. RESULTS: There were 2717 patients with positive thyroid antibodies in the dataset including 227 patients (78% female, age 54 ± 19 years) who met inclusion criteria. Twelve patients (5%) met HE criteria, 30 (13%) had other neuroimmunological disorders, 32 (14%) had unexplained neurological symptoms, and 153 (67.4%) had incidental disorders. In addition to cognitive dysfunction, seizures, movement disorders, motor weakness, and psychosis, HE patients were also more likely to have cerebellar dysfunction, language impairment, and sensory deficits. They were more likely to carry a Hashimoto's thyroiditis diagnosis and had higher titers of thyroid antibodies. They all had a robust response to steroids. CONCLUSION: The neurological spectrum of HE may be wider than previously reported, including frequent cerebellar, sensory, and language dysfunction. A subgroup of thyroid antibody positive patients with unexplained neurological symptoms may represent further expansion of thyroid antibody-related neurological disorders.

Spinal movement disorders in NMOSD, MOGAD, and idiopathic transverse myelitis: a prospective observational study.

BACKGROUND: Retrospective studies suggest that spinal movement disorders, especially tonic spasms, are prevalent in NMOSD. However, there have been no prospective studies evaluating spinal movement disorders in NMOSD, MOGAD, and idiopathic transverse myelitis (ITM). METHODS: Patients referred to a tertiary neuroimmunology clinic for spinal cord demyelination (excluding MS) were evaluated. All patients answered a movement disorders survey and underwent a movement disorder-focused exam. Movement disorders were compared among patients with NMOSD with and without AQP4-IgG, MOGAD, and ITM. Patients with and without involuntary movements were also compared to identify predictors of spinal movement disorders. RESULTS: Sixty-three patients were evaluated from 2017 to 2021 (71% females, median age 49 years, range 18-72 years, median disease duration 12 months, range 1-408). Of the total, 49% had ITM, 21% had NMOSD without AQP4-IgG, 19% had NMOSD with AQP4-IgG, and 11% had MOGAD. Movement disorders were present in 73% of the total patients and were most frequent in NMOSD with AQP4-IgG (92%) and least frequent in MOGAD (57%). The most frequent spinal movement disorders were tonic spasms (57%), focal dystonia (25%), spinal tremor (16%), spontaneous clonus (9.5%), secondary restless limb syndrome (9.5%), and spinal myoclonus (8%). Multivariate analysis showed that longitudinally extensive myelitis and AQP4-IgG are independent risk factors for the development of spinal movement disorders, while MOG-IgG and African American race were associated with a lower risk of developing these movement disorders. CONCLUSIONS: Spinal movement disorders are highly prevalent in non-MS demyelinating disorders of the spinal cord. Prevalence rates exceed those reported in MS and retrospective NMOSD studies.

Unilateral cortical autoimmune encephalitis: A case series and comparison to late-onset Rasmussen's encephalitis.

OBJECTIVE: To report a novel anatomical pattern of autoimmune encephalitis characterized by strictly unilateral cortical inflammation and a clinical picture overlapping with late-onset Rasmussen's encephalitis. METHODS: We retrospectively gathered data of patients identified at two tertiary referral academic centers who met inclusion criteria. RESULTS: We identified twelve cases (average age 65, +/- 19.8 years, 58% female). All patients had unilateral cortical inflammation manifesting with focal seizures, cognitive decline, hemicortical deficits, and unilateral MRI and/or EEG changes. Six cases were idiopathic, two paraneoplastic, two iatrogenic (in the setting of immune checkpoint inhibitors), and two post-COVID-19. Serologically, ten patients were seronegative, one had high titer anti-GAD65, and one had anti-NMDAR. Five patients met Rasmussen's encephalitis criteria, and six did not fully meet the criteria but had symptoms significantly overlapping with the condition. Most patients had significant improvement with immunotherapy. DISCUSSION: Unilateral cortical AE seems to be more prevalent in the elderly and more frequently idiopathic and seronegative. Patients with this anatomical variant of autoimmune encephalitis have overlapping features with late-onset Rasmussen's encephalitis but are more responsive to immunotherapy. In cases refractory to immunotherapy, interventions used in refractory Rasmussen's encephalitis may be considered, such as functional hemispherectomy.

Sex ratio and age of onset in AQP4 antibody-associated NMOSD: a review and meta-analysis.

