Souraya El Sankari

Cerebral hypoperfusion: a new pathophysiologic concept in multiple sclerosis?

The exact pathogenesis of multiple sclerosis (MS) is incompletely understood. Although auto-immune responses have an important role in the development of hallmark focal demyelinating lesions, the underlying mechanism of axonal degeneration, the other key player in MS pathology and main determinant of long-term disability, remains unclear and corresponds poorly with inflammatory disease activity. Perfusion-weighted imaging studies have demonstrated that there is a widespread cerebral hypoperfusion in patients with MS, which is present from the early beginning to more advanced disease stages. This reduced cerebral blood flow (CBF) does not seems to be secondary to loss of axonal integrity with decreased metabolic demands but appears to be mediated by elevated levels of the potent vasospastic peptide endothelin-1 in the cerebral circulation. Evidence is evolving that cerebral hypoperfusion in MS is associated with chronic hypoxia, focal lesion formation, diffuse axonal degeneration, cognitive dysfunction, and fatigue. Restoring CBF may therefore emerge as a new therapeutic target in MS.

Ventricular arrhythmia in a male MS patient on fingolimod.

Fingolimod is a structural analogue of sphingosine-1phosphate approved as the first oral agent for the treatment of relapsing remitting multiple sclerosis. Apart from its effects on the immune system, fingolimod is known to have a negative chronotropic effect upon first dose intake. Little is known, however, about the longer term potential effects of fingolimod on ventricular rhythm. We document an increase in ventricular premature complexes (VPCs) in a patient on fingolimod who experienced three unexplained syncopes while on treatment. VPC frequency decreased significantly and no further syncopes occurred after stopping fingolimod. This suggests that, in predisposed patients, fingolimod might potentiate the occurrence of ventricular arrhythmia. A 49-year-old male patient with relapsing–remitting multiple sclerosis was included in a 4-month phase 3b trial, involving fingolimod [1]. The patient provided written informed consent both for trial inclusion and this case report. At screening, his neurological examination was unremarkable, apart from pyramidal signs. His EDSS score was 1.0. He had no previous history of cardiovascular events and had no other cardiovascular risk factor apart from smoking (approximately 8 pack years). He was not taking any concomitant medication. Holter-ECG recordings were performed at screening and treatment initiation, showing VPCs (Table 1). After review by a cardiologist, as required per study protocol, this was not considered as an exclusion criterion. Monitoring of the first dose was unremarkable, without bradyarrhythmia. Nine months after starting treatment by fingolimod and 5 months after the trial ended, the patient presented with a first syncope. A third Holter-ECG was performed at month 10 showing an increase in the number of VPCs. These were monomorphic, with occasional bigeminism. At months 13 and 16, the patient presented again two unexplained syncopes. These occurred in resting state, without predisposing factors. The patient reported no prodromal symptoms. A fourth HolterECG performed at month 18 again showed numerous polymorphic VPCs. There was recurrent bigeminism and trigeminism (Fig. 1). Following referral to a cardiologist, a cardiac work-up was performed. 12-lead resting electrocardiogram was normal. Echocardiography showed clinically insignificant mitral and aortic valve insufficiency and preserved left ventricular function. Exercise stress testing with myocardial scintigraphy showed that VPCs persisted during exercise but reasonably excluded underlying coronaropathy. Treatment with fingolimod was stopped at month 18. Nineteen months later, no further syncopes have occurred. Holter-ECG recordings performed 2, 7 and 19 months after stopping fingolimod show a significant decrease in the number of VPCs (Table 1). The patient is clinically stable, as well as his brain MRI. Disease-modifying treatment has not been reintroduced until now. This case report illustrates a possible potentiating effect of fingolimod therapy on the occurrence of VPCs, which has not previously been described. Binding of fingolimod, a sphingosine 1-phospate receptor modulator, to G-proteinV. van Pesch (&) S. El Sankari C. Sindic Neurology Department, Cliniques Universitaires St-Luc, 10 Avenue Hippocrate, 1200 Brussels, Belgium e-mail: vincent.vanpesch@uclouvain.be

Early disturbances in multimodal evoked potentials as a prognostic factor for long-term disability in relapsing-remitting multiple sclerosis patients

