Archive for category Pharmacological

[Abstract + References] How safe is switching antiepileptic drug manufacturers?

A nationwide German study of prescription data has demonstrated that switching to an antiepileptic drug from a different manufacturer increases the risk of seizure relapse. This finding sparks a debate about the reason for seizure worsening after switching and whether or not it is a pharmacological issue.


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via How safe is switching antiepileptic drug manufacturers? | Nature Reviews Neurology

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[Abstract + References] Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis



Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability.


The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques.


Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs).


Four trials involving 550 patients with Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1–31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8–28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07–2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55–8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I2 = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28–7.41; p = 0.657) and 4.20 (95% CI 1.82–9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87–16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22–12.86; p = 0.626) and 6.89 (95% CI 2.28–20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11–1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.


Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.


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via Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis | SpringerLink

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[WEB SITE] Memory-enhancing drug reverses effects of traumatic brain injury in mice

The radial-arm water maze is a common test to assess working memory in rodents.

Whether caused by a car accident that slams your head into the dashboard or repeated blows to your cranium from high-contact sports, traumatic brain injury can be permanent. There are no drugs to reverse the cognitive decline and memory loss, and any surgical interventions must be carried out within hours to be effective, according to the current medical wisdom. But a compound previously used to enhance memory in mice may offer hope: Rodents who took it up to a month after a concussion had memory capabilities similar to those that had never been injured.

The study “offers a glimmer of hope for our traumatic brain injury patients,” says Cesario Borlongan, a neuroscientist who studies brain aging and repair at the University of South Florida in Tampa. Borlongan, who reviewed the new paper, notes that its findings are especially important in the clinic, where most rehabilitation focuses on improving motor—not cognitive—function.

Traumatic brain injuries, which cause cell death and inflammation in the brain, affect 2 million Americans each year. But the condition is difficult to study, in part because every fall, concussion, or blow to the head is different. Some result in bleeding and swelling, which must be treated immediately by drilling into the skull to relieve pressure. But under the microscope, even less severe cases appear to trigger an “integrated stress response,” which throws protein synthesis in neurons out of whack and may make long-term memory formation difficult.

In 2013, the lab of Peter Walter, a biochemist at the University of California, San Francisco (UCSF), discovered a compound—called ISRIB—that blocked the stress response in human cells in a dish. Surprisingly, when tested in healthy mice, ISRIB boosted their memory. Wondering whether the drug could also reverse memory impairment, Walter teamed up with UCSF neuroscientist Susanna Rosi to study mouse models of traumatic brain injury. First, they showed that the stress response remains active in the hippocampus, a brain region important for learning and memory, for at least 28 days in injured mice. And they wondered whether administering ISRIB would help.

Rosi and her team first used mechanical pistons to hit anesthetized mice in precise parts of their surgically exposed brains, resulting in contusive injuries, focused blows that can also result from car accidents or being hit with a heavy object. After 4 weeks of rest, Rosi trained the mice to swim through a water maze, where they used cues to remember the location of a hidden resting platform. Healthy mice got better with practice, but the injured ones didn’t improve. However, when the injured mice were given ISRIB 3 days in a row, they were able to solve the maze just as quickly as healthy mice up to a week later, the researchers report today in the Proceedings of the National Academy of Sciences.

“We kept replicating experiments, thinking maybe something went wrong,” Rosi says. So the team decided to study ISRIB in a second model of traumatic brain injury known as a closed head injury, which resembles a concussion from a fall. They again used a mechanical piston, but this time landed a broad blow to the back of the skull. Two weeks later, the mice were trained on a tougher maze, full of bright lights and loud noise. They had to scurry around a tabletop with 40 holes, looking for the one with an escape hatch. Again, while the uninjured mice improved at the task, the concussed mice never got the hang of it. But after four daily doses of ISRIB, the concussed mice performed as well as their healthy counterparts. “This is the most exciting piece of work I’ve ever done, no doubt,” Rosi says.

“Paradigm shift is not too strong a term to use,” says Ramon Diaz-Arrastia, neurologist and director of clinical traumatic brain injury research at the University of Pennsylvania. “This … shows for the first time that a therapy in the chronic period of traumatic brain injury can have pretty potent effects.” Walter agrees. “Normally you would give up on these mice and say nothing can be done here,” he says. “But ISRIB just magically brings the cognitive ability back.”

Still, Borlongan cautions that studies in animals often don’t pan out when tested in humans. He says that this drug has a leg up, though, because it was tested in two models and also readily crosses the blood-brain barrier, which prevents many drugs that look good on paper from entering the brain and having an effect.

