Archive for category Pharmacological

[WEB SITE] Efficacy of methylphenidate for the treatment of mental sequelae after traumatic brain injury

BACKGROUND: This study aimed to evaluate the effect of methylphenidate for treating mental sequelae after traumatic brain injury (TBI).
METHODS: Thirty-six patients with TBI were randomly divided into the intervention group and placebo group. The participants in the intervention group received methylphenidate, while subjects in the placebo group were administered a placebo.
This study was conducted from January 2014 to December 2016. The outcome measurements included Mental Fatigue Scale, Choice Reaction Time, Compensatory Tracking Task, Mental Arithmetic Test, Digit Symbol Substitution Test, Mini-Mental State Examination (MMSE), Beck Depression Inventory (BDI), and Hamilton Rating Scale for Depression. In addition, safety was also recorded and assessed.
RESULTS: A total of 33 subjects completed the study. Methylphenidate showed greater efficacy than placebo, with decreased scores on the Mental Fatigue Scale, Choice Reaction Time, and Compensatory Tracking Task in the intervention group compared to the placebo group (P < .01, respectively). Furthermore, increased scores on the Mental Arithmetic Test, Digit Symbol Substitution Test, and MMSE in the intervention group, compared to those in the placebo group (P < .01 respectively), were observed. In addition, a significant difference in the scores on the BDI (P = .04) and Hamilton Rating Scale for Depression (P = .005) was observed between the 2 groups. The safety at the end of the 30 week-treatment was similar between the 2 groups (P > .05).
CONCLUSION: The results of this study demonstrated that methylphenidate could effectively improve mental fatigue and cognitive functions in patients with TBI.

Source: Traumatic Brain Injury Resource Guide – Research Reports – Efficacy of methylphenidate for the treatment of mental sequelae after traumatic brain injury

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[WEB SITE] This FDA Approved Drug Could Permanently Repair Brain Damage in Victims

In Brief
  • Using a drug already approved for clinical trials, researchers were able to reduce brain damage and boost the growth of new brain cells in mice suffering from strokes.
  • The research offers new hope to those dealing with the aftermath of strokes, which are the fifth leading cause of death in the United States.

Old Drug, New Treatment

Researchers from the University of Manchester have developed a new treatment that could limit the damage caused by strokes and also promote repair in the affected area of the brain. What’s more, the drug they’re using has already been clinically approved.

The researchers’ study is published in Brain, Behavior and Immunityand it recounts how they developed their treatment using mice bred to develop ischemic strokes, the most prevalent type of stroke and one that occurs when an artery that supplies oxygen-rich blood to the brain is blocked. Soon after the mice experienced a stroke, the researchers treated them with interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory drug that is already licensed for use in treating rheumatoid arthritis.

They noticed a reduction in the amount of brain damage typically observed after a stroke and also noted that the drug boosted neurogenesis (the birth of new cells) in the areas that did experience brain damage in the days following the treatment. The mice even regained the motor skills they lost due to the stroke.

Hope for a Cure

Stroke is the fifth leading cause of death in the United States and about 800,000 people suffer from one each year, according to the Centers for Disease Control and Prevention (CDC). They occur when the flow of blood to the brain is interrupted, usually due to a blood clot or a buildup of fat that broke off from the arteries and traveled to the brain. The condition is extremely dangerous because brain cells can die within a few minutes of the stroke, causing permanent damage or even death.

We still don’t have a treatment to adequately prevent or reverse the damage to the brain caused by strokes, but the Manchester researchers believe that their development could change that. Though they are still in early stages of clinical trials, they hope to eventually move on to larger trials and eventually human testing. Together with other research, this new study offers hope to the thousands of people whose lives are impacted by strokes worldwide.

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[WEB PAGE] Faster-acting antidepressants may soon be a reality

Understanding where antidepressants act is the key to improving their function.


Using cutting-edge techniques, researchers have investigated the mechanism by which common antidepressants work, finally pinning down the specific receptors responsible for their action. The findings might pave the way to designing improved, faster-acting antidepressants.

Depression is characterized by persistent low mood and feelings of hopelessness, and it is one of the most common mental disorders in the United States. In 2014, there were an estimated 15.7 million U.S. adults who experienced at least one major depressive episode, representing around 6.7 percent of the country’s adults.

