Expanding clinical profiles and prognostic markers in stiff person syndrome spectrum disorders.

OBJECTIVE: To describe the clinical features of a cohort of individuals with stiff person syndrome spectrum disorders (SPSD) and identify potential early predictors of future disability. BACKGROUND: There is a need to better understand the full spectrum of clinical and paraclinical features and long-term impact of SPSD. DESIGN/METHODS: Observational study from 1997 to 2022 at Johns Hopkins. Clinical phenotypes included classic SPS, partial SPS (limb or trunk limited), SPS-plus (classic features plus cerebellar/brainstem involvement), and progressive encephalomyelitis with rigidity and myoclonus (PERM). Outcome measures were modified Rankin scale (mRS) and use of assistive device for ambulation. Multivariate logistic regression was used to assess significant predictors of outcomes. RESULTS: Cohort included 227 individuals with SPSD with mean follow-up of 10 years; 154 classic, 48 SPS-plus, 16 PERM, and 9 partial. Mean age at symptom onset was 42.9 ± 14.1 years, majority were white (69.2%) and female (75.8%). Median time to diagnosis was 36.2 months (longest for SPS-plus and PERM) and 61.2% were initially misdiagnosed. Most had systemic co-morbidities and required assistive devices for ambulation. Female sex (OR 2.08; CI 1.06-4.11) and initial brainstem/cerebellar involvement (OR 4.41; CI 1.63-14.33) predicted worse outcome by mRS. Older age at symptom onset (OR 1.04; CI 1.01-1.06), female sex (OR 1.99; CI 1.01-4.01), Black race (OR 4.14; CI 1.79-10.63), and initial brainstem/cerebellar involvement (OR 2.44; CI 1.04-7.19) predicted worse outcome by use of assistive device. Early implementation of immunotherapy was associated with better outcomes by either mRS (OR 0.45; CI 0.22-0.92) or use of assistive device (OR 0.79; CI 0.66-0.94). CONCLUSIONS: We present the expanding phenotypic variability of this rare spectrum of disorders and highlight potential predictors of future disability.

Early factors associated with later conversion to multiple sclerosis in patients presenting with isolated myelitis.

OBJECTIVE: To identify early clinical and paraclinical factors that may help predict later conversion to multiple sclerosis (MS) in patients presenting with isolated myelitis (ie, 'transverse myelitis' without clinical or radiological evidence of inflammation/demyelination elsewhere in the central nervous system). METHODS: In this retrospective cohort study, we included patients with isolated myelitis who were followed clinically and radiologically at our specialised myelopathy clinic. We excluded patients with MS at the onset, aquaporin-4-IgG seropositivity, myelin oligodendrocyte glycoprotein-IgG seropositivity or other identified aetiology. Logistic regression was used to identify factors predictive of conversion to MS (defined by the 2017 McDonald criteria). RESULTS: We included 100 patients, followed for a median of 4.3 years. Conversion to MS occurred in 25 of 77 patients (32%) with short-segment myelitis (longest lesion spanning <3 vertebral segments on MRI) as compared with 0 of 23 patients (0%) with longitudinally extensive myelitis (p=0.002). Among patients with short-segment myelitis, factors identified as highly predictive of conversion to MS using multivariate logistic regression included cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCB) (OR (OR) 9.2, 95% CI 2.1 to 41.0, p=0.004), younger age (OR 1.1 for each year younger, 95% CI 1.0 to 1.1, p=0.04) and longer follow-up (OR 1.3 for each year longer, 95% CI 1.0 to 1.6, p=0.04). Conversion to MS occurred at a median of 2.8 years after myelitis onset. CONCLUSIONS: Short-segment MRI cord lesion(s), CSF-restricted OCB, younger age and longer follow-up are all factors predictive of conversion to MS in patients presenting with isolated myelitis.

Neuro-ophthalmic Complications of Immune-Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have revolutionized the field of oncology by modulating the immune cell-cancer cell interaction and thereby promoting immune system disinhibition in order to target several types of malignancies. There are three classes of immune checkpoint inhibitors (ICIs): anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), anti-programmed cell death protein-1 (PD-1), and anti-programmed cell death ligand-1 (PD-L1).It is not uncommon for physicians across all specialties to encounter a patient with a history of malignancy and ICI exposure, necessitating familiarity with their potential complications. In this review article, we discuss the most common immune-related adverse events (irAEs) pertaining to the central and peripheral nervous systems and their potential afferent and efferent neuro-ophthalmic manifestations. Early recognition and treatment of these irAEs, and discontinuation of the offending ICI are all critical steps to prevent morbidity and mortality.

AQP4-IgG and MOG-IgG Related Optic Neuritis-Prevalence, Optical Coherence Tomography Findings, and Visual Outcomes: A Systematic Review and Meta-Analysis.

