Frequency, characteristics, predictors and treatment of relapsing myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may have a monophasic or relapsing disease course. To date, factors that may predict a relapsing disease course remain largely unknown and only limited data exist regarding the efficacy of different utilized immunotherapy regimens at preventing or reducing relapses. OBJECTIVES: To assess the characteristics, predictors, and immunotherapy of relapsing MOGAD. METHODS: This multicenter retrospective analysis included all MOGAD cases at the University of Florida, Baylor College of Medicine and the University of California San Diego with minimum follow-up time of 6 months. Cox proportional hazards regression analyses, corrected for age and sex, were performed to evaluate hazard ratios (HR) of predictors of a relapsing disease course and to compare relapse hazards for utilized immunotherapies. RESULTS: The majority of included participants (51/79 [64.6 %]) had a relapsing course, and of these individuals, 68.6 % (35/51) experienced their first relapse within the first year. However, 10/51 (19.6 %) participants experienced their first relapse ≥5 years (5-15 years) after the initial presentation. Predictors of a relapsing course were CSF pleocytosis (>150 cells/mm3; HR 3.3 [1.18 - 9.24]; p = 0.023), a pediatric disease onset at age < 9 years (HR 2.69 [1.07-6.75]; p = 0.035), and an initial presentation with the clinical syndrome of meningoencephalitis (HR 3.42 [1.28 - 9.17]; p = 0.015),. In participants with a relapsing course, 13/24 (54.2 %) patients remained relapse-free on rituximab, 4/8 (50 %) on mycophenolate mofetil, and 11/14 (78.6 %) on scheduled immunoglobulins. Patients treated with immunoglobulins had significantly fewer relapses compared to patients treated with other immunotherapies (HR: 0.1 [0.2 - 0.63]; p = 0.014). CONCLUSIONS: In our cohort, the majority of MOGAD patients relapsed. The initial relapse occurred most frequently within the first year, but first relapses also took place over a decade after the initial presentation. Prepubertal onset, severe CSF pleocytosis, and the clinical syndrome of meningoencephalitis may be predictors of a relapsing course. Of the currently available off-label steroid-sparing treatments, scheduled immunoglobulins may be the most effective in relapse prevention.

Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

For over two centuries, clinicians have been aware of various conditions affecting white matter which had come to be grouped under the umbrella term multiple sclerosis. Within the last 20 years, specific scientific advances have occurred leading to more accurate diagnosis and differentiation of several of these conditions including, neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody disease. This new understanding has been coupled with advances in disease-modifying therapies which must be accurately applied for maximum safety and efficacy.

Multiple Sclerosis: Clinical Update and Clinically-Oriented Radiologic Reporting.

Multiple sclerosis (MS) is a chronic inflammatory disease of the nervous system. MR imaging findings play an integral part in establishing diagnostic hallmarks of the disease during initial diagnosis and evaluating disease status. Multiple iterations of diagnostic criteria and consensus guidelines are put forth by various expert groups incorporating imaging of the brain and spine, and efforts have been made to standardize imaging protocols for MS. Emerging ancillary imaging findings have also attracted increasing interests and should be sought for on radiologic examination. In this paper, the authors review the clinical guidelines and approach to imaging of MS and related disorders, focusing on clinically impactful image interpretation and MR imaging reporting.

Ocrelizumab B-cell repopulation-guided extended interval dosing versus standard dosing - similar clinical efficacy with decreased immunoglobulin M deficiency rates.