Treatments for depression generally include talking therapies in conjunction with medication. The class of drugs most commonly prescribed is selective serotonin reuptake inhibitors (SSRIs), and these include brands such as Prozac and Zoloft.

SSRIs can help some people with depression, but they are not perfect; not everyone responds well to them, and side effects including nausea, insomnia, agitation, and erectile dysfunction can be unpleasant.

Also, SSRIs can take some time to kick in; although some people might feel some benefit within hours or even minutes, most people do not feel the full antidepressant effect until they have been taking the drugs for weeks or even months.

How do SSRIs work?

In the brain, messages are sent between neurons by releasing neurotransmitters into a gap between the cells, or the synapse. Serotonin is one such neurotransmitter. It is released from the first neuron and binds to receptors on the second neuron.

Normally, once serotonin has been released into the synapse and relayed its message, the majority is reabsorbed into the first nerve cell for reuse at a later date. SSRIs prevent serotonin from being reabsorbed. In this way, they ensure that serotonin hangs around in the synapse for a longer time, exerting more of an effect.

Although SSRIs have been known to medical science since the 1950s, their exact mechanism is not understood. This is because there are at least 1,000 types of neuron that can be influenced by a surge in serotonin, and some of these neurons may be excited, while others might be inhibited.

The mixed response is because there are 14 subtypes of serotonin receptor throughout the body and any single nerve could have a cocktail of receptor types. Teasing out which receptor subtype is playing the most significant role has proven challenging.

The role of the dentate gyrus

A group of scientists from Rockefeller University in New York City, NY, recently set out to take a closer look at the action of SSRIs on a particular type of nerve cell. The team was headed up by Lucian Medrihan and Yotam Sagi, both research associates in the Laboratory of Molecular and Cellular Neuroscience, and Paul Greengard, Nobel laureate.

Their findings were recently published in the journal Neuron.

Many different types of synapses throughout the brain use serotonin as their neurotransmitter. An issue of major importance has been to identify where in the myriad of neurons the antidepressants initiate their pharmacological action.”

Paul Greengard

The team concentrated on a group of cells in the dentate gyrus (DG). According to the authors, they chose the DG because previous work has established that “SSRI treatment promotes a variety of synaptic, cellular, and network adaptations in the DG.”

Specifically, the team investigated cholecystokinin (CCK)-expressing neurons within the DG. These neurons were of interest because they are heavily influenced by neurotransmitter systems that are associated with mood disorders, such as depression.

Finding the right receptor

Using a technique called translating ribosome affinity purification, the team were able to identify the serotonin receptors on CCK cells. Sage explains, “We were able to show that one type of receptor, called 5-HT2A, is important for SSRIs’ long-term effect, while the other, 5-HT1B, mediates the initiation of their effect.

The next step in the study involved efforts to mimic SSRIs’ effects by manipulating CCK neurons in mice. They used chemogenetics to switch nerve cells on or off and implanted tiny electrodes inside the mouse brains.

The findings were clear. When the CCK neurons were inhibited, the pathways important for the mediation of SSRI responses lit up. In other words, the scientists had recreated a Prozac-like effect without using the drug.

To back up these findings, the team used behavioral experiments in a pool and observed swimming patterns. Again, silencing the CCK neurons created behavior that was similar to that displayed by the mice that had been given SSRIs: they swam for longer with increased vigor.

According to the researchers, understanding the importance of the DG and the specific cells important for treating depression will help to design faster-acting, more effective antidepressants with fewer side effects.

The work was carried out using techniques that would have been impossible just 5 years ago, and the studies that follow are likely to improve our understanding even further.

Source: Faster-acting antidepressants may soon be a reality

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[ARTICLE] Dose-Dependent Effects of Abobotulinumtoxina (Dysport) on Spasticity and Active Movements in Adults With Upper Limb Spasticity: Secondary Analysis of a Phase 3 Study – Full Text



AbobotulinumtoxinA has beneficial effects on spasticity and active movements in hemiparetic adults with upper limb spasticity (ULS). However, evidence-based information on optimal dosing for clinical use is limited.


To describe joint-specific dose effects of abobotulinumtoxinA in adults with ULS.


Secondary analysis of a phase 3 study (NCT01313299).


Multicenter, international, double-blind, placebo-controlled clinical trial.