OBJECTIVE The aim of this study was to investigate whether early alterations in evoked potentials (EPs) have a prognostic value in relapsing-remitting multiple sclerosis (RRMS). METHODS We retrospectively selected 108 early MS patients with a neurological follow-up ranging from 5 to 15years, in whom multimodal EPs (visual, brainstem auditory, somatosensory and motor) were performed at diagnosis. A conventional ordinal score was used to quantify the observed abnormalities. RESULTS The extent of change in the composite EP score was well correlated to the Expanded Disability Status Scale (EDSS) at ten years (Y10) and up to 15years (Y11-15) after disease onset. Analysis of the predictive value of the EP score showed an increased risk of disability progression at Y10 and Y11-15 of 60% (p<0.0001) and 73% (p<0.0001) respectively in patients with an EP score >4. Conversely, the risk of disability progression at Y10 and Y11-15 associated with a lower EP score (⩽4) was reduced to 16% and 20% respectively. CONCLUSIONS Our data support the good predictive value for long-term disability progression of multimodal EPs performed early after disease onset in RRMS patients. SIGNIFICANCE This study, performed in a homogeneous RRMS cohort with long term follow-up, demonstrates the value of an early comprehensive neurophysiological assessment as a marker for future disability.

Thyroid disorders in alemtuzumab-treated multiple sclerosis patients: a Belgian consensus on diagnosis and management

This paper deals with thyroid disease that can occur after treatment with alemtuzumab (humanized monoclonal anti-CD52) for relapsing–remitting multiple sclerosis (MS). The 5-year incidence of thyroid adverse events in phase 3 clinical trials is up to 40.7%. In most cases, the thyroid dysfunction is mild and easily manageable and only few serious thyroid adverse events have been reported. The need for patient education on the risk of thyroid dysfunction, as well as regular clinical and biochemical thyroid function screening is well described. However, practical clinical guidance in case of abnormal thyroid-related findings prior to or after alemtuzumab treatment is currently lacking. Therefore, a Belgian taskforce consisting of MS and thyroid experts was created in 2016, with the objective of issuing a clinical thyroid management algorithm based on available scientific evidence and personal experience with regard to alemtuzumab treatment-related thyroid adverse events.

Fatigue and physical fitness of mildly disabled persons with multiple sclerosis: a cross-sectional study

Fatigue is frequent and disabling in persons with multiple sclerosis (pwMS) with mild neurological disability. These patients also have impaired physical fitness. Whether mildly disabled pwMS are deconditioned, and this deconditioning is linked to fatigue, remains unknown. Our aim is to determine the physical fitness of mildly disabled patients with multiple sclerosis and study its relationship with perceived fatigue and to link perceived fatigue with other parameters. Twenty patients (14 women; mean age: 45.5 years) with mild disability (Expanded Disability Status Scale 0–4) underwent a 2-min walking test, Timed Up-and-Go test, aerobic capacity testing, and isometric knee extension testing to assess strength and neuromuscular fatigability. They completed questionnaires assessing perceived fatigue, psychological status, and physical activity. Correlation coefficients and multivariate regression were used to analyze the relationships among variables. Seventeen (85%) patients reported a high level of fatigue. Thirteen (65%) patients had subnormal aerobic capacity. Fatigue was weakly to moderately associated with aerobic capacity, mobility, walking capacity, depression, and neuromuscular fatigability. An association of disease duration, aerobic capacity, and the neuromuscular fatigability index explained 65.1% of fatigue. A high proportion of pwMS with mild neurological disability are fatigued and deconditioned. Perceived fatigue is linked to aerobic capacity, neuromuscular fatigability, depression, mobility, and walking capacity. Focusing on these parameters could help in the management of fatigue.

Auto-immune hepatitis in a patient with multiple sclerosis treated with alemtuzumab.