BACKGROUND: Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody used in treatment of multiple sclerosis. The standard dosing (SD) regimen consists of OCR maintenance infusions every 6 months. In B-cell repopulation-guided extended interval dosing (EID), repeat infusions are delayed until there is evidence for B-cell repopulation. OBJECTIVES: To compare frequencies of 'no evidence of disease activity' (NEDA-3) and immunoglobulin G (hypo-IgG; <600 mg/dL) and M (hypo-IgM; <40 mg/dL) deficiencies in persons with multiple sclerosis (PwMS) treated with OCR B-cell repopulation-guided EID versus SD. METHODS: Two-center retrospective study comparing frequencies of NEDA-3 and hypo-IgG and hypo-IgM in PwMS treated with OCR B-cell repopulation-guided EID versus SD using a multivariate generalized linear model adjusted for age, sex, and treatment duration. RESULTS: A total of 112 OCR-treated PwMS were included (B-cell repopulation-guided EID n = 52; SD n = 60) with average infusion intervals of 319 (246-485) days (EID) and 184 (170-218) days (SD). There was no significant difference in NEDA-3 (EID: 47/52 [90.4 %]; SD: 50/60 [83.3 %]; p = 0.161) or hypo-IgG (EID: 1/52 [1.9 %]; SD: 4/60 [6.7 %]; p = 0.298) rates. Hypo-IgM was significantly less common in EID (EID: 9/52 [17.3 %] vs. SD: 34/60 [55 %]; p<0.001) upon assessment 1099 (475-1436) days (EID) and 980 (409-1846) days (SD) post-initiation of OCR. Hypo-IgM was associated with average infusion interval length (p = 0.005) and total number of OCR cycles (p = 0.003). CONCLUSIONS: OCR B-cell repopulation-guided EID may be a safe alternative to traditional SD with similar efficacy and significantly less hypo-IgM rates.

Progressive multifocal leukoencephalopathy without overt immunosuppression.

Progressive multifocal leukoencephalopathy (PML) is a central nervous system disease caused by the human polyomavirus 2 that usually occurs in a setting of immunodeficiency. PML without overt immunosuppression is considered a rare occurrence but has been described in multiple previous case reports and series. Its prevalence, overall frequency, and prognosis are largely unknown. This is a single-center retrospective review of all University of Florida cases with the ICD10 PML diagnosis code (A81.2). PML without overt immunosuppression was defined as absence of human immunodeficiency virus (HIV) infection, hematological malignancy, immunomodulatory/-suppressive medications, autoimmune conditions with a propensity for PML (sarcoidosis, systemic lupus erythematosus). Cases that did not fulfill criteria for clinically or histologically definite PML were excluded. Of 52 patients with the ICD10 code A 81.2, 17 fulfilled definite diagnostic criteria for PML. Overt immunosuppression was identified in 15/17 (88.2%) cases (10/17 (58.8%): human immunodeficiency virus; 5/17 (29.4%): immunomodulatory/-suppressive medication). Two/seventeen (11.8%) cases were consistent with PML without overt immunosuppression. Possible contributing factors were a preceding dog bite and mild hypogammaglobulinemia M (39 mg/dL) in case 1 and significant alcohol use without evidence for liver disease in case 2. Both cases were fatal within 6 (case 1) and 2 (case 2) months. The results suggest that PML without overt immunosuppression may be more common than previously described. Therefore, PML should be considered even in the absence of overt immunosuppression if clinical and radiographic findings are suggestive of the diagnosis.

Longitudinal evaluation of neurologic-post acute sequelae SARS-CoV-2 infection symptoms.

OBJECTIVE: To assess the initial features and evolution of neurologic Postacute Sequelae of SARS-CoV-2 infection (neuro-PASC) in patients with and without prior neurologic disease. METHODS: Participants with neurologic symptoms following acute SARS-CoV-2 infection were recruited from October 9, 2020 to October 11, 2021. Clinical data included a SARS-CoV-2 infection history, neurologic review of systems, neurologic exam, Montreal cognitive assessment (MoCA), and symptom-based self-reported surveys at baseline (conducted after acute infection) and 6-month follow-up assessments. RESULTS: Fifty-six participants (69% female, mean age 50 years, 29% with prior neurologic disease such as multiple sclerosis) were enrolled, of which 27 had completed the 6-month follow-up visit in this ongoing study. SARS-CoV-2 infection severity was largely described as mild (39.3%) or moderate (42.9%). At baseline, following acute infection, the most common neurologic symptoms were fatigue (89.3%) and headaches (80.4%). At the 6-month follow-up, memory impairment (68.8%) and decreased concentration (61.5%) were the most prevalent, though on average all symptoms showed a reduction in reported severity score at the follow-up. Complete symptom resolution was reported in 33.3% of participants by 6 months. From baseline to 6 months, average MoCA scores improved overall though 26.3% of participants' scores decreased. A syndrome consisting of tremor, ataxia, and cognitive dysfunction (PASC-TAC) was observed in 7.1% of patients. INTERPRETATION: Early in the neuro-PASC syndrome, fatigue and headache are the most commonly reported symptoms. At 6 months, memory impairment and decreased concentration were most prominent. Only one-third of participants had completed resolution of neuro-PASC at 6 months, although persistent symptoms trended toward improvement at follow-up.

