Cladribine tablets after treatment with natalizumab (CLADRINA) - rationale and design.

Background: Individual disease modifying therapies approved for multiple sclerosis (MS) have limited effectiveness and potentially serious side effects, especially when administered over long periods. Sequential combination therapy is a plausible alternative approach. Natalizumab is a monoclonal therapeutic antibody that reduces leukocyte access to the central nervous system that is associated with an increased risk of progressive multifocal leukoencephalopathy and disease reactivation after its discontinuation. Cladribine tablets act as a synthetic adenosine analog, disrupting DNA synthesis and repair, thereby reducing the number of lymphocytes. The generation of prospective, rigorous safety, and efficacy data in transitioning from natalizumab to cladribine is an unmet clinical need. Objectives: To test the feasibility of transitioning patients with relapsing forms of MS natalizumab to cladribine tablets. Design: Cladribine tablets after treatment with natalizumab (CLADRINA) is an open-label, single-arm, multicenter, collaborative phase IV, research study that will generate hypothesis regarding the safety, efficacy, and immunological impact of transition from natalizumab to cladribine tablets in patients with relapsing forms of MS. Methods and analysis: Participants will be recruited from three different sites. The primary endpoint is the absolute and percent change from baseline of lymphocytes and myeloid cell subsets, as well as blood neurofilament light levels. The secondary endpoint is the annualized relapse rate over the 12- and 24-month trial periods. Exploratory endpoints include the expanded disability status scale, and magnetic resonance imaging outcomes. Discussion: The CLADRINA trial will generate data regarding the safety, efficacy, and immunological impact of the transition from natalizumab to cladribine. As the pace of immunological knowledge of MS continues, insight into disease modifying therapy transition strategies is needed.

A narrative review of neuro-ophthalmologic disease in African Americans and Hispanics with multiple sclerosis.

Multiple sclerosis (MS) is the most common non-traumatic cause of disability in young people, with vision loss in the disease representing the second largest contributor to disability. In particular, African-American patients with MS are noted to have lower vision than their Caucasian counterparts. In this review, we examine the disparities in eye diseases in the MS population with our gaps in knowledge and discuss the underlying nature of pathological disparities.

Disease associations of excessive daytime sleepiness in multiple sclerosis: A prospective study.

Background: Excessive daytime sleepiness (EDS) in multiple sclerosis (MS) can be a significant source of disability. Despite this, its prevalence as a patient-reported outcome in this condition has not been well established, and its causes are not well understood. Methods: We prospectively assessed EDS as part of an observational study for patients referred for diagnostic neuro-ophthalmological testing. EDS was evaluated by the Epworth Sleepiness Scale (ESS), and visual data were also collected as part of a research protocol. Analysis with patient data was performed following the exclusion of patients with known primary sleep disorders. Results: A total of 69 patients with MS were included in the analysis. The mean ESS was 6.5 with a SD of 4.3. ESS ≥ 10 was present in 23% of the cohort even in the presence of minimal mean neurological disability (Patient Determined Disease Steps (PDDS) = 1.5). The ESS score was not associated with age, sex, disease-related disability, retinal nerve fiber layer (RNFL), or optic neuritis (ON), but displayed an association with visual dysfunction. Conclusions: There is an increased prevalence of EDS in MS. The increased values of the ESS are not explained by other sleep disorders, suggesting separate mechanisms. Further study of the underlying mechanisms is warranted.

Autoimmune Encephalitis Misdiagnosis in Adults.

