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Background: In experimental autoimmune encephalomyelitis, inhibition of the renin-angiotensin system with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors resulted in a significantly ameliorated disease course. We evaluated the effects of ARBs and ACE inhibitors on the efficacy of interferon beta-1b in patients with relapsing-remitting multiple sclerosis (RRMS)., Methods: In this post hoc analysis of the BEYOND (Betaferon Efficacy Yielding Outcomes of a New Dose) study, clinical and MRI end points were compared between patients treated with interferon beta-1b 250 or 500 µg and concomitant ARBs or ACE inhibitors and patients treated with interferon beta-1b 250 or 500 µg only (reference group)., Results: Patients in the ARB group (n = 22) tended to have a higher relapse rate (0.48 vs. 0.23, p = 0.051) and a higher number of new gadolinium-enhancing lesions (0.6 vs. 0.3, p = 0.057) than patients in the reference group. Patients in the ACE inhibitor group (n = 49) also tended to have a higher relapse rate (0.29 vs. 0.22, p = 0.357). No differences were observed for the other end points., Conclusion: In the BEYOND study cohort, a concomitant medication with ARBs or ACE inhibitors did not have a beneficial effect in patients with RRMS treated with interferon beta-1b. As patients appeared to have a higher relapse rate, our results warrant further investigation., (© 2014 S. Karger AG, Basel.)

Background: Natalizumab is a humanized monoclonal antibody directed against very late activation antigen 4 (VLA-4) and has a potent effect on disease activity in multiple sclerosis. Blockade of VLA-4 with natalizumab may not only interfere with autoimmunological mechanisms but also with central nervous system immune surveillance., Methods: Longitudinal ex vivo and in vitro study to determine the effect of natalizumab on the frequency of distinct immune cells and on the frequency and suppressive function of natural CD4+CD25+ regulatory T cells (Tregs)., Results: Natalizumab binding to VLA-4 was more marked for B cells than for T cells (49% reduction in VLA-4-expressing B cells compared to 24.5% reduction of T cells). There was an increase in circulating B cells over T cells (2.6 vs. 1.5 fold, p < 0.001). Natural killer cells increased 1.5-fold (p = 0.01). Natalizumab led to a relative decrease in CD4+CD25+ Tregs from 18.9 to 14.1% (p = 0.04). The impaired suppressive capacity of Tregs was not restored., Conclusion: Natalizumab reduces VLA-4 expression on all investigated immune cells, but changes were most marked for B cells. Further differential effects on immune cells may be relevant to opportunistic central nervous system infections during treatment with natalizumab., ((c) 2010 S. Karger AG, Basel.)

CD4+CD25+ regulatory T (T(reg)) cells play a major role in controlling autoimmunity by suppressing self-reactive T cells. Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system, where T cells are of major importance. T(reg) cell frequency and function are potential therapeutic targets of MS treatment. Mitoxantrone (MX) is a potent immunosuppressant for the treatment of active MS. We investigated the long-term effects of MX on the suppressive function of T(reg) after mitogen and myelin basic protein (MBP) stimulation in 20 MX-treated patients. MX therapy did not restore the reduced suppressive activity of a mixture of CD25(intermediate) or CD25(high) expressing T(reg) (healthy controls, MBP: 37.3%; MS patients, MBP: -1.9 vs. 6.6% suppression after MX treatment for 6 months, p > 0.2). The frequency of T(reg) cells was not affected by MX. A single infusion of MX (10 mg/m(2) body surface) induced a selective and persistent reduction of approximately 30% of absolute and relative counts of B lymphocytes (p < 0.05). MX therapy does not influence T(reg) cell frequency or function. MX seems to exhibit its efficacy in MS mainly by a suppression of humoral immunity., (2008 S. Karger AG, Basel.)

