Long-term endurance exercise improves aerobic capacity in patients with relapsing–remitting Multiple Sclerosis: Impact of baseline fatigue

Little is known about the sustainability of exercise effects in patients with relapsing–remitting Multiple Sclerosis (RRMS). We present the results of a prospective, observer-blinded, single-center case control study using a “pre–post” design including 89 ambulatory patients with RRMS and an EDSS score of ≤ 3.5 who participated in an individualized 12 month aerobic endurance exercise program.Peak oxygen consumption (VO₂ peak) increased and fatigue levels decreased significantly over time (p = 0.03, p < 0.02). Subgroup analysis of patients with fatigue (FSS > 4) revealed that the increase of VO₂ peak remained significant after 12 months whereas patients without fatigue did not improve any further after six months. A significant decrease of the FSS score was only observed after nine months (p < 0.03) In conclusion, aerobic exercise leads to a sustainable improvement of VO₂ peak over an extended exercise period of 12 months. There is a weak, but significant effect on fatigue levels which becomes detectable only after nine months. Since subgroup analysis revealed that MS patients behaved differently according to their baseline fatigue levels, adjustment to the individual fatigue levels is recommended for future exercise interventions in RRMS patients.     

Assessment of cardiorespiratory and neuromotor fitness in children with developmental coordination disorder

The decreased participation in physical activity by children with probable developmental coordination disorder (pDCD) has raised concerns about their aerobic fitness and lung function levels. The purpose of the present study was to examine assessment of cardiorespiratory and neuromotor fitness, using laboratory-based tests during an incremental treadmill protocol in healthy children with and without pDCD. Twenty sex children ages 6–9 years took part in this study. Motor coordination was assessed using the Movement Assessment Battery for Children (MABC). All participants performed a cardiopulmonary exercise test (CPET) on a cycle ergometer. Pulmonary function was assessed by spirometric measurements (forced vital capacity: FVC, forced expiratory volume in 1 s: FEV₁) and walking distance (6MWD) was assessed using the 6-min walking test. The children with pDCD had lower VO_2 max than children without pDCD (p < 0.01). Moreover, FVC and FEV₁ were significantly higher in children without pDCD than in children with the disorder (p < 0.05, p < 0.01 respectively). Likewise, children with pDCD had poorer performance on the 6MWD than children without pDCD (p < 0.01). A significant correlation between the absolute value for FEV₁ and 6MWD (r = 0.637, p < 0.05) in pDCD group was observed. We found a significant correlation between VO_2 max and MABC score (r = −0.612, p < .001) and between VO_2 max and 6MWD (r = 0.502, p < .001) for all children. Moreover, a significant correlation between VO_2 max and FEV₁ (r = 0.668, p < .05) was found in children with pDCD. Overall, the reduced aerobic capacity of DCD was associated with decreased of lung function, as well as an alteration of peripheral muscle responses.     

Heart rate recovery and variability following combined aerobic and resistance exercise training in adults with and without Down syndrome

Persons with Down syndrome (DS) are at high risk for cardiovascular morbidity and mortality, and there is compelling evidence of autonomic dysfunction in these individuals. The main purpose of this study was to determine whether a combined aerobic and resistance exercise intervention produces similar results in cardiac autonomic function between adults with and without DS. Twenty-five participants (13 DS; 12 non-DS), aged 27–50 years, were included. Aerobic training was performed 3 days/week for 30 min at 65–85% of peak oxygen uptake (VO_2peak). Resistance training was prescribed for 2 days/week and consisted of two rotations in a circuit of 9 exercises at 12-repetition-maximum. There was a significant improvement in the VO_2peak and muscle strength of participants with and without DS after training. Heart rate recovery improved at 1 min post-exercise, but only in participants with DS. Both groups of participants exhibited a similar increase in normalized high frequency power and of decrease in normalized low frequency power after training. Therefore, 12 weeks of exercise training enhanced the heart rate recovery in adults with DS, but not in those without DS. Contrasting, the intervention elicited similar gains between groups for cardiovagal modulation.     

