COVID-19 vaccination in patients with multiple sclerosis: What we have learnt by February 2021.

BACKGROUND: Since vaccination against coronavirus disease 2019 (COVID-19) became available, risks related to vaccinating patients with multiple sclerosis (MS) need to be carefully assessed. OBJECTIVE: Characterize safety and occurrence of immediate relapses following COVID-19 vaccination in a large cohort of MS patients. METHODS: We assessed the safety of BNT162b2 COVID-19 vaccination in adult MS patients. RESULTS: Between 20 December 2020 and 25 January 2021, 555 MS patients received the first dose of BNT162b2 vaccine and 435 received the second dose. There were three cases of COVID-19 infection encountered after the first dose. Safety profile of COVID-19 vaccine was characterized by pain at the injection site, fatigue, and headache. No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively. The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, similar to the rate in non-vaccinating patients during the corresponding period. Mild increase in the rate of adverse events was noted in younger patients (18-55 years), among patients with lower disability (Expanded Disability Status Scale (EDSS) ⩽3.0), and in patients treated with immunomodulatory drugs. CONCLUSION: COVID-19 BNT162b2 vaccine proved safe for MS patients. No increased risk of relapse activity was noted.

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response.

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement.

Highly active immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced multiple sclerosis.

OBJECTIVE: To evaluate variability and predictability of disability trajectories in moderately advanced and advanced multiple sclerosis (MS), and their modifiability with immunomodulatory therapy. METHODS: The epochs between Expanded Disability Status Scale (EDSS) steps 3-6, 4-6 and 6-6.5 were analysed. Patients with relapse-onset MS and having reached 6-month confirmed baseline EDSS step (3/4/6) were identified in MSBase, a global observational MS cohort study. We used multivariable survival models to examine the impact of disease-modifying therapy, clinical and demographic factors on progression to the outcome EDSS step (6/6.5). Sensitivity analyses with varying outcome definitions and inclusion criteria were conducted. RESULTS: For the EDSS 3-6, 4-6 and 6-6.5 epochs, 1560, 1504 and 1231 patients were identified, respectively. Disability trajectories showed large coefficients of variance prebaseline (0.92-1.11) and postbaseline (2.15-2.50), with no significant correlations. The probability of reaching the outcome step was not associated with prebaseline variables, but was increased by higher relapse rates during each epoch (HRs 1.58-3.07; p<0.001). A greater proportion of each epoch treated with higher efficacy therapies was associated with lower risk of reaching the outcome disability step (HRs 0.72-0.91 per 25%; p≤0.02). 3 sensitivity analyses confirmed these results. CONCLUSIONS: Disease progression during moderately advanced and advanced MS is highly variable and amnesic to prior disease activity. Lower relapse rates and greater time on higher efficacy immunomodulatory therapy after reaching EDSS steps 3, 4 and 6 are associated with a decreased risk of accumulating further disability. Highly effective immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced relapse-onset MS.

Seasonal variation of relapse rate in multiple sclerosis is latitude dependent.

OBJECTIVE: Previous studies assessing seasonal variation of relapse onset in multiple sclerosis have had conflicting results. Small relapse numbers, differing diagnostic criteria, and single region studies limit the generalizability of prior results. The aim of this study was to determine whether there is a temporal variation in onset of relapses in both hemispheres and to determine whether seasonal peak relapse probability varies with latitude. METHODS: The international MSBase Registry was utilized to analyze seasonal relapse onset distribution by hemisphere and latitudinal location. All analyses were weighted for the patient number contributed by each center. A sine regression model was used to model relapse onset and ultraviolet radiation (UVR) seasonality. Linear regression was used to investigate associations of latitude and lag between UVR trough and subsequent relapse peak. RESULTS: A total of 32,762 relapses from 9,811 patients across 30 countries were analyzed. Relapse onset followed an annual cyclical sinusoidal pattern with peaks in early spring and troughs in autumn in both hemispheres. Every 10° of latitude away from the equator was associated with a mean decrease in UVR trough to subsequent relapse peak lag of 28.5 days (95% confidence interval = 3.29-53.71, p = 0.028). INTERPRETATION: We demonstrate for the first time that there is a latitude-dependent relationship between seasonal UVR trough and relapse onset probability peak independent of location-specific UVR levels, with more distal latitude associated with shorter gaps. We confirm prior meta-analyses showing a strong seasonal relapse onset probability variation in the northern hemisphere, and extend this observation to the southern hemisphere.