Background: The pathophysiology of multiple sclerosis (MS)-associated fatigue is poorly understood. Immunological mechanisms may play a role. Alterations in immunological profile indicate a chronic immune activation in MS patients with fatigue. T-regulatory (Treg) cells seem to play a key role in coordinating autoimmune mechanisms in MS. This is the first study investigating the relationship between Treg cell function and fatigue in MS patients., Methods: In this cross-sectional in vitro, ex vivo study, we isolated peripheral blood mononuclear cells (PBMCs) from 20 MS patients with fatigue, determined lymphocyte subsets by flow cytometry and suppressive function of Treg cells in PBMC cultures with antigen stimulation. Forkhead box protein 3 expression was evaluated by PCR. Results were compared with 20 MS patients without fatigue and with 19 healthy controls., Results: Leukocytes and lymphocyte subsets including Treg cell frequency did not differ in patients with and without fatigue. Co-culturing of Treg cells with CD4+CD25- cells did not lead to a significant suppression of myelin basic protein- and pokeweed mitogen-induced proliferation in MS patients in contrast to healthy controls. There were no statistical differences between MS patients with and without fatigue regarding this suppression activity., Conclusions: Fatigue seems not to be associated with impaired function of Treg cells in untreated MS patients.

In order to analyze aspects of pain patient care in neurology, we conducted a survey among German neurology departments that aimed to determine different structural aspects of neurological pain medicine. A 5-page questionnaire was sent to 391 neurological departments, and a return rate of 59.8% was achieved. Some 70% of university-based neurology departments have established their own outpatient clinic, and some 80% of these departments actively take part in interdisciplinary pain services. University hospitals operate an interdisciplinary pain clinic in 94.7%. Almost all neurological departments admit pain patients, especially for further diagnosis and neurological treatment. These fields are accepted as important neurological tasks. The quality of care is reported to be excellent. Routine questioning for pain of all admitted patients is carried out by 85% of all hospitals, and an extensive pain history is taken by almost 90% of departments. Our survey data confirm that the documentation of medical, psychological and psychosocial pain histories and the process of pain patient care are partly fulfilled, yet need improvement. Routine application of validated instruments and regular inquiry of the presence/course of pain may improve the process of care and--as the basis of outcome--pain management in neurology., (Copyright 2008 S. Karger AG, Basel.)

Fatigue is one of the most frequent and most disabling symptoms in multiple sclerosis (MS). We investigated the possible association of the MS-related fatigue syndrome with the available disease-modifying therapies and the main disease characteristics in a cross-sectional study on 320 consecutive patients. The prevalence of severe fatigue (Fatigue Severity Scale score > or =5) was 50%. In a multivariate regression model controlling for age, disease subtype, duration and disability we did not find a significant association between the use of immunosuppressive or immunomodulatory drugs compared to no treatment (OR = 1.34, p = 0.38 for immunosuppressants; OR = 0.95, p = 0.85 for immune-modulating agents). Although all used disease-modifying agents successfully reduce disease activity and inflammation, they do not appear to exhibit a significant effect on MS-related fatigue., (Copyright 2007 S. Karger AG, Basel.)

Acute interferon-beta (IFN-beta) administration transiently activates the hypothalamic-pituitary-adrenal (HPA) axis, increases granulocytes, and reduces lymphocytes in peripheral blood. To test whether these effects are still present after long-term treatment, 13 patients with relapsing-remitting multiple sclerosis were analyzed at baseline, and 1, 2, 4, and 8 h after IFN-beta 1a injection at two occasions: at the initial administration and after 1 year of continuous treatment. Long-term treatment reduced the responsiveness of the HPA axis to the injection, and abolished the distributional changes in leukocyte numbers. One-year treatment with IFN-beta 1a did not induce mood alterations as assessed by the Profile of Mood States. These results suggest that long-term IFN-beta therapy has a profound impact on leukocyte distribution and the neuroendocrine response to the drug., (Copyright 2005 S. Karger AG, Basel.)