Background: Optic neuritis (ON) is a cardinal manifestation of multiple sclerosis (MS), aquaporin-4 (AQP4)-IgG-, and myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease. However, the prevalence of AQP4-IgG seropositivity and MOG-IgG seropositivity in isolated ON is unclear, and studies comparing visual outcomes and optical coherence tomography (OCT)-derived structural retinal measures between MS-ON, AQP4-ON, and MOG-ON eyes are limited by small sample sizes. Objectives: (1) To assess the prevalence of AQP4-IgG and MOG-IgG seropositivity among patients presenting with isolated ON; (2) to compare visual outcomes and OCT measures between AQP4-ON, MOG-ON, and MS-ON eyes. Methods: In this systematic review and meta-analysis, a total of 65 eligible studies were identified by PubMed search. Statistical analyses were performed with random effects models. Results: In adults with isolated ON, AQP4-IgG seroprevalence was 4% in non-Asian and 27% in Asian populations, whereas MOG-IgG seroprevalence was 8 and 20%, respectively. In children, AQP4-IgG seroprevalence was 0.4% in non-Asian and 15% in Asian populations, whereas MOG-IgG seroprevalence was 47 and 31%, respectively. AQP4-ON eyes had lower peri-papillary retinal nerve fiber layer (pRNFL; -11.7 µm, 95% CI: -15.2 to -8.3 µm) and macular ganglion cell + inner plexiform layer (GCIPL; -9.0 µm, 95% CI: -12.5 to -5.4 µm) thicknesses compared with MS-ON eyes. Similarly, pRNFL (-11.2 µm, 95% CI: -21.5 to -0.9 µm) and GCIPL (-6.1 µm, 95% CI: -10.8 to -1.3 µm) thicknesses were lower in MOG-ON compared to MS-ON eyes, but did not differ between AQP4-ON and MOG-ON eyes (pRNFL: -1.9 µm, 95% CI: -9.1 to 5.4 µm; GCIPL: -2.6 µm, 95% CI: -8.9 to 3.8 µm). Visual outcomes were worse in AQP4-ON compared to both MOG-ON (mean logMAR difference: 0.60, 95% CI: 0.39 to 0.81) and MS-ON eyes (mean logMAR difference: 0.68, 95% CI: 0.40 to 0.96) but were similar in MOG-ON and MS-ON eyes (mean logMAR difference: 0.04, 95% CI: -0.05 to 0.14). Conclusions: AQP4-IgG- and MOG-IgG-associated disease are important diagnostic considerations in adults presenting with isolated ON, especially in Asian populations. Furthermore, MOG-IgG seroprevalence is especially high in pediatric isolated ON, in both non-Asian and Asian populations. Despite a similar severity of GCIPL and pRNFL thinning in AQP4-ON and MOG-ON, AQP4-ON is associated with markedly worse visual outcomes.

A Neurologist's Perspective on Understanding Myasthenia Gravis: Clinical Perspectives of Etiologic Factors, Diagnosis, and Preoperative Treatment.

Myasthenia gravis (MG) is a disease of neuromuscular transmission caused by antibodies directed toward proteins concentrated at the neuromuscular junction. Mild to life-threatening weakness varies in severity over time and with level of activity. Therefore, clinical diagnosis is often challenging. MG may be categorized by autoantibody type, thymic pathologic condition, and age of onset. Treatments are tailored for each group. A key management concern is severe exacerbation of weakness resulting from infections or exposure to certain medications, including antibiotics, which may be severe enough to produce respiratory decompensation. The article reviews key diagnostic issues and treatment options.

Effects of low-frequency electrical stimulation of the anterior piriform cortex on kainate-induced seizures in rats.

OBJECTIVE: Recent evidence in animals and humans suggests that low-frequency stimulation (LFS) has significant antiepileptic properties. The anterior piriform cortex (APC) is a highly susceptible seizure-trigger zone and may be critical for the initiation and propagation of seizures originating from cortical and limbic foci. We used the kainic acid (KA) seizure model in rats to assess the therapeutic effect of LFS of the APC on seizures. METHODS: Adult male Sprague-Dawley rats were implanted with electrodes in the left APC and recording electrodes bilaterally in the hippocampal CA3 regions. Rats were monitored continuously with video-EEG after the emergence of spontaneous recurrent seizures that followed induction of status epilepticus by intraperitoneal KA. After two weeks of baseline recordings to determine seizure frequency, LFS of the APC was applied 60-min On 15-min Off, for two weeks with 1Hz biphasic square waves, 0.2ms pulse width, at 200µA. Another 2-week period of video-EEG monitoring was done after the cessation of LFS to study the carry-over effect. Changes in seizure frequency, severity, and duration between baseline, during LFS, and post-LFS were analyzed using the Poisson regression model. RESULTS: Overall seizure frequency decreased during the post-LFS period to 5% of that at baseline (p=0.003). Severe seizures (stages 4 and 5 on the Racine scale) decreased to 0% of the baseline during the post-LFS period. CONCLUSIONS: Two weeks of LFS of the APC reduced spontaneous seizure frequency and severity in the KA model with the effect outlasting the stimulation. Our findings suggest that the APC can be an important therapeutic target for stimulation in epilepsy.

Primary stabbing "ice-pick" headache.

Primary stabbing "ice-pick" headache is rarely reported in children. It is characterized by transient, sharp stabbing pain that occurs within a localized area of the scalp for seconds. Five children were diagnosed according to the International Classification of Headache Disorders Diagnostic Criteria, Second Edition. Ages at diagnosis ranged from 6-16 years (mean age, 9.8 years), with signs lasting for 3-12 months (mean, 6.5 months) before assessment. All children presented with recurrent daily to monthly headaches that were very brief, lasting for seconds. The headache was orbital in one child, temporal in one child, and occipital in three children. Three children manifested other associated migraine headache types, and two had a positive family history of migraine. Amitriptyline was prescribed to two patients because of headache frequency and severity. The signs gradually subsided in all patients during follow-up of 3 months to 5 years (mean, 27 months). Primary stabbing headache may occasionally occur in children with features different from those encountered in adults. The headache is less frequent and often occipital in location. Its signs respond well to amitriptyline. However, larger prospective pediatric studies are needed to describe this syndrome further.