If the therapy translates to humans, it could be a boon for soldiers returning from war, who sometimes wait weeks between leaving the battlefield and arriving home for treatment. Brian Head, a neurobiologist at the VA San Diego Healthcare System in California notes that traumatic brain injury is still hard to diagnose, especially with veterans that show up to the clinic long after the injury. “But right now nothing else is working, and giving a compound [that works] a month later is really impressive.”

In 2015, ISRIB was licensed to the secretive Google spinout company Calico, which studies the biology of aging and life span. Walter says his lab has a research agreement with Calico to pursue “basic mechanistic work” on ISRIB, but that the new study was not funded by Calico. Google declined to comment on the new research.

Although the protein target of ISRIB is known, the exact manner in which the drug restores memory is hazy. The team hypothesizes that ISRIB may work by allowing normal protein synthesis—essential for making new neuronal connections and thus forming new memories—to resume, which would otherwise be blunted by the integrated stress response. “Even if this drug doesn’t materialize, other ways of manipulating the integrated stress response may lead to an effective treatment in the future,” Walter says.

via Memory-enhancing drug reverses effects of traumatic brain injury in mice | Science | AAAS

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[Abstract + References] New Treatment Approaches on the Horizon for Spastic Hemiparesis – PM&R


This article presents 2 recent articles that propose novel interventions for treating spastic hemiparesis by changing biological infrastructure. In 18 patients with unilateral spastic arm paralysis due to chronic cerebral injury greater than 5 years’ duration, Zheng et al transferred the C7 nerve from the nonparalyzed side to the side of the arm that was paralyzed. Over a follow-up period of 12 months, they found greater improvement in function and a reduction of spasticity compared to rehabilitation alone. Using functional magnetic resonance imaging, they also found evidence for physiological connectivity between the ipsilateral cerebral hemisphere and the paralyzed hand. In the second article, Raghavan et al examine the concept of stiffness, a common symptom in patients with spastic hemiparesis, as a physical change in the infrastructure of muscle. Raghavan’s non-neural hyaluronan hypothesis postulates that an accumulation of hyaluronan within spastic muscles promotes the development of muscle stiffness in patients with an upper motor neuron syndrome (UMNS). In a case series of 20 patients with spastic hemiparesis, Raghavan et al report that upper limb intramuscular injections of hyaluronidase increased passive and active joint movement and reduced muscle stiffness. Interventions that change biological infrastructure in UMNS is a paradigm on the horizon that bears watching.


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via New Treatment Approaches on the Horizon for Spastic Hemiparesis – PM&R

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[ARTICLE] Effects of a 6-month self-rehabilitation programme in addition to botulinum toxin injections and conventional physiotherapy on limitations of patients with spastic hemiparesis following stroke (ADJU-TOX): protocol study for a randomised controlled, investigator blinded study -Full Text


Introduction Home-based self-rehabilitation programmes combined with botulinum toxin injections (BTIs) appear to be a relevant approach to increase the recommended intensive rehabilitation of patients with spasticity following a stroke. The literature highlights a lack of evidence of beneficial effects of this adjuvant therapy to reduce limitations of patients with stroke. The aim of this study is to assess the effects of a 6-month self-rehabilitation programme in adjunction to BTI, in comparison with BTI alone, to reduce limitations of patients with spasticity following a stroke.


Methods and analysis 220 chronic patients will participate to this multicentre, prospective, randomised, controlled, assessor blinded study. All patients will benefit from two successive BTI (3 months apart), and patients randomised in the self-rehabilitation group will perform in adjunction 6 months of self-rehabilitation at home. All patients continue their conventional physiotherapy. The main outcome is the primary treatment goal (PTG), which will be determined jointly by the patient and the medical doctor using Goal Attainment Scaling. Impairments and functions, quality of life, mood and fatigue will be assessed. Botulinum toxin will be injected into the relevant muscles according to the PTG. Patients in the self-rehab group will be taught the self-rehabilitation programme involving respectively 10 min of stretching, 10 min of strengthening and 10 min of task-oriented exercises, corresponding to their PTG. Compliance to the self-rehabilitation programme will be monitored.

Strengths and limitations of this study

  • This study is the first to assess the effects of a self-rehabilitation in addition of usual treatments over a long period (6 months).

  • This study will include a large sample with patients from 16 hospitals across all the country.

  • The design of this study (randomised, controlled, assessor blinded study) tends to meet the highest level of evidence.

  • This study would permit to apply recommendations to improve patients limitations with little additional cost to the already limited health system budget.