Comparative effectiveness of glatiramer acetate and interferon beta formulations in relapsing-remitting multiple sclerosis.

BACKGROUND: The results of head-to-head comparisons of injectable immunomodulators (interferon ß, glatiramer acetate) have been inconclusive and a comprehensive analysis of their effectiveness is needed. OBJECTIVE: We aimed to compare, in a real-world setting, relapse and disability outcomes among patients with multiple sclerosis (MS) treated with injectable immunomodulators. METHODS: Pairwise analysis of the international MSBase registry data was conducted using propensity-score matching. The four injectable immunomodulators were compared in six head-to-head analyses of relapse and disability outcomes using paired mixed models or frailty proportional hazards models adjusted for magnetic resonance imaging variables. Sensitivity and power analyses were conducted. RESULTS: Of the 3326 included patients, 345-1199 patients per therapy were matched (median pairwise-censored follow-up was 3.7 years). Propensity matching eliminated >95% of the identified indication bias. Slightly lower relapse incidence was found among patients treated with glatiramer acetate or subcutaneous interferon ß-1a relative to intramuscular interferon ß-1a and interferon ß-1b (p≤0.001). No differences in 12-month confirmed progression of disability were observed. CONCLUSION: Small but statistically significant differences in relapse outcomes exist among the injectable immunomodulators. MSBase is sufficiently powered to identify these differences and reflects practice in tertiary MS centres. While the present study controlled indication, selection and attrition bias, centre-dependent variance in data quality was likely.

Sex as a determinant of relapse incidence and progressive course of multiple sclerosis.

The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10(-12)). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10(-12)). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.

Cladribine treatment for highly active multiple sclerosis: Real-world clinical outcomes for years 3 and 4.

INTRODUCTION: Cladribine is an effective immunomodulatory treatment used for relapsing forms of multiple sclerosis (MS). OBJECTIVES: To describe the clinical outcomes and rates of no evidence of disease activity (NEDA) in patients with highly-active disease treated with 2 years cumulative dose of cladribine, for years 3 and 4. METHODS: We used the Sheba Multiple Sclerosis computerized data registry to retrospectively evaluate year-3 and year-4 clinical outcomes and NEDA-2 rates in highly active RRMS patients who completed the 2-dose 2-year cladribine treatment protocol (3.5 mg/kg cumulative dose over 2 years). The first week of treatment in year 1 was considered as baseline. Data analyses were performed using Python (version 3.0) and SAS® (version 9.4 SAS Institute, Cary, NC). RESULTS: Among 128 patients with highly-active MS that received cladribine treatment, 61 patients, 43 females, were studied for year-3 clinical outcomes, and 35 patients, 23 females, also for year-4. At the initiation of cladribine treatment, the mean ± SD age was 39.6 ± 10.74 years (45.9% of the patients were between 18 and 40 years), disease duration 12.7 ± 9.08 years, Expanded Disability Status Scale (EDSS) 3.7 ± 1.86 (54% had EDSS score > 3.0), and the annual relapse rate was 1.6 ± 0.9. The annual relapse rate decreased to 0.36 in year-3 and was 0.17 in year-4; 68.9% (42/61) of the patients were relapse-free in year-3, and 82.9% (29/35) were relapse-free in year-4. Disability at year-3 was 3.1 ± 2.07; 83.6% (51/61) of the patients remained neurologically stable (33, 54.1%) or improved (18, 29.5%). In year-4, EDSS was 3.2 ± 1.91, and 85.7% (30/35) of the patients remained stable (20, 57.1%) or improved (10, 28.6%). NEDA-2 was achieved for 59.0% (36/61) of patients in year-3, and for 74.3% (26/35) in year-4 of cladribine treatment. CONCLUSIONS: In the real-world cladribine proved to be clinically effective in year-3 and year-4 of treatment in the majority of highly active RRMS patients.