A total of 243 adults with ULS >6 months after stroke or traumatic brain injury, aged 52.8 (13.5) years and 64.3% male, randomized 1:1:1 to receive a single-injection cycle of placebo or abobotulinumtoxinA 500 U or 1000 U (total dose).


The overall effect of injected doses were assessed in the primary analysis, which showed improvement of angles of catch in finger, wrist, and elbow flexors and of active range of motion against these muscle groups. This secondary analysis was performed at each of the possible doses received by finger, wrist, and elbow flexors to establish possible dose effects.

Main Outcome Measures

Angle of arrest (XV1) and angle of catch (XV3) were assessed with the Tardieu scale, and active range of motion (XA).


At each muscle group level (finger, wrist, and elbow flexors) improvements in all outcome measures assessed (XV1, XV3, XA) were observed. In each muscle group, increases in abobotulinumtoxinA dose were associated with greater improvements in XV3 and XA, suggesting a dose-dependent effect.


Previous clinical trials have established the clinical efficacy of abobotulinumtoxinA by total dose only. The wide range of abobotulinumtoxinA doses per muscle groups used in this study allowed observation of dose-dependent improvements in spasticity and active movement. This information provides a basis for future abobotulinumtoxinA dosing recommendations for health care professionals based on treatment objectives and quantitative assessment of spasticity and active range of motion at individual joints.


Upper limb spasticity (ULS) is a common symptom after stroke and traumatic brain injury (TBI) and is associated with impaired self-care and additional burden of care [1-5]. Among several treatment strategies, guidelines recommend intramuscular botulinum toxin injections as a first-line treatment for adults with ULS [6-11].

Botulinum toxin type A (BoNT-A) injections may target upper extremity muscle groups from the shoulder, to decrease adductor and internal rotation tone, to the elbow, wrist, fingers, and thumb, to decrease flexor tone [12,13]. Specific muscle selection is based on the pattern of muscle overactivity, functional deficits, and patient goals [6]. These goals include increased passive and active range of motion, improved function (feeding and dressing), easier care (palmar and axillary hygiene), and reduction of pain [13].

Evidence-based information on optimal dosing for clinical use is relatively sparse. Dosing is not interchangeable between different BoNT-A products; therefore, improving our understanding of product-specific dosing will minimize confusion among injectors and improve the quality of patient care [13].

Among BoNT-A formulations, abobotulinumtoxinA (Dysport; Galderma Laboratories, LP, Fort Worth, TX) has been shown to decrease muscle tone (as measured by the Modified Ashworth Scale [MAS]) [13-17] and pain [18] and to facilitate goal attainment [19] in adults with ULS. A recent systematic review [13] of 12 randomized controlled trials (RCTs) in ULS concluded that abobotulinumtoxinA (total dose range, 500-1500 U) was generally well-tolerated, with “strong evidence” to support reduced muscle tone.

This paper presents the results of a secondary analysis from a recently published large international clinical trial, demonstrating improved active range of motion after abobotulinumtoxinA treatment in adults with hemiparesis and ULS >6 months after stroke or TBI [20]. This phase 3, randomized, double-blind, placebo-controlled study demonstrated that a total dose of either 500 U or 1000 U abobotulinumtoxinA injected in the upper extremity also resulted in decreased muscle tone and improvements in global physician-assessed clinical benefit compared with placebo.

Apart from a systematic measurement of active range of motion (XA) against finger, wrist, and elbow flexors, another unique aspect of the trial was the assessment of spasticity at the finger, wrist, and elbow flexor groups with the Tardieu scale (TS) [21,22]. The TS is a standardized evaluation used to assess the angle of arrest at slow speed (ie, passive range of motion, XV1) and the angle of catch at fast speed (XV3). The trial demonstrated improvements for finger, wrist, and elbow joints at week 4 in XV3 at both abobotulinumtoxinA doses and in XA at 1000 U; for the 500-U dose, improvements in XA were seen in the finger flexors. Both doses were associated with a favorable safety profile [20]. This analysis aims to provide a detailed description of improvements in spasticity and the active range of motion for individual muscle groups by dose and to provide information on muscle-specific dosing, which can be used in future recommendations for injectors.