Submaximal oxygen cost during incremental exercise in children with developmental coordination disorder

There has been minimal evidence examining the differences in submaximal aerobic power between children with and without probable developmental coordination disorder (pDCD). This is important as most activities of daily living are performed at submaximal levels. The aim of this study was to examine the oxygen cost of work (VO₂) performed during an incremental exercise protocol on a cycle ergometer. Subjects with pDCD (n = 63) were matched for age and gender to 63 typically developing controls (12–13 years of age) using a nested case–control design. Motor coordination was assessed using the Movement Assessment Battery for Children. Children with pDCD had significantly lower VO2 peak values relative to controls (35.0 vs. 42.9 ml/kg/min, p < 0.0001). At the submaximal level, mixed effects modeling demonstrated that, after controlling for relative body fat, and VO₂ peak, children with pDCD had consistently greater oxygen cost (VO₂ ml/kg/min) compared to controls at any given exercise intensity (p = 0.0006). A significant interaction between pDCD and workload indicated that the difference in VO₂ at higher workloads is greater than that at lower workloads (p = 0.0004). Children with pDCD utilize more oxygen to sustain the same submaximal workload. The implication of these findings is that children with pDCD may experience earlier fatigue than well coordinated individuals when engaging in physical activity.     

Arterial stiffness response to exercise in persons with and without Down syndrome

This study compared arterial stiffness and wave reflection at rest and following maximal exercise between individuals with and without Down syndrome (DS), and the influence of body mass index (BMI), peak oxygen uptake (VO₂peak) on changes in arterial stiffness. Twelve people with DS (26.6 ± 2.6 yr) and 15 healthy controls (26.2 ± 0.6 yr) completed this study. Intima-media thickness (IMT) and stiffness of common carotid artery was examined. Hemodynamic and arterial variables were measured before and 3-min after exercise. Persons with DS had higher BMI and lower VO₂peak than controls. IMT did not differ between groups. At rest, carotid β stiffness was significantly higher in persons with DS (P < 0.05) but there was no difference in between groups for any of the other arterial stiffness measures. After exercise, persons with DS exhibited attenuated arterial stiffness responses in AIx-75, carotid β stiffness and Ep in contrast with controls (significant group-by-time interactions). When controlling for BMI and VO₂peak, the interactions disappeared. In both groups combined, BMI was correlated significantly with carotid Ep and β at rest. VO₂peak correlated significantly with AIx-75 and its pre-post change (r = ?0.45, P = 0.029; r = 0.47, P = 0.033, respectively). The arterial stiffness responses to maximal exercise in persons with DS were blunted, potentially reflecting diminished vascular reserve. Obesity and particularly VO₂peak influenced these findings. These results suggest impaired vascular function in people with DS.     

A randomized,double-blind, 6-week,dose-ranging study of pregabalin in patients with restless legs syndrome

ObjectiveThis study evaluated the dose-related efficacy and safety of pregabalin in patients with idiopathic restless legs syndrome (RLS).MethodsThis six-arm, double-blind, placebo-controlled, dose–response study randomized patients (N = 137) with moderate-to-severe idiopathic RLS in an equal ratio to placebo or pregabalin 50, 100, 150, 300, or 450 mg/day. The dose–response was characterized using an exponential decay model, which estimates the maximal effect (E_max) for the primary endpoint, the change in the International Restless Legs Study Group Rating Scale (IRLS) total score from baseline to week 6 of treatment. Secondary outcomes included Clinical Global Impressions-Improvement Scale (CGI-I) responders, sleep assessments, and safety.ResultsThe separation of treatment effect between placebo and pregabalin began to emerge starting at week 1 which continued and increased through week 6 for all dose groups. The IRLS total score for pregabalin was dose dependent and well characterized for change from baseline at week 6. The model estimated 50% (ED₅₀) and 90% (ED₉₀) of the maximal effect in reducing RLS symptoms that occurred at pregabalin doses of 37.3 and 123.9 mg/day, respectively. A higher proportion of CGI-I responders was observed at the two highest doses of pregabalin (300 and 450 mg/day) versus placebo. Dizziness and somnolence were the most common adverse events and appeared to be dose-related.ConclusionsIn this 6-week phase 2b study, pregabalin reduced RLS symptoms in patients with moderate-to-severe idiopathic RLS. The symptom reduction at week 6 was dose-dependent with 123.9 mg/day providing 90% efficacy. Pregabalin was safe and well tolerated across the entire dosing range.     

