Steffen Pfeuffer

Simultaneous early-onset immune thrombocytopenia and autoimmune thyroid disease following alemtuzumab treatment in relapsing-remitting multiple sclerosis

Objective: We report two cases of patients with relapsing-remitting multiple sclerosis with early-onset thrombocytopenia and autoimmune thyroid disease after the first treatment course with 60-mg alemtuzumab. Methods: Case series and review of the literature. Results: Both patients showed severe thrombocytopenia with platelet counts of 2 × 109 and 11 × 109/L, respectively, as well as increased thyroid antibodies within only a few months after initiating alemtuzumab treatment (11 and 9 months). Both patients responded considerably well to medical therapy including corticosteroids and intravenous immunoglobulins with slow platelet recovery over several weeks. Interestingly, both patients were previously treated with fingolimod and showed a marked lymphocytopenia that led to discontinuation. Conclusion: These cases emphasize the necessity of careful clinical surveillance and proper education of patients treated with alemtuzumab as proposed by the safety-monitoring program. Previous severe lymphocytopenia under therapy with other disease-modifying therapies may be a risk factor for the development of immune thrombocytopenia.

Acute cholecystitis during treatment with alemtuzumab in 3 patients with RRMS

Alemtuzumab is an effective therapeutic option for patients with active forms of relapsing-remitting multiple sclerosis (RRMS).1 The adverse event profile comprises an increased risk for the development of secondary autoimmune disorders as well as infusion-associated reactions. Alemtuzumab infusion is often associated with an acute cytokine release syndrome.2 Among other side effects, patients may experience headache, rash, pyrexia, and to a lesser extent hypotension, cardiac arrhythmia, and rarely anaphylactic shock. These symptoms are usually limited to the first days of infusion and do not lead to sustained impairment.1

Failed, interrupted and inconclusive trials on relapsing multiple sclerosis treatment: update 2010–2015

ABSTRACT The treatment of multiple sclerosis (MS) remains challenging despite the great efforts made in the development of novel therapies. Driven by the growing knowledge of the immunopathogenesis of the disease, a plethora of new pharmacological agents have been developed and tested in clinical trials. However, the therapeutic advantages and positive clinical trials of some of these agents are outweighed by studies of promising agents that either failed due to negative or inconclusive results or had to be withdrawn because of serious unexpected adverse events. Most failed clinical trials did not lack a well-considered pathophysiological rationale, but concepts from experimental models were proven wrong in humans. Lessons learned from these discrepancies help to optimize future study design and, potentially more importantly, provide further insight into the immunopathogenesis of MS. Here, we summarize trials on MS treatments since 2010 that failed or were interrupted, identifying potential underlying reasons for failure or inconclusiveness.

Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis:

Background: The course of multiple sclerosis (MS) shows substantial inter-individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors. Objective: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course. Methods: Untreated patients (n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (Ɛ2) and rs429358 (Ɛ4) in APOE. Linear regression analyses were applied based on the three SNPs, smoking and BMI as exposures and MRI surrogate markers for disease severity as outcomes. Results: Current smoking was associated with reduced gray matter fraction, lower brain parenchymal fraction and increased cerebrospinal fluid fraction in comparison to non-smoking, whereas no effect was observed on white matter fraction. BMI and the SNPs in HLA and APOE were not associated with structural MRI parameters. Conclusions: Smoking may have an unfavorable effect on the gray matter fraction as a potential measure of MS severity already in early MS. These findings may impact patients’ counseling upon initial diagnosis of MS.

Sarcoidosis following alemtuzumab treatment: Autoimmunity mediated by T cells and interferon-γ

Among the therapeutic options for relapsing-remitting multiple sclerosis (RRMS), alemtuzumab certainly stands out as it can induce a long-lasting remission in the absence of further treatment in formerly active patients. It rapidly depletes most lymphocytes from the peripheral blood and each treatment course is followed by differential repopulation of the affected cell lines. The exact mechanisms controlling this so-called immune reconstitution are still only partially understood.1

Alemtuzumab Improves Cognitive Processing Speed in Active Multiple Sclerosis—A Longitudinal Observational Study

Background Several disease-modifying drugs have shown promising effects on cognitive impairment in multiple sclerosis (MS). Alemtuzumab, a humanized monoclonal antibody, is effective in controlling disease activity, however, has not been evaluated for its effects on cognition in detail so far. Objective To explore the influence of alemtuzumab on cognitive impairment in active relapsing–remitting MS (RRMS) as well as possible clinical and neuroimaging predictors of cognitive changes during the first year of therapy. Methods Extensive neuropsychological assessment was administered to 21 patients with active RRMS at baseline and again after the second treatment with alemtuzumab (mean time span: 15.05 months). Clinical and routine structural neuroimaging markers were explored for their capacity to predict individual courses of cognitive change. Results Overall cognitive functioning remained stable or improved during the observational period of alemtuzumab treatment on average. Scores on two neuropsychological tests of processing speed significantly improved and clinically relevant individual gains of processing speed were seen in the majority of patients. Linear regression models showed that clinical and routine neuroimaging measures of disease activity could not fully account for these cognitive changes. Conclusion Results suggest that alemtuzumab treatment in active RRMS stabilizes overall cognitive functioning and furthermore positively affects cognitive processing speed. Changes in processing speed were independent from clinical and structural neuroimaging parameters of disease activity and may thus represent an underrated and independent outcome measure to evaluate treatment effects.

An Enigmatic Case of Acute Mercury Poisoning: Clinical, Immunological Findings and Platelet Function

Severe mercury intoxication is very rare in developed countries, but still occurs as the result of volatile substance abuse, suicide attempts, occupational hazards, or endemic food ingestion as reported in the cases of public health disasters in Iraq and in Minamata Bay, Japan. Here, we describe the dramatic physical and cognitive decline of a 23-year-old patient caused by a severe methyl mercury (MeHg) intoxication of unknown origin. We show serial magnetic resonance imaging (MRI) of the patient’s brain, as well as ex vivo analyses of blood and cerebrospinal fluid including multicolor flow cytometric measurements, functional assays of hemostaseologic efficacy, and evaluation of regulatory effector molecules. Together with the clinical history, our findings show the progressive neuronal degeneration accompanying the deterioration of the patient. Moreover, the ex vivo analyses display alterations of thrombocyte function and coagulation, as well as an immunological milieu facilitating autoimmunity. Despite the successful reduction of the MeHg concentration in the patient’s blood with erythrocyte apheresis and chelator therapy, his condition did not improve and led to a persistent vegetative state. This case illustrates the neurotoxicity of MeHg following severe intoxication for the first time by serial MRI. Data on immune-cell and thrombocyte function as well as on coagulation in mercury poisoning reveal potential implications for anticoagulation and immunomodulatory treatment.

NMO-Spektrum-Erkrankungen

ZusammenfassungNMO-Spektrum-Erkrankungen sind eine Gruppe chronisch-entzündlicher ZNS-Erkrankungen, die vorrangig, aber nicht ausschließlich, durch rezidivierende Optikusneuritiden und/oder entzünd-liche Veränderungen des Rückenmarkes charakterisiert sind. Ausgehend von der Neuromyelitis optica wurden in den letzten Jahren wesentliche klinische, bildmorphologische und pathologische Erscheinungsformen charakterisiert, die nun unter dem Begriff der NMOSD firmieren. Im Juli 2015 wurden die bisherigen Diagnosekriterien revidiert und der vereinheitlichende Terminus „NMO-Spektrum-Erkrankung“ (NMOSD) eingeführt.