Alexandra Schröder

Interleukin 6 Receptor Blockade in Patients With Neuromyelitis Optica Nonresponsive to Anti-CD20 Therapy

OBJECTIVE To report first experiences with interleukin 6 receptor inhibition in therapy-resistant neuromyelitis optica (NMO). DESIGN Retrospective case series. SETTING Neurology department at a tertiary referral center. PATIENTS Patients with an aggressive course of NMO switched to tocilizumab after failure of anti-CD20 therapy. MAIN OUTCOME MEASURES Annualized relapse rate and disability progression measured by the Expanded Disability Status Scale. RESULTS We report 3 female patients with a median age of 39 years (range, 26-40 years) and aquaporin 4-positive NMO. All patients had been treated with different immunosuppressive and immunomodulating agents, followed by 1 to 3 cycles of rituximab. Despite complete CD20-cell depletion during rituximab therapy, the median annualized relapse rate was 3.0 (range, 2.3-3.0) and the median Expanded Disability Status Scale score increased from 5.0 (range, 4.5-7.0) to 6.5 (range, 5.0-7.0). After the switch to tocilizumab (median duration of therapy, 18 months), the median annualized relapse rate decreased to 0.6 (range, 0-1.3). A total of 2 relapses occurred; however, they were mild and there were no changes in clinical disability. CONCLUSIONS Interleukin 6 receptor-blocking therapy can be effective in therapy-resistant cases of NMO. Larger controlled studies are needed to confirm the efficacy of tocilizumab.

Successful Management of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy and Immune Reconstitution Syndrome in a Patient With Multiple Sclerosis

OBJECTIVE To describe a case of successful clinical management of natalizumab-associated progressive multifocal leukoencephalopathy (PML) and immune reconstitution syndrome (IRIS) in a patient with multiple sclerosis. DESIGN Case report. SETTING University hospital. PATIENT A 41-year-old woman with relapsing-remitting multiple sclerosis developed PML after 29 natalizumab infusions. INTERVENTIONS Immediate plasma exchange was combined for removal of natalizumab with application of mefloquine and mirtazapine to limit viral replication and oligodendrocyte infection. A subsequent IRIS was treated with glucocorticosteroids. RESULTS After 3 months of treatment, cerebrospinal fluid tested negative for JC virus. There was a favorable outcome, and the Expanded Disability Status Scale score remained stable at 3.5 compared with before PML. CONCLUSIONS In the setting of early diagnosis and consequent treatment, natalizumab-associated PML can be well managed in some cases. This situation differs from the course of PML in other conditions, eg, after the application of depleting monoclonal antibodies, in which irreversible cellular effects are associated with very high mortality.

["Chronic cerebrospinal venous insufficiency" and multiple sclerosis: critical analysis and first observation in an unselected cohort of MS patients].