Depression and recovery of reflex amplitude during electrical stimulation after spinal cord injury

ObjectiveThe aim of this study was to quantify, for the first time, H-reflexes evoked during prolonged trains of wide-pulse neuromuscular electrical stimulation (WP-NMES) in individuals with chronic spinal cord injury (SCI). We hypothesised that after the first H-reflex, reflex amplitudes would be depressed (due to post-activation depression), but would recover and this recovery would be enhanced after a “burst” of 100 Hz WP-NMES.MethodsSoleus M-waves and H-reflexes evoked during WP-NMES (1 ms pulse width) of the tibial nerve were quantified in nine individuals with SCI. WP-NMES was delivered in two patterns: “constant-frequency” (15 or 20 Hz for 12 s) and “burst-like” (15-100-15 Hz or 20-100-20 Hz; 4 s each phase) at an intensity that evoked an M-wave between 10% and 15% of the maximal M-wave (M_max).ResultsDuring constant frequency stimulation, after the initial depression from the first to the second H-reflex (1st: 57% M_max; 2nd: 25% M_max), H-reflexes did not recover significantly and were 37% M_max at the end of the stimulus train. During the burst-like pattern, after the initial depression (1st: 62% M_max; 2nd: 30%), reflexes recovered completely by the end of the stimulation (to 55% M_max) as they were not significantly different from the first H-reflex. M-waves were initially depressed (1st: 12% M_max; 2nd: 7% M_max) then did not change throughout the stimulation and were not significantly different between stimulation patterns. An analysis of covariance indicated that the depression in M-wave amplitude did not account for the depression in H-reflex amplitude.ConclusionsRelatively large H-reflexes were recorded during both patterns of NMES. The brief burst of 100 Hz stimulation restored H-reflexes to their initial amplitudes, effectively reversing the effects of post-activation depression.SignificanceFor individuals with chronic SCI, generating contractions through central pathways may help reduce muscle atrophy and produce contractions that are more fatigue-resistant for rehabilitation, exercise programs, or to perform activities of daily living.     

Reliability and validity of the 6-min walk test in adults and seniors with intellectual disabilities

IntroductionAdults with intellectual disabilities (ID) have significantly lower rates of physical activity and fitness than adults without ID. The 6-min walk test (6MWT) is an inexpensive and simple way to test mobility and submaximal work capacity.PurposeTo evaluate the test–retest reliability and validity of the 6MWT in adults and seniors with ID and explore factors contributing to the 6MWT distance (6MWD).Methods46 participants with mild, moderate and severe ID levels (age = 41 ± 11 years) performed the 6MWT three times (T1; T2; T3) to determine test–retest reliability. To test validity, peak oxygen uptake (VO₂ peak) was measured using a treadmill protocol. To analyze factors contributing to the 6MWD, sex, height, fat mass % and fat free mass %, ID level, isometric leg strength and relative VO₂ peak were also measured.ResultsThe walking distances for T1, T2 and T3 were 460.3 ± 76.9; 489.4 ± 81.2 and 491.4 ± 77.9 m, respectively. The 6MWDs between T1–T2 and T1–T3 were significantly different (p < 0.001), but T2 and T3 were not different. The intraclass correlation coefficient between T2 and T3 was 0.96 indicating high reliability. Relative VO₂ peak and isometric leg strength significantly contributed to the 6MWD (R² = 0.55).ConclusionsThe 6MWT is an easy, inexpensive, reliable and valid test in adults and seniors with ID. Familiarization is necessary to obtain reliable values. Relative VO₂ peak and leg strength have significant impact on the distance walked.     

Influence of repeated maximal exercise testing on biomarkers and fatigue in sarcoidosis

Fatigue in the immune mediated inflammatory disease sarcoidosis is thought to be associated with impaired exercise tolerance. This prospective study assessed fatigue and recuperative capacity after repeated exercise, and examined whether changing concentrations in biomarkers upon exercise are associated with fatigue.Twenty sarcoidosis patients and 10 healthy volunteers performed maximal cardiopulmonary exercise tests on two successive days. Concentrations of cytokines, stress hormones, ACE and CK were assessed before and after the two exercise tests, and 3 days thereafter. All participants completed a sleep diary.Severely fatigued patients showed significant lower VO₂ max (p = 0.038, p = 0.022) and maximal workload (p = 0.034, p = 0.028) on both exercise tests compared to healthy controls. No impairment of maximal exercise testing was demonstrated during the second cycling test in any group. Fatigue was not correlated with changes in concentrations of biomarkers upon exercise. Severely fatigued patients rated both tests as significantly more fatiguing, and reported significant lower mean subjective night sleeping time during the testing period.Fatigue in sarcoidosis patients cannot be objectified by reduction of exercise capacity after repeated maximal exercise testing, and is not correlated with significant changes in biomarkers. Severe fatigue is only and consistently featured by patient reported outcomes.     