A Comparison of Pediatric- and Adult-Onset Aquaporin-4 Immunoglobulin G-Positive Neuromyelitis Optica Spectrum Disorder: A Review of Clinical and Radiographic Characteristics.

BACKGROUND: The identification of immunoglobulin G antibodies against the aquaporin-4 channel (AQP-IgG) in the majority of adult patients differentiates neuromyelitis optica as a distinct disease entity. The high specificity of AQP4-IgG for neuromyelitis optica has allowed the identification of seropositive patients with atypical presentations of this disease. Neuromyelitis optica spectrum disorder has been increasingly recognized in children who demonstrate patterns of clinical involvement beyond the traditional boundaries of the optic pathways and spinal cord. METHODS: This is a single-center, retrospective review comparing demographic, clinical/paraclinical, and laboratory features of children and adults with a serologically confirmed diagnosis of AQP4-IgG-positive neuromyelitis optica spectrum disorder. RESULTS: Of 151 reviewed patient charts, 12 pediatric-onset and 31 adult-onset patients had AQP4-IgG-positive neuromyelitis optica spectrum disorder. The mean age of pediatric-onset neuromyelitis optica spectrum disorder was 12 ± 3.58 years with a female predilection (3:1). Pediatric patients showed more frequent involvement of the brainstem (6/12 [50%]); P = .008) and diencephalon (3/12 [25%]; P = .018). A preceding infection was identifiable in only 3 of 12 (25%) pediatric-onset patients. Moreover, disability as calculated on the expanded disability status scale was less severe in pediatric-onset cases compared to adult-onset cases in their most recent assessment (0 [0-9]) vs 6.5 [0-10]; P = .005). Pediatric-onset patients were also more likely to respond to treatment of acute episodes with corticosteroids ± intravenous immunoglobulin and/or plasmapheresis (Clinical Global Impression-Change scale: 2.5 [1-4] vs 4 [1-6], P = .009). INTERPRETATION: This retrospective study was able to compare and contrast pediatric- and adult-onset neuromyelitis optica spectrum disorder. Relative to their adult counterparts, pediatric-onset neuromyelitis optica spectrum disorder patients were more likely to respond to treatment and less likely to be disabled from their disease at follow-up. Therefore, pediatric-onset disease may represent a less virulent form of neuromyelitis optica spectrum disorder.

Therapeutic Advances in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system that causes significant disability and healthcare burden. The treatment of MS has evolved over the past three decades with development of new, high efficacy disease modifying therapies targeting various mechanisms including immune modulation, immune cell suppression or depletion and enhanced immune cell sequestration. Emerging therapies include CNS-penetrant Bruton's tyrosine kinase inhibitors and autologous hematopoietic stem cell transplantation as well as therapies aimed at remyelination or neuroprotection. Therapy development for progressive MS has been more challenging with limited efficacy of current approved agents for inactive disease and older patients with MS. The aim of this review is to provide a broad overview of the current therapeutic landscape for MS.

Quantification of smooth pursuit dysfunction in multiple sclerosis.

BACKGROUND: Smooth pursuit dysfunction is common in MS, but rarely quantified and may be missed on exam. METHODS: NeuroFitONE™ smooth pursuit performance measures were compared between MS (n = 20) and healthy control (n = 19) participants. RESULTS: Compared to controls, MS patients had lower proportion of smooth pursuit (0.63 vs. 0.73; p = 0.047), increased directional (10.1 vs. 8°; p = 0.014) and speed noise (4.3 vs. 3.1°/sec; p = 0.021) and reduced initiation acceleration (96.83 vs. 115.33°/sec2; p = 0.061). Significant univariate correlations with clinical scores (EDSS, T25-FW) were observed. CONCLUSION: Smooth pursuit dysfunction in MS can be readily quantified and distinguishes MS eyes from healthy controls.

Anti-MOG associated disorder-Clinical and radiological characteristics compared to AQP4-IgG+ NMOSD-A single-center experience.