Stroke is the second highest cause of death worldwide and the fourth leading cause of lost productivity (disability-adjusted life years) according to WHO. The annual incidence is around 130 000 new cases each year in France.1 Around half of survivors are left with some functional limitations as a result of multiple impairments including motor impairments with a loss of strength, stereotyped movements and changes in muscle tone.2 3 Following stroke, about one-third of people with motor deficits have complete upper limb recovery, one-third have a partial recovery, with capacity to carry a bag or to point to an object and, one-third have little to no recovery of function with often dependence for activities of daily living.4 Among impairments, positive signs of the upper motor neuron syndrome (spasticity, cocontraction and dystonia) are associated with active motor dysfunction and disabilities to use arm in daily living activities.5 6 Gait limitations following symptoms of upper motor neuron syndrome reduce also displacements and participation of patients with stroke.7 8 Although 65%–85% of stroke survivors regain the capacity to walk, their gait is slower and their cadence, step length and single support phase of gait cycle are reduced in comparison with healthy subjects.9 These spatio-temporal changes are associated with joint kinematics changes, such as reduced peak hip flexion,10 reduced peak knee flexion during swing (stiff knee gait)10 11 and reduced ankle dorsiflexion (equinus).10 Motor impairments are largely involved in these kinematic abnormalities, particularly spasticity of quadriceps reducing knee flexion in stiff knee gait11 and spasticity of the ankle plantar flexors contributing to the equinus.12

Physiotherapy has been shown to be effective for the treatment of motor impairment and the improvement of function following stroke.13 14 Different techniques have been developed, however, one has not been shown more effective than another.15 16 Nevertheless, it has been demonstrated that the intensity, the frequency and the specificity (to train specifically the task to improve) of physiotherapy is positively correlated with recovery.17–20 To increase the duration and the specificity of physiotherapy lead indeed to greater improvements in impairments and functional limitations. French et al 21 published a systematic review relating positive effects of repetitive functional task practice on upper and lower limb function in 1078 patients with stroke.21 Van de Port et al 22 showed indeed that intensive circuit training organised in specific workstations induced greater locomotor improvements than usual physiotherapy in 250 chronic outpatients with stroke.22 This likely suggests that patients do not attempt their maximal potential of recovery when they benefit of usual care. This means also that an adjuvant care might permit to the patients to reach their maximal capacity and thus reducing the impact of impairments and functional limitations. Moreover, many studies highlighted that improvements continue and are effective in chronic patients with stroke who follow intensive active rehabilitation.13 23 Currently, because of the constraints within the French health system, patients with stroke living at home usually receive only 1.7 sessions of 20–30 min of physiotherapy per week.24 These sessions, which last about 30 min, usually only consist of stretching and strengthening exercises. This contrasts with recommendations of intensive rehabilitation for chronic patients due to functional deteriorations observed when patients decrease or stop their rehabilitation.19 20 25 This suggests the necessity to develop novel approaches which could increase the intensity and specificity of rehabilitation for chronic patients with stroke living at home. A self-rehabilitation (SR) programme appears a relevant approach to increase the intensity of the oriented rehabilitation which is needed and further improve recovery of these patients.

The treatment commonly used to reduce spasticity and increase functions in patients with stroke is botulinum toxin injections (BTIs).12 26–28 In the upper limb, BTI appear associated with a global moderate treatment effect and depends of the parameters studied. A meta-analysis carried out by Foley et al 29 showed a relatively large effect size for the reduction of spasticity and the improvement of passive function and, a small effect size for the improvement of active functions such as prehension.29 This confirms the results of a previous international consensus statement in which authors consider BTI as effective for reduction of pain, deformity and improvement of washing and dressing (class I evidence, recommendation level A), but no clear benefit in active function (class III evidence, recommendations C).30 In the lower limb, several studies have evaluated the effects of BTI in the rectus femoris (RF) and triceps surae muscles in patients with stroke. Studies have shown that BTI in the triceps surae reduced passive resistance to ankle dorsiflexion, pain and the requirement of a gait aid and increased gait speed of patients with hemiparesis.31 32 An open-label study found a significant increase of 8° peak knee flexion during swing following BTI in the RF in patients with hemiparesis with inappropriate RF activity in mid-swing.33 However, there were no significant improvements in functional tests of gait capacity (gait speed, gait distance assessed during the 6 min walking test, stairs). Taken together, the results obtained in the upper and lower limbs after a single BTI session suggest that, although this treatment reduces muscle tone and increases passive function, its impact on active function is low and it does not improve activities of daily living. Some authors state that conventional outcome measures used in these previous studies are not suitable.30 34 35 They suggest using an individually based approach such as the Goal Attainment Scaling (GAS) which showed significant improvements following BTI.34 35 GAS determined the primary treatment goal which is the main treatment objective determined jointly by the patient and the therapist.

