Selecting informative patients for phase 2 progressive trials in MS: Design considerations for phase 2 clinical trials in progressive MS.

While relapsing-remitting multiple sclerosis (MS) has many therapeutic options, progressive forms of MS remain largely untreatable. Phase 2 clinical trials are our main tool to advance new treatments for progressive MS. Given the complexities of progressive MS, it will likely require many phase 2 trials to improve its treatment. To conduct informative and efficient phase 2 trials, it is important that such trials are designed in a way that they can identify a successful treatment as quickly and with as few participants as possible. In this topical review, we discuss cohort selection, outcome selection, cohort enrichment, and dosing selection as strategies to optimize the efficiency of phase 2 clinical trials in progressive MS.

Serum neurofilament-light and glial fibrillary acidic protein levels in hydroxychloroquine-treated primary progressive multiple sclerosis.

BACKGROUND: In a recent trial, hydroxychloroquine (HCQ) treatment reduced the expected rate of disability worsening at 18 months in primary progressive multiple sclerosis (PPMS). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are emerging biomarkers in multiple sclerosis. METHODS: We measured NfL and GFAP levels in serum samples from 39 patients with inactive PPMS included in a phase II clinical trial of HCQ treatment in PPMS at multiple time points over 18 months, and investigated the association of these biomarkers with clinical disability at screening and during follow-up. Screening and 12-month retinal nerve fiber layer (RNFL) thickness was also recorded and analyzed. RESULTS: NfL and GFAP levels increased over time, but only significantly from screening to month 6. NfL and GFAP levels did not significantly increase from month 6 up to month 18. At screening, NfL and GFAP levels did not correlate with the Expanded Disability Status Scale (EDSS), and GFAP but not NfL modestly correlated with Timed 25-Foot Walk test (T25FW). Screening NfL and GFAP levels did not predict disability worsening (≥20% worsening on the T25FW) at month 18. RNFL thickness decreased significantly from screening to month 12 and independently predicted disability worsening. CONCLUSIONS: In this cohort of people with inactive PPMS, HCQ treatment attenuated the increase of NfL and GFAP after 6 months of treatment and up to 18 months of follow-up, suggesting a treatment effect of HCQ over these biomarkers. RNFL thickness, a marker of neuroaxonal atrophy, was associated with disability worsening, and should be explored further as a prognostic marker in this population.

Gastrointestinal Dysfunction in Stroke.

Gastrointestinal (GI) complications are seen in over 50% of ischemic stroke survivors; the most common complications are dysphagia, constipation, and GI bleeding. The bidirectional relationship of the gut-brain axis and stroke has recently gained traction, wherein stroke contributes to gut dysbiosis (alterations in the normal host intestinal microbiome) and gut dysbiosis perpetuates poor functional neurologic outcomes in stroke. It is postulated that the propagation of proinflammatory cells and gut metabolites (including trimethylamine N-oxide and short-chain fatty acids) from the GI tract to the central nervous system play a central role in gut-brain axis dysfunction. In this review, we discuss the known GI complications in acute ischemic stroke, our current knowledge from experimental stroke models for gut-brain axis dysfunction in stroke, and emerging therapeutics that target the gut-brain axis.

Minocycline treatment in clinically isolated syndrome and serum NfL, GFAP, and metalloproteinase levels.

BACKGROUND: In the trial of Minocycline in Clinically Isolated Syndrome (MinoCIS), minocycline significantly reduced the risk of conversion to clinically definite multiple sclerosis (CDMS). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are emerging biomarkers in MS, and minocycline modulates matrix metalloproteinases (MMPs). OBJECTIVE: To assess the value of blood NfL and GFAP as a biomarker of baseline and future disease activity and its utility to monitor treatment response in minocycline-treated patients with clinically isolated syndrome (CIS). METHODS: We measured NfL, GFAP, and MMPs in blood samples from 96 patients with CIS from the MinoCIS study and compared biomarkers with clinical and radiologic characteristics and outcome. RESULTS: At baseline, NfL levels correlated with T2 lesion load and number of gadolinium-enhancing lesions. Baseline NfL levels predicted conversion into CDMS at month 6. GFAP levels at baseline were correlated with T2 lesion volume. Minocycline treatment significantly increased NfL levels at 3 months but not at 6 months, and decreased GFAP levels at month 6. Minocycline decreased MMP-7 concentrations at month 1. DISCUSSION: Blood NfL levels are associated with measures of disease activity in CIS and have prognostic value. Minocycline increased NfL levels at month 3, but reduced GFAP and MMP-7 levels.