Functional remission and employment among patients with schizophrenia in Malaysia

ObjectiveThe study aimed to determine the rates of functional remission and employment as well as the factors associated with functional remission among patients with Schizophrenia, receiving community psychiatric service in an urban setting in Malaysia.MethodsFrom a total of 250 patients randomly selected, 155 fulfilled the study requirement and were assessed on their functional remission status using the Personal and Social Performance Scale. The relationships between functional remission and socio-demographic factors, clinical factors, social support, symptom remission and rates of hospitalization were examined.ResultsThe results revealed that 74% (n = 115) of the respondents had functional remission with only 20% (n = 31) currently employed. Functional remission was found to be significantly associated with good social support (84.4% versus 36.4% p < 0.001, OR = 9.487 [95% CI = 4.008–22.457]); shorter illness duration of less than 10 years (81.2% versus 66.7% p = 0.038, OR = 2.167 [95% CI = 1.035–4.535]); good medication compliance (79.1% versus 50.0% p = 0.002, OR = 3.778 [95% CI = 1.570–9.090]); hospital admissions of lower than 3 per year (80.5% versus 44.4% p < 0.001 OR = 5.150 [95% CI = 2.145–12.365]) and; symptomatic remission (87.3% versus 37.4% p < 0.001 [95% CI = 0.070 (0.029–0.168]). A multiple regression analysis revealed only social support, lower hospitalization rate and symptom remission, as significant predictors of functional remission.ConclusionA majority of patients with Schizophrenia in this study achieved functional remission, however, only a small percentage of them were employed. Functional remission was influenced by severity of illness and levels of social support in these patients.     

Immune and inflammation responses to a 3-day period of intensified running versus cycling

Functional overreaching has been linked to alterations in immunity and host pathogen defense, but little is known as to whether or not running and cycling evoke different responses. This study compared inflammation, muscle damage and soreness, and innate immune function responses to a 3-day period of intensified exercise in trained long distance runners (N = 13, age 34.4 ± 2.4 year) and cyclists (N = 22, age 36.6 ± 1.7 year, P = 0.452). Upper respiratory tract infection (URTI) symptomatology was monitored for 12 weeks using the Wisconsin Upper Respiratory Symptom Survey (WURSS), and subjects from both athletic groups came to the lab during week five and exercised 2.5 h/day for 3 days in a row at 70% VO_2max. Blood samples were collected before and after the 3-day period of exercise, with recovery samples collected 1-, 14-, and 38 h-post-exercise. Samples were analyzed for muscle damage [creatine kinase (CK), myoglobin (MYO)], inflammation (CRP, IL-6, IL-8, IL-10, MCP), and innate immunity [granulocyte and monocyte phagocytosis (GR-PHAG and MO-PHAG) and oxidative burst activity (GR-OBA and MO-OBA)]. Runners compared to cyclists experienced significantly more muscle damage (CK 133% and MYO 404% higher post-3 days exercise), inflammation (CRP 87%, IL-6 256%, IL 8 61%, IL-10 32%, MCP 29%), and delayed onset of muscle soreness (DOMS, 87%). The 3-day period of exercise caused significant downturns in GR-PHAG, MO-PHAG, GR-OBA, MO-OBA by 14- and 38 h-recovery, but the pattern of change did not differ between groups. No group differences were measured for 12-week URTI severity (18.3 ± 5.6 and 16.6 ± 4.0, P = 0.803) and symptom scores (33.4 ± 12.6 and 24.7 ± 5.8, P = 0.477). These data indicate that a 3-day period of functional overreaching results in substantially more muscle damage and soreness, and systemic inflammation in runners compared to cyclists, but without group differences for 12-week URTI symptomatology and post-exercise decrements in innate immune function.     