ZusammenfassungÜber die Hypothese eines möglichen ursächlichen Zusammenhangs von Störungen der zerebralen venösen Hämodynamik und der Entstehung der Multiplen Sklerose (MS) wird aktuell kontrovers diskutiert. Die neue „venöse Hypothese“ postuliert, dass Abflussstörungen des zervikalen Venensystems eine Stauung und Druckerhöhung des intrakraniellen Venensystems mit nachfolgender Entzündungsreaktion bedingen. Diese Hypothese wird unter drei Gesichtspunkten analysiert und bewertet: (1) Validität der publizierten Befunde, (2) Plausibilität im Licht derzeitig akzeptierter Pathogenesemodelle der MS und (3) Kompatibilität mit ersten eigenen Untersuchungen.Die Autoren kommen zu der Schlussfolgerung, dass die „venöse Hypothese“ als ausschließliche Ursache die MS keinesfalls erklären kann. Lediglich 20% unseres unselektierten MS-Kollektivs erfüllten zwei der neu aufgestellten neurosonologischen Kriterien einer „chronischen zerebrospinalen venösen Insuffizienz“. Die pathogenetische Relevanz dieser subtilen Veränderungen der venösen Flussverhältnisse ist derzeit völlig offen. Ebenfalls ist unklar, inwieweit diese Veränderungen Grund oder Folge der MS sind. Keinesfalls lassen sich damit nach derzeitigem Erkenntnisstand invasive „therapeutische“ Maßnahmen rechtfertigen, insbesondere nicht außerhalb kontrollierter Studienprotokolle.SummaryCurrently, the hypothesis that altered venous hemodynamics might play a causative role in the pathogenesis of multiple sclerosis (MS) is being controversially discussed. This new „venous hypothesis“ postulates that obstructions of the cervical venous system cause an increased pressure of the intracranial venous system and that in turn intracranial congestion disintegrates the blood-brain barrier initiating the inflammatory process in MS.The „venous hypothesis“ is analyzed and evaluated with regard to the following aspects: first concerning the validity of published data, second with regard to the plausibility in view of the currently approved pathogenetic model of MS, and third with regard to the compatibility with preliminary neurosonological findings in a small but unselected cohort of patients at our department.The authors conclude that the „chronic cerebrospinal venous insufficiency (CCSVI)“ cannot represent the exclusive pathogenetic factor in the pathogenesis of MS. In our cohort, only 20% of the patients fulfilled the required neurosonological features of CCSVI. So far, the pathogenetic relevance of these findings remains speculative. Thus, based on the current scientific position we cannot justify invasive „therapeutic“ approaches, especially if they are performed outside of clinical trials.

Plasmapheresis for neurological disorders.

Apheresis is a general term that describes removal of abnormal blood constituents by extracorporeal blood purification methods. To date, therapeutic plasma exchange (PE) is the most common apheresis procedure. Here, plasma is separated from corpuscular blood constituents and replaced with a substitution fluid. In contrast to immunoadsorption, PE is a nonspecific treatment modality with elimination of the entire plasma. The therapeutic effect is based on the removal of circulating, pathogenic immune factors including autoantibodies. Currently, PE is used for treatment of several immune-mediated neurological disorders. While first experiences relate to acute life-threatening conditions, such as treatment of Guillain–Barré syndrome or myasthenic crisis, therapeutic success was also shown in chronic diseases where immunosuppressive therapy is often required for long-term management. PE has been applied successfully in chronic inflammatory demyelinating polyneuropathy, paraproteinemic polyneuropathy, stiff person syndrome, and may also be tried in several diseases of paraneoplastic origin. In recent years, PE was also established as an escalation therapy for steroid-unresponsive relapses of multiple sclerosis, and thus has gained more widespread attention. Adding to its increasing application in clinical practice, the procedure is usually well tolerated. Possible adverse reactions mainly relate to vascular access, the use of replacement fluids and the need for anticoagulation.

Successful Treatment of Anti-Caspr2 Syndrome by Interleukin 6 Receptor BlockadeThrough Tocilizumab

IMPORTANCE A patient with a Caspr2 autoantibodies-associated syndrome had an unusual clinical triad and an excellent response to B-cell-anergizing therapy using the humanized monoclonal antibody tocilizumab directed against the interleukin 6 (IL-6) receptor. OBSERVATIONS A 55-year-old man had an atypical clinical triad of epilepsy, dysarthria, and paroxysmal kinesigenic dystonia, and a high titer of Caspr2 antibodies was detected in his serum and cerebrospinal fluid. Screening for underlying neoplasias was negative. With initial methylprednisolone sodium succinate and alternate treatment using plasma exchange and immunoabsorption as well as subsequent IL-6 receptor blockade through tocilizumab, a complete and stable remission of symptoms has been achieved throughout the follow-up period of 7 months. CONCLUSIONS AND RELEVANCE In our patient, the implementation of a B-cell-anergizing therapy using tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, has shown an excellent response. Larger case series or even controlled studies are needed to confirm the efficacy of tocilizumab in autoimmune synaptic or presynaptic diseases.

