Radiologically Isolated Syndrome and the Multiple Sclerosis Prodrome in Pediatrics: Early Features of the Spectrum of Demyelination.

Radiologically isolated syndrome refers to the clinical scenario in which individuals have imaging concerning for multiple sclerosis and would otherwise satisfy radiographic dissemination in space criteria, but do not have any attributable signs or symptoms. Radiologically isolated syndrome has been increasingly recognized in the pediatric population and it is understood certain individuals will transition to a formal diagnosis of multiple sclerosis over time. This review aims to outline the available data within this unique population including the diagnostic criteria, epidemiology, risk factors associated with transitioning to multiple sclerosis, and the current therapeutic landscape. Radiologically isolated syndrome will also be positioned within a broader spectrum of demyelinating disease as recent data has pointed towards a likely prodromal phase that precedes a first clinical event and diagnosis of multiple sclerosis. Characterizing the radiographic features, clinical symptoms, and biomarkers that constitute this prodromal phase of multiple sclerosis would help identify patients who may most benefit from early intervention in the future.

Clinical Reasoning: A 73-Year-Old Woman With Episodic Dysarthria and Horizontal Binocular Diplopia.

A 73-year-old woman presented with transient episodes of dysarthria and horizontal diplopia. She had stereotactic radiosurgery 18 years prior for a retroclival meningioma. Neurologic examination was notable for right-sided tongue deviation, tongue fasciculations, and intermittent impaired abduction of the right eye. MRI ruled out recurrence or progression of the retroclival meningioma. EEG failed to reveal electrographic seizures. EMG showed spontaneous depolarizations in bursts that sounded like "marching soldiers" in the right hemitongue, consistent with myokymia. Focal myokymia is an unusual EMG finding that is usually seen in demyelinating disorders, after radiation, or in neoplastic/inflammatory conditions. The clinical presentation and EMG findings were most consistent with delayed radiation-induced myokymia. Similar cases of transient dysarthria and tongue myokymia from radiation have been infrequently reported in the literature; however, this case uniquely exhibited additional episodes of transient horizontal diplopia, which was possibly from ocular myokymia or neuromyotonia. Although there are limited data, sodium channel inhibitors (e.g., carbamazepine, oxcarbazepine, and lacosamide) have shown some success to provide symptomatic relief, most likely secondary to their ability to inhibit underlying peripheral nerve hyperexcitability. Our patient was started on lacosamide 50 mg twice a day with a notable decrease in symptom frequency. This case illustrates the importance of detailed clinical and electrodiagnostic studies in making the diagnosis of delayed radiation-induced myokymia with episodic dysarthria and provides guidance on potential therapeutics.

A New England COVID-19 Registry of Patients With CNS Demyelinating Disease: A Pilot Analysis.

BACKGROUND AND OBJECTIVES: We sought to define the risk of severe coronavirus disease 2019 (COVID-19) infection requiring hospitalization in patients with CNS demyelinating diseases such as MS and the factors that increase the risk for severe infection to guide decisions regarding patient care during the COVID-19 pandemic. METHODS: A pilot cohort of 91 patients with confirmed or suspected COVID-19 infection from the Northeastern United States was analyzed to characterize patient risk factors and factors associated with an increased severity of COVID-19 infection. Univariate analysis of variance was performed using the Mann-Whitney U test or analysis of variance for continuous variables and the χ2 or Fisher exact test for nominal variables. Univariate and stepwise multivariate logistic regression identified clinical characteristics or symptoms associated with hospitalization. RESULTS: Our cohort demonstrated a 27.5% hospitalization rate and a 4.4% case fatality rate. Performance on Timed 25-Foot Walk before COVID-19 infection, age, number of comorbidities, and presenting symptoms of nausea/vomiting and neurologic symptoms (e.g., paresthesia or weakness) were independent risk factors for hospitalization, whereas headache predicted a milder course without hospitalization. An absolute lymphocyte count was lower in hospitalized patients during COVID-19 infection. Use of disease-modifying therapy did not increase the risk of hospitalization but was associated with an increased need for respiratory support. DISCUSSION: The case fatality and hospitalization rates in our cohort were similar to those found in MS and general population COVID-19 cohorts within the region. Hospitalization was associated with increased disability, age, and comorbidities but not disease-modifying therapy use.

Community economic factors influence outcomes for patients with primary malignant glioma.

