Background: Treatment of tremor in MS is an unmet need. OnabotulinumtoxinA (BoNT‐A) has shown promising results; however, little is known regarding its effects on the brain. The clinical presentation of tremor MS is shown to depend on subcortical neural damage and cortical neural plasticity. This study aimed to identify effects of onabotulinumtoxinA (BoNT‐A) on brain activation in MS and upper‐limb tremor using functional MRI. Methods: Forty‐three MS participants with tremor were randomized to receive intramuscular injections of placebo (n = 22) or BoNT‐A (n = 21). Tremor was quantified using the Bain score (0–10) for severity, handwriting and Archimedes drawing at baseline, 6 weeks and 12 weeks. Functional MRI activation within two previously identified clusters, ipsilateral inferior parietal cortex (IPL) and premotor/supplementary motor cortex (SMC) of compensatory activity, was measured at baseline and 6 weeks. Results: Treatment with BoNT‐A resulted in improved handwriting tremor at 6 weeks (p = 0.049) and 12 weeks (p = 0.014), and tremor severity ‐0.79 (p = 0.007) at 12 weeks. Furthermore, the patients that received BoNT‐A showed a reduction in activation within the IPL (p = 0.034), but not in the SMC. The change in IPL activation correlated with the reduction in tremor severity from baseline to 12 weeks (β = 0.608; p = 0.015) in the BoNT‐A group. No tremor and fMRI changes were seen in the placebo treated group. Conclusion: We have shown that reduction in MS‐tremor severity after intramuscular injection with BoNT‐A is associated with changes in brain activity in sensorimotor integration regions.
Background and purpose: The literature provides contrasting results on the efficacy of levetiracetam (LEV) in multiple sclerosis (MS) patients with cerebellar signs. It was sought to evaluate the efficacy of LEV on upper limb movement in MS patients. Methods: In this multicenter double‐blind placebo‐controlled crossover study, MS patients with prevalently cerebellar signs were randomly allocated into two groups: LEV followed by placebo (group 1) or placebo followed by LEV (group 2). Clinical assessments were performed by a blinded physician at T0 (day 1), T1 (day 22), T2 (2‐week wash‐out period, day 35) and T3 (day 56). The primary outcome was dexterity in the arm with greater deficit, assessed by the nine‐hole peg test (9HPT). Secondary clinical outcomes included responders on the 9HPT (∆9HPT >20%), tremor activity of the daily living questionnaire and self‐defined upper limb impairment, through a numeric rating scale. Kinematic evaluation was performed using a digitizing tablet, providing data on normalized jerk, aiming error and centripetal acceleration. Results: Forty‐eight subjects (45.2 ± 10.4 years) were randomly allocated into two groups (n = 24 each). 9HPT significantly improved in the LEV phase in both groups (P < 0.001). The LEV treatment phase led to a significant improvement (P < 0.01) of all clinical outcomes in group 1 and in dexterity in group 2. No significant changes were reported during both placebo phases in the two groups. Considering the kinematic analysis, only normalized jerk significantly improved after treatment with LEV (T0–T1) in group 1. Conclusions: Levetiracetam treatment seems to be effective in improving upper limb dexterity in MS patients with cerebellar signs.
OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A in disabling multiple sclerosis (MS)-related upper limb tremor. METHODS: Twenty-three patients with MS contributed data from 33 upper limbs to this study. Each limb was randomized in a crossover design to receive botulinum toxin type A or placebo at baseline and the reverse treatment at 12 weeks. The 3 main outcomes were the median changes in Bain tremor rating scores for tremor severity, writing, and drawing an Archimedes spiral from baseline to 6 and 12 weeks after treatment with botulinum toxin type A compared with those after treatment with saline placebo. An independent rater scored randomized video assessments performed every 6 weeks over 6 months. RESULTS: There was a significant improvement after botulinum toxin compared with that after placebo treatment in the Bain score for tremor severity at 6 weeks (p = 0.0005) and 12 weeks (p = 0.0001), writing at 6 weeks (p = 0.0001) and 12 weeks (p = 0.0003), and Archimedes spiral drawing at 6 weeks (p = 0.0006) and 12 weeks (p = 0.0002). More patients developed weakness after botulinum toxin treatment (42.2%) than after placebo injection (6.1%; (p = 0.0005). Weakness was mild (just detectable) to moderate (still able to use limb) and resolved within 2 weeks. CONCLUSIONS: Targeted botulinum toxin type A injections significantly improve arm tremor and tremor-related disability in patients with MS. Classification of evidence: This study provides Class III evidence that targeted injection of botulinum toxin type A is associated with significant improvement in MS-related upper limb tremor. Neurology(R) 2012;79:92-99.