Continue —> Dose-Dependent Effects of Abobotulinumtoxina (Dysport) on Spasticity and Active Movements in Adults With Upper Limb Spasticity: Secondary Analysis of a Phase 3 Study – ScienceDirect


Figure 1. Change from baseline of Tardieu scale parameters and of active range of motion week 4 postinjection in (A) extrinsic finger flexors, (B) wrist flexors, and (C) elbow flexors. Dose groups were as follows (lowest to highest dose): 500 U/non-PTMG, 500 U/PTMG, 1000 U/non-PTMG, and 1000 U/PTMG. Standard deviations and mean change from baseline values are detailed in Table 3. PTMG = primary targeted muscle group; XV1 = passive range of motion; XV3 = angle of catch at fast speed; XA = active range of motion.

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Objective: The main aim of this study was to determine
the utilization patterns and effectiveness of onabotulinumtoxinA (Botox®) for treatment of spasticity in clinical practice.

Design: An international, multicentre, prospective, observational study at selected sites in North America, Europe, and Asia.

Patients: Adult patients with newly diagnosed or established focal spasticity, including those who had previously received treatment with onabotulinumtoxinA.

Methods: Patients were treated with onabotulinumtoxinA, approximately every 12 weeks, according to their physician’s usual clinical practice over a period of up to 96 weeks, with a final follow-up interview at 108 weeks. Patient, physician and caregiver data were collected.

Results: Baseline characteristics are reported. Of the 745 patients enrolled by 75 healthcare providers from 54 sites, 474 patients had previously received onabotulinumtoxinA treatment for spasticity. Lower limb spasticity was more common than upper limb spasticity, with stroke the most common underlying aetiology. The Short-Form 12 (SF-12) health survey scores showed that patients’ spasticity had a greater perceived impact on physical rather than mental aspects.

Conclusion: The data collected in this study will guide the development of administration strategies to optimize the effectiveness of onabotulinumtoxinA in the management of spasticity of various underlying

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[Abstract] Efficacy and safety of botulinum toxin type A for upper limb spasticity after stroke or traumatic brain injury: a systematic review with meta-analysis.



Muscle spasticity is a positive symptom after stroke and traumatic brain injury. Botulinum toxin type A (BoNT-A) injection is widely used for treating post stroke and traumatic brain injury spasticity. This study aimed to evaluate efficacy and safety of BoNT-A for upper limb spasticity after stroke and traumatic brain injury and investigate reliability and conclusiveness of available evidence for BoNT-A intervention.


We searched electronic databases from inception to September 10 of 2016. Randomized controlled trials comparing the effectiveness between BoNT-A and placebo in stroke or traumatic brain injury adults with upper limb spasticity were included. Reliability and conclusiveness of the available evidence were examined with trial sequential analysis.


From 489 citations identified, 22 studies were included, reporting results for 1804 participants. A statistically significant decrease of muscle tone was observed at each time point after BoNT-A injection compared to placebo (SMD at week 4=-0.98, 95% CI: -1.28 to -0.68; I2=66%, P=0.004; SMD at week 6=-0.85, 95% CI: -1.11 to -0.59, I2=1.2%, P=0.409; SMD at week 8=-0.87, 95% CI: -1.15 to -0.6, I2=0%, P=0.713; SMD at week 12=-0.67, 95% CI: -0.88 to -0.46, I2=0%, P=0.896; and SMD over week 12=-0.73, 95% CI: -1.21 to -0.24, I2=63.5%, P=0.065).Trial sequential analysis showed that as of year 2004 sufficient evidence had been accrued to show significant benefit of BoNT-A four weeks after injection over placebo control. BoNT-A treatment also significantly reduced Disability Assessment Scale Score than placebo at 4, 6 and 12-week follow-up period (WMD=-0.33, 95% CI: -0.63 to -0.03, I2=60%, P=0.114; WMD=-0.54, 95% CI: -0.74 to -0.33, I2= 0%, P=0.596 and WMD=-0.3, 95% CI: -0.45 to -0.14, I2=0%, P=0.426 respectively), and significantly increased patients’ global assessment score at week 4 and 6 after injection (SMD=0.56, 95% CI: 0.28 to 0.83; I2=0%, P=0.681 and SMD=1.11, 95% CI: 0.4 to 1.77; I2=72.8%, P=0.025 respectively). No statistical difference was observed in the frequency of adverse events between BoNT-A and placebo group (RR=1.36, 95% CI [0.82, 2.27]; I2=0%, P=0.619).


As compared with placebo, BoNT-A injections have beneficial effects with improved muscle tone and well-tolerated treatment for patients with upper limb spasticity post stroke or traumatic brain injury.