Biomarkers of intestinal barrier function in multiple sclerosis are associated with disease activity.

BACKGROUND: Recent evidence suggests a role for the gut-brain axis in the pathophysiology of multiple sclerosis (MS). MATERIALS AND METHODS: We studied biomarkers of intestinal permeability in 126 people with MS (57 relapsing-remitting multiple sclerosis (RRMS) and 69 progressive MS) and in a group of healthy controls for comparison. Serum/plasma concentrations of zonulin (a regulator of enterocyte tight junctions), tight junction proteins (ZO-1 and occludin), intestinal fatty acid binding protein (IFABP)/ileal bile acid binding protein (IBABP), D-lactate, and lipopolysaccharide (LPS) binding protein were measured. RESULTS: Zonulin concentrations were significantly higher when a concurrent magnetic resonance imaging (MRI) confirmed the presence of blood-brain barrier (BBB) disruption (Gad+ RRMS) and were correlated with tight junction proteins. IBABP and D-lactate were elevated in people with RRMS compared to controls, but did not discriminate between Gad+ and Gad- subgroups. Baseline zonulin concentrations were associated with 1-year disease progression in progressive MS. CONCLUSIONS: People with MS have altered biomarkers of intestinal barrier integrity. Zonulin concentrations are associated with 1-year disease progression in progressive MS and closely mirror BBB breakdown in RRMS. Zonulin may mediate breakdown of both the intestinal barrier and the BBB in gut dysbiosis through the regulation of tight junctions. This could explain how the gut-brain axis modulates neuroinflammation in MS.

Area postrema syndrome: A short history of a pearl in demyelinating diseases.

In this topical review, we discuss the history of the area postrema syndrome, with special attention given to early studies aimed at identifying the area postrema and its function, possible early cases of the syndrome and its current relevance in neuroimmunology and demyelinating diseases. In 1896, Retzius named a structure in the posterior medulla oblongata as the area postrema. The work of Borison in the middle of the 20th century led to the elucidation of its function as a "vomiting center." The historical medical literature is filled with excellent examples that could be described as "area postrema syndrome." While severe and bilateral optic neuritis and transverse myelitis still constitute the classic components of neuromyelitis optica spectrum disorder (NMOSD), intractable vomiting and hiccups due to area postrema involvement is now recognized as essentially pathognomonic, indeed a shiny pearl in neuroimmunology and demyelinating diseases.

The intestinal barrier in multiple sclerosis: implications for pathophysiology and therapeutics.

Biological barriers are essential for the maintenance of homeostasis in health and disease. Breakdown of the intestinal barrier is an essential aspect of the pathophysiology of gastrointestinal inflammatory diseases, such as inflammatory bowel disease. A wealth of recent studies has shown that the intestinal microbiome, part of the brain-gut axis, could play a role in the pathophysiology of multiple sclerosis. However, an essential component of this axis, the intestinal barrier, has received much less attention. In this review, we describe the intestinal barrier as the physical and functional zone of interaction between the luminal microbiome and the host. Besides its essential role in the regulation of homeostatic processes, the intestinal barrier contains the gut mucosal immune system, a guardian of the integrity of the intestinal tract and the whole organism. Gastrointestinal disorders with intestinal barrier breakdown show evidence of CNS demyelination, and content of the intestinal microbiome entering into the circulation can impact the functions of CNS microglia. We highlight currently available studies suggesting that there is intestinal barrier dysfunction in multiple sclerosis. Finally, we address the mechanisms by which commonly used disease-modifying drugs in multiple sclerosis could alter the intestinal barrier and the microbiome, and we discuss the potential of barrier-stabilizing strategies, including probiotics and stabilization of tight junctions, as novel therapeutic avenues in multiple sclerosis.

Severe hypertriglyceridemia associated with teriflunomide in a patient with multiple sclerosis: A case report.

OBJECTIVE: To describe a case of severe hypertriglyceridemia in a patient receiving teriflunomide. METHODS: This is a case study. RESULTS: Our patient developed severe hypertriglyceridemia (>5000 mg/dL) while on teriflunomide. The drug was withdrawn. Resolution began over 3 weeks later. CONCLUSION: We describe the first probable case of teriflunomide-associated severe hypertriglyceridemia in a patient with multiple sclerosis, an adverse event previously associated with leflunomide in patients with rheumatologic diseases. Clinicians should be aware of this rare but potentially dangerous adverse event.