BACKGROUND: Community economics and other social health determinants influence outcomes in oncologic patient populations. We sought to explore their impact on presentation, treatment, and survival in glioma patients. METHODS: A retrospective cohort of patients with glioma (World Health Organization grades III-IV) diagnosed between 1999 and 2017 was assembled with data abstracted from medical record review. Patient factors included race, primary care provider (PCP) identified, marital status, insurance status, and employment status. Median household income based on zip code was used to classify patients as residing in high-income communities (HICs; ie, above the median state income) or low-income communities (LICs; ie, below the median state income). The Kaplan-Meier method was used to assess overall survival (OS); Cox proportional hazards regression was used to explore associations with OS. RESULTS: Included were 312 patients, 73% from LICs. Survivors residing in LICs and HICs did not differ by age, sex, race, tumor grade, having a PCP, employment status, insurance, time to presentation, or baseline performance status. Median OS was 4.1 months shorter for LIC patients (19.7 vs 15.6 mo; hazard ratio [HR], 0.75; 95% CI: 0.56-0.98, P = 0.04); this difference persisted with 1-year survival of 66% for HICs versus 61% for LICs at 1 year, 34% versus 24% at 3 years, and 29% versus 17% at 5 years. Multivariable analysis controlling for age, grade, and chemotherapy treatment showed a 25% lower risk of death for HIC patients (HR, 0.75; 95% CI: 0.57-0.99, P < 0.05). CONCLUSIONS: The economic status of a glioma patient's community may influence survival. Future efforts should investigate potential mechanisms such as health care access, stress, treatment adherence, and social support.

A Pilot Study Assessing the Impact of rs174537 on Circulating Polyunsaturated Fatty Acids and the Inflammatory Response in Patients with Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of death and disability in persons under age 45. The hallmark secondary injury profile after TBI involves dynamic interactions between inflammatory and metabolic pathways including fatty acids. Omega-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) have been shown to provide neuroprotective benefits by minimizing neuroinflammation in rodents. These effects have been less conclusive in humans, however. We postulate genetic variants influencing PUFA metabolism in humans could contribute to these disparate findings. Therefore, we sought to (1) characterize the circulating PUFA response and (2) evaluate the impact of rs174537 on inflammation after TBI. A prospective, single-center, observational pilot study was conducted to collect blood samples from Level-1 trauma patients (N = 130) on admission and 24 h post-admission. Plasma was used to quantify PUFA levels and inflammatory cytokines. Deoxyribonucleic acid was extracted and genotyped at rs174537. Associations between PUFAs and inflammatory cytokines were analyzed for all trauma cases and stratified by race (Caucasians only), TBI (TBI: N = 47; non-TBI = 83) and rs174537 genotype (GG: N = 33, GT/TT: N = 44). Patients with TBI had higher plasma DHA levels compared with non-TBI at 24 h post-injury (p = 0.013). The SNP rs174537 was associated with both PUFA levels and inflammatory cytokines (p < 0.05). Specifically, TBI patients with GG genotype exhibited the highest plasma levels of DHA (1.33%) and interleukin-8 (121.5 ± 43.3 pg/mL), which were in turn associated with poorer outcomes. These data illustrate the impact of rs174537 on the post-TBI response. Further work is needed to ascertain how this genetic variant directly influences inflammation after trauma.

Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration.

Mutations in parkin lead to early-onset autosomal recessive Parkinson's disease (PD) and inactivation of parkin is thought to contribute to sporadic PD. Adult knockout of parkin in the ventral midbrain of mice leads to an age-dependent loss of dopamine neurons that is dependent on the accumulation of parkin interacting substrate (PARIS), zinc finger protein 746 (ZNF746), and its transcriptional repression of PGC-1α. Here we show that adult knockout of parkin in mouse ventral midbrain leads to decreases in mitochondrial size, number, and protein markers consistent with a defect in mitochondrial biogenesis. This decrease in mitochondrial mass is prevented by short hairpin RNA knockdown of PARIS. PARIS overexpression in mouse ventral midbrain leads to decreases in mitochondrial number and protein markers and PGC-1α-dependent deficits in mitochondrial respiration. Taken together, these results suggest that parkin loss impairs mitochondrial biogenesis, leading to declining function of the mitochondrial pool and cell death.

Transcranial magnetic stimulation: A potential new treatment for depression associated with traumatic brain injury.

BACKGROUND: Each year, more than 1.7 million Americans suffer a traumatic brain injury (TBI) and the lifetime prevalence of major depressive disorder following TBI is between 25-50%. There are no validated established strategies to treat TBI depression. Repetitive transcranial magnetic stimulation (rTMS) is a novel putative treatment option for post-TBI depression, which, compared with standard pharmacological agents, may provide a more targeted treatment with fewer side-effects. However, TBI is associated with an increased risk of both early and late spontaneous seizures, a significant consideration in evaluating rTMS as a potential treatment for TBI depression. Whilst the risk of seizure from rTMS is low, underlying neuropathology may somewhat increase that risk. REVIEW: This review focuses on the safety aspects of rTMS in TBI patients. The authors review why low frequency rTMS might be less likely to trigger a seizure than high frequency rTMS and propose low frequency rTMS as a safer option in TBI patients. Because there is little data on the safety of rTMS in TBI, the authors also review the safety of rTMS in patients with other brain pathology. CONCLUSION: It is concluded that pilot safety and tolerability studies should be first conducted in persons with TBI and neuropsychiatric comorbidities. These results could be used to help design larger randomized controlled trials.