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Medical cannabis in children with complex motor disorders
... Beberapa negara telah lebih dulu memanfaatkan ganja sebagai terapi medis. Seperti Jerman yang pada tahun 2017 resmi memperbolehkan warga negaranya untuk mengonsumsi ganja dengan syarat yaitu sedang sakit parah, telah berkonsultasi dengan dokter, dan tidak memiliki alternatif terapi medis lainnya (Berlinger, 2016). Kemudian di Kanada, ganja dapat digunakan untuk kepentingan medis dengan ketentuan telah terotorisasi dengan penyedia layanan kesehatan yang resmi dan terdaftar dengan perusahaan yang telah memiliki lisensi penjualan ganja dari pemerintah atau departemen kesehatan Kanada (Government of Canada, 2020). ...
... Sementara itu beberapa peneliti telah mempublikasikan sejumlah manfaat dari ganja medis yakni dapat untuk mengobati mual dan muntah yang disebabkan oleh kemoterapi (Whitcomb et al., 2019), gangguan motorik kompleks pada anak (Blimkin et al., 2017), juga kejang epilepsi (Maa & Figi, 2014). Dalam penelitian lainnya, pemakaian ganja medis dalam dosis rendah untuk pengobatan neuropatik terbukti aman tidak memiliki efek jangka pendek, meskipun masih perlu ada penelitian lanjutan untuk melihat efek jangka panjang dari pemakaian ganja medis tersebut (Lee, Grovey, Furnish, & Wallace, 2018). ...
Kebijakan terkait penggunaan ganja untuk pengobatan, meredakan, atau mengurangi gejala penyakit masih menjadi perdebatan di banyak negara, termasuk Indonesia. Artikel ini bertujuan untuk mengetahui narasi yang dibangun oleh pemerintah terkait dengan kebijakan ganja medis di Indonesia, menganalisis hambatan dari narasi kebijakan ganja medis, dan merumuskan alternatif strategi yang dapat dilakukan oleh pemerintah untuk menguatkan kebijakan ganja medis di Indonesia. Penelitian ini menggunakan Analisis Naratif Kebijakan (Narrative Policy Analysis/NPA) untuk menganalisis disparitas naratif dari kebijakan pemerintah tentang ganja medis dan menentukan bentuk naratifnya seperti tingkat analisis, setting, karakter, plot, dan moral dari narasi kebijakan. Data dikumpulkan dari dokumen online terpercaya seperti data publik, pemberitaan media, atau transkrip pidato yang relevan dengan masalah penelitian dari Januari 2019 s/d Desember 2020. Kesimpulan dari penelitian ini adalah 1) Pemerintah tetap melarang adanya pemanfaatan ganja untuk kepentingan medis dengan tujuan untuk melindungi seluruh masyarakat Indonesia dari masalah baru yang berisiko muncul; 2) Hambatan dari narasi kebijakan yang dibangun oleh pemerintah yaitu adanya perbedaan belief system terhadap tanaman ganja serta belum adanya kajian empiris tentang pemanfaatan ganja untuk kepentingan medis di Indonesia; 3) Rekomendasi strategi untuk memperkuat narasi kebijakan pemerintah terkait dengan pemanfaatan ganja medis di antaranya membuka ruang diskusi dengan kelompok masyarakat yang kontra narasi, melakukan uji empiris dengan melibatkan akademisi untuk memperkuat argumen dan narasi kebijakan pemerintah, serta mensosialisasikan kebijakan ganja medis ke berbagai stakeholder terkait.
Marijuana and marijuana-based products have been used to treat medical disease. Recently, derivatives of the plant have been separated or synthesized to treat various neurological disorders, many of them affecting children. Unfortunately, data are sparse in regard to treating children with neurologic illness. Therefore, formal conclusions about the potential efficacy, benefit, and adverse effects for these products cannot be made at this time. Further robust research using strong scientific methodology is desperately needed to formally evaluate the role of these products in children.
© The Author(s) 2015.
This retrospective study aimed to assess the safety of patients with severe cerebral palsy (CP), who received allogeneic umbilical cord blood stem cells (UCBSCs) treatment from August 2009 to December 2012 in Guangdong Provincial Hospital of Chinese Medicine. A total of 47 patients with average age of
5.85
±
6.12
years were evaluated in this study. There was no significant association with allogeneic UCBSCs treatments found in the data of the laboratory index . No casualties occurred. Some adverse events during treatments were found in 26 (55.3%) patients, including fever (42.6%) and vomiting (21.2%). Intrathecal infusion and the ages at the initiation of treatment (≤10 years old) were risk factors for the occurrence of adverse events by logistic regression analysis. However, all adverse events disappeared after symptomatic treatment. No treatment related serious adverse events were found in follow-up visits within 6 months. In conclusion, allogeneic UCBSCs treatment was relatively safe for severe CP patients.
