Multiple sclerosis (MS) is an autoimmune disorder of myelin destruction. Blood-brain-barrier (BBB) disruption precedes pathological or clinical findings and could involve mediators from perivascular brain mast cells, such as histamine and vascular endothelial growth factor (VEGF). Mast cells could be activated by many triggers, including acute stress that has been correlated with MS exacerbations. We considered that the histamine-1 (HI) receptor antagonist hydroxyzine, which also partially inhibits brain mast cells and has anxiolytic properties, may reduce MS symptoms. This open label, pilot, clinical trial investigated the effect on MS of an oral solution of hydroxyzine (100 mg per day), together with caffeine (200 mg per day) to reduce sedation. Twenty patients (8 males; 12 females) with relapsing-remitting or relapsing-progressive MS completed the study (12 ± 1 months) and were evaluated using disability scales. Most patients on hydroxyzine (75%) remained stable or improved neurologically and all but one showed improved mood. Hydroxyzine could be used as an adjuvant in MS, but the small number of patients enrolled and the short duration of the study precludes any definitive conclusions. A double-blind, placebo-controlled study is warranted.Multiple sclerosis (MS) is a human demyelinating disease characterized by brain edema and perivascular infiltrates ("cuffing") of mononuclear cells accompanied by various degrees of neurologic disability (1-2). Affected areas fill with fibrotic tissue forming the MS plaques that also contain activated mast cells (3). Blood-brain-barrier (BBB) breakdown precedes any pathological or clinical signs of MS (4-5). Acute stress can disrupt the BBB in rats (6). Most recently, acute stress was shown to increase BBB permeability to 99 Technetium-g1uceptatethrough the involvement ofbrain mast cells (7) and corticotropinreleasing-hormone (eRR) (7). It is, therefore, of interest that MS symptoms can be precipitated by psychological stress (8-9); a meta analysis and two recent publications confirmed a correlation between stress and MS attacks (10).Mast cells are typically activated by 19E and specific antigen in allergic reactions, as well as in innate and acquired (11) immunity. They have also been increasingly implicated in neuroinflammatory conditions, especially those worsened by stress (12). Mast cells have been associated with brain demyelination (13)(14) and are activated in

Pharmacological data and early clinical experience have suggested that the calcium entry blocker flunarizine may be a valuable gain in the prophylaxis of migraine. This was supported by a study in 20 patients with classical migraine who were, after a drug free run-in phase, orally treated with either placebo or flunarizine (10 mg at night) for 3 to 4 months. Flunarizine significantly reduced the frequency, duration and severity of the migraine attacks. A corrected migraine index, based on these 3 variables was reduced by 82% in the drug group but increased by 66% in the control patients. Only 1 patient did not clearly benefit from flunarizine. In some cases flunarizine should be administered for at least 4 months before judging its efficacy. No side-effects occurred.