Several studies showed moreover that repeated BTI induce better improvements of muscle tone, active movements, functions and quality of life of patients with stroke than single injection.27 36–38

In view of all these studies, it appears essential to develop a combined therapy approach to improve the treatment of spasticity and functional activities in daily life. To increase the intensity of the oriented rehabilitation following BTI would be indeed relevant. Sun et al 39 highlighted greater improvements of spasticity, active function and use of the paretic upper limb of patients with stroke when a constraint-induced therapy is coupled with BTI in comparison with less intensive rehabilitation.39 Similarly, Roche et al showed that a 30 min daily SR programme of 4 weeks coupled with a single session of BTI in the lower limb significantly improved several gait-related activities compared with BTI alone.40 The SR programme was developed to combine safe and feasible exercises combining 10 min of strengthening, 10 min of stretching and 10 min of task-oriented gait-related exercises. Eighty-three per cent of the patients in the SR group carried out 33 min exercises per day more than 5 days per week.40 These results show that combining SR at home with BTI seems effective, well accepted and well tolerated. Results of these pilot studies with restricted sample suggest effectiveness of adding sessions of specific exercises following BTI in patients with stroke, which corresponds to the conclusions of two recent reviews.41 42 These reviews recommend however further study with large sample size, long duration and robust methodology.

The aim of this study is to assess the effects of a 6 months SR programme in adjunction to BTI, in comparison with BTI alone, to reduce limitations of patients with spasticity having a stroke. All previous results lead us to the hypothesis that the addition of a specific 30 min SR programme to repeated BTI and usual physiotherapy should increase the proportion of patients who attain their primary treatment goal (impairments and functions assessed with GAS) more than usual care (involving repeated BTI and conventional physiotherapy), in poststroke outpatients with spasticity. Secondary objectives are to compare the effects of the two therapeutic strategies on impairments and functional status, on quality of life, mood, fatigability and fatigue of patients with stroke and evaluate the time course of the effects. Another aim is to assess compliance with, and tolerability of the SR programme, and to define the characteristics of compliant and non-compliant patients.[…]

Continue —> Effects of a 6-month self-rehabilitation programme in addition to botulinum toxin injections and conventional physiotherapy on limitations of patients with spastic hemiparesis following stroke (ADJU-TOX): protocol study for a randomised controlled, inves… | BMJ Open

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[WEB SITE] OnabotulinumtoxinA for Post-Stroke Spasticity: Treatment Strategies and Limitations

Spasticity is a common occurrence following stroke, with an estimated 20% to 40% of patients developing spasticity that hampers activities of daily living (ADL). Lower limb spasticity in particular is associated with impairments of gait and mobility.1

The main constraint to botulinum toxin use for spasticity is dosage limitation.Current Treatment

Several types of therapy are available to facilitate post-stroke recovery of movement, including the use of botulinum toxin injections, as well as physical therapy and anti-spasmodic medications as first-line options. Other therapies such as ultrasound, magnetic stimulation, and transcutaneous electrical stimulation may be added to the treatment plan to improve motor performance, but no one treatment stands out as superior to the others. In the most severe and persistent cases, surgery is a final option.

Improvements with these therapies are often less than optimal, according to David M. Simpson, MD, FAAN, director, Clinical Neurophysiology Laboratories and director of the neuromuscular division, Icahn School of Medicine, Mount Sinai Medical Center in New York City. He told Neurology Advisor, “Treatment goals are individualized for each patient. In some more severely affected patients, only passive goals are possible, such as improvement in limb position, caregiver dressing, or applying braces. In others, higher level active functional goals are possible, such as improved arm use and gait.”

In an interview with Neurology Advisor, Randie M. Black-Schaffer, MD, MA, medical director of the stroke program, director of the Stroke Research and Recovery Institute at Spaulding Rehabilitation Hospital in Boston, Massachusetts, and assistant professor of physical medicine and rehabilitation, Harvard Medical School in Cambridge, Massachusetts, explained the common clinical approach to these rehabilitative therapies. “Typically, physical medicine and rehabilitation physicians (physiatrists) recommend physical therapy first to see if a regular stretching program for the spastic muscles will adequately control the muscle tone. If not, the second option is a trial of muscle relaxant medications, [al]though the sedative effects of these medications often limit or preclude their use in neurologically impaired patients. If neither of these approaches provides adequate relief, the next step would be to evaluate the patient for botulinum toxin injections and/or phenol nerve block.”

Botulinum Toxin Type A for Spasticity

“Botulinum toxin is proven as a safe and effective treatment for spasticity and is FDA [US Food and Drug Administration]-approved for that indication,” reported Dr Simpson, who is the co-investigator in several studies on botulinum toxin for upper limb spasticity.2-4  “While there are few head-to-head studies of other treatments, we have published a placebo-controlled trial showing superior tolerability and efficacy of onabotulinumtoxinA compared with oral tizanidine (TZD) for upper extremity spasticity,” he said.2 That study concluded that botulinum toxin was both safer and more effective than TZD in reducing tone and disfigurement in upper extremity spasticity and recommended that it be used as first-line therapy.2

“In the lower extremities, these injections are effective in reducing spastic equinovarus posturing, painful toe flexion, stiff knee, flexed knee posturing, and scissoring leg movements that can interfere with gait, positioning, and/or hygiene,” Dr Black-Schaffer said. “In the upper extremities, injections can reduce painful shoulder adduction, and hand clenching, as well as excessive elbow flexion.”