Aim:
The purpose of this study was to review published research on the use of the Gross Motor Function Measure (GMFM-88) and (GMFM-66) as outcome measures to determine if these tools detect changes in gross motor function in children with cerebral palsy (CP) undergoing interventions.
Methods:
A comprehensive literature search was conducted using Medline and PubMed to identify studies published from January 2000 through January 2011 that reported the accuracy of GMFM-88 and GMFM-66 to measure changes over time in children with CP undergoing interventions. The keywords used for the search were "GMFM" and "CP". Two of the authors (M.A. and S.B.) reviewed the titles and abstracts found in the databases. The methodological quality of the studies was assessed by using the Critical Review Form-Quantitative Studies.
Results:
Of 62 papers initially identified, 21 studies fulfilled the inclusion criteria. These articles consist of three longitudinal studies, six randomized controlled trials, four repeated measure design, six pre-post test design, a case series and one non-randomized prospective study. The included studies were generally of moderate to high methodological quality. The studies included children from a wide age range of 10 months to 16 years. According to the National Health and Medical Research Council, the study designs were level II, III-2, III-3 and IV.
Conclusion:
The review suggests that the GMFM-88 and GMFM-66 are useful as outcome measures to detect changes in gross motor function in children with CP undergoing interventions. Implications for Rehabilitation Accurate measurement of change in gross motor skill acquisition is important to determine effectiveness of intervention programs in children with cerebral palsy (CP). The Gross Motor Function Measure (GMFM-88 and GMFM-66) are common tools used by rehabilitation specialists to measure gross motor function in children with CP. The GMFM appears to be an effective outcome tool for measuring change in gross motor function according to a small number of randomized control studies utilizing participant populations of convenience.
Background:
The Gross Motor Function Measure (GMFM-88) is commonly used in the evaluation of gross motor function in children with cerebral palsy (CP). The relative reliability of GMFM-88 has been assessed in children with CP. However, little information is available regarding the absolute reliability or responsiveness of GMFM-88.
Objective:
The purpose of this study was to determine the absolute and relative reliability and the responsiveness of the GMFM-88 in evaluating gross motor function in children with CP.
Design:
A clinical measurement design was used.
Methods:
Ten raters scored the GMFM-88 in 84 children (mean age=3.7 years, SD=1.9, range=10 months to 9 years 9 months) from video records across all Gross Motor Function Classification System (GMFCS) levels to establish interrater reliability. Two raters participated to assess intrarater reliability. Responsiveness was determined from 3 additional assessments after the baseline assessment. The interrater and intrarater intraclass correlation coefficients (ICCs) with 95% confidence intervals, standard error of measurement (SEM), smallest real difference (SRD), effect size (ES), and standardized response mean (SRM) were calculated.
Results:
The relative reliability of the GMFM was excellent (ICCs=.952-1.000). The SEM and SRD for total score of the GMFM were acceptable (1.60 and 3.14, respectively). Additionally, the ES and SRM of the dimension goal scores increased gradually in the 3 follow-up assessments (GMFCS levels I and II: ES=0.5, 0.6, and 0.8 and SRM=1.3, 1.8, and 2.0; GMFCS levels III-V: ES=0.4, 0.7, and 0.9 and SRM=1.5, 1.7, and 2.0).
Limitations:
Children over 10 years of age with CP were not included in this study, so the results should not be generalized to all children with CP.
Conclusions:
Both the reliability and the responsiveness of the GMFM-88 are reasonable for measuring gross motor function in children with CP.
There are many misconceptions about what constitutes 'quality of life' (QoL). It is often difficult for researchers and clinicians to determine which instruments will be most appropriate to their purpose. The aim of the current paper is to describe QoL instruments for children and adolescents with neurodisabilities against criteria that we think are important when choosing or developing a QoL instrument.
QoL instruments for children and adolescents with neurodisabilities were reviewed and described based on their purpose, conceptual focus, origin of domains and items, opportunity for self report, clarity (lack of ambiguity), potential threat to self-esteem, cognitive or emotional burden, number of items and time to complete, and psychometric properties.
Several generic and condition-specific instruments were identified for administration to children and adolescents with neurodisabilities - cerebral palsy, epilepsy and spina bifida, and hydrocephalus. Many have parent-proxy and self-report versions and adequate reliability and validity. However, they were often developed with minimal involvement from families, focus on functioning rather than well-being, and have items that may produce emotional upset.
As well as ensuring that a QoL instrument has sound psychometric properties, researchers and clinicians should understand how an instrument's theoretical focus will have influenced domains, items, and scoring.
Because of the availability of new knowledge about the neurobiology of developmental brain injury, information that epidemiology and modern brain imaging is providing, the availability of more precise measuring instruments of patient performance, and the increase in studies evaluating the efficacy of therapy for the consequences of injury, the need for reconsideration of the definition and classification of cerebral palsy (CP) has become evident. Pertinent material was reviewed at an international symposium participated in by selected leaders in the preclinical and clinical sciences. Suggestions were made about the content of a revised definition and classification of CP that would meet the needs of clinicians, investigators, and health officials, and provide a common language for improved communication. With leadership and direction from an Executive Committee, panels utilized this information and have generated a revised Definition and Classification of Cerebral Palsy. The Executive Committee presents this revision and welcomes substantive comments about it.