[Impacto en el desenlace funcional en pacientes con ictus: experiencia de una unidad de cuidados neurovasculares].

Background and objective: Neurovascular care units (NCU) have a positive impact on the functional prognosis of stroke patients. The effectiveness of NCUs in Mexico has not been evaluated. Our objective was to determine the impact of an NCU in a third-level academic hospital in northeastern of Mexico. Method: We performed a prospective observational, analytic cohort study. The population was divided into two periods: the first one consisted of those patients admitted before the implementation of the NCU (2008-2010), and the second period consisted of patients admitted after the implementation of the UCN (2010-2014). Functional status was assessed with the modified Rankin scale at discharge and 3 months. Results and conclusions: 598 patients were included (period 1: 246; period 2: 352). Patients in period 2 had a higher deep venous thrombosis prophylaxis (odds ratio [OR]: 3.235; 95 % confidence interval [95 % CI]: 2.18-4.80; p = 0.01), a shorter hospital stay (OR: 0.42; 95 % CI: 0.29-0.62; p = 0.01) and less severe disability (Rankin ≥ 3) at 3 months of follow-up (OR: 0.42; 95 % CI: 0.29-0.62; p = 0.01). The implementation of an NCU in a third-level academic hospital improved the functional outcome at 3 months and decreased the days of in-hospital stay of patients with stroke.

Antecedentes y objetivo: Las unidades de cuidados neurovasculares (UCN) impactan favorablemente en el pronóstico funcional del paciente con ictus en comparación con las salas de internamiento general. La efectividad de las UCN en México no ha sido evaluada. Nuestro objetivo fue determinar el impacto que tiene una UCN en un hospital académico de tercer nivel del noreste de México. Método: Estudio de cohorte prospectivo, observacional y analítico. La población fue dividida en dos periodos: el primero consistió en aquellos pacientes ingresados antes de la implementación de la UCN (2008-2010), y el segundo consistió en pacientes ingresados posterior a la implementación de la UCN (2010-2014). Se evaluó el estado funcional al egreso y a los 3 meses. Resultados y conclusiones: Se incluyeron 598 pacientes (periodo 1: 246; periodo 2: 352). En el periodo 2 se incrementó la profilaxis de trombosis venosa profunda (razón de momios [RM]: 3.235; intervalo de confianza del 95 % [IC 95 %]: 2.18-4.80; p = 0.01) y se redujeron la estancia hospitalaria (RM: 0.42; IC 95 %: 0.29-0.62; p = 0.01) y la discapacidad funcional grave (Rankin ≥ 3) a los 3 meses de seguimiento (RM: 0.42; IC 95 %: 0.29-0.62; p = 0.01). La implementación de una UCN mejoró el desenlace funcional a 3 meses y disminuyó los días de estancia intrahospitalaria de pacientes con ictus.

Alterations in balance and mobility in people with epilepsy.

PURPOSE: People with epilepsy (PWE) are burdened by physical disability and side effects of antiepileptic drugs (AED) such as drowsiness and blurred vision. These factors place them at risk for reduced mobility and falls. The purpose of this study was to evaluate mobility and balance in PWE. METHODS: This was a cross-sectional study of PWE and age- and sex-matched controls. We evaluated mobility and balance using the Timed Up and Go Test (TUG) and the Tinetti Mobility Test (TMT). Self-reported confidence in balance was assessed using the Activities-Specific Balance Confidence Scale (ABC). Clinical and demographic characteristics and particularly epilepsy-related variables were recorded. RESULTS: We included 33 PWE and 33 controls. PWE had a mean age of 36.7years, and 61% were male. They had a mean of 1.52 of seizures per month and used a mean of 1.6 anti-epileptic drugs (AEDs). PWE scored significantly worse in all measures (TUG, TMT, ABC) when compared with controls. PWE had poor performance in 60.6% of cases in the TUG and in 48.5% of cases in the TMT, compared to none in the control group. There was good correlation between the three instruments. TUG scores were correlated with epilepsy duration, but not age, seizure control or AED use. On multivariate logistic regression, poor performance TMT was significantly associated with poor confidence in balance, according to the ABC. CONCLUSIONS: PWE have significant alterations in balance and mobility, independently of AED use or seizure control. These alterations are reflected in a poor self-reported confidence in carrying out daily activities.