“The effect of injections usually starts 3 to 8 days after the injections, peaks at 2 to 3 weeks, and lasts for 2-1/2 to 3 months,” Dr Black-Schaffer noted, adding that, “There’s no medical contraindication to repeated botulinum toxin injections in the same muscles over time. Gradually, after years of botulinum toxin injections to the same muscles, they develop some degree of atrophy, which may enable reduction of the dose.”

Treatment Strategies

The main constraint to botulinum toxin use for spasticity is dosage limitation. Concerns over the potential development of resistant antibodies from too frequent injections that might reduce the therapeutic efficacy of the agent led to restrictions of total dosage to a maximum of 400 units every 3 months. As Dr Black-Schaffer pointed out, “Many patients after a stroke have spasticity throughout both their affected arm and affected leg, with many more muscles involved than a physician can inject, given that limitation. So, the physician must evaluate the patient carefully to decide which muscles it will be most helpful to inject and why.”

Dr Black-Schaffer outlined her rationale for determining when to use botulinum toxin following stroke. “The usual reasons for injecting [a patient] are to improve function or ease of ADL performance. For example, it is often possible to increase gait speed and cadence and reduce gait deviations such as inversion and hip hiking by injection of the plantar-flexor and invertor muscles of the effected leg,” she said. “A third reason is to reduce pain that may be caused by the muscle stiffness. An example is painful shoulder due to severe adductor tone in the arm, which can be significantly improved by botulinum toxin injection to the pectoralis major muscle. This may not improve the patient’s ability to move the arm, but can reduce pain with passive abduction, [such] as for bathing and dressing.”

Phenol nerve block injections are also commonly used as a botulinum-toxin-sparing strategy, she reported, explaining that phenol nerve block is an older technique utilized extensively before botulinum toxin became available, that can have muscle-relaxing effects similar to botulinum toxin in large muscles, such as the hip adductors, plantar flexors, and invertors of the affected leg. Injecting phenol into the obturator nerve, for example, reduces contractility of all the hip adductor muscles, saving doses of botulinum toxin for other smaller sites phenol does not have effects on, according to Dr Black-Schaffer.

Dr Simpson pointed to the need to begin therapy when spasticity is first detected. “As soon as spasticity is functionally disabling, one might consider treatment with botulinum toxin,” he said. “Once spasticity has become established in a patient’s muscles, it rarely resolves spontaneously,” Dr Black-Schaffer added.

Some patients, however, have such severe spasticity that 400 units of botulinum toxin provides little relief. “For those patients, there are additional treatment options, including the intrathecal baclofen pump and surgical lengthening of the tendons of specific spastic muscles. The baclofen pump can relieve muscle stiffness with less baclofen and less sedation than when the patient takes baclofen by mouth,” Dr Black-Schaffer said, adding that, “On the other hand, the baclofen pump is more effective for lower than upper extremity spasticity and requires visits to a specialized center several times per year for refills. In addition, there are several possible complications such as catheter dislodgement, breakage, and pump site infection, and the pump itself must be surgically replaced when its battery dies.”


  1. Nakawah MO, Lai EC. Post-stroke dyskinesias. Neuropsychiatr Dis Treat. 2016;12:2885-2893.
  2. Simpson DM, Gracies JM, Yablon SA, et al. Botulinum neurotoxin versus tizanidine in upper limb spasticity: a placebo-controlled study. J Neurol Neurosurg Psychiatry. 2009;80:380-385.
  3. Gracies JM, Bayle N, Goldberg S, Simpson DM. Botulinum toxin type B in the spastic arm: a randomized, double-blind, placebo-controlled, preliminary study. Arch Phys Med Rehabil.2014;95:1303-1311.
  4. Kaku M, Simpson DM. Spotlight on botulinum toxin and its potential in the treatment of stroke-related spasticity. Drug Des Devel Ther. 2016;10:1085-1099.

via OnabotulinumtoxinA for Post-Stroke Spasticity: Treatment Strategies and Limitations

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[ARTICLE] Efficacy of physical therapy associated with botulinum toxin type A on functional performance in post-stroke spasticity: A randomized, double-blinded, placebo-controlled trial – Full Text