Source: Efficacy and safety of botulinum toxin type A for upper limb spasticity after stroke or traumatic brain injury: a systematic review with meta-analy… – PubMed – NCBI

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[ARTICLE] Rehabilitation plus OnabotulinumtoxinA Improves Motor Function over OnabotulinumtoxinA Alone in Post-Stroke Upper Limb Spasticity: A Single-Blind, Randomized Trial – Full Text HTML


Background: OnabotulinumtoxinA (BoNT-A) can temporarily decrease spasticity following stroke, but whether there is an associated improvement in upper limb function is less clear. This study measured the benefit of adding weekly rehabilitation to a background of BoNT-A treatments for chronic upper limb spasticity following stroke. Methods: This was a multi-center clinical trial. Thirty-one patients with post-stroke upper limb spasticity were treated with BoNT-A. They were then randomly assigned to 24 weeks of weekly upper limb rehabilitation or no rehabilitation. They were injected up to two times, and followed for 24 weeks. The primary outcome was change in the Fugl–Meyer upper extremity score, which measures motor function, sensation, range of motion, coordination, and speed. Results: The ‘rehab’ group significantly improved on the Fugl–Meyer upper extremity score (Visit 1 = 60, Visit 5 = 67) while the ‘no rehab’ group did not improve (Visit 1 = 59, Visit 5 = 59; p = 0.006). This improvement was largely driven by the upper extremity “movement” subscale, which showed that the ‘rehab’ group was improving (Visit 1 = 33, Visit 5 = 37) while the ‘no rehab’ group remained virtually unchanged (Visit 1 = 34, Visit 5 = 33; p = 0.034). Conclusions: Following injection of BoNT-A, adding a program of rehabilitation improved motor recovery compared to an injected group with no rehabilitation.

1. Introduction

While several blinded and open-label studies have demonstrated the ability of botulinum toxin to temporarily decrease spasticity following stroke, as measured by standard assessments such as the Modified Ashworth Scale [1,2,3,4,5,6,7,8], the ability of botulinum toxin to improve upper limb function following stroke is less clear, with some studies [1,3,4,5,6,7,8], though not all [2,7], reporting functional improvement. Two recent meta-analyses of randomized controlled trials demonstrated that botulinum toxin treatment resulted in a moderate improvement in upper limb function [9,10]. Despite large clinical trials [2,3,11] and FDA approval, the exact timing, use of adjunct rehabilitation, and continuation of lifelong botulinum toxin treatment remains unclear [12,13].
A recent Cochrane Review included three randomized clinical trials for post-stroke spasticity involving 91 participants [14]. It aimed to determine the efficacy of multidisciplinary rehabilitation programs following treatment with botulinum toxin, and found some evidence supporting modified constraint-induced movement therapy and dynamic elbow splinting. There have been varied study designs exploring rehabilitation in persons after the injection of botulinum toxin or a placebo [13,15], rehabilitation in persons after the injection of botulinum toxin or no injection [16], or rehabilitation after the injection of botulinum toxin with no control condition [17]. As the use of botulinum toxin expands and is beneficial in reducing spasticity and costs [18], the benefit of adding upper limb rehabilitation continues to be questioned. We designed this multi-center, randomized, single-blind clinical trial to assess improvement in patient sensory and motor outcome following the injection of onabotulinumtoxinA (BoNT-A), comparing the effects of rehabilitation versus no rehabilitation, using the upper extremity portion of the Fugl–Meyer Assessment of Sensorimotor Recovery After Stroke [19] as the primary outcome measure. While patients could not be blinded to their randomization to receive additional rehabilitation versus no rehabilitation, the assessments of all of the outcome measures were performed by evaluators blinded to rehabilitation assignment in this single-blind design.