BACKGROUND AND PURPOSE: The aim of this study was to evaluate the activity measured by kinematic analysis, tolerability and efficacy of levetiracetam (LEV) in multiple sclerosis (MS) patients affected by cerebellar symptoms, in a randomized single‐blind, placebo‐controlled cross‐over study. METHODS: Eight MS subjects with cerebellar signs (five female and three male; mean EDSS: 4.77; mean disease duration 9.2) performed a reaching task on a digitizing tablet and their trajectories went through a kinematic analysis. The subjects were assessed at baseline, after 21 days of treatment, after wash‐out period (day 35) and after 21 days of treatment (day 56). LEV was used at the maximum dosage of 1500 mg daily. The primary outcome was the modification on smoothness (JERK) whilst aiming error (AAI) and centripetal acceleration (CA) were considered as secondary outcomes. RESULTS: Two subjects were excluded from the final analysis. Primary outcome (i.e. JERK) was significantly affected by the administration of LEV overtime (nine arms in active treatment versus three arms in placebo decreased the mean values of their JERK). Regarding secondary outcomes CA was significantly affected by the administration of LEV. No statistical significant results were found comparing clinical scales during the four assessments. DISCUSSION: The results indicate that LEV was able to modify kinematic parameter so the medication was active but no improvement in clinical scales was observed. LEV needs to be tested in a larger group of subjects designed to verify treatment efficacy using higher dosage of the medication.
OBJETIVO: Para probar la eficacia y seguridad a largo plazo de los cannabinoides en la esclerosis múltiple (EM), en seguimiento a los principales cannabinoides en el estudio de la esclerosis múltiple (CAMS).
MÉTODOS: En total, 630 pacientes con EM estable con espasticidad muscular de 33 centros del Reino Unido fueron aleatorizados para recibir Delta oral (9) tetrahidrocannabinol (delta (9) THC), extracto de cannabis, o placebo en el estudio principal 15 semanas CÁMARAS. El resultado primario fue el cambio en la escala de espasticidad de Ashworth. Los resultados secundarios fueron el Índice de Movilidad Rivermead, cronometrado 10 metros a pie, Reino Unido neurológica Discapacidad Score, postal Índice de Barthel, General de Salud Cuestionario-30, y una serie de nueve escalas categoría de calificación. Tras el estudio principal, se invitó a los pacientes a continuar con la medicación, doble ciego, para un máximo de 12 meses en el estudio de seguimiento se informó aquí.
RESULTADOS: Intención de tratar el análisis de los datos del 80% de los pacientes seguidos durante 12 meses mostraron evidencia de un pequeño efecto del tratamiento sobre la espasticidad muscular, medido por el cambio en la puntuación de Ashworth desde el inicio hasta 12 meses (Delta (9) THC reducción media 1,82 (n = 154, 95% intervalo de confianza (IC) 0,53 a 3,12), extracto de cannabis 0,10 (n = 172; IC del 95%: -0,99 a 1,19), placebo -0,23 (n = 176; IC del 95%: -1,41 a 0,94 ); p = 0,04 sin ajustar para el estado y el centro ambulatorio, p = 0,01 ajustado). No hubo evidencia sugerente de los efectos del tratamiento de Delta (9) THC sobre algunos aspectos de la discapacidad. No hubo grandes problemas de seguridad. En general, los pacientes sintieron que estas drogas eran útiles en el tratamiento de su enfermedad.
