Acute relapse after initiation of Siponimod in a patient with secondary progressive MS.

Sphingosine 1-phosphate (S1P) is a signaling molecule that binds to five G protein-coupled receptors (Proc Natl Acad Sci USA 108:751-756, 2011). Modulation of these receptors has been associated with pleiotropic biological effects in the immune, cardiovascular, and central nervous systems (CNS). The functional S1P receptor antagonist fingolimod was the first member of this class of pharmacotherapeutics to be approved for treatment of relapsing multiple sclerosis (MS). Siponimod is currently in clinical trial in patients with secondary progressive (SP) MS, a clinical trial for which there is an unmet need for disease-modifying agents. 10 weeks into the trial, the patient awoke with blurry vision in his left eye, and was subsequently diagnosed with an acute optic neuritis. Despite discontinuation of siponimod and treatment with pulse corticosteroids, the patient did not regain visual function in the affected eye. This is the first report of disease reactivation shortly after initiating siponimod in a patient with SPMS. This case illustrates that the known changes in lymphocyte numbers and composition in the CNS associated with S1P receptor antagonism during the SPMS disease stage may have adverse outcomes in some patients during treatment initiation, and that close clinical and paraclinical monitoring is advised.

Multiple sclerosis disease progression and paradichlorobenzene: a tale of mothballs and toilet cleaner.

IMPORTANCE: Environmental factors are thought to be critical in the initiation and perpetuation of multiple sclerosis disease activity. OBSERVATIONS: We describe the case of a woman in her late 30s with a diagnosis of relapsing-remitting multiple sclerosis, who continued to accumulate neurological disability despite long-term natalizumab treatment. The patient continued to have visual symptoms, left leg weakness, and gait instability. In addition, she subacutely developed an encephalopathy. Our investigations revealed that the patient had a long-standing history of chewing on toilet bowl deodorizing cakes. The main ingredient in this product is 99.9% paradichlorobenzene, which is also used in mothballs. CONCLUSIONS AND RELEVANCE: This case illustrates that environmental causes for neurological deterioration should be investigated in patients with multiple sclerosis who display a rapidly progressive disease course and in whom potent pharmacotherapies fail. One possible cause is the ingestion of paradichlorobenzene-containing mothballs and toilet cleaners.

Heat exposure and bicycling trigger recurrent aseptic meningitis: a case report.

BACKGROUND: Aseptic meningitis associated with herpes simplex virus type 2 often has a relapsing-remitting clinical phenotype. Factors that lead to disease activation and reactivation are currently incompletely understood. CASE PRESENTATION: We describe the case of a 49-year-old Caucasian man who developed recurrent episodes of herpes simplex virus type 2-associated aseptic meningitis in the setting of heat exposure and bicycling. This case is compelling in that substantial data were available to the examining physicians on the amount of physical exercise and heat exposure. Strenuous physical activities or heat exposure in isolation did not cause re-occurrence of clinical signs and symptoms. CONCLUSIONS: This case illustrates that the dual activation of mechanical and temperature receptors in dorsal root ganglia may lead to the recurrent reactivation and afferent dissemination of latent herpes simplex virus type 2 in some patients.

No cerebral or cervical venous insufficiency in US veterans with multiple sclerosis.

OBJECTIVE: To determine if chronic cerebral venous insufficiency exists in patients with multiple sclerosis (MS) using ultrasonography and 4-dimensional color Doppler ultrasonography examination and unverified criteria proposed by Zamboni et al. DESIGN: Patients with MS and clinically isolated syndrome were matched by age and sex with subjects with migraine or no neurological disease. All subjects underwent gray-scale, color, and spectral Doppler ultrasonography examination of the internal jugular veins (IJVs), vertebral veins, and deep cerebral veins for stenosis, absence of signal, and reflux. SETTING: Academic MS center. PATIENTS: All patients with MS fulfilled revised McDonald criteria for the diagnosis of MS. Patients with clinically isolated syndrome exhibited a typical transient focal neurological deficit and had magnetic resonance imaging lesions typical of MS. Control subjects were recruited from the VA migraine clinic or staff. MAIN OUTCOME MEASURES: Five parameters of venous outflow used by Zamboni et al were examined: (1) IJV or vertebral vein reflux, (2) deep cerebral vein reflux, (3) IJV stenosis, (4) absence of flow in IJVs or vertebral veins, and (5) change in cross-sectional area of the IJV with postural change. RESULTS: There was no significant difference in the number and type of venous outflow abnormalities in patients with MS compared with controls. CONCLUSION: This study does not support the theory that chronic cerebral venous insufficiency exists in MS.

Multiple sclerosis and chronic cerebrospinal venous insufficiency: a critical review.

Chronic cerebrospinal venous insufficiency (CCSVI) was recently proposed as a contributing factor in the pathology of multiple sclerosis. This concept has gained remarkable attention, partly because endovascular neurointervention has been suggested as a treatment strategy. This review summarizes available evidence and provides a critical analysis of the published data. Currently, there is inconclusive evidence to support CCSVI as an etiological factor in patients with multiple sclerosis. Endovascular procedures should not be undertaken outside of controlled clinical trials.

Chronic cerebrospinal venous insufficiency and multiple sclerosis.

Chronic cerebrospinal venous insufficiency has recently been proposed to be etiologic to multiple sclerosis. Independent investigation into this theory during the past 2 years has not succeeded in verifying this relationship. A critical analysis of the scientific methods used in the original studies of chronic cerebrospinal venous insufficiency in multiple sclerosis reveals several methodological problems with regard to potential bias and confounding. The current evidence calls into question whether chronic cerebrospinal venous insufficiency in multiple sclerosis exists at all.

Translational research in neurology and neuroscience 2010: multiple sclerosis.

Over the past 2 decades, enormous progress has been made with regard to pharmacotherapies for patients with multiple sclerosis. There is perhaps no other subspecialty in neurology in which more agents have been approved that substantially alter the clinical course of a disabling disorder. Many of the pharmaceuticals that are currently approved, in clinical trials, or in preclinical development were initially evaluated in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis. Two Food and Drug Administration-approved agents (glatiramer acetate and natalizumab) were developed using the experimental autoimmune encephalomyelitis model. This model has served clinician-scientists for many decades to enable understanding the inflammatory cascade that underlies clinical disease activity and disease surrogate markers detected in patients.

Factors that influence adherence with disease-modifying therapy in MS.

BACKGROUND: The complexity and cost of injection treatment can represent a formidable challenge for patients affected by a chronic illness, particularly those whose treatment is primarily preventative and only modestly effective on the more conspicuous symptomatic aspects of the disease process. The aim of this investigation was to identify which factors most influenced nonadherent behavior with the available disease-modifying injection therapies for multiple sclerosis (MS). METHODS: A multicenter, observational (three-wave) study using surveys was developed and administered to patients with MS through the World Wide Web. Healthcare providers at 17 neurology clinics recruited patients for the study. RESULTS: A total of 798 patients responded to the baseline wave of the study (708 responded to all three waves). The nonadherence rates for all patients (missing one or more injections) across these waves remained relatively stable at 39%, 37%, and 36%, respectively. The most common reason participants listed for missing injections was that they simply forgot to administer the medication (58%). Other factors including injection-site reactions, quality of life, patients' perceptions on the injectable medications, hope, depression, and support were also assessed in relation to adherence. CONCLUSIONS: This study characterizes factors that are associated with failure to fully adhere with disease modifying injection therapy for MS and underscores the principles associated with optimizing adherence and its implications for effective treatment of the disease process in MS.