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Magnetic resonance imaging (MRI) enhanced with gadolinium-based contrast agents (GBCAs) is an essential tool in the diagnosis and management of many neurologic diseases, including multiple sclerosis, brain tumors, and infections. The clinical utility of GBCAs is evidenced by their widespread use. GBCAs are produced in macrocyclic and linear forms. Since 2014, evidence has suggested that repeated administration of GBCAs can lead to gadolinium deposition in the brain. We review the literature on gadolinium deposition, including both animal and human studies, as well as the literature on GBCA-associated health outcomes. Additionally, we summarize and discuss the updated medical society recommendations and perspectives on GBCA use in clinical practice. The first publication reporting gadolinium deposition in the human brain was published in 2014. Since that seminal report, multiple studies have demonstrated that exposure to linear GBCAs is associated with gadolinium deposition in the dentate nucleus and globus pallidus as seen on brain MRI. Macrocyclic GBCA exposure has not convincingly been associated with gadolinium deposition evident on brain MRI. Clear evidence demonstrates that GBCAs lead to gadolinium deposition in the brain in a dose-dependent manner; however, only linear GBCAs have been associated with gadolinium deposition visualized on MRI. To date, no evidence links gadolinium deposition with any adverse health outcome. Updated medical society guidelines emphasize the importance of an individualized risk-benefit analysis with each administration of GBCAs.

Recent seroepidemiologic and pathologic evidence suggests that prior infection with Epstein-Barr virus (EBV) may be necessary for the development of multiple sclerosis (MS). EBV infects more than 90% of all humans, most of whom remain healthy. In contrast, 99% of MS patients have evidence of prior infection with EBV. EBV infects resting B lymphocytes, immortalizing them into long-lived memory B cells that survive largely undetected by the immune system in the peripheral circulation. MS patients show elevated titers to EBV years before developing any neurologic symptoms. Postmortem pathologic analysis of brains of patients with MS has revealed diffuse EBV-associated B-cell dysregulation in all forms of MS. Theories of pathogenesis of EBV in MS include antigenic mimicry, immortalization of B-cell clones, and cytotoxic T-cell dysfunction against virally infected B cells. This article reviews the existing evidence of the relationship between EBV and MS and considers the therapeutic implication of this evidence.

Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is an autoimmune disorder first described in 2007. It can cause severe neurologic and psychiatric symptoms, and patients often are misdiagnosed with a primary psychiatric disorder. Anti-NMDA-R encephalitis is an important differential diagnosis of psychosis, as the condition can be treated with the appropriate therapy. A 42-year-old female with a history of hypothyroidism presented for evaluation of agitation and weakness. Six months prior to her presentation at our hospital, she had complained of headache, and neuroimaging showed a small right frontal hyperintensity on fluid-attenuated inversion recovery imaging. Workup was largely unremarkable, and she improved briefly with steroids at the outside institution. She then developed psychiatric symptoms and had 4 admissions to separate inpatient psychiatric facilities. She was tried on various antipsychotic medications and mood stabilizers with no improvement and lost 30 pounds in 3 months. When the patient was transferred to our facility, her neuroimaging was stable, and serum and cerebrospinal fluid were positive for antithyroid peroxidase and NMDA-R antibodies. She was treated with intravenous immunoglobulin (IVIG), high-dose steroids, and rituximab. Positron emission tomography scan revealed a parotid mass that was resected and determined to be a pleomorphic adenoma. The patient improved remarkably to her baseline and was able to return to full duties at work within 6 months. In the 2 years since her initial admission, she has had minor relapses that have responded well to rituximab and IVIG. This case demonstrates a typical presentation of anti-NMDA-R encephalitis, as well as the challenges that can delay diagnosis. Symptoms vary and are often psychiatric, making these patients difficult to diagnose clinically, and they therefore require thorough investigation. This case illustrates the necessity to be inquisitive and to challenge the diagnosis when a clinical picture is not congruent because an accurate diagnosis is imperative in guiding appropriate treatment.

There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18–65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5–6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15–27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81–2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies. This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis. MedDay Pharmaceuticals.

The Perceived Deficits Questionnaire (PDQ) is a part of the Multiple Sclerosis (MS) Quality of Life Inventory that assesses self-perceived cognitive difficulties. We used baseline data from 49 MS subjects participating in a clinical trial to evaluate the correlation of the PDQ with two measures of cognitive impairment, the Paced Auditory Serial Addition Test (PASAT) and the California Verbal Learning Test, 2nd edition (CVLT-II), total score, and one measure of depression, the Beck Depression Inventory-Amended (BDI-IA). The PDQ correlated significantly (r = 0.42; 95% confidence interval [CI], 0.15 to 0.62; p = 0.003) with the BDI-IA scores but not with either the PASAT (r = -0.22; 95% CI, -0.48 to 0.06; p = 0.2) or the CVLT-II total (r = -0.17; 95% CI, -0.43 to 0.12; p = 0.25). A subset of 38 of these subjects who scored worse than 0.5 standard deviation below the mean on the PASAT or CVLT-II received a more extensive neuropsychological battery of tests. No significant correlations were found between any of these tests and the PDQ. These results suggest that self-perceived cognitive dysfunction relates more to depression than to objective cognitive dysfunction.

To evaluate the potential effects of medications with central nervous system (CNS) activity on cognitive function and fatigue in multiple sclerosis (MS), we performed a retrospective analysis of medication use among 70 subjects with MS who were participating in a clinical trial for evaluation of the effects of yoga and exercise programs on cognition and fatigue. Among these MS subjects, 74% were taking at least one potentially CNS-active medication. These 70 subjects were divided into two groups: those taking at least one CNS-active medication (n = 52) and those not on any medications with potential CNS activity (n = 18). We compared assessments of cognitive function and fatigue using an analysis of covariance. MS subjects on CNS-active medication had greater impairment on measures of processing speed, sustained attention, and fatigue than those not on these medications. While these findings do not establish a causal relationship between medication use and cognitive impairment and fatigue, the data indicate that researchers need to control for use of CNS-active medications when conducting studies of cognitive impairment and fatigue in MS subjects.