Einsatz von Rituximab in der Behandlung neuroimmunologischer Erkrankungen

ZusammenfassungDer chimärisierte monoklonale Anti-CD20-Antikörper Rituximab wurde bereits erfolgreich in der Behandlung hämatologischer und auch rheumatologischer Erkrankungen eingesetzt. Der Wirkmechanismus von Rituximab beruht auf der Depletion CD20-positiver B-Zellen, die unter anderem über komplement- und antikörperabhängige Zytotoxizität und Apoptose vermittelt wird. Neuere histopathologische und auch immunologische Studien weisen auf eine zentrale Funktion von B-Zellen in der Pathogenese vieler neuroimmunologischer Erkrankungen hin, dies gilt insbesondere auch für die Multiple Sklerose. Einzelfallbeschreibungen und Fallserien zum Einsatz von Rituximab bei der Neuromyelitis optica (NMO), der Myasthenia gravis und Immunneuropathien sowie randomisierte Studien bei der schubförmigen Multiplen Sklerose zeigen vielversprechende Ergebnisse, die im Rahmen dieser Übersicht diskutiert werden.SummaryRituximab, a human-mouse chimeric CD20 monoclonal antibody that depletes CD20-positive B cells, has already demonstrated efficacy in hematologic and rheumatologic diseases. Treatment with rituximab results in depletion of CD20-positive cells via multiple mechanisms, including complement-mediated or antibody-dependent cytotoxicity and apoptosis. Recent histopathologic and immunologic studies reveal an influence of B cells on the development and perpetuation of many chronic inflammatory diseases of the nervous system. Promising results with rituximab were already reported in the therapy of myasthenia gravis, immunoneuropathies, neuromyelitis optica, and multiple sclerosis, in which first controlled studies have been recently published. In this review we summarize available data from these reports and also discuss possible underlying molecular mechanisms.Rituximab, a human-mouse chimeric CD20 monoclonal antibody that depletes CD20-positive B cells, has already demonstrated efficacy in hematologic and rheumatologic diseases. Treatment with rituximab results in depletion of CD20-positive cells via multiple mechanisms, including complement-mediated or antibody-dependent cytotoxicity and apoptosis. Recent histopathologic and immunologic studies reveal an influence of B cells on the development and perpetuation of many chronic inflammatory diseases of the nervous system. Promising results with rituximab were already reported in the therapy of myasthenia gravis, immunoneuropathies, neuromyelitis optica, and multiple sclerosis, in which first controlled studies have been recently published. In this review we summarize available data from these reports and also discuss possible underlying molecular mechanisms.

Increase of angiotensin II type 1 receptor auto-antibodies in Huntington’s disease

BackgroundIn the recent years, a role of the immune system in Huntington’s disease (HD) is increasingly recognized. Here we investigate the presence of T cell activating auto-antibodies against angiotensin II type 1 receptors (AT1R) in all stages of the disease as compared to healthy controls and patients suffering from multiple sclerosis (MS) as a prototype neurologic autoimmune disease.ResultsAs compared to controls, MS patients show higher titers of anti-AT1R antibodies, especially in individuals with active disease. In HD, anti-AT1R antibodies are more frequent than in healthy controls or even MS and occur in 37.9% of patients with relevant titers ≥ 20 U/ml. In a correlation analysis with clinical parameters, the presence of AT1R antibodies in the sera of HD individuals inversely correlated with the age of onset and positively with the disease burden score as well as with smoking and infection.ConclusionsThese data suggest a dysfunction of the adaptive immune system in HD which may be triggered by different stimuli including autoimmune responses, infection and possibly also smoking.