Acute toxic leukoencephalopathy associated with a non-prescription weight loss supplement: a report of two cases.

Weight loss dietary supplements are used with some frequency by an increasingly overweight population. Some products are not adequately regulated and may pose potential health risks. We report two new cases of acute toxic leukoencephalopathy (ATL) due to the use of a supplement marketed as a thermogenic weight loss aid. ATL is a heterogeneous clinic-radiological entity that has been associated with various compounds, such as chemotherapeutic drugs and immunomodulators. It is characterized by an often reversible periventricular and infratentorial demyelination. The commercialization of non-regulated weight loss products continues to be a health risk in our population.

Affective symptoms and determinants of health-related quality of life in Mexican people with epilepsy.

Epilepsy is known to be associated with multiple psychiatric comorbidities, such as depression, sleep-disorders, and anxiety. The objective of this study was to determine the prevalence and impact of affective symptoms over health-related quality of life (QOL) in Mexican people with epilepsy (PWE). We performed a cross-sectional observational study on 73 consecutive PWE and corresponding age- and sex-matched controls. HrQOL was assessed using the QOLIE-10 (QOL in Epilepsy-10) instrument. Clinical and demographic characteristics were recorded, and instruments evaluating depressive/anxiety symptoms, sleep quality, and insomnia were completed. PWE had more depressive/anxiety symptoms when compared with controls. QOLIE-10 scores were significantly inversely correlated with poor sleep quality, insomnia symptoms, depressive/anxiety symptoms, and number of anti-epileptic drugs used, but not with seizure type or number of seizures per month. A poor QOL was independently associated only with anti-epileptic drug polytherapy. PWE are burdened with depressive/anxiety symptoms at alarming rates. The presence of depressive symptoms along with sleep disturbances and more significantly, anti-epileptic drug polytherapy, appears to negatively impact QOL, to a greater degree than short-term seizure control.

Abdominal Aortic Dissection and Cold-Intolerance After Whole-Body Cryotherapy: A Case Report.

Whole-body cryotherapy (WBC) involves short exposures to air temperatures below -100°C and is purported to enhance recovery after exercise and accelerate rehabilitation after injury. It is generally considered a procedure with few side effects, but there are no large studies that have established its safety profile. We present the case of a 56-year-old patient who developed an abdominal aortic dissection after receiving 15 sessions of WBC. The patient had no other strong risk factors for aortic dissection. Exposure to cold temperatures, including WBC, has multiple hemodynamic effects, including increases in blood pressure, heart rate, and an adrenergic response. We suggest that these changes could act as a trigger for the onset of aortic dissections. This could be the first reported cardiovascular complication associated with WBC.

Prevalence and impact of irritable bowel syndrome in people with epilepsy.

PURPOSE: Epilepsy is known to be associated with affective disorders and sleep alterations, as well as with gastrointestinal conditions such as peptic ulcers and inflammatory bowel disease. There is comparatively little evidence linking epilepsy and gastrointestinal functional disorders. The objective of this study was to determine the prevalence and impact of irritable bowel syndrome (IBS) in patients with epilepsy. METHODS: We carried out a cross-sectional observational study on 65 consecutive people with epilepsy (PWE) and age- and sex-matched controls. Irritable bowel syndrome and functional dyspepsia (FD) diagnosis were based on Rome III criteria. Clinical and demographic characteristics were recorded, and instruments evaluating sleep quality, depressive/anxiety symptoms, insomnia, and health-related quality of life were also completed. RESULTS: Irritable bowel syndrome prevalence was significantly different between groups (3% in controls and 16% in patients with epilepsy; p=0.04), while no difference was found in FD (2% vs. 6%, respectively). People with epilepsy with IBS had significantly more insomnia and depressive and anxiety symptoms. No demographic or clinical characteristics were significantly different between groups. The presence of IBS did not affect health-related quality of life in PWE. On multivariate analysis, insomnia and depressive and anxiety symptoms did not independently predict IBS diagnosis. CONCLUSION: Irritable bowel syndrome was more frequent in PWE compared with that in healthy controls. Irritable bowel syndrome does not appear to affect health-related quality of life but is associated with a greater burden of affective symptoms and insomnia.