Nicolas Dubuisson

Takotsubo syndrome (TKS): A possible mechanism of sudden unexplained death in epilepsy (SUDEP)

We report a case of Takotsubo syndrome after epilepsy, and review the literature. We identified 59 cases of Takotsubo syndrome after focal or generalised epilepsy. As in Takotsubo syndrome in general, the patients were mostly female (84%), with a mean age of 63 years, and the evolution was generally favourable. There was one death and one stroke, and 4 cases were of relapsing Takotsubo after a new seizure. Takotsubo syndrome may induce cardiac arrhythmias. A near-SUDEP (sudden unexplained death in epilepsy) was reported in one patient. Animal models of SUDEP have shown similar cardiac lesions to those seen in Takotsubo syndrome, and strengthen the hypothesis of a link between these conditions. Takotsubo syndrome after epilepsy may be relatively common; we suggest measurement of serum troponin levels in high-risk patients and cardiac follow-up.

Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells

BackgroundThe mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown.ObjectiveTo determine whether cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells.MethodsA cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable cladribine. The relative proportions and absolute numbers of peripheral blood B lymphocyte subsets were measured using flow cytometry. Cell-subtype expression of genes involved in cladribine metabolism was examined from data in public repositories.ResultsCladribine markedly depleted class-switched and unswitched memory B cells to levels comparable with alemtuzumab, but without the associated initial lymphopenia. CD3+ T cell depletion was modest. The mRNA expression of metabolism genes varied between lymphocyte subsets. A high ratio of deoxycytidine kinase to group I cytosolic 5′ nucleotidase expression was present in B cells and was particularly high in mature, memory and notably germinal centre B cells, but not plasma cells.ConclusionsSelective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by cladribine. These may offer a new target, possibly with potential biomarker activity, for future drug development.

Disease modification in advanced MS: Focus on upper limb function.

Pivotal disease-modifying treatment (DMT) trials for people with multiple sclerosis (pwMS) commonly employ the Expanded Disability Status Scale (EDSS) as the primary outcome.1 The upper EDSS limit set by sponsors for trial eligibility almost invariably excludes patients who have become dependent on wheelchairs. As a result, successful trial data may not support an application for licensing of new DMTs to treat people with advanced MS (pwAMS; EDSS ⩾6.5).

Validation of an environmentally-friendly and affordable cardboard 9-hole peg test

BACKGROUNDnIn multiple sclerosis (MS) upper limb neurological impairments, are an important driver of disability and handicap. The gold standard for assessing upper limb function is the 9-hole peg test (9HPT). One disadvantage of the current plastic version is its price, which prevents its widespread use as a self-monitoring tool by the MS community.nnnOBJECTIVEnTo develop and validate an affordable cardboard version of 9HPT for patients to self-monitor upper limb function at home. The aim is not to replace the plastic version, which would stay the gold standard in MS centers.nnnMETHODSnWe enrolled 177 volunteers, 68 healthy controls and 109 people with MS (pwMS) at varying stages of their disease. Volunteers performed two trials of the 9HPT with their dominant hand and two with their non-dominant hand using both plastic 9HPT and cardboard 9HPT. The primary comparison parameter was the time needed to perform the task.nnnRESULTSnThe mean score for the cardboard 9HPT was 24.58 (SEM 1.54s) seconds compared to 26.03 (SEM 1.44s) seconds for the plastic 9HPT (p = 0.007). However, the two versions of the tests correlated very strongly, r = 0.96 (p < 0.001). The coefficient of variation, repeat-repeat testing, showed less variability with the cardboard version than in the plastic one with 10% and 14%, respectively. Two-thirds of pwMS preferred using the cardboard version.nnnCONCLUSIONnThis study demonstrates that the cardboard version is at least equivalent to the plastic version of the test with arguably better design attributes making it the preferred option for self-monitoring.

Science is 1% inspiration and 99% biomarkers:

Neurodegeneration plays a key role in multiple sclerosis (MS) contributing to long-term disability in patients. The prognosis is, however, unpredictable coloured by complex disease mechanisms which can only be clearly appreciated using biomarkers specific to pathobiology of the underlying process. Here, we describe six promising neurodegenerative biomarkers in MS (neurofilament proteins, neurofilament antibodies, tau, N-acetylaspartate, chitinase and chitinase-like proteins and osteopontin), critically evaluating the evidence using a modified Bradford Hill criteria.