Comparison of VO2 maximum obtained from 20 m shuttle run and cycle ergometer in children with and without developmental coordination disorder

Oxygen consumption at peak physical exertion (VO₂ maximum) is the most widely used indicator of cardiorespiratory fitness. The purpose of this study was to compare two protocols for its estimation, cycle ergometer testing and the 20 m shuttle run, among children with and without probable developmental coordination disorder (pDCD).The shuttle run test was conducted during regular school hours, usually in the gymnasium. Children were then invited to a lab to complete the cycle ergometer protocol. Children were categorized as possible cases of DCD using the Movement-ABC-2. The analysis was performed using cut-points at both the 5th (n = 38) and 15th (n = 51) percentiles. The average age of children in the study was 12 years (SD = 0.5). Children with pDCD had poorer VO₂ maximum when compared to typically developing children based on both the shuttle run and the cycle ergometer. The correlation between tests is in the moderate to high range (r = 0.71, p < 0.001); 0.78 for girls, and 0.73 for boys. The overall difference in correlations between typically developing children and children with pDCD based on the 15th percentile was 0.12 (p = 0.27). For children with pDCD based on the 5th percentile however, the difference between groups was larger (difference in r = 0.25), and was statistically significant (p = 0.02). In multivariate analyses, there was no difference in the effect of the shuttle run results in predicting VO₂ maximum obtained through the cycle ergometer test for children with pDCD compared to those without the condition. Regardless of the test, the patterns of association between children with pDCD and typically developing children were the same reinforcing the findings of previous field-based reports. Moderate to good correlations, at the 15th percentile cut-point, between tests suggests that the shuttle run test is a reliable substitute in this population when lab based assessments of VO₂ maximum are not feasible.     

Long-term efficacy and limitations of cyclophosphamide in myasthenia gravis

Myasthenia gravis (MG) is a chronic autoimmune disorder with a fluctuating clinical course. The aim of immunotherapy is to bring about long-term remission. We evaluated the safety and efficacy of cyclophosphamide in generalized MG. We also highlight the limitations of cyclophosphamide therapy in inducing long-term remission. Data from 22 patients with generalized MG who received cyclophosphamide therapy were analyzed in terms of its safety and outcome. Twelve patients completed at least six pulses of intravenous cyclophosphamide therapy, and all improved symptomatically at 6 months. At 1 year, only seven patients reported sustained benefit and five had discontinued oral pyridostigmine. During a follow-up period of 56.67 months, all but one patient relapsed and required alternative immunomodulatory therapy. The average time to remission after the initiation of intravenous pulse cyclophosphamide (n = 12) was 3.6 months (standard deviation [SD] 1.6 months, range 1–6 months), while the mean duration of remission was 20.3 months (SD 8.8 months, range 12–39 months). Forty-six adverse events were documented in 11 patients over 127 cyclophosphamide pulses. Most of the adverse events were managed symptomatically. In four patients, cyclophosphamide had to be discontinued due to adverse events. Intravenous pulse cyclophosphamide is effective in the management of MG; however remission may be short, necessitating long-term follow-up and alternative immunomodulation. Careful monitoring for adverse events should be mandatory.     

Anti-gravity training improves walking capacity and postural balance in patients with muscular dystrophy

Recent studies in patients with muscular dystrophies suggest positive effects of aerobic and strength training. These studies focused training on using bicycle ergometers and conventional strength training, which precludes more severely affected patients from participating, because of their weakness. We investigated the functional effects of combined aerobic and strength training in patients with Becker and limb-girdle muscular dystrophies with knee muscle strength levels as low as 3% of normal strength.Eight patients performed 10 weeks of aerobic and strength training on an anti-gravity treadmill, which offered weight support up to 80% of their body weight. Six minute walking distance, dynamic postural balance, and plasma creatine kinase were assessed 10 weeks prior to training, immediately before training and after 10 weeks of training. Training elicited an improvement of walking distance by 8 ± 2% and dynamic postural balance by 13 ± 4%, indicating an improved physical function. Plasma creatine kinase remained unchanged. These results provide evidence that a combination of aerobic and strength training during anti-gravity has the potential to safely improve functional ability in severely affected patients with Becker and limb-girdle muscular dystrophies.     