Immune response to the third COVID-19 vaccine dose is related to lymphocyte count in multiple sclerosis patients treated with fingolimod.

BACKGROUND: The majority of multiple sclerosis [MS] patients treated with fingolimod fail to develop a protective level of IgG humoral and adaptive cellular immune responses following full BNT162b2 SARS-CoV-2 vaccination. OBJECTIVE: To compare the efficacy of the third COVID-19 vaccine dose in vaccine non-responders fingolimod-treated MS patients. STUDY DESIGN: This is a prospective 3-month, single-center, randomized clinical trial. METHODS: Twenty relapsing MS patients who had been on fingolimod therapy ≥ 12 months and failed to develop humoral IgG immune response to 2-dose Pfizer BNT162b2 COVID-19 vaccination were randomized into two groups: fingolimod-continuation group and fingolimod-discontinuation group. Humoral and memory cellular immune responses were assessed within 1 and 3 months following the third Pfizer BNT162b2 vaccine dose and compared between the groups. RESULTS: A higher rate of patients in the fingolimod-discontinuation group [n = 8/10] compared to fingolimod-continuation group [n = 2/10] developed positive SARS-COV-2 IgG. Median IgG titer 1 month following the third dose was 202.3 BAU/ml vs. 26.4 BAU/ml, respectively, p = 0.022. The development of IgG humoral response correlated with absolute lymphocyte count. Specific SARS-COV-2 memory B cell and T cell immune responses were not detected in both groups, either at 1 month or 3 months following the third COVID-19 vaccine dose. CONCLUSIONS: Short period of fingolimod treatment discontinuation was associated with the development of humoral protection but not with adaptive cellular immunity.

SARS-CoV-2 memory B and T cell profiles in mild COVID-19 convalescent patients.

OBJECTIVES: Antiviral adaptive immunity involves memory B cells (MBC) and memory T cells (MTC). The dynamics of MBC and MTC in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescents warrant further investigation. METHODS: In this cross-sectional and longitudinal study, blood-derived MBC and MTC responses were evaluated in 68 anti-spike IgG-positive mild coronavirus disease 2019 (COVID-19) convalescents at visit 1, between 1 and 7 months (median 4.1 months) after disease onset. SARS-CoV-2 anti-spike IgG was determined by ELISA, MBC by SARS-CoV-2-specific receptor binding domain (RBD) ELISpot, and interferon gamma (IFN-γ)-, interleukin 2 (IL2)-, and IFN-γ+IL2-secreting MTC by IFN-γ and IL2 SARS-CoV-2 FluoroSpot. For 24 patients sampled at the first visit, the IgG, MBC, and MTC analyses were also performed 3 months later at the second visit. RESULTS: Seventy-two percent of convalescents were both MBC- and MTC-positive, 18% were MBC-positive and MTC-negative, and 10% were MTC-positive and MBC-negative. The peak MBC response level was detected at 3 months after COVID-19 onset and persisted up to 7 months post infection. Significant MTC levels were detected 1 month after onset in response to S1, S2_N, and SNMO peptide pools. The frequency and magnitude of the MTC response to SNMO was higher than those to S1 and S2_N. Longitudinal analysis demonstrated that even when specific humoral immunity declined, the cellular immunity persisted. CONCLUSIONS: The study findings demonstrate the durability of adaptive cellular immunity at least for 7 months after SARS-CoV-2 infection, suggesting long-lasting protection.

COVID-19 vaccination in patients with multiple sclerosis: Safety and humoral efficacy of the third booster dose.