Stability of cognitive functions under mitoxantrone therapy in patients with progressive multiple sclerosis: A pilot analysis

OBJECTIVE Mitoxantrone (MX) is a potent immunosuppressant that is licensed as escalation therapy for the treatment of active multiple sclerosis (MS). METHODS In an open-label, retrospective analysis, we investigated effects of MX therapy on parameters of cognitive functions in patients with progressive MS and significant disability. Twenty patients received a total of 42 mg/m(2) MX in 4 cycles. Six patients who fulfilled the criteria for MX therapy, yet did not receive this treatment, served as controls. Before initiation of therapy and after a mean observation period of 24 months, neurological examination and a neuropsychological test battery were performed. Neuropsychological analyses comprised tests for cognitive flexibility as a part of executive functioning, and verbal as well as non-verbal tests for memory and attention. Additionally, intelligence and symptoms of depression were investigated. RESULTS While there was stability of EDSS over time, there were no differences in cognitive functions before and after MX treatment. In contrast, patients not receiving MX showed a worsening of verbal short term memory and cognitive flexibility over the same time period. CONCLUSION In conclusion, this preliminary observational study points at stability of cognitive functions under MX therapy in patients with progressive multiple sclerosis.

Rituximab in treatment for neuroimmunological diseases

ZusammenfassungDer chimärisierte monoklonale Anti-CD20-Antikörper Rituximab wurde bereits erfolgreich in der Behandlung hämatologischer und auch rheumatologischer Erkrankungen eingesetzt. Der Wirkmechanismus von Rituximab beruht auf der Depletion CD20-positiver B-Zellen, die unter anderem über komplement- und antikörperabhängige Zytotoxizität und Apoptose vermittelt wird. Neuere histopathologische und auch immunologische Studien weisen auf eine zentrale Funktion von B-Zellen in der Pathogenese vieler neuroimmunologischer Erkrankungen hin, dies gilt insbesondere auch für die Multiple Sklerose. Einzelfallbeschreibungen und Fallserien zum Einsatz von Rituximab bei der Neuromyelitis optica (NMO), der Myasthenia gravis und Immunneuropathien sowie randomisierte Studien bei der schubförmigen Multiplen Sklerose zeigen vielversprechende Ergebnisse, die im Rahmen dieser Übersicht diskutiert werden.SummaryRituximab, a human-mouse chimeric CD20 monoclonal antibody that depletes CD20-positive B cells, has already demonstrated efficacy in hematologic and rheumatologic diseases. Treatment with rituximab results in depletion of CD20-positive cells via multiple mechanisms, including complement-mediated or antibody-dependent cytotoxicity and apoptosis. Recent histopathologic and immunologic studies reveal an influence of B cells on the development and perpetuation of many chronic inflammatory diseases of the nervous system. Promising results with rituximab were already reported in the therapy of myasthenia gravis, immunoneuropathies, neuromyelitis optica, and multiple sclerosis, in which first controlled studies have been recently published. In this review we summarize available data from these reports and also discuss possible underlying molecular mechanisms.Rituximab, a human-mouse chimeric CD20 monoclonal antibody that depletes CD20-positive B cells, has already demonstrated efficacy in hematologic and rheumatologic diseases. Treatment with rituximab results in depletion of CD20-positive cells via multiple mechanisms, including complement-mediated or antibody-dependent cytotoxicity and apoptosis. Recent histopathologic and immunologic studies reveal an influence of B cells on the development and perpetuation of many chronic inflammatory diseases of the nervous system. Promising results with rituximab were already reported in the therapy of myasthenia gravis, immunoneuropathies, neuromyelitis optica, and multiple sclerosis, in which first controlled studies have been recently published. In this review we summarize available data from these reports and also discuss possible underlying molecular mechanisms.

PE in der Eskalationstherapie der MS

Verlaufsdaten von 54 Patienten mit steroidrefraktären Schüben (40 RRMS, 5 SPMS mit überlagerten Schüben, 3 NMO, 6 CIS, mittleres Alter 36 Jahre, 36 weiblich, 18 männlich, Krankheitsdauer bis zu 25 Jahren) wurden mittels EDSS, MSFC und evozierten Potenzialen erhoben. Die PE (50 ml/kgKG, 5% Humanalbumin) erfolgte im Mittel 3 Wochen nach Symptombeginn nach Durchführung von durchschnittlich 2 Kortisonpulstherapien (10 g Methylprednisolon).