The aim was to investigate if botulinum toxin type A (BTx-A) associated with physical therapy is superior to physical therapy alone in post stroke spasticity. A randomized, double-blinded controlled trial was performed in a rehabilitation unit on Northeastern, Brazil. Patients with post stroke spasticity were enrolled either to BTx-A injections and a pre-defined program of physical therapy or saline injections plus physical therapy. Primary endpoint was functional performance evaluated through time up and go test, six minutes walking test and Fugl-Meyer scale for upper limb. Secondary endpoint was spasticity improvement. Confidence interval was considered at 95%. Although there was a significant decrease in upper limbs flexor tonus (P<0.05) in the BTx-A group, there was no difference regarding functional performance after 9 months of treatment. When analyzing gait speed and performance, both groups showed a significant improvement in the third month of treatment, however it was not sustained over time. Although BTx-A shows superiority to improve muscle tone, physical therapy is the cornerstone to improve function in the upper limbs of post stroke patients.


Stroke is the major cause of permanent and temporary functional incapacity worldwide among adults, affecting limb strength, motor control, balance and mobility.1 Spasticity is characterized by an increase in tonic stretch reflex movement velocity dependent and post-stroke spasticity is frequently associated with poor functional performance due to abnormal postural patterns, leading to retractions, atrophy, selective movement control loss, limb weakness, fibrosis and structured contractions.2 Moreover, impairment in activities of daily living (ADL) such as feeding, locomotion, proper hygiene and sleeping habits results in poor quality of life (QOL) and increased burden to relatives and caregivers.3

Several trials support the efficacy and safety of botulinum toxin type A (BTx-A) on spasticity treatment, reducing muscle permanent contraction and abnormal postural patterns, therefore, favoring rehabilitation process.4 Physical therapy has been described to be effective in post-stroke spastic patients through prevention of secondary incapacities and promoting behavioral reeducation, based on biomechanical and neurophysiological patterns. These techniques include physical exercises that focus on functional rehabilitation, reduction of limb spasticity, muscle strength improvement and sustained joint movement amplitude, besides proprioceptive and sensorial stimuli.5

Several trials with BTx-A show functional improvement in post-stroke spastic patients when compared to placebo, however, none have studied the impact of physical therapy alone.4

The aim of this trial was to investigate if BTx-A treatment associated with physical therapy is superior to physical therapy alone on functional performance in post-stroke spastic patients.[…]


Continue —> Efficacy of physical therapy associated with botulinum toxin type A on functional performance in post-stroke spasticity: A randomized, double-blinded, placebo-controlled trial

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[ARTICLE] Intensive therapy after botulinum toxin in adults with spasticity after stroke versus botulinum toxin alone or therapy alone: a pilot, feasibility randomized trial – Full Text



Botulinum toxin-A is provided for adults with post-stroke spasticity. Following injection, there is a variation in the rehabilitation therapy type and amount provided. The purpose of this study was to determine if it is feasible to add intensive therapy to botulinum toxin-A injections for adults with spasticity and whether it is likely to be beneficial.


Randomized trial with concealed allocation, assessor blinding, and intention to treat analysis. Thirty-seven adults (n = 3 incomplete or lost follow-up) with spasticity in the upper or lower limb were allocated to one of three groups: experimental group received a single dose of botulinum toxin-A plus an intensive therapy for 8 weeks, control group 1 received a single dose of botulinum toxin-A only, and control group 2 received intensive therapy only for 8 weeks. Feasibility was measured by examining recruitment, intervention (adherence, acceptability, safety), and measurement. Benefit was measured as goal achievement (Goal Attainment Scale), upper limb activity (Box and Block Test), walking (6-min walk test) and spasticity (Tardieu scale), at baseline (week 0), immediately after (week 8), and at three months (week 12).


Overall recruitment fraction for the trial was 37% (eligibility fraction 39%, enrolment fraction 95%). The 26 participants allocated to receive intensive rehabilitation attended 97% of clinic-based sessions (mean 11 ± 2 h) and an averaged 58% (mean 52 ± 32 h) of prescribed 90 h of independent practice. There were no study-related adverse events reported. Although participants in all groups increased their goal attainment, there were no between-group differences for this or other outcomes at week 8 or 12.


Providing intensive therapy following botulinum toxin-A is feasible for adults with neurological spasticity. The study methods are appropriate for a future trial. A future trial would require 134 participants to detect a between-group difference of 7 points on Goal Attainment Scale t-scores with an alpha of 0.05 and power of 80%.


Spasticity affects approximately 20% of stroke survivors [14] and is thought to significantly contribute to falls after stroke [56] as well as decreased activity participation [34]. Unsurprisingly, higher costs are thus incurred by patients with spasticity during the first year of survival [7]. Health professionals identify that addressing spasticity is a high priority during rehabilitation [8], and there is international consensus that localized spasticity (i.e., in the upper or lower limbs) is best managed with a combination of botulinum toxin and physical therapy [910]. While these consensus papers appear to agree, clinical management remains diverse [1112] and provides an ongoing challenge for both therapists and health services alike.

