Volker Limmroth

Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF.

Background: Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML). Objective: We aimed to assess the effect of natalizumab on cellular composition and functional B cell parameters including patients with natalizumab-associated PML (n=37). Methods: Cellular composition by flow cytometry, levels of immunoglobulin (Ig)G/IgM by immunonephelometry, and oligoclonal bands by isoelectric focusing were studied in blood and cerebrospinal fluid. Results: In MS patients treated with natalizumab without PML (n=59) the proportion of CD19+ B cells was higher in blood, but lower in cerebrospinal fluid compared with MS patients not treated with natalizumab (n=17). The CD4/CD8-ratio in cerebrospinal fluid was lower, and IgG and IgM levels as well as the IgG index dropped in longitudinal samples during natalizumab therapy. Oligoclonal bands persisted, but the total amount of the intrathecally produced IgG fraction, and the polyclonal intrathecal IgG reactivity to measles, rubella, and zoster declined. At the time of diagnosis of PML patients with natalizumab-associated PML had low total IgG levels in blood and cerebrospinal fluid. Conclusions: Natalizumab impacts B and T cell distribution and exerts an inhibitory effect on surrogates of B cell function in periphery and in cerebrospinal fluid, potentially contributing to the increased risk of developing PML.

Duplication of the common carotid artery and the ipsilateral vertebral artery with a fenestration of the contralateral common carotid artery

Neurology India | October-December 2008 | Vol 56 | Issue 4 with Cushing’s disease is approximately 80% whereas in children and adolescents it is approximately 47%.[1] The causes of hypertension in patients with Cushing’s disease are multifactorial. These include intrinsic glucocorticoid activity, activation of the renin-angiotensin system, and suppression of the vasodilatory systems.[1] Hypertension has been regarded as the most prevalent and powerful of the risk factors for intracerebral hemorrhage. The mechanism is thought to involve a hypertension-induced degeneration of the walls of small arteries (lipohyalinosis) that leaves them prone to rupture. Accelerated atherosclerosis after prolonged corticosteroid administration has been shown in both animals[2,3] and humans.[4] Faggiano, et al. found a higher prevalence of atherosclerotic damage in patients with Cushing’s disease.[5] Also, patients with Cushing’s disease have elevated plasma endothelin levels. There are reasons to assume that elevated endothelin levels mediate the accelerated early atherosclerosis and hypertension typical of this disorder.[6] Hence, theoretically patients with Cushing’s disease are at an increased risk of developing intracerebral bleeds both due to hypertension and the accelerated atherosclerosis. Despite this, the incidence of reported hypertensive intracerebral bleeding in a case with Cushing’s disease is extremely rare. Our patient also had radiological features that suggested pituitary apoplexy. Apoplexy is most often obvious and discrete but may have a more subtle onset, or even be clinically silent.[7] Hypertension is also known to precipitate pituitary apoplexy.

Update on the cardiovascular profile of fingolimod in the therapy of relapsing-remitting multiple sclerosis (MS).

BACKGROUND Fingolimod (FTY720) has been approved as the first oral representative of the class of sphingosine-1-phosphate (S1P) receptor modulators for the treatment of relapsing-remitting multiple sclerosis (MS). Besides inducing vaso-relaxation, fingolimod can also influence electrical conduction in the myocardium and vascular endothelium by having a transient negative chronotropic effect on the sinus node. METHODS Cardiac safety and tolerability of fingolimod in the cardiac sense were reviewed by analysing the data collected from the FREEDOMS and TRANSFORMS studies -both relevant studies for marketing authorisation, from their extension studies, as well as the clinical data collected from a practice-related MS patient cohort with cardiovascular risk factors and corresponding co-medication (FIRST study). RESULTS The safety analyses on file gave no indication of any increased cardiovascular risk. The 2-3mmHg increase in blood pressure observed after the first dose of fingolimod has no therapeutic consequences. The first dose of 0.5mg fingolimod resulted in an average decrease in heart rate of 7-8beats/min. The onset of effect occurred approximately 1-2h after the first dose and the nadir was reached after approximately 4-5h. This negative chronotropic effect returned to normal after internalisation of the S1P1 receptors on maintenance therapy. There were no indications that patients with cardiac risk factors required closer observation beyond the monitoring recommended by the EMA following the first dose of fingolimod. Case study observations from the routine clinical setting show that patients accept this method of monitoring, which they assess as being a positive aspect of attentive medical care and concern.

Letter to the editor to the paper: "Acute and long-term effects of fingolimod on heart rhythm and heart rate variability in patients with multiple sclerosis".

Akbulak et al. (2017) recently reported results of Holter ECG monitoring (HEM) following the first dose of fingolimod in a cohort of 64 MS patients. In this small cohort, the authors reported five (7.8%) patients with new-onset transient AV-block (AVB) (ranging from firstdegree to second-degree type II (Mobitz)). In 4/5 patients (80%), the AVB could only be detected in the 72 h HEM with a median time of occurrence at 14 h. Although only one patient was symptomatic (dizziness), fingolimod treatment was discontinued in all of these mostly asymptomatic patients. There are several issues with both the methodology and the results of this study: