Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis.

BACKGROUND: Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population. METHODS: In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 µg per week for up to 2 years. The primary end point was the annualized relapse rate. RESULTS: Of a total of 215 patients, 107 were assigned to fingolimod and 108 to interferon beta-1a. The mean age of the patients was 15.3 years. Among all patients, there was a mean of 2.4 relapses during the preceding 2 years. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; P<0.001). The key secondary end point of the annualized rate of new or newly enlarged lesions on T2-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient). CONCLUSIONS: Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIGMS ClinicalTrials.gov number, NCT01892722 .).

Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND: No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis. METHODS: In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25-65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2-10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov, number NCT00731692. The study is now closed. FINDINGS: 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years [SD 8·4], mean EDSS 4·67 [SD 1·03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87-82·51) of patients in the fingolimod group versus 80·3% (73·31-87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80-1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%). INTERPRETATION: The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis. FUNDING: Novartis Pharma AG.

Effects of natalizumab on circulating B cells, T regulatory cells and natural killer cells.

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.

Natalizumab reduces clinical and MRI activity in multiple sclerosis patients with high disease activity: results from a multicenter study in Switzerland.

BACKGROUND: Natalizumab has been recommended for the treatment of relapsing-remitting multiple sclerosis (RRMS) in patients with insufficient response to interferon-beta or glatiramer acetate (disease-modifying treatments-DMT) or in aggressive MS. The pivotal trials were not designed to investigate natalizumab monotherapy in these patient populations. AIM: To investigate the efficacy of natalizumab after treatment failure of previous DMT and in highly active MS. METHODS: A retrospective, multicenter study in Switzerland. Three major MS centers reported all RRMS patients who initiated natalizumab>or=12 months prior to study conduction. RESULTS: 85 RRMS patients were included (72% female, mean age 37.3 years, mean Expanded Disability Status Scale 3.1; 88.2% were pretreated with DMT), and mean treatment duration with natalizumab was 18.4+/-2.6 months. 79% of the patients were relapse-free during the observational period. The annualized relapse rate decreased from 2.0+/-0.6 to 0.27+/-0.2, and 92.9% were progression-free after 12 months (p<0.001). The mean number of gadolinium-enhancing lesions decreased from 1.2+/-1.2 to 0.1+/-0.1 at 12 months' follow-up (91.7% reduction).Discontinuation rate was 11.8% (7.1% for antibody positivity). CONCLUSIONS: Patients who initiate natalizumab after previous high disease activity experience a marked reduction of clinical and MRI disease activity.

Headache in multiple sclerosis.

Pain, including headache, is a frequent complaint of individuals with multiple sclerosis (MS). Prevalence of headache in patients with MS was reported to be higher than 50%, but it is uncertain if this is different than what is seen in the general population. Nonetheless, it is possible that MS and headaches are comorbid. Case reports illustrated that isolated MS lesions (eg, in "strategic" regions like the midbrain) may cause severe headaches often resembling migraine. Furthermore, the role of MS disease-modifying agents needs to be taken into consideration. Mode of action and side effect profiles differ, and treatment per se may sometimes trigger headache in patients with MS. Thorough evaluation of headache in patients with MS is crucial to optimize patient management to help improve quality of life.

Mitoxantrone does not restore the impaired suppressive function of natural regulatory T cells in patients suffering from multiple sclerosis. A longitudinal ex vivo and in vitro study.

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.

Fatigue is not associated with impaired function of regulatory T cells in untreated patients with multiple sclerosis.

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.

Prevalence and severity of multiple-sclerosis-associated fatigue in treated and untreated patients.

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.

Habituation of the auditory startle response in cervical dystonia and Parkinson's disease.

The auditory startle response (ASR) is a brainstem reflex elicited by an unexpected acoustic stimulus. In focal dystonia (FD), the excitability of brainstem neurons is abnormally enhanced. To identify a possible impact of this pathology on the processing of acoustic stimuli, we studied the habituation of the ASR in patients (n = 11) with FD and compared the findings to those of patients with Parkinson's disease (PD; n = 11) and controls (n = 11). Latencies in FD patients did not differ from those of controls but were delayed in PD patients compared to controls (p < 0.0001). Habituation was normal at the orbicularis oculi muscles but reduced at the sternocleidomastoid muscles in FD (p = 0.005). Habituation in PD was comparable to controls. Normal latencies and sequence activation indicate intact neural pathways mediating the ASR in FD. Impaired habituation of the ASR points towards a reduced inhibition of acoustic stimuli in FD.