BACKGROUND: The discovery of two immunoglobulin G (IgG) antibodies against aquaporin 4 (anti-AQP4) and myelin oligodendrocyte glycoprotein (anti-MOG) has led to the distinction of the disorders anti-AQP4 immunoglobulin G positive neuromyelitis spectrum disorder (AQP4-IgG+ NMOSD) and anti-MOG associated disorder (MOGAD). Different clinical and radiological features have been proposed to distinguish these two demyelinating CNS diseases. METHODS: This is a single-center retrospective review at the University of Florida (UF) including all patients with the diagnostic code ICD G36 ("other acute disseminated demyelination") from October 2015 to January 2020 (n=141) and all charts included in the clinical NMOSD database of the UF Division of Neuroimmunology (n=36). A total of 151 cases were reviewed for presence of anti-MOG and anti-AQP4 antibodies and NMOSD diagnostic criteria. Differences in MOGAD and AQP4-IgG+ NMOSD were compared. RESULTS: Of the 151 reviewed patient charts, 11 were consistent with MOGAD and 43 with AQP4-IgG+ NMOSD. Patients with MOGAD were significantly younger at symptom onset compared to patients with AQP4-IgG+ NMOSD (14 [1-33] years vs. 37 [6-82] years; p=0.005). In comparison with AQP4-IgG+ NMOSD, optic neuritis in MOGAD was more frequently associated with bilateral optic nerve involvement: (6/11 [54.5%] vs. 6/43 [13.9%]; p=0.009) and fundoscopic presence of optic disc edema (5/11 [45.5%] vs. 3/43 [7%]; p=0.006). Perineuritis was a common radiological feature in MOGAD (present in 4 cases). In case of myelitis, there was more frequent involvement of the conus medullaris in MOGAD (4/11 [36.4%] vs. 2/43 [4.7%]; p=0.012). Symptomatic cerebral syndrome with supratentorial white matter lesions was seen in MOGAD patients with pediatric onset (pediatric onset: 4/6 [66.7%] vs. adult onset: 0/5 [0%]. In MOGAD, evidence for combined central and peripheral demyelination and increased intracranial pressure was present in one patient each. A preceding inciting event (illness/postpartum) was more frequently identifiable in MOGAD (4/11 [36.4%] vs. 4/43 [7%]; p=0.045). Disability as calculated on the Expanded Disability Status Scale was less severe in MOGAD compared to AQP-IgG+ NMOSD (most severe presentation: 5 [2-7] vs. 7 [1-10]; p=0.015; most recent assessment: 2 [0-5] vs. 5 [0-10]; p=0.045) and patients were more likely to respond to treatment of acute attacks with corticosteroids and/or plasmapheresis (Clinical Global Impression-Global Change scale: 1 [1-4] vs. 3 [1-6]; p=0.001). INTERPRETATION: The study confirms that simultaneous bilateral optic neuritis, presence of optic disc edema, transverse myelitis with conus involvement and a less severe disease course are distinctive features of MOGAD.

Anti-JCV antibody index does not change during ocrelizumab-treatment.

OBJECTIVE: To prospectively assess anti-JCV antibody index (AI) and its relationship to immunoglobulin levels in ocrelizumab-treated MS patients. METHODS: Monocentric prospective observational study over 24 months assessing anti-JCV AI and immunoglobulin levels in MS patients before and after initiation of ocrelizumab. RESULTS: No significant change in anti-JCV AI titers was observed 458 ± 300 days after initiation of ocrelizumab (n = 45, 0.7 ± 2.21 vs. 0.6 ± 2.06, p = 0.8). Seroconversion occurred in 1/20 initially anti-JCV seronegative patients. There was no correlation between changes in anti-JCV AI and immunoglobulins. CONCLUSION: Treatment with ocrelizumab is not associated with an increase in anti-JCV AI titers.

Corticosteroids lead to short-term improvement in cerebral amyloid angiopathy-related inflammation.

BACKGROUND: Cerebral amyloid angiopathy - related inflammation (CAA-ri) is an uncommon manifestation of CAA. METHODS: Single-center, retrospective review of all charts with ICD-code I68.0 (CAA) from 2/2/2016-1/1/2020. RESULTS: Of 152 CAA cases, 13 (8.6%) were consistent with CAA-ri. Corticosteroid-treatment led to short-term reduction in modified Rankin Scale scores (2.6 ± 1.4 vs. 1.6 ± 1.5; p = 0.01) and T2/FLAIR lesion volume (78.1 ± 52.2 cm3 vs. 30 ± 30.9 cm3, p < 0.01) as well as short-term improvement in post-treatment Clinical Global Impression - Global Change scores compared to pre-treatment scores (clinical: 6 ± 1 vs. 2.6 ± 1.3, p = 0.03; radiological: 4.6 ± 1.9 vs. 1.2 ± 0.4, p = 0.03). INTERPRETATION: Corticosteroid-treatment leads to clinical and radiological short-term improvement (class IV evidence).