BACKGROUND: As immunity against SARS-COV-2 wanes following first and second doses of vaccination, a third dose is administered in several countries around the world. Similarly to the first doses, risks related to vaccination and humoral immune response in patients with multiple sclerosis (MS) need to be assessed. OBJECTIVE: Characterize safety and humoral immune response following the third dose of COVID-19 vaccination in a large cohort of MS patients. METHODS: We assessed the safety of the third dose of the BNT162b2-COVID-19 mRNA vaccination in adult MS patients and evaluated SARS-CoV-2 IgG response. RESULTS: Two hundred and eleven adult MS patients received a third dose of BNT162b2 COVID-19 vaccination. Median follow up time was 66 days from vaccine administration (IQR 54-84). The frequency of any adverse event was 54.5%, with the most common reported adverse events being fatigue, local pain at the injection site, fever and muscle or joint pain. Transient increase in MS symptoms was reported in 3.8% of patients, none of them requiring treatment. The rate of acute relapses treated with IV steroids was 3.3%. In a sub-group of 55 patients, 20 untreated and 35 treated with vaccination-safe disease-modifying treatments, SARS-CoV-2 IgG levels increased 21-fold (median ± SD 21.6 ± 53.05). CONCLUSIONS: The third dose of COVID-19-BNT162b2 vaccine proved safe for MS patients, with no increased risk of relapse activity. Untreated patients and patients treated with vaccination-safe disease-modifying treatments show significant increase in SARS-CoV-2 IgG levels following the third dose of vaccination.

Humoral immune response in multiple sclerosis patients following PfizerBNT162b2 COVID19 vaccination: Up to 6 months cross-sectional study.

Appropriate immune response following COVID-19 vaccination is important in the context of disease-modifying treatments (DMTs). In a prospective cross-sectional study, we determined SARS-COV-2 IgG response up to 6 months following PfizerBNT162b2 vaccination in 414 multiple sclerosis (MS) patients and 89 healthy subjects. Protective response was demonstrated in untreated MS patients (N = 76, 100%), treated with Cladribine (N = 48, 100%), Dimethyl fumarate (N = 35, 100%), Natalizumab (N = 32, 100%), and Teriflunomide (N = 39, 100%), similarly to healthy subjects (N = 89, 97.8%). Response was decreased in Fingolimod (N = 42, 9.5%), Ocrelizumab (N = 114, 22.8%) and Alemtuzumab (N = 22, 86.4%) treated patients. IgG response can help tailor adequate vaccine guidelines for MS patients under various DMTs.

Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies.

BACKGROUND AND AIMS: The National Multiple Sclerosis Society and other expert organizations recommended that all patients with multiple sclerosis (MS) should be vaccinated against COVID-19. However, the effect of disease-modifying therapies (DMTs) on the efficacy to mount an appropriate immune response is unknown. We aimed to characterize humoral immunity in mRNA-COVID-19 MS vaccinees treated with high-efficacy DMTs. METHODS: We measured SARS-CoV-2 IgG response using anti-spike protein-based serology (EUROIMMUN) in 125 MS patients vaccinated with BNT162b2-COVID-19 vaccine 1 month after the second dose. Patients were either untreated or under treatment with fingolimod, cladribine, or ocrelizumab. A group of healthy subjects similarly vaccinated served as control. The percent of subjects that developed protective antibodies, the titer, and the time from the last dosing were evaluated. RESULTS: Protective humoral immunity of 97.9%, 100%, 100%, 22.7%, and 3.8%, was observed in COVID-19 vaccinated healthy subjects (N = 47), untreated MS patients (N = 32), and MS patients treated with cladribine (N = 23), ocrelizumab (N = 44), and fingolimod (N = 26), respectively. SARS-CoV-2 IgG antibody titer was high in healthy subjects, untreated MS patients, and MS patients under cladribine treatment, within 29.5-55 days after the second vaccine dose. Only 22.7% of patients treated with ocrelizumab developed humoral IgG response irrespective to normal absolute lymphocyte count. Most fingolimod-treated MS patients had very low lymphocyte count and failed to develop SARS-COV-2 antibodies. Age, disease duration, and time from the last dosing did not affect humoral response to COVID-19 vaccination. CONCLUSIONS: Cladribine treatment does not impair humoral response to COVID-19 vaccination. We recommend postponing ocrelizumab treatment in MS patients willing to be vaccinated as a protective humoral response can be expected only in some. We do not recommend vaccinating MS patients treated with fingolimod as a protective humoral response is not expected.

