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.

Reliability and repeatability of the Hoffmann sign.

OBJECTIVE: To determine the inter-rater, intrarater, and intrasubject reliability of the Hoffmann sign. DESIGN: Observational, cross-sectional study. SETTING: Veterans Affairs medical center. PATIENTS: Fifty-two consenting subjects without amputation of the first through third fingers, fixed finger contractures, relapsing remitting multiple sclerosis, or any acute central neurological illness or injury within the past 3 months requiring hospital admission were recruited from inpatients and outpatients in the Spinal Cord Injury and Physical Medicine and Rehabilitation services. INTERVENTIONS: The Hoffmann sign was elicited by 1 primary and 3 secondary investigators who used a standardized technique. The Hoffmann sign was considered positive if any reflexive flexion of the distal phalanx of the thumb or any of the fingers was present. In the first session, the primary and one secondary examiner performed 2 trials on both hands of each subject. Each investigator pair repeated the procedure in a second session. MAIN OUTCOME MEASURES: Cohen's κ coefficient was calculated to determine (1) inter-rater reliability, calculated per investigator pair per hand, for the first trial of a session; (2) intrarater reliability, calculated between the 2 trials of each session per investigator; and (3) intrasubject reliability, calculated per hand of each subject between the first trials of the 2 sessions. RESULTS: Inter-rater κ was 0.65 (188 pairs), intrarater κ was 0.89 (384 pairs), and intrasubject κ was 0.73 (178 pairs). All κ values were obtained with P < .01. CONCLUSIONS: The Hoffmann sign has substantial inter-rater and intrasubject reliability, in addition to outstanding intrarater reliability, when tested with the use of a standardized technique.