2. Results

Thirty-one patients with post-stroke upper limb spasticity were enrolled, with 29 completing the study (Figure 1). The strokes occurred an average of 6 years prior to study entry, with a range of 6 months to 16½ years. The upper extremity postures treated included flexed elbow, pronated forearm, flexed wrist, flexed fingers, and clenched fist, and were evenly distributed between the treatment groups (the initial dose of BoNT-A administered was left up to the clinician’s judgment based on the amount of spasticity present, and did not differ between groups). One participant (‘no rehab’, injected at Visits 1 and 3A) left the study after Visit 3A due to a deterioration in general health and an inability to travel to study visits. A second participant (‘no rehab’, injected at Visits 1 and 3A) left the study after Visit 4 due to a fall with a broken affected wrist. All of the participants were injected at Visit 1, 19 were injected at Visit 3 (8 ‘rehab’; 11 ‘no rehab’), and 7 were injected at Visit 3A (3 ‘rehab’; 4 ‘no rehab’). Those participants who did not receive injections at Visits 3 or 3A had a level of spasticity that either did not meet the injection criteria due to an Ashworth score of <2 in the wrist (and/or fingers) or one that was felt to be too low to warrant injection. Table 1 provides a description of each group with regard to age, sex, race, whether the stroke occurred in the dominant hemisphere, and clinical measures. At baseline, the treatment groups did not differ on any demographic or clinical variables. […]

Continue—>  Toxins | Free Full-Text | Rehabilitation plus OnabotulinumtoxinA Improves Motor Function over OnabotulinumtoxinA Alone in Post-Stroke Upper Limb Spasticity: A Single-Blind, Randomized Trial | HTML

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[Abstract] Effects of dextroamphetamine in subacute traumatic brain injury: A randomized, placebo‐controlled pilot study


Psychostimulants that affect neurotransmitters implicated in cognitive function and neural plasticity have potential to enhance the rate and extent of recovery after traumatic brain injury (TBI). Ten milligrams dextroamphetamine (DEX) or an identical placebo was administered daily for 3 weeks to 32 participants with moderate to severe TBI, engaged in inpatient rehabilitation, at a mean of 2 months post injury. A variety of outcome measures assessing cognitive function and overall functional status was administered at weekly intervals, to examine effect sizes that may inform a larger trial, and to evaluate safety. Results indicated trivial-to-small effect sizes for DEX-placebo differences, with the largest effects seen on speed of information processing (more improvement with DEX) and agitation (exacerbation with DEX). Examination of adverse events and vital signs suggested safety of DEX, but the pattern of results did not suggest accelerated recovery due to the drug. Future trials of DEX in this population need to consider the impact of floor effects of commonly used measures of cognitive and physical function, and the heterogeneity of TBI. Although the small sample precludes definitive conclusions, these findings are not encouraging with regard to clinical trials of DEX in subacute TBI.

Source: Effects of dextroamphetamine in subacute traumatic brain injury: A randomized, placebo‐controlled pilot study

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[ARTICLE] Practice patterns for spasticity management with phenol neurolysis – Full Text HTML


Objective: To present practice patterns for phenol neurolysis procedures conducted for spasticity management.

Design: A retrospective review of 185 persons with spasticity who underwent phenol neurolysis procedures (n = 293) at an academic rehabilitation hospital and clinic. Patient demographics, concomitant spasticity treatments, and procedure relevant information were collected.

Results: The cohort included 71.9% males and 61.6% inpatient procedures. Neurological diagnoses included stroke (41.0%), traumatic brain injury (28.6%) and spinal cord injury (24.3%). Musculoskeletal diagnoses included spastic hemiplegia or paresis (51.3%), tetraplegia (38.4) and paraplegia (9.2%). At the time of phenol neurolysis, most patients (77.5%) received concomitant pharmacological treatments for spasticity. Injection guidance modalities included electrical stimulation and ultrasound (69.3%) or ultrasound only (27.3%). A mean of 3.48 ml of phenol were injected per nerve and 10.95 ml of phenol were used per procedure. Most commonly injected nerves included the obturator nerve (35.8%) and sciatic branches to the hamstrings and adductor magnus (27.0%). Post-phenol neurolysis assessment was recorded in 54.9% of encounters, in which 84.5% reported subjective benefit. Post-procedure adverse events included pain (4.0%), swelling and inflammation (2.7%), dysaesthesia (0.7%) and hypotension (0.7%).

Conclusion: Phenol neurolysis is currently used to reduce spasticity for various functional goals, including preventing contractures and improving gait. Depending on the pattern of spasticity displayed, numerous peripheral nerves in the upper and lower extremities can be targeted for treatment with phenol neurolysis. Further research into its role in spasticity management, including studies exploring its cost-effectiveness and pharmacological and side-effects compared with other treatment options are needed.