Cognitive dysfunction evaluation in multiple sclerosis patients treated with interferon beta-1b: an open-label prospective 1 year study.

BACKGROUND: The cognitive impairment (frontal, parietal) in many patients with multiple sclerosis does not correlate with the degree of neurological disability and disease duration. Frontal/prefrontal cognitive impairment requires neuropsychological diagnostic tools. OBJECTIVES: To evaluate the clinical effect of IFNbeta-1b (Betaferon) treatment on cognitive function and event-related potential as compared to the clinical course (EDSS) in MS patients during 1 year of follow-up. METHODS: This prospective open-label design study included 16 consecutive patients with relapsing forms of MS attending the MS outpatient clinic. Mean EDSS score was calculated prior to starting treatment. Parietal lobe event-related potential P300 was elicited using an auditory physical stimulus to an alert subject. Mean P300 amplitude and latency were calculated for the group before treatment. The Wisconsin Card Sorting Test, which measures frontal lobe functions, was performed before the treatment. After 1 year of treatment a second P300 and Wisconsin test were performed and the mean change between visit 1 and baseline was calculated for each parameter. Correlation between the change in P300 and the Wisconsin test score at baseline was measured using the paired t-test. RESULTS: There was a significant reduction in P300 amplitude and latency after 1 year of treatment with IFNbeta-1b: from 20.3 +/- 8.3 microv to 13.1 +/- 10.6 microv (P = 0.026) for amplitude, and from 312.9 +/- 15.6 msec to 302.0 +/- 17.0 msec (P = 0.002) for latency. The Perseverative Response (raw score) and the Perseverative Response U.S. Census age-matched standard score showed a significant improvement--from 20.7 +/- 30.7 to 13.1 +/- 10.6 (P = 0.001) and 96.7 +/- 15.7 to 100.1 +/- 11.1 (P = 0.0025) respectively--after 1 year of treatment. A mild but not significant improvement was observed on the EDSS after 1 year of treatment: 2.9 +/- 0.5 to 2.8 +/- 1.1. CONCLUSIONS: A cognitive decline in MS patients may have a negative impact on the quality of life, affecting all active daily living domains. IFNbeta-1b, a disease-modifying therapy, has demonstrated a positive therapeutic effect on cognitive dysfunction, unrelated to its effect on the EDSS score and course of the disease.

Approach to benign paroxysmal positional vertigo in old age.

BACKGROUND: Benign paroxysmal positional vertigo is a common and treatable vestibular disorder characterized by attacks of positional vertigo. Although elderly patients often complain about unsteadiness, the symptom of positional vertigo is seldom reported. Several studies on BPPV in the elderly reveal a low success rate in the treatment of this entity. OBJECTIVES: To assess the clinical characteristics and treatment outcome of BPPV in elderly patients and to compare them with those of the general population treated at our dizziness clinic. METHODS: We reviewed the medical records of 23 patients above age 75 who were treated at our dizziness clinic for BPPV during the years 1998-2004. Their clinical data, BPPV characteristics and treatment outcome were compared with the data of 30 consecutive BPPV patients who represented the general population. RESULTS: No differences in gender distribution, duration of BPPV, treatment responsiveness or recurrence rate were found between elderly patients as compared to the general population. The duration of the last attack of positional vertigo was found to be longer in the elderly, probably due to the delay in recognition of symptoms and accessibility of a dizziness clinic. CONCLUSIONS: Our study shows that BPPV characteristics and treatment effectiveness, as measured by negative Dix-Hallpike maneuver, are not age-dependent and there is no need for a special approach or cautiousness in prognosis prediction. It is important to search actively for this condition since treatment leads to amelioration of unsteadiness and improved well-being in these patients.