Lamotrigine serum levels: Ceiling effect in people with epilepsy in remission?

BackgroundAntiepileptic drug titration in epilepsy remains mostly empirical. Since in practice seizure remission may be obtained with low doses, we aimed to determine whether patients in remission have lower lamotrigine levels than those with ongoing seizures.MethodsRetrospective comparison of the distribution of lamotrigine levels among unselected patients in remission and with ongoing seizures. Remission was defined as 3 times the longuest interseizure interval and at least one year. Only trough levels were analyzed.ResultsBetween 2009 and 2014, we identified 93 adults, among whom 10 were in remission. Patients in remission had significantly (p = 0.008) lower serum levels (median 2.3 mg/L, range: 0.7–8.2) than those with ongoing seizures (median 5.4 mg/L, range: 1.1–18.2). We did not find any patient in remission with levels higher than 8.2 mg/L. Distribution of dosages also differed among the groups, but less significantly (median: 175 vs 300 mg, p = 0.03).ConclusionAn association between lamotrigine serum levels and seizure response can be observed. This suggests the existence of a ceiling level, above which remission is unlikely and should prompt antiepileptic medication switch rather than further up-titration of lamotrigine in drug-naïve patients with epilepsy.     

Comparison between MRI-derived ADC maps and 18FLT-PET in pre-operative glioblastoma

Background and purposeAmong principal MRI sequences used for a better pre-therapeutic characterization of glioblastoma (GBM), DWI-derived ADC is expected to be a good parameter for the evaluation of cellularity, due to restricted water diffusivity. We aimed here to compare ADC maps to ¹⁸FLT-PET, a proliferation tracer, in GBM cases.Materials and methodsPatients underwent ¹⁸FLT-PET, followed by multiparametric magnetic resonance imaging (MRI) just prior to surgery. We analysed in this study twenty GBM confirmed patients. The 5th percentile (5p) of the ADC values were thresholded to define the ADC_min ROI, while the 95th percentile (95p) of the SUV FLT values were used to define the FLT_max ROI. The statistical and spatial correlations between these two groups of ROIs were analyzed.ResultsWe did not observe any significant correlations between ADC_min and FLT_max cut-off values (R² = 0.0285), neither between ADC_min and FLT_max ROIs (mean Dice = 0.09 ± 0.12). Mean ADC values in the FLT_max defined ROI were significantly higher than the values in the ADC_min ROI (P < 0.001). Mean FLT values in the FLT_max ROI were significantly higher than the values in the ADC_min ROI (P < 0.001).ConclusionsWhen comparing ADC maps to ¹⁸FLT uptake, we did not observe significant anatomical overlap nor correlation, between the regions of low ADC and high FLT disabling to clearly link ADC values to cellular proliferation. The exact significance of ADC maps in GBM has yet to be elaborated.     

Physical fitness assessment in multiple sclerosis patients: A controlled study

There is growing evidence to show the effectiveness of physical exercise for multiple sclerosis (MS) patients. Aim of this study was to evaluate aerobic capacity, strength, balance, and the rate of perceived exertion (RPE) after exercise, in ambulatory patients with mild MS and matched control healthy participants. Seventeen MS patients aged 48.09 ± 10.0 years, with mild MS disability (Expanded Disability Status Scale: EDSS 1.5 to 4.5) and 10 healthy sedentary age matched (41.9 ± 11.2 years) subjects volunteered for the study. MS patients underwent medical examination with resting electrocardiogram, arterial blood pressure, EDSS, and Modified Fatigue Impact Scale-MFIS. Both groups also underwent physical assessment with the Berg Balance Scale^, test (Berg), Six Minutes Walking Test (6MWT), maximal isometric voluntary contraction (MIVC) of forearm, lower limb, shoulder strength test, and the Borg 10-point scale test. The one-way ANOVA showed significant differences for MFIS (F_1.19 = 9.420; p < 0.01), Berg (F_1.19 = 13.125; p < 0.01), handgrip MIVC (F_1.19 = 4.567; p < 0.05), lower limbs MIVC (F_1.19 = 7.429; p < 0.01), and 6MWT (F_1.19 = 28.061; p < 0.01) between groups. EDSS, Berg test and Borg scores explained 80% of 6MWT variation. Mild grade EDSS patients exhibited impaired balance, muscle strength, and low self pace-6MWT scores, whereas RPE response after the exercise was similar to that of sedentary individuals. Both groups showed similar global physiological adjustments to exercise.     