BACKGROUND: Aquaporin-4 (AQP4) antibody-associated neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system. We have undertaken a systematic review and meta-analysis to ascertain the sex ratio and mean age of onset for AQP4 antibody associated NMOSD. We have also explored factors that impact on these demographic data. METHODS: A systematic search of databases was conducted according to the PRISMA guidelines. Articles reporting sex distribution and age of onset for AQP4 antibody-associated NMSOD were reviewed. An initially inclusive approach involving exploration with regression meta-analysis was followed by an analysis of just AQP4 antibody positive cases. RESULTS: A total of 528 articles were screened to yield 89 articles covering 19,415 individuals from 88 population samples. The female:male sex ratio was significantly influenced by the proportion of AQP4 antibody positive cases in the samples studied (p < 0.001). For AQP4 antibody-positive cases the overall estimate of the sex ratio was 8.89 (95% CI 7.78-10.15). For paediatric populations the estimate was 5.68 (95% CI 4.01-8.03) and for late-onset cases, it was 5.48 (95% CI 4.10-7.33). The mean age of onset was significantly associated with the mean life expectancy of the population sampled (p < 0.001). The mean age of onset for AQP4 antibody-positive cases in long-lived populations was 41.7 years versus 33.3 years in the remainder. CONCLUSIONS: The female:male sex ratio and the mean age of onset of AQP4 antibody-associated NMOSD are significantly higher than MS. The sex ratio increases with the proportion of cases that are positive for AQP4 antibodies and the mean age of onset increases with population life expectancy.

Predictors of hypogammaglobulinemia and serious infections among patients receiving ocrelizumab or rituximab for treatment of MS and NMOSD.

BACKGROUND AND OBJECTIVES: Ocrelizumab and rituximab are monoclonal antibodies targeting the CD20 marker on B lymphocytes. The enhanced efficacy of B lymphocyte depleting therapies poses a greater risk of decreased immunoglobulin (Ig) levels. The rate and risk factors of hypogammaglobulinemia in MS and NMOSD patients treated with anti-CD20 therapies are unknown. METHODS: A retrospective study was conducted among patients who received anti-CD20 therapy for the treatment of MS, NMOSD, and other related neurological disorders. The goal was to determine the incidence and risk factors of hypogammaglobulinemia and serious infections in patients receiving ocrelizumab versus rituximab. The secondary goals were to determine the rates of lymphopenia, neutropenia, and early B cell repopulation among patients on anti-CD20 therapy. RESULTS: Overall, 184 patients (mean age 48.4 ± 13.7, 66.8% female) met inclusion criteria; 152 patients received ocrelizumab and 32 patients received rituximab. A total of 22 patients (12%) developed hypogammaglobulinemia. Patients who developed hypogammaglobulinemia were more likely to have been ≥50 years of age (p = .0275) with lower baseline IgG (p = .001) and IgA (p = .0038) levels. Serious infections were observed in 21 patients (11%) and seen more commonly in those that developed total lymphopenia (<1.0 × 109/L) and had longer duration of B-cell therapy. Multivariate analysis identified age ≥ 50 years, white race, and rituximab as independent predictors of hypogammaglobulinemia, and absolute lymphopenia as an independent risk factor for serious infections. DISCUSSION: Among patients receiving anti-CD20 therapy, 12% of patients experienced hypogammaglobulinemia which was seen more commonly in white patients, at least 50 years old, with lower baseline IgG and IgA levels and in those treated with rituximab. Serious infections were seen more commonly in patients with total lymphopenia and longer exposure to anti-CD20 therapy.

Predicting the final clinical phenotype after the first attack of optic neuritis.

BACKGROUND AND OBJECTIVES: To evaluate the factors determining the final clinical phenotype after an initial isolated attack of optic neuritis (ON). ON could be an isolated event or the initial presentation of a chronic neuroimmunological condition. METHODS: This was a retrospective analysis of patients presenting to University Hospitals Cleveland Medical Center for an initial, isolated attack of ON. Final clinical phenotypes were idiopathic ON, multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein associated disease (MOGAD), or secondary ON (e.g. neurosarcoidosis). Several potential predictors at the time of initial presentation were compared among the different phenotypes to determine early predictors. Categorical variables were compared using Pearson χ2 or Fisher's exact test, and continuous variables were compared using independent t-test. RESULTS: Sixty-four patients met criteria (average age 41.3 ± 13.3, 78.1% females). Average time to final diagnosis was 8.3 months, and average follow-up was 47 months. The final phenotypes were MS (22, 34%), idiopathic ON (14, 22%), MOGAD (11, 17%), NMOSD (10, 16%), and secondary ON (7, 11%). White race, unilateral ON, short segment hyperintensity on orbital MRI, classical demyelination on brain MRI, and not requiring PLEX were associated with MS. Older age, poor steroid responsiveness, and requiring PLEX were associated with NMOSD. African American race, bilateral ON, papillitis on fundoscopy, long segment hyperintensity on orbital MRI, and normal brain MRI were associated with MOGAD. Normal or thinned retinal nerve fiber layer on OCT, short segment hyperintensity on orbital MRI, and normal brain MRI were associated with idiopathic ON. CONCLUSION: The final clinical phenotype may be predictable at the time of initial ON presentation. This requires a careful evaluation of patient demographics, treatment response, funduscopic findings, OCT, and orbital and brain MRIs. Utilizing early predictors in clinical practice could better inform prognosis and management decisions.