The effect of additional ankle and midfoot mobilizations on plantar fasciitis: a randomized controlled trial.

STUDY DESIGN: A single-blind randomized controlled trial. OBJECTIVE: To evaluate the efficacy of ankle and midfoot mobilization on pain and function of patients with plantar fasciitis (PF). BACKGROUND: Plantar fasciitis is a degenerative process of the plantar fascia, with a lifetime prevalence of approximately 10%. Limited ankle dorsiflexion is a common finding and apparently acts as a contributing factor to the development of PF. METHODS: Fifty patients with PF, aged 23 to 73 years, were randomly assigned to either the intervention or control group. Both groups received 8 treatments, twice a week, consisting of stretching exercises and ultrasound. In addition, the intervention group received mobilization of the ankle and midfoot joints. Dorsiflexion range of motion was measured at the beginning and at the end of treatment. The results were evaluated by 3 outcomes: the numeric pain-rating scale, Lower Extremity Functional Scale, and algometry. RESULTS: No significant difference was found between groups in any of the outcomes. Both groups showed a significant difference in the numeric pain-rating scale and Lower Extremity Functional Scale. Both groups significantly improved in dorsiflexion range of motion, with no difference between groups. CONCLUSION: The addition of ankle and foot joint mobilization aimed at improving dorsiflexion range of motion is not more effective than stretching and ultrasound alone in treating PF. The association between limited ankle dorsiflexion and PF is most probably due to soft tissue limitations, not the joints. Trial registered at ClinicalTrials.gov (registration number NCT01439932). LEVEL OF EVIDENCE: Therapy, level 1b.

Copolymer 1 (glatiramer acetate) in relapsing forms of multiple sclerosis: open multicenter study of alternate-day administration.

Daily 20-mg doses of Copolymer 1 have been shown to significantly decrease the relapse rate in patients with multiple sclerosis (MS). In the present open-label study, patients with relapsing MS were treated with the same dose of Copolymer 1 administered on alternate days. Sixty-eight patients were recruited: fifty-one and forty-one patients completed 1 and 2 years of treatment respectively. The relapse rate during the 2 years of treatment decreased by 80.8% compared with the 2 years before treatment (means, 0.56 +/- 1.02 versus 2.91 +/- 1.10, respectively; p < 0.0001). This lower rate is comparable with that obtained with daily open-label administration previously reported by the authors. The score on the Expanded Disability Status Scale did not differ from that at baseline after the first year of treatment, although it increased somewhat at the end of the second year (baseline = 2.72 +/- 1.55, 1 year = 2.71 +/- 1.59, 2 years = 2.97 +/- 1.80; p < 0.008). The drug was very well tolerated. This preliminary open-label study suggests that alternate-day therapy has beneficial effects and is well tolerated, comparing favorably with the effects of daily injections of Copolymer 1 in patients with relapsing MS. These results should be confirmed by randomized double-blind examinations.

Phobic postural vertigo: a new proposed entity.

BACKGROUND: Dizziness and vertigo can be a complaint in various psychiatric conditions where it usually constitutes only one of the features of the syndrome. Lately, a somatoform disorder characterized by almost mono-symptomatic dizziness and unsteadiness has been described. Since phobic postural vertigo usually presents without anxiety or other psychological symptomatology, patients with this condition seek help at neurologic and otolaryngologic clinics where they are often misdiagnosed as suffering from organic vertigo. OBJECTIVES: To present the clinical features of 55 consecutive patients diagnosed with phobic postural vertigo at our clinic during 1998-2002. METHODS: We conducted a retrospective review of patients' medical records and report two typical cases for illustration. RESULTS: The patients presented with complaints of unsteadiness with or without dizziness, and attacks of sudden veering that caused them to grasp for support. Accompanying anxiety was admitted by only 5% and vegetative symptoms were reported in 18%. In 16% the symptoms resulted in avoidance behavior. A stressful life event or an unrelated somatic disease triggered the onset of PPV in 35% of patients, whereas a vestibular insult preceded the symptoms in 13%. The mean duration of symptoms was 26.7 +/- 39.1 months (range 0.5-20 years). In 72% of patients the symptoms resolved after the psychological mechanism of their symptoms was explained to them; 24% improved with antidepressant treatment (selective serotonin reuptake inhibitors or tricyclic antidepressants), and only in 4% did the symptoms persist. CONCLUSIONS: Since PPV is a frequently encountered diagnosis at some specialized dizziness clinics, familiarity with this entity resulting in early diagnosis can avoid unnecessary examinations and lead to effective treatment.