Conclusiones: Estos datos proporcionan pruebas limitadas de un efecto del tratamiento a largo plazo de los cannabinoides. Un estudio placebo controlado a largo plazo se necesita ahora para establecer si los cannabinoides pueden tener un papel más allá de la mejora de los síntomas de la EM.
The objective was to determine whether a cannabis-based medicinal extract (CBME) benefits a range of symptoms due to multiple sclerosis (MS). A parallel group, double-blind, randomized, placebo-controlled study was undertaken in three centres, recruiting 160 outpatients with MS experiencing significant problems from at least one of the following: spasticity, spasms, bladder problems, tremor or pain. The interventions were oromucosal sprays of matched placebo, or whole plant CBME containing equal amounts of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) at a dose of 2.5-120 mg of each daily, in divided doses. The primary outcome measure was a Visual Analogue Scale (VAS) score for each patient's most troublesome symptom. Additional measures included VAS scores of other symptoms, and measures of disability, cognition, mood, sleep and fatigue. Following CBME the primary symptom score reduced from mean (SE) 74.36 (11.1) to 48.89 (22.0) following CBME and from 74.31 (12.5) to 54.79 (26.3) following placebo [ns]. Spasticity VAS scores were significantly reduced by CBME (Sativex) in comparison with placebo (P =0.001). There were no significant adverse effects on cognition or mood and intoxication was generally mild.
ANTECEDENTES: la desactivación de temblor es común en pacientes con esclerosis múltiple (EM). Los datos de experimentos en modelos animales y estudios objetivos y subjetivos pequeño con pacientes sugieren que el cannabis puede ser un tratamiento eficaz para el temblor asociado a la EM. Hasta donde sabemos, no se han publicado ensayos doble ciego controlados aleatorios de cannabis como tratamiento para el temblor en pacientes con EM.
MÉTODOS: Los autores realizaron un estudio aleatorizado, doble ciego y controlado con placebo cruzado para examinar el efecto de Cannador oral (extracto de cannabis) en 14 pacientes con EM con temblores extremidades superiores. Hubo ocho mujeres y seis hombres, con una edad media de 45 años y la media ampliada del estado de discapacidad puntuación en la escala de 6,25. Los pacientes fueron asignados aleatoriamente para recibir cada tratamiento y las dosis escalada de más de un período de 2 semanas antes de cada evaluación. El resultado primario fue el cambio en un índice de temblor, medida mediante una escala validada de clasificación temblor. El estudio fue diseñado para detectar una mejoría funcional significativa del 50% en el índice de temblor. Los resultados secundarios incluyeron la acelerometría, una escala ataxia, dibujo espiral, intervención de los dedos, y de nueve hoyos rendimiento pegboard test.
RESULTADOS: El análisis de los datos mostró ninguna mejora significativa en ninguna de las medidas objetivas del temblor del miembro superior con extracto de cannabis en comparación con el placebo. Finger tapping fue más rápido en el grupo placebo en comparación con el extracto de cannabis (p <0,02). Sin embargo, hubo una tendencia no significativa para los pacientes que experimentan un alivio más subjetiva de sus temblores mientras que en el extracto de cannabis en comparación con el placebo.
Conclusiones: El extracto de cannabis no produce una mejoría funcional significativa en MS-asociado temblor.