Characterized by hyperexcitable stretch reflexes that increase muscle tonicity and exaggerate tendon jerks, spasticity is a common motor disorder that follows a variety of central nervous system insults (1). Implicated neurological insults most often include stroke, traumatic brain injury (TBI) or spinal cord injury (SCI). Spasticity is often associated with various complications including joint contractures, muscle shortening and postural deformities (1) that lead to multiple impairments. Early goal-directed spasticity management is instrumental in helping increase the likelihood of good outcomes and limiting complications (1, 2). Unfortunately, a lack of universally standardized management and an abundance of therapeutic options make spasticity management a challenging task.

Currently, spasticity is frequently managed through a combination of therapeutic modalities, pharmaceutical options and surgical procedures (3). Pharmaceutical options include medications delivered orally, via local injections, or through intrathecal pumps. Oral medications, including baclofen and tizanidine, help decrease spasticity (3). However, systemic side-effects, such as generalized muscle weakness, sedation, confusion, and hypotension, preclude the use of higher dosages that might be warranted for control of moderate-to-severe spasticity (3, 4). Intrathecal baclofen pump (ITB) is often indicated in treating severe and/or diffuse spasticity as a means to deliver high-dosage baclofen with less concern for systemic side-effects (4). Although ITB treatment is very effective, numerous complications and the requirement for commitment to maintenance associated with this treatment makes it favourable only for some patients with severe spasticity (4, 5).

Chemoneurolysis via localized injections can help provide focal spasticity relief (1, 3, 6). In addition, the use of single-event multi-level chemoneurolysis helps treat several areas of muscle spasticity, each with varying severities (7). Medications used in chemo-neurolysis procedures include botulinum neurotoxin (BoNT), phenol, and alcohol neurolysis (3–7). Compared with phenol and the understudied alcohol neurolysis, BoNT usage in treating spasticity is documented extensively in the literature with regards to pharmacodynamics, adverse effects and clinical benefits (7–9). However, the response to chemodenervation with BoNT often requires 3–5 days to generate spasticity benefit, which generally lasts approximately 3 months. Although clinical standards permit repeating chemodenervation every 3 months, the majority of patients with spasticity prefer an increased frequency for maintaining clinical benefit (10–12). BoNT injections are associated with significant costs, and repeated injections are often further restricted by financial feasibility. In the USA, depending on the insurance being used, the approved dosage of BoNT is only 400–600 units of every 3 months. These limitations prevent the sole utility of chemodenervation for a multi-pattern treatment, e.g. elbow flexion, clenched fist, stiff knee gait, and equinovarus of the foot. Consequently, phenol neurolysis (PN) and BoNT are used in complement, with PN frequently reserved for proximal nerves and BoNT used for distal musculature.

In contrast, PN produces an almost-immediate effect that manifests within minutes of injection, which may last as long as 6 months depending on the dosage used (1, 13). In addition, PN is significantly less expensive. PN may also be re-injected before 3 months, unlike BoNT. However, the safety and efficacy of PN is less-commonly documented in the literature than BoNT chemodenervation. PN also requires a higher level of expertise to administer, and has a worse side-effect profile, which includes hypotension, prolonged pain, dysaesthesias, site inflammation, and joint fibrosis (1, 13, 14). These disadvantages for phenol usage are associated with safety concerns relative to neurotoxins, thus making BoNT a vastly more popular option for chemoneurolysis. Phenol is therefore being used increasingly less in the USA and is poorly documented in the spasticity literature. Given its advantages, PN may be superior to chemodenervation with BoNT in certain clinical scenarios. Thus, the primary purpose of the current study is to describe the utilization pattern of PN at a single site.


Continue —> Journal of Rehabilitation Medicine – Practice patterns for spasticity management with phenol neurolysis – HTML

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[ARTICLE] Role of Interleukin-10 in Acute Brain Injuries – Full Text


