Andreas Lysandropoulos

'Hidden' factors influencing quality of life in patients with multiple sclerosis.

Traditional outcome measures for patients with multiple sclerosis (MS), whether in clinical trials or clinical practice, are currently in question. The combination of relapses, physical disability progression and magnetic resonance imaging (MRI) disease activity reflect only part of the impact that MS has on a patients daily life. Quality of life (QoL) is considered by many to be the ideal outcome measure. Since it captures the patients own perspective of well‐being, QoL should be the primary focus when evaluating a patient and the main objective of MS management. Nevertheless, whilst numerous instruments to measure QoL in MS patients are available or proposed, there is no current consensus regarding which is the best tool to use and under what circumstances. QoL in patients with MS is determined by several factors beyond the more obvious; these include coping with the MS diagnosis, understanding the disease and the disease process, dealing with so‐called ‘hidden’ symptoms such as fatigue, cognitive impairment and sexual disturbances, and managing the many associated personal challenges such as social isolation, family issues and working difficulties. Evidence is emerging that psychological interventions may be beneficial in MS patients although more research is required to confirm their utility. This article examines some factors that influence QoL in MS patients which may be overlooked in the general busyness of routine clinical practice.

Immune-reconstitution Inflammatory Syndrome in Multiple Sclerosis Patients Treated With Natalizumab: A Series of 4 Cases.

PURPOSE Natalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). Progressive multifocal leukoencephalopathy (PML) is a rare complication of NTZ treatment. In patients developing PML, NTZ cessation causes a reconstruction of cellular immunity, a rapid transition of cells through the blood-brain barrier, and significant inflammation in the central nervous system, leading to immune-reconstitution inflammatory syndrome (IRIS), with potentially poor outcomes. The occurrence of this syndrome is accelerated by plasmapheresis, the standard treatment for NTZ-PML, due to enhanced clearance of NTZ and thus rapid reconstitution of cellular immunity. IRIS can also occur after cessation of NTZ in the absence of PML. METHODS We describe 4 patients who developed IRIS after NTZ cessation. FINDINGS For the first patient, treatment was switched to fingolimod to avoid risk of developing PML. Despite plasmapheresis, corticosteroids, and other therapies, the outcome in this patient was fatal. For the 3 other patients, PML was detected early on magnetic resonance imaging, and IRIS after NTZ cessation was managed with a favorable outcome; 1 of these patients was managed without plasmapheresis or corticosteroid treatment. IMPLICATIONS These cases demonstrate the need to consider and manage therapeutic strategies relative to the individual patients risk for PML or IRIS. NTZ cessation to avoid PML risk can lead to severe IRIS without PML. On the other hand, if PML develops and is detected early, plasmapheresis may not be considered necessary and IRIS may be limited, with a favorable outcome. These 2 scenarios should be considered when managing NTZ MS patients.

Severe auto-immune hemolytic anemia in a fingolimod-treated multiple sclerosis patient

A 19-year-old multiple sclerosis (MS) patient was admitted to the emergency department with acute symptoms of fever, jaundice, nausea and fatigue. The patient did not have any history of hematological or systemic disease and was taking no medication but fingolimod for the last 10 months. Laboratory assessments confirmed the diagnosis of immune-mediated acute hemolytic anemia, as suggested by hematological and biochemical findings (hemoglobin 6.0 g/dl (11.8–15.5), serum bilirubin 2.3 mg/dl (< 1.2), serum unconjugated bilirubin 0.84 mg/dl (< 0.5), serum lactate dehydrogenase (LDH) 537 UI/l (< 214), serum haptoglobin < 5 mg/dl (30–200)). Liver enzymes and reticulocytes were in the normal range. Direct antiglobulin test (DAT) was positive (immunoglobulin (Ig)G-positive, C3d-negative) and cold agglutinins test was negative. Glucose-6-phosphate dehydrogenase test, antinuclear antibodies and lymphocyte immunophenotype analysis, serological tests (hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), parvovirus B19, Epstein-Barr virus (EBV), human herpes virus 6 (HHV6)) and abdominal ultrasound did not reveal any abnormality. The bone marrow analysis showed no sign of hematological malignancy, but a lack of mature red blood cell precursors, probably reflecting concomitant accelerated immune-mediated destruction of red blood precursors within the marrow as previously described.1 Two weeks later and despite an initial whole blood transfusion and methylprednisolone treatment (2 mg/kg/day) and an LDH and bilirubin improvement, hemoglobin was still at admission levels. Only after fingolimod cessation did biological parameters start to improve. Corticosteroids were tapered over a two-month period and laboratory findings remain normal several months later. Fingolimod (FTY720), a sphingosine-1-phosphatereceptor modulator, is the first oral treatment for relapsing– remitting MS. It is the first time that an autoimmune hemolytic anemia is reported in a patient treated with fingolimod. In our opinion, the causal link is quite probable, considering the absence of any other comorbidity and the improvement of biological parameters only after fingolimod cessation. No additional laboratory experiment could clarify the origin of this IgG hemolytic anemia, since in this kind of autoimmune phenomenon, antibodies are drug independent (drug need not be present to detect antibodies in vitro) and so it presents clinically and serologically as an autoimmune hemolytic anemia (AIHA) with red cell (RBC) autoantibodies in patients’ sera and in eluates from their RBCs.2 The causality in this particular patient could be proven only if the same adverse event appeared once again after fingolimod re-introduction, which could not be an option from the ethical point of view. Fingolimod has been shown to effect in several ways cell survival, from triggering apoptosis to even protecting against cell death.3 An in vitro apoptotic effect of fingolimod in erythrocytes partially due to an increase in cytosolic Ca2+ concentration has been reported. It is of interest that although fingolimod is considered to be effective as an antiinflammatory agent following a phosphorylation and subsequent stimulation of sphingosine phosphate receptor S1P1,4 erythrocytes are not able to phosphorylate FTY7205 and thus its apoptotic effect may be mediated by its nonphosphorylated form. In our opinion, particular attention should be paid to patients receiving drugs or suffering from disorders simulating eryptosis, since sensitivity to fingolimod could be enhanced.