Disease activity in progressive multiple sclerosis can be effectively reduced by cladribine

BACKGROUNDnEvidence suggests people with non-relapsing deteriorating (progressive) multiple sclerosis (pwPMS) may benefit from disease-modifying immune therapy (DMT). However, only one such treatment (ocrelizumab) has been licensed and is highly restricted to pwPMS suffering from the primary progressive phenotype. The difficulties assessing treatment outcome in pwPMS is one important reason for the lack of respective DMT. The concentration of neurofilaments in the cerebrospinal fluid (CSF) provides a biomarker of neuro-axonal damage, and both neurofilament light (NfL) and heavy chain (NfH) levels have been used as outcome indices and to guide treatment choices.nnnMETHODSnWe report on two pwPMS, who were treated with subcutaneous cladribine undergoing CSF NfL testing, alongside MRI and clinical follow-up, before and after treatment.nnnRESULTSnCladribine treatment was well tolerated without any side effects. CSF NfL after treatment revealed significant reduction (by 73% and 80%, respectively) corroborating the MRI detectable drop in disease activity. Disability mildly progressed in one, and remained stable in the other pwPMS.nnnCONCLUSIONSnpwPMS with detectable disease activity (MRI, elevated NfL) should be considered for DMT. NfL appears to be a sensitive index of treatment effect in pwPMS, and may be a useful outcome in clinical trials targeting this patient group. Over and above its licensed indication (relapsing MS), cladribine may be an effective treatment option for pwPMS.

Inclusion criteria used in trials of people with progressive multiple sclerosis

Introduction The clinical phenotype ‘progressive multiple sclerosis’ (PMS) has commonly been divided into two subgroups, primary progressive multiple sclerosis (PPMS) characterised by progressive worsening of neurological function and secondary progressive multiple sclerosis (SPMS), where progressive neurological worsening occurs after an initially relapsing period (RMS) of variable duration.1

Alemtuzumab depletion failure can occur in multiple sclerosis

Alemtuzumab is a lymphocyte‐depleting antibody and one of the most effective treatments for relapsing multiple sclerosis. However, it also causes loss of immune‐tolerance leading to secondary autoimmunity and marked anti‐drug antibody responses. Although these anti‐drug responses have been reported to be of no significance, we hypothesized that they will affect the depleting capacity and treatment response in some individuals. This was found following analysis of the regulatory submission of the pivotal phase III trials, which was obtained from the European Medicines Agency. At the population level there was lack of influence of ‘ever‐positive’ alemtuzumab‐specific antibody responses on lymphocyte depletion, clinical efficacy and adverse effects during the 2‐year trial. This was not surprising as no one before the first infusion, and only 0·6% of people before the second‐infusion, had pre‐infusion, neutralizing antibodies (NAbs). However, at the individual level, NAbs led to poor lymphocyte depletion. Importantly, it was evident that 31% of people had NAbs and 75% had binding antibodies at the end of treatment‐cycle 2, which suggests that problems may occur in people requiring additional alemtuzumab cycles. In addition, we also identified individuals, following ‘post‐marketing’ alemtuzumab use, whose lymphocyte level was never effectively depleted after the first infusion cycle. Hence, although alemtuzumab depletes lymphocytes in most individuals, some people fail to deplete/deplete poorly, probably due to biological‐response variation and NAbs, and this may lead to treatment failure. Monitoring depletion following infusion and assessment of the neutralizing response before re‐infusion may help inform the decision to retreat or switch therapy to limit treatment failure.

PO124 Validation of an environmentally-friendly and affordable cardboard 9-hole peg test

Background In multiple sclerosis (MS) upper limb neurological impairments, are an important driver of disability and handicap. The gold standard for assessing upper limb function is the 9-hole peg test (9HPT). One disadvantage of the current plastic version is its price, which prevents its widespread adoption by the MS community. Objective To develop and validate an affordable 9HPT for patients to self-monitor upper limb function. Methods We enrolled 177 volunteers, 68 healthy controls and 109 people with MS (pwMS) at varying stages of their disease. Volunteers performed two trials of the 9HPT with their dominant hand and two with their non-dominant hand using both plastic 9HPT and cardboard 9HPT. The primary comparison parameter was the time needed to perform the task. Results The mean score for the cardboard 9HPT was 24.58 (SEM 1.54u2009s) seconds compared to 26.03 (SEM 1.44u2009s) seconds for the plastic 9HPT (p=0.007). However, the two versions of the tests correlated very strongly, r=0.96 (p<0.001). The coefficient of variation, repeat-repeat testing, showed less variability with the cardboard version than in the plastic one with 10% and 14%, respectively. Two-thirds of pwMS preferred using the cardboard version. Conclusion This study demonstrates that the cardboard version is at least equivalent to the plastic version of the test with arguably better design attributes making it the preferred option for self-monitoring.