In two large phase III clinical studies with relapsing–remitting multiple sclerosis (RR-MS) patients, alemtuzumab (ATZ) has demonstrated high efficacy on the risk of relapse, sustained accumulation of disability, and MRI endpoints [1]. Among the side effects of ATZ, secondary organ-specific autoimmunity has been described, mainly directed towards the thyroid. We report the first case of an early autoimmune hepatitis (AIH) occurring in a MS patient after completion of two treatment cycles with ATZ. A 25-year-old female patient was diagnosed with RR-MS in September 2011. She declined a first-line treatment proposal. During the subsequent year, she presented with four relapses and was started on monthly infusions of natalizumab in December 2012. This treatment was interrupted after 22 infusions due to JC virus seroconversion and fear of progressive multifocal leukoencephalopathy. The patient received two courses of ATZ in November 2014 and 2015 successively. She remained stable with an EDSS score of 4 and no recurrence of disease activity on brain MRI. Eleven months following the last ATZ course, laboratory assessments revealed hyperthyroidism attributed to Grave’s disease. l-thyroxin and thiamazol were rapidly initiated. An increase in liver enzymes occurred 1 month later, while thyroid function was normalized. Despite interruption of thiamazol, liver dysfunction persisted. The patient presented with gradual asthenia and jaundice. Laboratory assessment confirmed the diagnosis of biological hepatitis with elevated levels of aspartate (AST) and alanine-(ALT) aminotransferases, by, respectively, 32and fivefold, associated with a 14-fold increase in serum bilirubin and mild hepatocellular insufficiency, as shown by hypoalbuminemia and elevated INR associated with low factor V. Serological testing for hepatitis A, B, C and E viruses were negative, while it showed acquired immunity against cytomegalovirus and Epstein-Barr virus. Serum globulins were elevated, particularly the IgG subclass, increased to 47.7 g/dl. Autoantibody testing showed positive titers of anti-neutrophil cytoplasm (ANCA titer 1:40), antinuclear (ANA titer 1:80) and antismooth muscle antibodies (SMA titer > 1:40), with F-actin titers increased to 81. Antibodies against soluble liver antigen and liver pancreas antigen, against liver cytosol and liver–kidney microsome 1 were negative. Liver biopsy showed a diffuse, severe and mixed inflammatory infiltrate, composed of lymphocytes, eosinophils and neutrophils, infiltrating the limiting plate, surrounding the portal triad, and sparing the biliary tract. These inflammatory features, characteristic of “interface hepatitis” were associated with extensive fibrosis. Immuno-staining was positive for plasma cells. Immunohistochemistry showed predominance of IgGpositive plasma cells and of T-lymphocytes. The diagnosis of type 1 AIH was retained. Standard treatment, consisting of 1 mg/kg/day of prednisolone, was initiated, with a transient episode of encephalopathy, resolving after corticosteroid dose reduction (to 0.5 mg/kg/day). 1 month later, the patient improved clinically and her laboratory abnormalities resolved (Fig. 1); prednisolone doses were then slowly decreased, and immunosuppressive treatment with azathioprine was introduced. AIH is a generally progressive, sometimes subacute hepatitis, for which the diagnosis is based on characteristic clinical and biochemical findings, as well as on histological abnormalities. It occurs usually in young females and is associated with a high prevalence (up to 30%) of extrahepatic autoimmune diseases, mainly thyroid, skin or celiac disorders, but infrequently with MS [2]. However, an increase in the prevalence of AIH is reported in MS patients [3] as compared to the general population (0.17 vs 0.02%). * Souraya El Sankari Souraya.elsankari@uclouvain.be

Long-term safety and real-world effectiveness of fingolimod in relapsing multiple sclerosis

With a growing number of disease-modifying therapies becoming available for relapsing multiple sclerosis, there is an important need to gather real-world evidence data regarding long-term treatment effectiveness and safety in unselected patient populations. Although not providing as high a level of evidence as randomized controlled trials, and prone to bias, real-world studies from observational studies or registries nevertheless provide crucial information on real-world outcomes of a given therapy. In addition, evaluation of treatment satisfaction and impact on quality of life are increasingly regarded as complementary outcome measures. Fingolimod was the first oral disease-modifying therapy approved for relapsing multiple sclerosis. This review aims to summarize current knowledge on the long-term effectiveness and safety outcomes of multiple sclerosis patients on fingolimod. Impact on treatment satisfaction and quality of life will be discussed according to available data.