Pure left hippocampal stroke: a transient global amnesia-plus syndrome

Dear Sirs, Human and animal studies have provided undeniable evidence that the hippocampus is critically involved in supporting declarative–recollective memory [1, 2]. Isolated unilateral first-ever ischemic stroke that is specifically confined to the hippocampal region is an extremely rare event [3, 4] and similar cases have not generally been studied with standardized neuropsychological assessment in the acute phase. A 41-year-old right-handed office worker presented abruptly with a dense amnesic syndrome (both anterograde and retrograde memory deficit) resembling transient global amnesia (TGA). Knowledge of personal identity was maintained, other cognitive domains were spared and he repeatedly asked questions such as ‘‘where am I?, what are we doing?’’. However, differently than what is generally expected with TGA, the patient had frequent anomic pauses in spontaneous speech and committed significant errors in naming tests, mostly omissions (‘‘amnesic aphasia’’). Brain MRI at day 3 after admission (Fig. 1) showed a unique acute infarction of the dorsal part of the left hippocampal body, most likely explained by occlusion of the most distal PCA branches (middle or posterior hippocampal artery as suggested in [3]). The etiology was a large patent foramen ovale as other disorders were not identified. The amnesic syndrome resolved within 24–48 h (including retrograde amnesia) but verbal anterograde memory deficits persisted over 4 weeks and afterwards normalized. The neuropsychological assessment was performed within the first week after stroke. The patient performances were in the norms in the following domains: attention (WAIS code, TMT-A, TAP), immediate memory (Hebb and Corsi test), calculation (Barcelona battery), gestural praxis (Florida Apraxia Battery), visuo-perceptive attitudes (Rey-complex figure copy, bisection and cancelation tasks, face recognition, Hooper test), executive functions (FAB, WCST, BADS, Ruff Figural Fluency, TMT B, color stroop), reasoning (SPM47), retrograde memory (autobiographical memory interview). Language (Monreal Toulouse Protocol) was normal except for mild anomia and reduced literal fluencies. There was a dissociation of performance between verbal (forward 4, backward 3) and visual (forward 7, backward 6) span tests. Verbal learning was assessed through the Rey auditory verbal learning test (15 words), nonverbal learning by means of the Rey visual design learning test (15 designs), the recall phase of the Rey-complex figure (RCF) and recognition memory test for words and faces. In the verbal modality, free recall (sum of five trials: 27, 30-min delayed recall: 1) and delayed recognition (score: 4) were impaired, while the same domains were within normal limits in the visual modality (sum of five trials: 45, 30-min recall: 11, recognition: 13) (Fig. 2a). Intrusions (sum of five trials: 28) and errors in recognition (score: 10) of the learning tests were limited to the verbal modality (Fig. 2b). The results of the RCF immediate and delayed recall were in the normal range (40 and 50 percentile). A. Carota (&) Hildebrand Clinic, Rehabilitation Center, 6614 Brissago, Switzerland e-mail: a.carota@bluewin.ch

Improving fatigue in multiple sclerosis by smartphone-supported energy management: The MS TeleCoach feasibility study