Influence of histocompatibility genes on disease susceptibility and treatment response in patients with relapsing-remitting multiple sclerosis treated with interferon ß-1a.

Multiple sclerosis (MS) is the most common, non-traumatic cause of neurological disability in young adults. The aim of this study was to investigate the influence of HLA class II alleles DRB1* and DQB1* on susceptibility to relapsing-remitting (RR) MS and response to interferon (IFN) ß-1a treatment. A prospective observational study was conducted. Seventeen patients with clinically definite RRMS, attending a tertiary referral center for multiple sclerosis in Israel and receiving treatment with subcutaneous IFN ß-1a, 22 mcg three times weekly were recruited between December 1998 and February 2000 and observed for 12 months. HLA genotyping was performed and clinical characteristics (relapse rate and disability progression) assessed at baseline and after 12 months. HLA data for a healthy control group were also used for comparison. HLA and the success of treatment with IFN ß-1a in this group of RRMS patients were assessed. The frequency of DRB1*03 was six times higher in patients treated with IFN ß-1a than in the healthy control group (n=100): 29% (5/17) versus 5% (5/100), respectively. Additionally, DQB1*03 and DQB1*02 were present in 82% (14/17) and 41% (7/17) of RRMS patients, but in only 33% (33/100) and 18% (18/100) of control patients, respectively. A better response to IFN ß-1a treatment was seen in patients carrying these alleles than in patients without these alleles. Our results indicated that DRB1*03, DQB1*03 and DQB1*02 alleles may contribute to MS susceptibility and IFN ß-1a responsiveness, and warrant further verification in a larger population.

Approach to bilateral benign paroxysmal positioning vertigo.

BACKGROUND: Bilateral benign paroxysmal positioning vertigo (bBPPV) is rather rare, accounting for up to 10% in the reported benign paroxysmal positioning vertigo (BPPV) series. Inappropriate head positioning during testing in unilateral BPPV causes the otolith debris in the uppermost ear to move toward the cupula, resulting in an inhibitory nystagmus and mimicking bBPPV. PURPOSE: We analyzed the clinical data of patients with bilaterally positive Dix-Hallpike maneuver and compared them with the characteristics of patients with unilateral BPPV. We further tried to propose a simple schematic approach to the treatment of patients with bilaterally positive Dix-Hallpike maneuver. MATERIALS AND METHODS: Medical records of 232 patients treated for BPPV at our dizziness clinic during 1999 to 2003 were reviewed. An algorithm used for the treatment of patients with bilaterally positive BPPV is discussed. RESULTS: Twenty-eight patients with bilaterally positive Dix-Hallpike test were found. Sixteen were diagnosed with bBPPV, and 12 were diagnosed with unilateral mimicking bBPPV. Thirty patients with unilateral posterior canal BPPV served as control subjects. No difference in age, sex distribution, duration of symptoms, number of treatments per ear, and recurrence was found between bBPPV and unilateral BPPV. The female sex appeared to be predisposed for more treatments. The total duration of BPPV symptoms obtained by history was found to correlate with the number of recurrences after treatment. CONCLUSIONS: We conclude that bBPPV can be readily distinguished from unilateral mimicking bBPPV. Patients with bBPPV do not differ from patients with unilateral BPPV in clinical characteristics. The mechanism of otolith debris dislodgment appears to be the main cause of bilaterality, trauma being a more common trigger than other known causes of BPPV.