Cerebellar syndrome is one of the most disabling developments in multiple sclerosis (MS). In neurodegenerative disorders, cerebellar syndrome is thought to be related to a neurochemical deficit of 5‐hydroxytryptamine (5‐HT). Previous studies found that a levorotatory form of 5‐hydroxytryptophan, a 5‐HT precursor, and ondansetron, a 5‐HT(3) receptor antagonist, decreased cerebellar symptoms in Friedreich's ataxia and MS. We studied the effect of another 5‐HT(3) receptor antagonist, dolasetron mesilate, on cerebellar syndrome in MS patients.Thirty‐four MS patients were included in a placebo‐controlled double‐blind crossover study. They received a single dose of intravenous dolasetron mesilate or placebo. A quantitative evaluation of cerebellar syndrome using the nine‐hole peg test and an ataxia score comprising static and kinetic parameters were performed before and after each treatment. No statistical difference was observed in the dolasetron mesilate group, compared with the placebo group. There was, however, inter‐individual variability in the treatment response. This double‐blind study on cerebellar syndrome in MS patients did not confirm the positive effect of dolasetron mesilate suggested by previous studies.
<b>BACKGROUND: </b>Multiple sclerosis is associated with muscle stiffness, spasms, pain, and tremor. Much anecdotal evidence suggests that cannabinoids could help these symptoms. Our aim was to test the notion that cannabinoids have a beneficial effect on spasticity and other symptoms related to multiple sclerosis.<b>METHODS: </b>We did a randomised, placebo-controlled trial, to which we enrolled 667 patients with stable multiple sclerosis and muscle spasticity. 630 participants were treated at 33 UK centres with oral cannabis extract (n=211), Delta9-tetrahydrocannabinol (Delta9-THC; n=206), or placebo (n=213). Trial duration was 15 weeks. Our primary outcome measure was change in overall spasticity scores, using the Ashworth scale. Analysis was by intention to treat.<b>FINDINGS: </b>611 of 630 patients were followed up for the primary endpoint. We noted no treatment effect of cannabinoids on the primary outcome (p=0.40). The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0.32 (95% CI -1.04 to 1.67), and for those taking Delta9-THC versus placebo it was 0.94 (-0.44 to 2.31). There was evidence of a treatment effect on patient-reported spasticity and pain (p=0.003), with improvement in spasticity reported in 61% (n=121, 95% CI 54.6-68.2), 60% (n=108, 52.5-66.8), and 46% (n=91, 39.0-52.9) of participants on cannabis extract, Delta9-THC, and placebo, respectively.<b>INTERPRETATION: </b>Treatment with cannabinoids did not have a beneficial effect on spasticity when assessed with the Ashworth scale. However, though there was a degree of unmasking among the patients in the active treatment groups, objective improvement in mobility and patients' opinion of an improvement in pain suggest cannabinoids might be clinically useful.
Background: Treatment of tremor in MS is an unmet need. OnabotulinumtoxinA (BoNT‐A) has shown promising results; however, little is known regarding its effects on the brain. The clinical presentation of tremor MS is shown to depend on subcortical neural damage and cortical neural plasticity. This study aimed to identify effects of onabotulinumtoxinA (BoNT‐A) on brain activation in MS and upper‐limb tremor using functional MRI. Methods: Forty‐three MS participants with tremor were randomized to receive intramuscular injections of placebo (n = 22) or BoNT‐A (n = 21). Tremor was quantified using the Bain score (0–10) for severity, handwriting and Archimedes drawing at baseline, 6 weeks and 12 weeks. Functional MRI activation within two previously identified clusters, ipsilateral inferior parietal cortex (IPL) and premotor/supplementary motor cortex (SMC) of compensatory activity, was measured at baseline and 6 weeks. Results: Treatment with BoNT‐A resulted in improved handwriting tremor at 6 weeks (p = 0.049) and 12 weeks (p = 0.014), and tremor severity ‐0.79 (p = 0.007) at 12 weeks. Furthermore, the patients that received BoNT‐A showed a reduction in activation within the IPL (p = 0.034), but not in the SMC. The change in IPL activation correlated with the reduction in tremor severity from baseline to 12 weeks (β = 0.608; p = 0.015) in the BoNT‐A group. No tremor and fMRI changes were seen in the placebo treated group. Conclusion: We have shown that reduction in MS‐tremor severity after intramuscular injection with BoNT‐A is associated with changes in brain activity in sensorimotor integration regions.