Results of phase II pharmacokinetic study of levetiracetam for prevention of post‐traumatic epilepsy

Levetiracetam (LEV) has antiepileptogenic effects in animals and is a candidate for prevention of epilepsy after traumatic brain injury. Pharmacokinetics of LEV in TBI patients was unknown. We report pharmacokinetics of TBI subjects ≥ 6 years with high PTE risk treated with LEV 55 mg/kg/day orally, nasogastrically or intravenously for 30 days starting ≤ 8 h after injury in a phase II safety and pharmacokinetic study. Forty‐one subjects (26 adults and 15 children) were randomized to PK studies on treatment days 3 and 30. Thirty‐six out of forty‐one randomized subjects underwent PK study on treatment day 3, and 24/41 subjects underwent PK study on day 30. On day 3, mean T_max was 2.2 h, C_max was 60.2 μg/ml and AUC was 403.7 μg/h/ml. T_max was longer in the elderly than in children and non-elderly adults (5.96 h vs. 1.5 h and 1.8 h; p = 0.0001). AUC was non-significantly lower in children compared with adults and the elderly (317.4 μg/h/ml vs. 461.4 μg/h/ml and 450.2 μg/h/ml; p = 0.08). C_max trended higher in i.v.- versus tablet- or n.g.-treated subjects (78.4 μg/ml vs. 59 μg/ml and 48.2 μg/ml; p = 0.07). AUC of n.g. and i.v. administrations was 79% and 88% of AUC of oral administration. There were no significant PK differences between days 3 and 30. Treatment of TBI patients with high PTE risk with 55 mg/kg/day LEV, a dose with antiepileptogenic effect in animals, results in plasma LEV levels comparable to those in animal studies.     

Efficacy and long-term tuning parameters of vagus nerve stimulation in long-term treated depressive patients

Vagus nerve stimulation (VNS) is a promising neurostimulation tool for the treatment of treatment-resistant depression. Here, we report the effects of positive remission rates and tuning parameters in a group of 18 (6 female, 12 male, mean age 54) long-term treated patients.Treatment varied between 3 and 200 months (mean 104.9 months). Mean stimulation intensity was 1.46 mA, ranging from 0.5 to 2.0 mA and high-frequency stimulation of 20–25 Hz (mean 23.61 Hz).The remission rates in our study population clearly indicate ongoing positive effects of VNS and highlight stimulation tunings between 0.5 and 2.0 mA and 20–25 Hz as best dosage for achieving remittance in long-term treatment of VNS.     

Attaining and sustaining remission of predominant negative symptoms

BackgroundEvidence is lacking on remission in the presence of predominant negative symptoms.AimsTo examine remission rates and their variation by antipsychotic medication in predominant negative symptoms.MethodsData were reanalyzed on patients (n = 383) who had participated in two double blind randomized placebo-controlled clinical trials of predominant negative symptoms lasting to 84 and 360 days. Symptom remission was defined with the Remission in Schizophrenia Working Group remission criteria of attaining and maintaining mild ratings on eight SANS items. Remission rates were examined to 90 days, survival analysis computed to ascertain time to attain symptom remission, binary logistic models used to predict the remission rate and 2 persistent months of symptom remission, and ANCOVA used to predict percent time in remission.ResultsSymptomatic remission rates were: 22.72% at any visit during 90 days, and 3.66% lasting 2 months. Kaplan–Meier and Cox survival models to adjust for baseline symptom severity showed that compared with the placebo group the amisulpride group attained significantly (p < .05) more remission sooner (HR = 2.321, 95% CI = 1.36, to 3.97, p < .05). ANCOVA showed that compared with placebo the amisulpride group spent significantly (p < .05) more percent time in remission (ES = .28). Specificity analysis showed that: across trials the negative symptom remission rate was 25.1%; and in one 360-day trial the six-month remission criteria were attained and maintained by 6.4% of participants.ConclusionsPresented with predominant negative symptoms the Working Group Remission criteria appear not to be a pragmatic therapeutic objective. Modified remission symptom and time criteria may be an effective way to examine remission.