Interleukin-10 (IL-10) is an important anti-inflammatory cytokine expressed in response to brain injury, where it facilitates the resolution of inflammatory cascades, which if prolonged causes secondary brain damage. Here, we comprehensively review the current knowledge regarding the role of IL-10 in modulating outcomes following acute brain injury, including traumatic brain injury (TBI) and the various stroke subtypes. The vascular endothelium is closely tied to the pathophysiology of these neurological disorders and research has demonstrated clear vascular endothelial protective properties for IL-10. In vitro and in vivo models of ischemic stroke have convincingly directly and indirectly shown IL-10-mediated neuroprotection; although clinically, the role of IL-10 in predicting risk and outcomes is less clear. Comparatively, conclusive studies investigating the contribution of IL-10 in subarachnoid hemorrhage are lacking. Weak indirect evidence supporting the protective role of IL-10 in preclinical models of intracerebral hemorrhage exists; however, in the limited number of clinical studies, higher IL-10 levels seen post-ictus have been associated with worse outcomes. Similarly, preclinical TBI models have suggested a neuroprotective role for IL-10; although, controversy exists among the several clinical studies. In summary, while IL-10 is consistently elevated following acute brain injury, the effect of IL-10 appears to be pathology dependent, and preclinical and clinical studies often paradoxically yield opposite results. The pronounced and potent effects of IL-10 in the resolution of inflammation and inconsistency in the literature regarding the contribution of IL-10 in the setting of acute brain injury warrant further rigorously controlled and targeted investigation.


Stroke and traumatic brain injury (TBI) are devastating acute neurological disorders that can result in high mortality rates or long-lasting disability. Approximately 87% of strokes are ischemic and 13% are hemorrhagic, with 10 and 3% of the latter representing intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), respectively (1). Stroke is the fourth most common cause of death in the United States, and ischemic stroke (IS) in particular is the seventh most frequent emergency department presentation (2, 3). TBI and concussions have over twice the incidence of all strokes combined (4), with more than three million people in the United States alone living with long-term disability as a result of TBI (5). Collectively, stroke and TBI have very few treatments, and despite advances in clinical management of these disorders, they are still associated with significant disability and mortality (6, 7).

Inflammation plays a central role in the pathophysiology of stroke and TBI and can have both protective and harmful effects on brain tissue (815). Although there are some distinct differences in the inflammatory cascades following the various types of acute brain injury, there are also numerous commonalities. Acute neuroinflammation is characterized by the activation of resident central nervous system (CNS) immune surveillance glial cells that release cytokines, chemokines, and other immunologic mediators, which facilitate the recruitment of peripheral cells such as monocytes, neutrophils, and lymphocytes (8, 9, 12, 15). Collectively, this initial response is helpful in the clearance of toxic entities and the restoration and repair of damaged tissue. However, during the resolution phase, with an uncontrolled and prolonged inflammatory response, secondary damage results from overactivation of this inflammatory surge and release of additional factors that led to breakdown of the blood–brain barrier (BBB), cerebral edema, cerebral hypertension, and ischemia.

Interleukin-10 is generally known as an anti-inflammatory cytokine that exerts a plethora of immunomodulatory functions during an inflammatory response and is particularly important during the resolution phase. Expression of IL-10 in the brain increases with CNS pathology, promoting neuronal and glial cell survival, and dampening of inflammatory responses via a number of signaling pathways (16). IL-10 was originally described as cytokine synthesis inhibitory factor and in addition to attenuating the synthesis of proinflammatory cytokines, IL-10 also limits inflammation by reducing cytokine receptor expression and inhibiting receptor activation (16). Furthermore, IL-10 has potent and diverse effects on essentially all hematopoetic cells that infiltrate the brain following injury. For example, IL-10 reduces the activation and effector functions of T cells, monocytes, and macrophages, ultimately ending the inflammatory response to injury (17). The structure, function, and regulation of IL-10 have been extensively reviewed elsewhere, including a review of IL-10 in the brain (1620), although not in the context of the various forms of acute brain injury. Please refer to the aforementioned reviews for additional details, including the potential cellular sources, target cells, signal transduction, and mode of action of IL-10.

Given the intriguing multifactorial role of IL-10 in the resolution of inflammatory cascades that are important for promoting neurologic recovery from acute brain injury, here we present a comprehensive literature review of preclinical and clinical studies in this area. We focus on the contribution of IL-10 in modulating various important parameters and pathophysiologic processes important for IS, SAH, ICH, and TBI outcomes, and whether IL-10 has therapeutic or biomarker potential. A better understanding of the many functions of IL-10 in the brain after injury, particularly in the resolution phase of inflammatory processes, will promote our knowledge of the pathophysiology of these debilitating disorders and guide future development of novel therapeutic approaches.[…]

Continue —> Frontiers | Role of Interleukin-10 in Acute Brain Injuries | Neurology

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