Relapse Rate and MRI Activity in Young Adult Patients With Multiple Sclerosis: A Post Hoc Analysis of Phase 3 Fingolimod Trials.

BACKGROUND: Disease activity differs in young patients with multiple sclerosis (MS) compared with the overall adult MS population. OBJECTIVE: The objective of this paper is to evaluate the effect of fingolimod 0.5 mg on disease activity in young adults with MS from three randomized, double-blind Phase 3 trials. METHODS: Annualized relapse rate (ARR), number of new/newly enlarging T2 lesions (neT2), and no evidence of disease activity (NEDA-3) were estimated in the intent-to-treat population at age 20 (youngest) and 30 (young) and compared to the overall population. Models used included a negative binomial regression (ARR/neT2) and a logistic regression (NEDA), with age at baseline as a continuous covariate. RESULTS: ARRs were higher in younger patients (all p < 0.05), and significantly reduced with fingolimod versus placebo or interferon beta-1a (IFN ß-1a), with the percentage reduction inversely proportional to age. Fingolimod was significantly associated with a lower number of neT2 lesions versus placebo/IFN in all age groups except versus IFN in the youngest patients. Regardless of age, fingolimod-treated patients were more likely to achieve NEDA-3 versus placebo/IFN ß-1a, with strongest benefits in the youngest patients (all p < 0.05). CONCLUSIONS: Young adults show higher levels of MS disease activity, and may particularly benefit from fingolimod treatment compared with the overall study population.

Brain atrophy and disability worsening in primary progressive multiple sclerosis: insights from the INFORMS study.

Objective: To investigate the relationship between brain volume and disability worsening over ≥3 years in the natural history of primary progressive multiple sclerosis using data from the placebo group of the INFORMS trial (n = 487; clinicaltrials.gov NCT00731692). Methods: Magnetic resonance imaging scans were collected annually. Brain volume loss was determined using SIENA. Patients were stratified by baseline normalized brain volume after adjusting for demographic and disease-burden covariates. Results: Baseline normalized brain volume was predictive of disability worsening: Risk of 3-month confirmed disability progression was reduced by 36% for high versus low baseline normalized brain volume (Cox's model hazard ratio 0.64, P = 0.0339; log-rank test: P = 0.0297). Moreover, on-study brain volume loss was significantly associated with disability worsening (P = 0.012) and was evident in patients with or without new lesions or relapses. Brain volume loss depended significantly on baseline T2 lesion volume (P < 0.0001). Despite low inflammatory activity at baseline (13% of patients had gadolinium-enhancing lesions) and throughout the study (mean 0.5 new/enlarging T2 lesions and 172 mm3 T2 lesion volume increase per year), baseline T2 lesion volume was substantial (mean 10 cm3). Lower normalized brain volume at baseline correlated with higher baseline T2 volume and older age (both P < 0.0001). Interpretation: Baseline brain volume and the rate of ongoing brain atrophy are significantly associated with disability worsening in primary progressive multiple sclerosis. Brain volume loss is significantly related to baseline T2 lesion volume, but partially independent of new lesion activity, which might explain the limited efficacy of anti-inflammatory treatment.

Quality Assessment in Multiple Sclerosis Therapy (QUASIMS): a comparison of interferon beta therapies for relapsing-remitting multiple sclerosis.