In Australia, stroke rehabilitation is guided by the Stroke Foundation clinical practice guidelines [13]. These guidelines recommend that management of moderate to severe spasticity include the use of botulinum toxin type A in additionto physical therapy interventions [13]. Unfortunately, clinical survey data suggests that occupational therapists and physiotherapists report providing therapy post-botulinum toxin type A injections less than a quarter of the time (an estimated 16%) [12]. This low rate of therapy provision suggests ongoing uncertainty among clinicians as to how to treat patients with spasticity. Such uncertainty is likely to stem from the lack of research studies that describe the type, frequency, intensity, and duration of therapy that is effective for people who have received botulinum toxin injections. While there are previous studies which have tested the efficacy of botulinum toxin type A for spasticity management after stroke [1416], what remains unknown is whether or not therapy should be provided to this group of patients.

To inform best practice in the treatment and rehabilitation of spasticity in people with neurological conditions, understanding whether the suggested combined effects of using both therapy and botulinum toxin type A together is more beneficial than botulinum toxin-A alone or physiotherapy interventions alone is key. Given the lack of research in this area, a large, powered randomized controlled trial is required. In preparation for this trial, it is key to understand both the feasibility and likely effects of the interventions; therefore, the research questions posed in this pilot study were:

  1. In neurological patients with spasticity, is it feasible to add intensive therapy to botulinum toxin-A injections if the therapy includes both clinic-based and home-based therapy sessions?
  2. Is adding intensive therapy likely to be of any benefit to goal attainment, upper limb activity, walking, and spasticity over botulinum toxin-A alone or intensive therapy alone?[…]

Continue —> Intensive therapy after botulinum toxin in adults with spasticity after stroke versus botulinum toxin alone or therapy alone: a pilot, feasibility randomized trial

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[ARTICLE] Botulinum Toxin Type A Treatment Combined with Intensive Rehabilitation for Gait Poststroke: A Preliminary Study – Full Text


To examine the effects of botulinum toxin type A (BoNT-A) treatment combined with intensive rehabilitation for gait compared with intensive rehabilitation alone in patients with chronic stroke.

Materials and Methods

A comparative case series design was used. Subjects were 19 patients with chronic stroke and spastic hemiplegia. In 9 patients (group I), BoNT-A was injected into spastic muscles of the affected lower limbs, followed by a 4-week inpatient intensive rehabilitation program. In the other 10 patients (group II), a 4-week inpatient intensive rehabilitation program alone was first provided (control period) followed by the same treatment protocol in group I. The Modified Ashworth Scale (MAS) scores, range of motion (ROM), gait speed in the 10-Meter Walking Test, 6-Minute Walking Distance Test (6MD) scores, Timed Up and Go Test (TUG) scores, and Berg Balance Scale scores were evaluated every 4 weeks following baseline assessments.


All results except for the MAS score of knee flexor and the ROM of knee flexion improved in group I and the gait speed, 6MD, and TUG scores improved in group II. Intergroup comparisons at week 4 showed significantly greater improvements in the MAS score of ankle plantar flexor, ROM of ankle dorsiflexion, and 6MD in group I than in group II (P = .016, .011, and .009, respectively).


BoNT-A treatment for lower-limb spasticity, combined with intensive rehabilitation, was effective in improving spasticity and the 6MD compared with intensive rehabilitation alone in patients with chronic stroke.



Lower-limb spasticity is a major problem in the management of patients after stroke12 because it causes gait disturbance.3 Such patients often have difficulty performing ankle dorsiflexion effectively during the swing phase of the gait cycle because of muscle spasticity and the inability to activate the ankle dorsiflexors.4 Calf muscle spasticity typically causes foot deformity, which results in the loss of heel strike, reduced toe clearance, and an inadequate base of support.5 These impairments decrease gait ability: cadence, stride length, speed, capacity, and stability.678910 Thus, lower-limb spasticity causes gait disturbance, which limits activities of daily living and, eventually, quality of life. Effective treatment of lower-limb spasticity is important in improving gait ability and enhancing the independence of patients after a stroke.

One of the primary treatments for lower-limb spasticity is botulinum toxin type A (BoNT-A). Although BoNT-A has been shown to reduce lower-limb spasticity in patients after stroke,111213its effects on improving gait ability have not been consistent among different previous studies. Pittock et al,14 Kaji et al,15 and Burbaud et al1 reported that BoNT-A injection reduced lower-limb spasticity but did not significantly improve gait pattern or speed. By contrast, Hesse et al11 and Mancini et al16 reported that BoNT-A treatment was effective in improving gait speed as well as lower-limb spasticity. Similarly, a systematic review and meta-analysis recently showed that BoNT-A treatment for lower-limb spasticity was associated with a small but statistically significant increase in gait speed.17 Consequently, the effect of BoNT-A alone for improving gait ability has been considered minimal.