"Status myotonicus" in Nav1.4-M1592V channelopathy.

Nav1.4 channelopathies due to SCN4A mutations can present with episodic attacks of myotonia triggered by fluctuation in the potassium level (potassium-aggravated myotonia). We report a case of potassium-aggravated myotonia due to Nav1.4-M1592V channelopathy with severe and long-lasting focal attacks of myotonia resembling dystonic posturing with diffuse muscle edema in the affected muscles in magnetic resonance imaging and almost constant presence of myotonic discharges in electromyography that can best be described as focal "status myotonicus".

Dorsal Root Ganglion Stimulation as a Potentially Effective Treatment for Painful Hereditary and Idiopathic Axonal Polyneuropathy: A Retrospective Case Series.

OBJECTIVES: Dorsal root ganglion (DRG) stimulation has been demonstrated to be effective in treating painful diabetic polyneuropathy in a small case series. However, diabetic polyneuropathy only accounts for 41% of all polyneuropathies and the efficacy of DRG on other types of polyneuropathy is unclear. The objective of this study is to evaluate the efficacy of DRG stimulation in treating painful hereditary and idiopathic axonal polyneuropathy. MATERIALS AND METHODS: This is a monocentric retrospective case series. Two subjects with painful hereditary axonal polyneuropathy and two subjects with painful chronic idiopathic axonal polyneuropathy who underwent DRG stimulation trials were included in this study. All subjects were evaluated independently by neuromuscular neurologists with eletrophysiological studies and genetic testing. Permanent DRG stimulator was implanted if significant pain relief (>50%) was achieved over the trial period. Pain level were evaluated at baseline, during the trial, after the permanent implantation and at one, three, and six months. RESULTS: Pain was significantly reduced after the DRG stimulator trial with an average VAS reduction of 6.00 ± 2.83, or 65 ± 26.77% (p = 0.024). Three subjects subsequently underwent permanent DRG stimulator implantation. Pain remained significantly reduced after the permanent implantation. The average VAS reduction was 6.33 ± 2.31, or 67.5 ± 20.46% after permanent DRG implantation (p = 0.042), 7.67 ± 2.31, or 80.83 ± 15.88% at one month (p = 0.029), and 7.00 ± 2.00 or 74.17 ± 14.21% at three and six months (p = 0.026). No complications were observed. CONCLUSION: This small retrospective study suggests that DRG stimulation may be a safe and effective treatment for painful hereditary and idiopathic axonal polyneuropathy.

Sensitization of the Nociceptive System in Complex Regional Pain Syndrome.

BACKGROUND: Complex regional pain syndrome type I (CRPS-I) is characterized by sensory, motor and autonomic abnormalities without electrophysiological evidence of a nerve lesion. OBJECTIVE: Aims were to investigate how sensory, autonomic and motor function change in the course of the disease. METHODS: 19 CRPS-I patients (17 with acute, 2 with chronic CRPS, mean duration of disease 5.7±8.3, range 1-33 months) were examined with questionnaires (LANSS, NPS, MPI, Quick DASH, multiple choice list of descriptors for sensory, motor, autonomic symptoms), motor and autonomic tests as well as quantitative sensory testing according to the German Research Network on Neuropathic Pain at two visits (baseline and 36±10.6, range 16-53 months later). RESULTS: CRPS-I patients had an improvement of sudomotor and vasomotor function, but still a great impairment of sensory and motor function upon follow-up. Although pain and mechanical detection improved upon follow-up, thermal and mechanical pain sensitivity increased, including the contralateral side. Increase in mechanical pain sensitivity and loss of mechanical detection were associated with presence of ongoing pain. CONCLUSIONS: The results demonstrate that patients with CRPS-I show a sensitization of the nociceptive system in the course of the disease, for which ongoing pain seems to be the most important trigger. They further suggest that measured loss of function in CRPS-I is due to pain-induced hypoesthesia rather than a minimal nerve lesion. In conclusion, this article gives evidence for a pronociceptive pain modulation profile developing in the course of CRPS and thus helps to assess underlying mechanisms of CRPS that contribute to the maintenance of patients' pain and disability.