BACKGROUND Fatigue is a frequently occurring, often disabling symptom in MS with no single effective treatment. In current fatigue management interventions, personalized, real-time follow-up is often lacking. The objective of the study is to assess the feasibility of the MS TeleCoach, a novel intervention offering telemonitoring of fatigue and telecoaching of physical activity and energy management in persons with MS (pwMS) over a 12-week period. The goal of the MS TeleCoach, conceived as a combination of monitoring, self-management and motivational messages, is to enhance levels of physical activity thereby improving fatigue in pwMS in an accessible and interactive way, reinforcing self-management of patients. METHODS We conducted a prospective, open-label feasibility study of the MS TeleCoach in pwMS with Expanded Disability Status Scale ≤ 4 and moderate to severe fatigue as measured by the Fatigue Scale for Motor and Cognitive Functions (FSMC). Following a 2-week run-in period to assess the baseline activity level per patient, the target number of activity counts was gradually increased over the 12-week period through telecoaching. The primary efficacy outcome was change in FSMC total score from baseline to study end. A subset of patients was asked to fill in D-QUEST 2.0, a usability questionnaire, to evaluate the satisfaction with the MS TeleCoach device and the experienced service. RESULTS Seventy-five patients were recruited from 16 centres in Belgium, of which 57 patients (76%) completed the study. FSMC total score (p = 0.009) and motor and cognitive subscores (p = 0.007 and p = 0.02 respectively) decreased from baseline to week 12, indicating an improvement in fatigue. One third of participants with severe fatigue changed to a lower FSMC category for both FSMC total score and subscores. The post-study evaluation of patient satisfaction showed that the intervention was well accepted and that patients were very satisfied with the quality of the professional services. CONCLUSION Using MS TeleCoach as a self-management tool in pwMS suffering from mild disability and moderate to severe fatigue appeared to be feasible, both technically and from a content perspective. Its use was associated with improved fatigue levels in the participants who completed the study. The MS Telecoach seems to meet the need for a low-cost, accessible and interactive self-management tool in MS.

HLA genotype as a marker of multiple sclerosis prognosis: A pilot study

OBJECTIVE The identification of a biomarker with prognostic value is an unmet need in multiple sclerosis (MS). The objective of this study was to investigate a possible association of HLA genotype with disease status and progression in MS, based on comprehensive and sensitive clinical and magnetic resonance imaging (MRI) parameters to measure disease effects. METHOD A total of 118 MS patients (79 females, 39 males) underwent HLA typing. Patient MS status was assessed at two time points in a 2-year interval, based on clinical scores (including EDSS, MSSS, T25FW, 9-HPT, SDMT, BVMT, CVLT-II) and MRI evaluations. Quantitative brain MRI values were obtained for whole brain atrophy, FLAIR lesion volume change and number of new lesions using MSmetrix. Predefined HLA patient groups were compared as of disease status and progression. Global assessment was achieved by an overall t-statistic and assessment per measurement by a Welch test and/or Mann Whitney U test. The effects of multiple covariates, including age, gender and disease duration as well as scan parameters, were also evaluated using a regression analysis. RESULTS The HLA-A*02 allele was associated with better outcomes in terms of MSSS, EDSS and new lesion count (Welch test p-value<0.05). The HLA-B*07 and HLA-B*44 alleles showed a global negative effect on disease status, although none of the measurements reached significance (p-value<0.05). Results for the HLA-DRB1*15, HLA-DQB1*06 and HLA-B*08 alleles were inconclusive. The influence of the confounding variables on the statistical analysis was limited.

Human leucocyte antigen (HLA) class I and II typing in Belgian multiple sclerosis patients

This is one of the first studies to compare the frequencies of different human leucocyte antigen (HLA) class I and II alleles and haplotype HLA-DRB1*15-DQB1*06 in a cohort of 119 patients with multiple sclerosis (MS) and a cohort of 124 healthy controls in Belgium. An association with MS was found for the HLA-DRB1*15 (odds ratio [OR] 2.60 [95% confidence interval (CI) 1.51–4.50]) and HLA-DQB1*06 (OR 1.97 [95% CI 1.18–3.29]) alleles, and for haplotype DRB1*15-DQB1*06 (OR 2.63 [95% CI 1.52–4.56]). The HLA-B*07 allele also tended to be more frequent in MS patients (OR 1.46 [95% CI 0.80–2.65]) and more frequent among MS patients with than in those without the HLA-DRB1*15 allele (26/54 [48.1%] versus 6/65 [9.2%]; p value <0.0001). Other alleles were underrepresented in MS patients, such as the HLA-DRB1*07 (OR 0.39 [95% CI 0.21–0.73]) and HLA-A*02 (OR 0.56 [95% CI 0.34–0.94]), showing a protective role against the disease. The HLA-B*44 (OR 0.58 [95% CI 0.31–1.09]) and HLA-DRB1*04 (OR 0.75 [95% CI 0.42–1.34]) alleles tended to be less frequent in MS patients. Altogether, the significant results observed in this population are in line with those from other countries and confirm that propensity to MS can be due to a complex presence of various HLA class I and class II alleles.