Interferon-beta-1b (IFN-beta-1b) has been shown to reduce the relapse rate in patients with relapsing-remitting multiple sclerosis (MS) and disease progression in patients with secondary progressive MS. While acute administration of IFN-beta-1b is known to cause flu-like symptoms, chronic medication has been suggested to cause mood alterations and anxiety attacks, and secondary to this neuropsychological deficits that may impair daily life. It is unknown, however, whether the latter symptoms are induced by acute IFN-beta-1b administration. Therefore, we examined the impact of a single subcutaneous injection of IFN-beta-1b in 8 healthy males. In a crossover design, each subject was injected subcutaneously with either 8 million IU IFN-beta-1b or placebo (NaCl) at 8:00 h. Flu-like symptoms (body temperature, heart rate, blood pressure), mood status ['profile of mood states', Befindlichkeitsskala (BFS)] and neuropsychological performance (trail marking test, verbal memory test, d2 attention test) and were assessed at baseline, 4, 8 and 24 h after injection. IFN-beta-1b increased body temperature, heart rate and fatigue. Nevertheless, acute IFN-beta-1b injection did not impair any parameters of neuropsychological performance. Thus, although IFN-beta-1b produces physiological symptoms indicative of sickness behavior, these data suggest that IFN-beta-1b administration does not have an impact on the cognitive capacity following acute administration., (Copyright 2002 S. Karger AG, Basel)

Patients suffering from migraine, tension-type headache (TTH), or combined headache (CH) are at risk of developing drug-induced headache (DIH) due to regular use of analgesics, ergot alkaloids, and triptans. The aim of our study was to determine (1) the clinical features of DIH, (2) the outcome of withdrawal therapy using high methodological standards, and (3) predictors which could explain the high relapse rate (more than 40%) after a previously successful withdrawal therapy. We retrospectively reviewed 103 patients with migraine or TTH who underwent withdrawal therapy between 1994 and 1998. The long-term follow-up (2-4 years after therapy) was conducted by phone and by specially trained psychologists using a structured interview which enclosed characteristics of headache and medication behavior as well as patients global assessment of success. Complete sets of data were available from 83 patients (38 migraine, 26 TTH, 19 CH). The most frequently abused drugs were caffeine-combined analgesics (24%), followed by caffeine-combined ergotamines (19%), pure ergot alkaloids (17%), and monoanalgesics (17%). 48.5% of the patients suffered an abuse relapse within 4 years and developed the complete features of DIH again. Analgesic and ergot alkaloid combinations with caffeine lead significantly more often to a relapse. A long-term successful therapy is connected with a significant reduction of the frequency of headache attacks. Under relapse conditions, the patients reached their former headache frequency level. The data show a higher relapse rate than previously assumed and that certain substance groups bear a higher relapse risk., (Copyright 2001 S. Karger AG, Basel)

Vasoconstrictive agents have been widely used in the treatment of migraine. These types of drugs have various side effects and are not suitable for many patients. Due to nausea or vomiting, nonoral treatment is often required, but only a few nonvasoconstrictive drugs exist in a parenteral form and are suitable for the treatment of acute migraine in the emergency setting. In a randomized, double-blind, crossover trial we evaluated the efficacy of 1,000 mg lysine-acetylsalicylic acid i.v. (LAS) compared to 0.5 mg ergotamine s.c. in 56 patients (112 attacks) with acute migraine. To gain further insight into the possible role of vasoconstriction, blood flow velocities (BFV) were measured in intra- and extracranial arteries using duplex sonography and transcranial Doppler sonography. Both agents were equally potent in relieving headache. Intravenous LAS resulted in a significantly faster relief and had fewer side effects. LAS had no effect on BFV. Ergotamine increased BFV in the middle cerebral artery only. No correlation was found between changes in BFV and the relief of headache. This is the first trial to compare the intravenous formulation of LAS in the treatment of migraine with another antimigraine medication and suggests that it is an effective and safe drug for the parenteral treatment of acute migraine attacks.

Recent PET studies performed in humans during migraine attacks revealed a 'spreading depression-like' oligemia in the occipital cortex during the aura phase and a region of increased blood flow in the brainstem during the headache phase. Animal models were established to test new migraine drugs. A number of 5-HT agonists, the so-called 'triptans', will be available in future besides sumatriptan to treat acute migraine attacks. Migraine prophylaxis is still hampered by the fact that we do not understand the action of drugs used for this purpose and do not have an animal model. Nevertheless, new substances were introduced recently into the prophylaxis of migraine.