To improve gait ability, adjunctive rehabilitation has recently been recommended to optimize the effects of BoNT-A treatment for lower-limb spasticity in poststroke patients.181920212223Gastaldi et al21 reported that BoNT-A treatment for lower-limb spasticity combined with additional stretching and physical therapy improved gait speed and single- and double-limb support during the stance phase of the gait cycle. Similarly, Roche et al22 reported that BoNT-A treatment for lower-limb spasticity combined with self-rehabilitation improved gait speed, capacity, and time to ascend and descend a flight of stairs. By contrast, Demetrios et al23 suggested no significant improvement in gait speed for 2 groups receiving BoNT-A treatment for lower-limb spasticity combined with high- or low-intensity rehabilitation. However, they concluded that both groups received BoNT-A treatment combined with regular rehabilitation, so there may have been insufficient variation of intensity during the rehabilitation phase. Therefore, the capacity of BoNT-A treatment combined with more intensive rehabilitation to improve gait ability remains unclear in poststroke patients.

The aim of this study was to examine the effects of BoNT-A treatment for lower-limb spasticity combined with intensive rehabilitation on improving gait ability in patients with chronic stroke and spastic hemiplegia compared with intensive rehabilitation alone. This study hypothesized that BoNT-A treatment combined with intensive rehabilitation would improve lower-limb spasticity and gait ability more effectively than intensive rehabilitation alone.[…]


Continue —> Botulinum Toxin Type A Treatment Combined with Intensive Rehabilitation for Gait Poststroke: A Preliminary Study – ScienceDirect

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[WEB SITE] Medical Marijuana for Epilepsy: What We Know

Rahul Guha, MD, July 26, 2018

Earlier this year, the Virginia State Legislature voted to expand the medical cannabis oil program in the Commonwealth. I have patients ask me about medical marijuana during every clinic visit. Here are a few talking points that will help guide the discussion with your patients.

Patients usually start the conversation by saying, “I read on my cousin’s Facebook wall that smoking marijuana can treat my epilepsy.”

Let’s take a step back and talk about the clinically important compounds in marijuana. The first is tetrahydrocannabinol (THC). It exerts its effect through a pair of G protein-coupled cannabinoid receptors named, conveniently, CB1 and CB2. The effect of THC on synapses produces the typical “high” that allows you to tolerate 11-minute guitar solos and most items on Taco Bell’s late-night menu. Early animal models showed mixed effects of THC on epilepsy and, in some cases, worsening seizures. This is different from cannabidiol (CBD), which interacts with a variety of other receptors. More promising effects reported in early animal models and anecdotal evidence from case reports spurred the movement towards clinical trials measuring the effect of CBD on epilepsy.

Will medical marijuana help my epilepsy?

We don’t know which epilepsy syndromes are most responsive to CBD. We don’t know the long-term effects of CBD or THC in the brains of patients with epilepsy. We have not agreed on the best dosing strategy for these medications. The best evidence for CBD in epilepsy comes from two recently published trials studying the effect of the drug in patients with Lennox-Gastaut syndrome and Dravet syndrome.[1,2] These diseases develop in childhood or infancy due to underlying genetic changes and are resistant to treatment.

In the studies, patients who were taking an average of six other antiepileptic medications received CBD as an add-on therapy to conventional medications. At 3 months’ follow-up, patients who received the CBD experienced a statistically significant decrease in average seizure frequency compared with placebo.

Can I use commercially available CBD?

Unfortunately, many of the products that are available online or over the counter at your local vape shop are not consistent with labeling. Simply put, there’s no guarantee that you are getting what’s advertised. In addition to unknown dosing and concentrations of THC and CBD, there is a possibility of contaminants, such as pesticides or other drugs, in the product. We can only guarantee the safety and efficacy of US Food and Drug Administration (FDA)-approved products.

How will CBD affect my other medications?

CBD is metabolized by the liver and inhibits cytochrome P450 (CYP) isoenzymes. This inhibition leads to increased levels of topiramate, zonisamide, eslicarbazepine, rufinamide, clobazam, and valproic acid.

Is it legal?

The FDA recently approved a CBD formulation, but there is currently no formulation of CBD that can be prescribed with a Drug Enforcement Administration (DEA) license. Under federal law, cannabis is still considered a Schedule I drug. It is only available through clinical trials and rare compassionate-use exceptions. Patients and providers should familiarize themselves with local laws before recommending CBD for the treatment of epilepsy.


via Medical Marijuana for Epilepsy: What We Know


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