Postictal cortical visual impairment: A symptom of posterior reversible encephalopathy

We describe a patient presenting with a first generalized convulsion after alcohol consumption, in whom the early postictal finding of a rapidly regressive cortical visual impairment suggested the presence of a posterior reversible encephalopathy. This was confirmed radiologically, and probably represented the key factor in the seizure etiology.

Exacerbation of myasthenia gravis after postoperative radiotherapy for a thymoma

Acquired myasthenia gravis (MG) is a heterogeneous autoimmune disease mediated by autoantibodies, such as anti-acetylcholine receptor (AchR) or anti-muscle specific kinase (MuSK) antibodies that interfere with the function of the neuromuscular junction. Systemic illness, surgery, fever, pregnancy, emotional stress and various drugs are well-known factors that may exacerbate myasthenic symptoms [1]. In 80–90% of the cases, MG is associated with pathologic changes of the thymus. In about 10% of the AchRseropositive cases, MG is a paraneoplastic phenomenon linked to a subgroup of epithelial neoplasms of the thymus called thymomas [2]. The role of postoperative radiotherapy in thymomas remains controversial, but is well established in the advanced stages [3]. Postoperative radiotherapy in thymomas is associated to chest or heart complications [4, 5]. We report the case of a 47-year-old woman who experienced twice an exacerbation of her myasthenic symptoms clearly linked to postoperative radiotherapy for a thymoma. The patient who was complaining of fatigability and intermittent ptosis was diagnosed with anti-AchR-seropositive myasthenia. A decrement in compound muscle action potential (CMAP) amplitude of 26% was recorded with surface electrodes over trapezius. A treatment with pyridostigmine was initiated (60 mg, 3 times/day). A Masaoka stage 3 thymoma found during the diagnostic work-up was removed using a medial sternotomy without any complication. Due to the invasive nature of the thymoma, adjuvant radiotherapy was performed 2 months later. She received 5,600 cGy in 39 days. Right after the radiotherapy, the patient presented an important fatigability, difficulties in swallowing and mastication, eyelid drooping and proximal weakness. Checkup excluded any other possible reason for this exacerbation of myasthenia. The patient never showed any sign of depression or stress. 32 mg of methylprednisolone progressively tapered for 2 months were administered and the daily dose of pyridostigmine increased. 2 months later, the patient was markedly improved. The corticosteroids were then progressively withdrawn and the daily dose of pyridostigmine was decreased to the previous levels. 2 years later, positron emission tomography (PET) with fluorodeoxyglucose (FDG) showed a local recurrence of the thymoma. The patient had no particular neurological symptoms at that time. 1 month after a new surgery without any complication, a new cycle of radiotherapy (5,600 cGy in 39 days) was performed. 1 week after the initiation of the radiotherapy, the patient presented a generalized weakness, eyelid drooping, double vision, facial weakness, dysphonia and shortness of breath. A new checkup excluded any other possible reason for the exacerbation of MG. 32 mg of methylprednisolone progressively tapered for 1 month were administered and the daily dose of pyridostigmine increased. 2 months later, the patient was asymptomatic. The recurrence or even first manifestation of myasthenia after postoperative radiotherapy for a thymoma is extremely rarely reported in the literature. Five cases are described in two reports. Ishida [6] reported two cases with deterioration of MG after irradiation. Interestingly, the analysis of the subsets of peripheral blood lymphocytes A. P. Lysandropoulos (&) N. Mavroudakis Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Route de Lennik 808, 1070 Brussels, Belgium e-mail: Andreas.Lysandropoulos@erasme.ulb.ac.be

Diagnostic pitfalls: Posterior ischemic optic neuropathy mimicking optic neuritis

In young people, the most frequent cause of isolated monocular visual loss due to an optic neuropathy is optic neuritis. We present the case of a 27 year old woman who presented monocular visual loss, excruciating orbital pain and unusual temporal headache. The initial diagnosis of optic neuritis revealed later to be a posterior ischemic optic neuropathy (PION). In this case, PION was the first unique presentation of a non-traumatic carotid dissection, and it was followed 24h later by an ischemic stroke. Sudden monocular visual loss associated with a new-onset headache are clinical symptoms that should immediately prompt to a carotid dissection.