Lysophospholipids are a class of bioactive lipid molecules that produce their effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is perhaps the most studied lysophospholipid and has a role in a wide range of physiological and pathophysiological events, via signalling through five distinct GPCR subtypes, S1PR₁ to S1PR₅. Previous and continuing investigation of the S1P pathway has led to the approval of three S1PR modulators, fingolimod, siponimod and ozanimod, as medicines for patients with multiple sclerosis (MS), as well as the identification of new S1PR modulators currently in clinical development, including ponesimod and etrasimod. S1PR modulators have complex effects on S1PRs, in some cases acting both as traditional agonists as well as agonists that produce functional antagonism. S1PR subtype specificity influences their downstream effects, including aspects of their benefit:risk profile. Some S1PR modulators are prodrugs, which require metabolic modification such as phosphorylation via sphingosine kinases, resulting in different pharmacokinetics and bioavailability, contrasting with others that are direct modulators of the receptors. The complex interplay of these characteristics dictates the clinical profile of S1PR modulators. This review focuses on the S1P pathway, the characteristics and S1PR binding profiles of S1PR modulators, the mechanisms of action of S1PR modulators with regard to immune cell trafficking and neuroprotection in MS, together with a summary of the clinical effectiveness of the S1PR modulators that are approved or in late-stage development for patients with MS. Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: differential downstream receptor signalling and clinical profile effects (MP4 65540 kb)

Objective: To report that the syndrome of orthostatic headaches caused by CSF leak can be seen with persistently normal CSF pressures. Background: CSF leak or shunt overdrainage is known to cause orthostatic headaches and diffuse pachymeningeal gadolinium enhancement (DPGE), typically associated with unmeasurable or very low CSF pressures. Methods: Of 40 consecutive patients with orthostatic headaches and DPGE, all had low or unmeasurable CSF pressures, except seven patients who had consistently normal CSF pressures and are thus reported. All had undergone multiple CSF examinations. Results: Two patients had overdraining shunts, and five had documented CSF leaks. One refused treatment, but the other six patients responded to surgical treatment or epidural blood patch with complete resolution of symptoms and related MRI abnormalities. Conclusions: Some patients with symptomatic CSF leaks may have CSF opening pressures that are consistently within normal limits. In the presence of convincing clinical features and imaging abnormalities, a normal CSF pressure should not discourage the clinician from searching for a source of CSF leak.

Fingolimod, a structural analog of sphingosine derived from fungal metabolites, is a functional antagonist of the G-protein-coupled sphingosine 1-phosphate (S1P) receptors S1P_1,3,4,5. In the treatment of relapsing forms of multiple sclerosis (RMS), fingolimod acts by reversibly retaining central memory T cells and naïve T cells in lymph nodes, thereby reducing the recirculation of autoreactive lymphocytes to the central nervous system (CNS). Fingolimod also has differential effects on the trafficking and function of B-cell subtypes and natural killer (NK) cells in peripheral blood and the CNS. Fingolimod also crosses the blood–brain barrier (BBB) and accumulates in the CNS. Experimental evidence increasingly supports a direct action of fingolimod within the CNS on brain cells, providing protection against the neurodegenerative component of RMS. We review the direct influence of this compound on CNS pathogenesis in RMS, including the central effects of fingolimod in animal models of MS and on neural cell types that express S1P receptors, such as astrocytes, BBB endothelial cells, microglia, neurones, and oligodendrocytes, which are all involved in RMS pathology.

Despite its rarity among paraneoplastic autoantibodies recognized in clinical practice, antineuronal nuclear antibody type 2 (ANNA-2, also known as anti-Ri) is one of the most common serologic tests ordered in evaluating patients suspected of having a paraneoplastic neurologic disorder.^1-3 ANNA-2 is more common in women than in men and is a marker of neurologic autoimmunity initiated by carcinoma of the breast or lung. Other cancer associations have been reported, including carcinomas of fallopian tube, ovary, bladder, and gastric neuroendocrine cells, as well as seminoma and carcinoid tumor.^3-10 Two central nervous system neuronal proteins, 53 to 61 kDa and 79 to 94 kDa, account for ANNA-2 immunoreactivity.¹ The smaller antigen, Nova, is a highly conserved RNA-binding nuclear protein,^11,12 which is expressed in brainstem and ventral spinal cord in embryonic mice and adult rats.^11-13 Paraneoplastic opsoclonus-myoclonus syndrome is commonly presumed to be synonymous with ANNA-2–related autoimmunity. However, in a review of clinical accompaniments among 34 patients with ANNA-2 seropositivity identified in the Mayo Clinic Neuroimmunology Laboratory, Rochester, Minnesota,³ only 10 of 28 patients (35%) for whom clinical information were available had opsoclonus-myoclonus syndrome. ANNA-2 is associated with multifocal dysfunction of brainstem, cerebellum, and spinal cord.^1,14 The 2003 article mentioned jaw dystonia and laryngospasm as novel but surprisingly common and severe accompaniments of ANNA-2.³