Importance: Autoimmune encephalitis misdiagnosis can lead to harm. Objective: To determine the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis. Design, Setting, and Participants: This retrospective multicenter study took place from January 1, 2014, to December 31, 2020, at autoimmune encephalitis subspecialty outpatient clinics including Mayo Clinic (n = 44), University of Oxford (n = 18), University of Texas Southwestern (n = 18), University of California, San Francisco (n = 17), University of Washington in St Louis (n = 6), and University of Utah (n = 4). Inclusion criteria were adults (age ≥18 years) with a prior autoimmune encephalitis diagnosis at a participating center or other medical facility and a subsequent alternative diagnosis at a participating center. A total of 393 patients were referred with an autoimmune encephalitis diagnosis, and of those, 286 patients with true autoimmune encephalitis were excluded. Main Outcomes and Measures: Data were collected on clinical features, investigations, fulfillment of autoimmune encephalitis criteria, alternative diagnoses, potential contributors to misdiagnosis, and immunotherapy adverse reactions. Results: A total of 107 patients were misdiagnosed with autoimmune encephalitis, and 77 (72%) did not fulfill diagnostic criteria for autoimmune encephalitis. The median (IQR) age was 48 (35.5-60.5) years and 65 (61%) were female. Correct diagnoses included functional neurologic disorder (27 [25%]), neurodegenerative disease (22 [20.5%]), primary psychiatric disease (19 [18%]), cognitive deficits from comorbidities (11 [10%]), cerebral neoplasm (10 [9.5%]), and other (18 [17%]). Onset was acute/subacute in 56 (52%) or insidious (>3 months) in 51 (48%). Magnetic resonance imaging of the brain was suggestive of encephalitis in 19 of 104 patients (18%) and cerebrospinal fluid (CSF) pleocytosis occurred in 16 of 84 patients (19%). Thyroid peroxidase antibodies were elevated in 24 of 62 patients (39%). Positive neural autoantibodies were more frequent in serum than CSF (48 of 105 [46%] vs 7 of 91 [8%]) and included 1 or more of GAD65 (n = 14), voltage-gated potassium channel complex (LGI1 and CASPR2 negative) (n = 10), N-methyl-d-aspartate receptor by cell-based assay only (n = 10; 6 negative in CSF), and other (n = 18). Adverse reactions from immunotherapies occurred in 17 of 84 patients (20%). Potential contributors to misdiagnosis included overinterpretation of positive serum antibodies (53 [50%]), misinterpretation of functional/psychiatric, or nonspecific cognitive dysfunction as encephalopathy (41 [38%]). Conclusions and Relevance: When evaluating for autoimmune encephalitis, a broad differential diagnosis should be considered and misdiagnosis occurs in many settings including at specialized centers. In this study, red flags suggesting alternative diagnoses included an insidious onset, positive nonspecific serum antibody, and failure to fulfill autoimmune encephalitis diagnostic criteria. Autoimmune encephalitis misdiagnosis leads to morbidity from unnecessary immunotherapies and delayed treatment of the correct diagnosis.

Application of the International Interocular Difference Thresholds into Practice: Localising the Patient Experience.

Demyelinating diseases of the central nervous system (CNS) often have neuro-ophthalmological manifestations, and retinal examination can be helpful in making the diagnosis. The latest iteration of optical coherence tomography (OCT)-based criteria for optic neuritis in multiple sclerosis has been developed in the research realm, but its application to clinical practice, and to the more uncommon demyelinating diseases requires further study. The ability to use OCT data to distinguish between various CNS demyelinating disorders could provide additional paraclinical tools to accurately diagnose patients. Furthermore, neuro-ophthalmological testing can define the extent of inflammatory damage in the CNS, independent of patient-reported history. New referrals for OCT at a tertiary multiple sclerosis and neuro-immunology referral centre (n = 167) were analysed retrospectively for the self-reporting of optic neuritis, serological test results, and diagnosis. Only approximately 30% of patients with a clinical history of unilateral optic neuritis solely had a unilateral optic neuropathy, nearly 40% of those subjects actually having evidence of bilateral optic neuropathies. Roughly 30% of patients reporting a history of bilateral optic neuritis did not have any evidence of structural disease, with 20% of these patients having a separate, intervenable diagnosis noted on macular scans. OCT is a useful adjunct diagnostic tool in the evaluation of demyelinating disease and has the ability to aid in a more accurate diagnosis for patients. Application of the international interocular difference thresholds to a clinical patient population generally reproduces the original results, emphasising their appropriateness. The analysis distinguishing the demyelinating diseases needs to be replicated in a blinded, multi-centre setting.

Clinical Reasoning: A 59-Year-Old Man With Thymoma and Constitutional Symptoms, Seizures, and Multifocal CNS Lesions.

A 59-year-old man first presented for an episode of left arm numbness. During workup, a thymoma was incidentally discovered and resected. The symptoms in his left arm were attributed to a cardiac pathology. One month later, he began to experience fatigue, weight loss, and anorexia, followed by one generalized tonic-clonic seizure. Workup including toxic and metabolic screening and MRI Brain were unremarkable. He was started on an anti-seizure medication and did well for two years, when his symptoms recurred. Repeat MRI Brain showed multiple cortical T2/FLAIR hyperintense lesions without enhancement or diffusion restriction. Further workup included spinal MRI, CT chest/abdomen/pelvis, CSF studies, autoimmune/paraneoplastic panels in CSF and serum, all of which were unremarkable. Serum testing was positive for striational antibodies, acetylcholine receptor (AChR) binding antibodies, and AChR modulating antibodies. He received high dose steroids and plasma exchange with resolution of his symptoms, and has since been stable on mycophenolate mofetil. This presentation highlights the rare association between thymoma and encephalitis. Prompt identification and treatment is critical. This article discusses the diagnostic approach to this rare presentation including essential features of the clinical presentation, appropriate workup, pertinent differential diagnoses, and key points for the treatment of these patients.

Refractory Anti-NMDA Receptor Encephalitis in Early Pregnancy: A Case Report of Treatment Course and Pregnancy Outcomes.