Parkinsonism in multiple sclerosis patients: A prospective observational study.

BACKGROUND: Rare cases of coexisting multiple sclerosis and parkinsonism have been reported in the literature. However, the true prevalence, clinical characteristics, and causal relation between the two entities have not been systematically evaluated. OBJECTIVE: To evaluate the prevalence of parkinsonism in patients with multiple sclerosis and examine the causal relationship, if any. METHODS: Consecutive patients referred to the multiple sclerosis clinic were evaluated by a neurologist with double training in both neuroimmunology and movement disorders. All patients were specifically screened for movement disorders via a movement disorder survey and a focused exam. Video samples were independently rated by two blinded movement disorder raters. Pre-specified criteria were developed for five potential clinical scenarios: incidental idiopathic Parkinson's disease, incidental Parkinson-plus syndrome, drug-induced parkinsonism, acute symptomatic parkinsonism, and chronic symptomatic parkinsonism. RESULTS: From 2016 to 2021, 336 patients were evaluated. Of those, 12 patients (3.6%) had clinical parkinsonism (average age 68 years, 66% females). Nine patients (75%) were deemed to have incidental Parkinson's disease, 2 (17%) had drug-induced parkinsonism, and 1 (8.3%) was deemed to have demyelination-related chronic symptomatic parkinsonism. The latter presented with gradual and progressive parkinsonism without prodromal symptoms. Both blinded raters agreed with the parkinsonism phenomenology. In addition to typical enhancing and non-enhancing demyelinating lesions, the patient had lesions bilaterally in the basal ganglia. She had positive oligoclonal bands in the cerebrospinal fluid. DAT scan was normal. She was diagnosed with PPMS with activity and progression manifesting solely with secondary parkinsonism. Her disease stabilized with ocrelizumab. There were no cases of acute symptomatic parkinsonism or co-existing Parkinson-plus syndrome over the five-year duration of the study. Three of the incidental idiopathic Parkinson's disease cases had radiologically isolated syndrome. CONCLUSION: Parkinsonism in MS is rare and most cases are incidental. However, clinicians need to recognize the entity of demyelination-related chronic symptomatic parkinsonism in patients with progressive MS phenotypes and demyelinating lesions in the basal ganglia and/or upper midbrain. Parkinsonism may be the sole clinical presentation of progressive MS and the only indication for DMT initiation or escalation. There is an over-representation of radiologically isolated syndrome in patients with presumptive incidental demyelination and idiopathic Parkinson's disease. Prospective studies utilizing high-field MRI and longitudinal DAT scans are needed to better characterize the complex relationship between demyelination and parkinsonism.

Prevalence of iatrogenic CNS inflammation at a tertiary neuroimmunology clinic.

BACKGROUND: Various vaccines, tumor-necrosis-factor-alpha inhibitors (TNFAIs), immune-checkpoint inhibitors (ICIs), and other immunomodulators have been linked to inflammatory CNS events. The prevalence of iatrogenic events in the neuroimmunology clinic is unknown. OBJECTIVE: To evaluate the prevalence and clinical characteristics of iatrogenic CNS inflammation in a tertiary neuroimmunology clinic. METHODS: We analyzed 422 consecutive patients seen over five years at a tertiary neuroimmunology clinic who were systematically screened for exposure to vaccines, TNFAIs, ICIs, or other immunomodulators. In patients with suspected iatrogenic events, the Naranjo Adverse Drug Reaction Probability Scale was used to score the probability of iatrogenicity. RESULTS: In total, 27 potential iatrogenic events were observed, accounting for 6.4% of all new referrals. The average Naranjo score was 5.78 +/- 1.65 with 74% of the cases scored as probable and 26% scored as possible. The clinical phenotypes included MS relapses (37%); autoimmune encephalitis (30%); NMOSD attacks (15%); transverse myelitis (11%); optic neuritis (4%); and MOGAD attacks (4%). A monophasic course was observed in 44% of cases while 41% had a relapsing course. All patients stopped or interrupted treatment with the offending agent. In addition, 41% of the iatrogenic events were fully responsive to corticosteroids; 22% were partially responsive; and 15% resolved spontaneously. The most common potential triggers were vaccines (37%) followed by TNFAIs (33%) then ICIs (26%). A significantly higher number of probable iatrogenic events were observed among the ICI and vaccine groups compared to a higher number of possible events among the TNFAI group. The latter group also had a significantly longer interval since exposure. The ICI group was more likely to present with monophasic autoimmune encephalitis. CONCLUSION: Iatrogenic CNS inflammation is rare and typically involves steroid-responsive monophasic events. A subset of iatrogenic events can unmask or worsen relapsing disorders. The probability of iatrogenicity was higher in vaccine and ICI-related events compared to TNFAI-related events.