Interferon beta (IFN beta) preparations are the most frequently prescribed therapies for patients with relapsing multiple sclerosis (MS). Several open-label observational studies report similar efficacy among IFN beta preparations. The Quality Assessment in Multiple Sclerosis Therapy (QUASIMS) study is a large, open-label observational study designed to compare the effectiveness and tolerability of available IFN beta preparations as disease-modifying therapies for relapsing MS across a wide range of clinical practice settings. This retrospective, controlled cohort study was conducted by chart review at 510 sites in Germany, Austria, and Switzerland. Enrolled patients had received one of the four available IFN beta preparations/dosing regimens (intramuscular IFN beta-1a 30 microg 1x/week [Avonex], subcutaneous (SC) IFN beta-1a 22 or 44 microg 3 x/week [Rebif], or SC IFN beta-1b 250 microg 3.5x/week [Betaferon/Betaseron]) for >or= 2 years. Pre-planned outcomes at 1 and 2 years included change from baseline Expanded Disability Status Scale (EDSS) score, percentage of progression-free patients (< 1.0 EDSS point), annualised relapse rate (RR), percentage of relapse-free patients, and reasons for therapy change. Of 4754 evaluable patients, 3991 (84%) received IFN beta as initial therapy. There were no significant differences among IFN betas when used as initial or follow-up therapy on almost all outcome variables. Relapse rate was consistently higher and percentage of relapse-free patients consistently lower for all products used as follow-up versus initial therapy. Results of QUASIMS showed similar effectiveness among IFN beta products. Benefits were consistently superior when IFN beta was used as initial rather than follow-up therapy. Our results suggest that patients do not benefit in terms of disease outcome from switching between IFN beta preparations/dosing regimens.

A comparison of multiple sclerosis disease activity after discontinuation of fingolimod and placebo.

BACKGROUND: Cases of higher-than-expected disease activity have been reported following fingolimod discontinuation. OBJECTIVE: The objective of this paper is to assess the risk of substantially higher-than-expected disease activity post-study drug discontinuation (SDD) at the individual patient level using data from the Phase III, placebo-controlled FREEDOMS and FREEDOMS II trials. METHODS: Baseline gadolinium-enhancing T1-lesion volumes were used to statistically model the expected level of MRI disease activity post-SDD. Patients exceeding this level were classed as "MRI outliers." Patients with an unusually high increase in Expanded Disability Status Scale score, hospitalization for relapse, severe relapse, or relapse with incomplete recovery post-SDD were classed as "clinical outliers." RESULTS: In FREEDOMS, the number of MRI outliers post-SDD was 2/69 (2.9%), 1/65 (1.5%) and 7/83 (8.4%) for the placebo, fingolimod 0.5 mg, and fingolimod 1.25 mg groups, respectively. In FREEDOMS II, the corresponding numbers were 4/72 (5.6%), 6/79 (7.6%) and 3/73 (4.1%). The number of clinical outliers across both trials was low. No consistent evidence of placebo vs fingolimod, dose-related or inter-trial patterns was discernable. CONCLUSION: The low number of clinical and MRI outliers and lack of any discernible pattern within and between trials, including between placebo and fingolimod, argues against a systematic risk of higher-than-expected recurrence of disease activity following discontinuation of fingolimod.

CD4+CD25+FoxP3+ T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disorder directed against self antigens of the central nervous system. CD4(+)CD25(+)FoxP3(+) regulatory T cell (T(reg)) mediated suppression is an essential mechanism of self-tolerance. We studied whether changes in the suppressive function of a mixture of CD25(high) and CD25(intemediate) expressing T(reg) cells in myelin basic protein (MBP)-induced proliferation occurred in untreated MS patients. Suppression of MBP-induced proliferation was observed in 13 out of 29 (45%) MS patients; this was significantly (p<0.05) less compared with 17 out of 19 (89%) healthy individuals. Relative T(reg) counts was significantly increased in MS patients (mean+/-S.D.; 20+/-8%) compared with healthy individuals (15+/-5%). These findings suggest that impaired T(reg) function may be involved in pathogenesis of MS.

Longitudinal changes in self-reported walking ability in multiple sclerosis.

BACKGROUND: Patient-reported outcomes are increasingly used to understand the clinical meaningfulness of multiple sclerosis disability and its treatments. For example, the 12-item Multiple Sclerosis Walking Scale (MSWS-12) measures the patient-reported impact of the disease on walking ability. OBJECTIVE: We studied longitudinal changes in walking ability using the MSWS-12 in a cohort of 108 patients with relapsing-remitting multiple sclerosis and moderate-to-severe disability from a single US center cohort study investigating multiple sclerosis symptoms and physical activity. METHODS: The MSWS-12 was completed every 6 months over 2 years together with self-reported measures of disease impact on daily life (Multiple Sclerosis Impact Scale) and walking disability (Patient Determined Disease Steps scale). RESULTS: The results revealed a high frequency of self-reported changes in walking ability at the individual level, affecting approximately 80% of patients for all four time periods. MSWS-12 scores remained stable at the group level for all four time periods. The magnitude of observed changes at the individual level was higher than the proposed minimal clinically important differences of 4 or 6 points and correlated better with Multiple Sclerosis Impact Scale physical scores than psychological scores, but little with self-reported Patient Determined Disease Steps Scale scores. CONCLUSIONS: This novel finding of frequent fluctuations in self-reported walking ability is new and requires further investigation.

Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management.

IMPORTANCE: Varicella-zoster virus (VZV) infections increasingly are reported in patients with multiple sclerosis (MS) and constitute an area of significant concern, especially with the advent of more disease-modifying treatments in MS that affect T-cell-mediated immunity. OBJECTIVE: To assess the incidence, risk factors, and clinical characteristics of VZV infections in fingolimod-treated patients and provide recommendations for prevention and management. DESIGN, SETTING, AND PARTICIPANTS: Rates of VZV infections in fingolimod clinical trials are based on pooled data from the completed controlled phases 2 and 3 studies (3916 participants) and ongoing uncontrolled extension phases (3553 participants). Male and female patients aged 18 through 55 years (18-60 years for the phase 2 studies) and diagnosed as having relapsing-remitting MS were eligible to participate in these studies. In the postmarketing setting, reporting rates since 2010 were evaluated. INTERVENTIONS: In clinical trials, patients received fingolimod at a dosage of 0.5 or 1.25 mg/d, interferon beta-1a, or placebo. In the postmarketing setting, all patients received fingolimod, 0.5 mg/d (total exposure of 54,000 patient-years at the time of analysis). MAIN OUTCOMES AND MEASURES: Calculation of the incidence rate of VZV infection per 1000 patient-years was based on the reporting of adverse events in the trials and the postmarketing setting. RESULTS: Overall, in clinical trials, VZV rates of infection were low but higher with fingolimod compared with placebo (11 vs 6 per 1000 patient-years). A similar rate was confirmed in the ongoing extension studies. Rates reported in the postmarketing settings were comparable (7 per 1000 patient-years) and remained stable over time. Disproportionality in reporting herpes zoster infection was higher for patients receiving fingolimod compared with those receiving other disease-modifying treatments (empirical Bayes geometric mean, 2.57 [90% CI, 2.26-2.91]); the proportion of serious herpes zoster infections was not higher than the proportion for other treatments (empirical Bayes geometric mean, 1.88 [90% CI, 0.87-3.70]). Corticosteroid treatment for relapses might be a risk factor for VZV reactivation. CONCLUSIONS AND RELEVANCE: Rates of VZV infections in clinical trials were low with fingolimod, 0.5 mg/d, but higher than in placebo recipients. Rates reported in the postmarketing setting are comparable. We found no sign of risk accumulation with longer exposure. Serious or complicated cases of herpes zoster were uncommon. We recommend establishing the patient's VZV immune status before initiating fingolimod therapy and immunization for patients susceptible to primary VZV infection. Routine antiviral prophylaxis is not needed, but using concomitant pulsed corticosteroid therapy beyond 3 to 5 days requires an individual risk-benefit assessment. Vigilance to identify early VZV symptoms is important to allow timely antiviral treatment.

Effect of functional NMDA-antagonist flupirtine on automatic postural responses in Parkinson's disease.

Animal studies have demonstrated potent antiparkinsonian and other motor effects of the functional NMDA-antagonist flupirtine and suggest a therapeutic use in Parkinson's disease (PD). In healthy subjects flupirtine decreases the functionally destabilizing medium latency (ML) response following toe-up rotations of a moving platform. Because ML responses are known to be increased in PD, this study examined s the effects of flupirtine on postural responses in patients with PD. During 22 days 21 patients with PD took 50 mg, 100 mg flupirtine or placebo following a randomized, double-blind design. Clinical impairment was assessed by means of the Unified Parkinson's Disease Rating Scale (UPDRS). No significant difference between the effect of flupirtine and placebo on ML responses was observed. There was an unspecific improvement of overall UPDRS scores in placebo and flupirtine conditions compared with baseline measures which was more marked in the placebo condition. No improvement in the UPDRS motor subscale was observed. As no beneficial effect on the clinical presentation and no effect on postural responses could be demonstrated, flupirtine does not seem to be a therapeutic option in PD.