BACKGROUND AND OBJECTIVES: Anti-N-methyl d-aspartate receptor (NMDAR) encephalitis classically affects women of childbearing age, producing a disproportionate number of pregnant women with anti-NMDAR encephalitis. The typical presentation includes progressive neuropsychiatric symptoms, seizures, and alterations in consciousness, all of which present potential risks to the fetus. First-line and second-line treatments similarly pose teratogenic potential; therefore, randomized studies with supportive data on pregnancy and fetal outcomes are lacking. METHODS: We present a case of refractory anti-NMDAR encephalitis during the first and second trimesters of pregnancy with the successful use of rituximab and cyclophosphamide and resultant healthy pregnancy. RESULTS: The patient was treated with an escalating immunotherapy regimen from 11 to 15 weeks of gestation, including steroids, plasma exchange, IV immunoglobulins, and rituximab, with no clinical response. At 16 weeks of gestation, she received cyclophosphamide with clinical improvement after 4 weeks. She subsequently gave birth to a healthy, term baby boy, who continued to do well at the follow-up. DISCUSSION: This case illustrates the effective use of cyclophosphamide in the second trimester of pregnancy for anti-NMDAR encephalitis. The use of second-line therapies remains an individualized decision because the relative risk-to-benefit ratio in pregnant women is incompletely understood.

Low Recruitment in a Double-Blind, Placebo-Controlled Trial of Ocrelizumab for Autoimmune Encephalitis: A Case Series and Review of Lessons Learned.

INTRODUCTION: Observational data suggest that B-cell-depleting therapies are effective for antibody-mediated autoimmune encephalitis. However, randomized controlled trials are needed. Here, we report challenges encountered in a randomized, placebo-controlled trial of ocrelizumab for autoimmune encephalitis that failed to meet recruitment goals. METHODS: This was a single-center, 12-month, randomized, double-blind, placebo-controlled trial. Patients with autoimmune encephalitis were randomized in 1:1 fashion to placebo or ocrelizumab infusion after receiving first-line immunotherapy. The primary endpoint of the study was clinical worsening, defined as a perceived decline by the patient or clinician or a decrease in the Lawton and Brody Instrumental Activities of Daily Living Scale (IADL), along with either worsening on the Texas Functional Living Scale (TFLS) or hospitalization for symptoms of encephalitis. RESULTS: Among 16 eligible patients, only three enrolled in the study, which closed due to poor recruitment. Two participants were randomized to the ocrelizumab arm and one to the placebo arm. The single patient in the placebo arm (NMDAR+) met the primary endpoint at 12 weeks and received open-label ocrelizumab with improvement. In the ocrelizumab arm, one participant (NMDAR+) demonstrated marked improvement, and the second (LGI1+) remained clinically stable. There were no serious adverse events associated with ocrelizumab. CONCLUSION: Clinical trial recruitment for autoimmune encephalitis is challenging, and our trial did not meet recruitment goals. Large, multicenter clinical trials are still needed, and careful attention must be given to study design, endpoints, and patient selection. Instrumented functional rating scales will be valuable outcome measures for future studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03835728.

Primary peripheral T-cell central nervous system lymphoma.

BACKGROUND: Primary peripheral T-cell central nervous system lymphoma (PCNSL) is a rare, aggressive tumor that arises in the craniospinal axis and has an increased risk in individuals who are immunocompromised. This lesion often mimics other benign and malignant processes on radiographic imaging, leading to misdiagnosis and delays in treatment. We present a case of a patient with a history of Sjögren's syndrome and progressive neurologic symptoms who underwent craniotomy for diagnosis. CASE DESCRIPTION: A 61-year-old woman with a history of Sjögren's syndrome, progressive aphasia, left facial droop, and right-sided paresthesias for 4 months presented for evaluation and management. An enhancing, infiltrative lesion in the left frontal lobe with underlying vasogenic edema was appreciated and suggestive of a primary or metastatic neoplasm. The patient underwent an open biopsy for further evaluation of the lesion. Extensive histopathologic evaluation revealed a diagnosis of T-cell PCNSL. The patient was started on induction methotrexate and temozolomide followed by consolidative radiotherapy. CONCLUSION: Autoimmune conditions are a risk factor for T-cell PCNSL development. T-cell PCNSL has radiographic and gross histologic features that are consistent with a broad differential, including gliomas and inflammatory processes. Prompt diagnosis and extensive histopathological evaluation is essential to ensure appropriate treatment.

Antibody Testing for Neurological Autoimmune Disorders: Evaluation of Best Practices at a Tertiary Referral Center.

Background: Autoimmune neurology is a rapidly evolving field of study, where best practices for neurological antibody testing have yet to be determined. The growing number of options for antibody panel testing can create confusion amongst ordering clinicians and lead to ordering several concurrent panels (i.e., overlapping evaluations) or repeat panel evaluations. This study determined the frequency of these evaluations for autoimmune and paraneoplastic disorders and investigated how these practices informed clinical decision making and management. Methods: This was a retrospective observational study of adult patients presenting to University of Texas Southwestern (UTSW) in 2017 with requests for antibody panels for autoimmune encephalitis and paraneoplastic disorders. Individuals with more than one panel requested were defined as either an overlapping evaluation (more than one panel requested within 14 days) or repeat evaluation (more than one panel requested 14 or more days apart). For those individuals with repeat panel testing, the proportion of panels with a change in antibody status or subsequent changes in clinical diagnosis and decision making were recorded. Results: There was a total of 813 panels sent on 626 individuals. Twenty percent (126 individuals) had more than one panel requested. Only 10% of individuals had a matched serum and CSF evaluation. Forty-seven overlapping evaluations were performed in 46 (7.3%) of the individuals studied. Fifty-four (8.6%) individuals underwent 70 repeat evaluations encompassing 79 panels (9.7% of total panels ordered). Ten repeat evaluations showed a change in antibody status, of which only two were clinically significant. There was a single case where clinical management was affected by repeat autoantibody evaluation. Conclusions: Ordering practices for suspected autoimmune encephalitis and paraneoplastic disorders are suboptimal with frequent overlapping antibody panel evaluations and non-paired serum/CSF samples at our center. Repeat autoantibody testing is a commonplace practice yet yielded novel information in only a minority of cases. These new results were, as a rule, clinically irrelevant and changed clinical decision making in <1% of cases. There is limited utility in these practice patterns. Future efforts should be directed at the development and standardization of neurological autoimmune and paraneoplastic autoantibody testing practice standards.

Post-infectious neurological disorders.

A multitude of environmental factors can result in breakdown of immune tolerance in susceptible hosts. Infectious pathogens are among the most important environmental triggers in the pathogenesis of autoimmunity. Certain autoimmune disorders have a strong association with specific infections. Several neurological autoimmune disorders are thought to occur through post-infectious mechanisms. In this review, we discuss the proposed mechanisms underlying pathogen-induced autoimmunity, and highlight the clinical presentation and treatment of several post-infectious autoimmune neurological disorders. We also highlight post-infectious neurological disorders in the setting of recent outbreaks.

Neurological autoimmune disorders with prominent gastrointestinal manifestations: A review of presentation, evaluation, and treatment.

BACKGROUND: The identification of autoantibodies directed against neuronal antigens has led to the recognition of a wide spectrum of neurological autoimmune disorders (NAD). With timely recognition and treatment, many patients with NAD see rapid improvement. Symptoms associated with NAD can be diverse and are determined by the regions of the nervous system affected. In addition to neurological symptoms, a number of these disorders present with prominent gastrointestinal (GI) manifestations such as nausea, diarrhea, weight loss, and gastroparesis prompting an initial evaluation by gastroenterologists. PURPOSE: This review provides a general overview of autoantibodies within the nervous system, focusing on three scenarios in which nervous system autoimmunity may initially present with gut symptoms. A general approach to evaluation and treatment, including antibody testing, will be reviewed.

Assessing recent suicidal ideation and behavior in the adult epilepsy monitoring unit.

OBJECTIVES: The objective of the study was to describe the prevalence of recent suicidal ideation and behavior in adult patients admitted to a tertiary epilepsy monitoring unit (EMU) and to assess the difference between patients with epileptic seizures, psychogenic nonepileptic spells (PNES), and other inpatient populations. RESULTS: Over the 14-month period, 316 patients were included in the study. One hundred and seventy-nine (57%) were classified as having epilepsy (ES), 116 (37%) with PNES, and 21 (7%) with comorbid ES and PNES (ES/PNES). Overall, 25 patients (8%) were screened positive for suicide risk factors (recent suicidal ideation and/or suicidal behavior). Patients admitted to the EMU had double the risk of suicide ideation and behavior when compared with other inpatient populations. There was no significant difference in the risk of suicidal ideation and behavior among patients with ES, PNES, and comorbid ES/PNES. Patients with comorbid ES/PNES had the highest risk (14%), although this did not reach statistical significance. Across all groups, patients with any comorbid psychiatric disorder had increased rates of suicidal ideation and behavior (11% vs 5%, p = 0.04). CONCLUSIONS: The rate of suicidal ideation and behavior in this sample of EMU patients was higher compared with other inpatient populations. The presence of a psychiatric disorder was independently associated with a higher risk. There was no statistically significant difference in the risk between those with ES and PNES. Screening for suicide risk, suicidal ideation, and behavior is recommended for all patients admitted to the EMU.