Dystonia is one of the most frequent movement disorders in childhood. It can impede normal motor development and cause significant motor disability. The diagnostic evaluation of childhood dystonia is challenging due to the phenotypic variability and heterogeneous etiologies. Evidence to guide the diagnostic evaluation and treatment is limited. Assessment is primarily directed by clinical history and distinctive examination findings. Neuroimaging is typically necessary to evaluate for acquired or complex inherited dystonias. A trial of levodopa can be both diagnostic and therapeutic in children with dopa-responsive dystonia. However, for the majority of children with early-onset dystonia, treatment is symptomatic with varying efficacy. There is a paucity of therapeutic trials for childhood dystonia and most treatment recommendations are consensus or expert opinion driven. This review summarizes the available evidence and guidelines on the diagnostic evaluation and pharmacological treatment of childhood-onset dystonia and provides practical frameworks to approach both issues based on best evidence.
This article has no abstract; the first 100 words appear below.
Medicinal cannabis is a hot-button issue in the treatment of epilepsy. The issue of its use is frequently raised in medical consultations, in the lay press, in social media, and at scientific meetings where the lack of hard data is disheartening. Anecdotal media reports of spectacular results, coupled with the allure of using a “natural” compound and long-held beliefs surrounding its recreational use, plus the fact that medicinal cannabis remains illegal in many jurisdictions, have conspired to make it extremely difficult for physicians to provide advice in this area. That it has been advocated particularly for desperately ill children adds . . .
Disclosure forms provided by the authors are available with the full text of this editorial at NEJM.org.
Source Information
From the Epilepsy Research Centre, University of Melbourne at Austin Health, Heidelberg, VIC, Australia.
Background
The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.
Methods
In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.
Results
The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, −22.8 percentage points; 95% confidence interval [CI], −41.1 to −5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.
Conclusions
Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375.)
Background:
In non-walking children with severe spasticity, daily care can be difficult and many patients suffer from pain. Selective dorsal rhizotomy (SDR) reduces spasticity in the legs, and therefore has the potential to improve daily care and comfort.
Aim:
To examine effects of SDR on daily care and comfort in non-walking children with severe spasticity due to different underlying neurological conditions.
Methods:
Medical history, changes in daily care and comfort and satisfaction with outcome were assessed retrospectively in non-walking children who underwent SDR in our center, with a mean follow-up of 1y 7m (range 11m-4y 3m). All eligible patients (n = 24, years 2009-2014) were included.
Results:
Mean age at SDR was 12y 4m (SD 4y 3m, range 2y 8m-19y 3m). Associated orthopaedic problems were frequent. Seven patients underwent scoliosis correction in the same session. Most improvements were reported in dressing (n = 16), washing (n = 12) and comfort (n = 10). Median score for satisfaction was 7 on a scale of 10 (range 1-9). SDR resulted in reduction of spasticity in leg muscles. In nine patients dystonia was recorded post-operatively, mainly in children with congenital malformations and syndromes.
Interpretation:
SDR is a single event intervention that can improve daily care and comfort in non-walking children with severe spasticity, and can safely be combined with scoliosis correction. Despite the improvements, satisfaction is variable. Careful attention is necessary for risk factors for dystonia, which may be unmasked after SDR.
Deep Brain Stimulation (DBS) has become a mainstay of dystonia management in adulthood. Typically targeting electrode placement in the GPi, sustained improvement in dystonic symptoms are anticipated in adults with isolated genetic dystonias. Dystonia in childhood is more commonly a symptomatic condition, with dystonia frequently expressed on the background of a structurally abnormal brain. Outcomes following DBS in this setting are much more variable, the reasons for which have yet to be elucidated. Much of the focus on improving outcomes following DBS in dystonia management has been on the importance of patient selection, with, until recently, little discussion of the choice of target. In this review, we advance the argument that patient selection for DBS in childhood cannot be made separate from the choice of target nuclei. The anatomy of common DBS targets are considered, and factors influencing their choice for electrode insertion are discussed. We propose an ‘ABC” for DBS in childhood dystonia is proposed: Appropriate Child selected; Best nuclei chosen for electrode insertion; Correct position within that nucleus.
Background:
Cannabis extracts have a wide therapeutic potential but in many countries they have not been approved for treatment in children so far.
Objective:
We conducted an open, uncontrolled, retrospective study on the administration of dronabinol to determine the value, efficacy, and safety of cannabis-based medicines in the treatment of refractory spasticity in pediatric palliative care.
Design and participants:
Sixteen children, adolescents and young adults having complex neurological conditions with spasticity (aged 1.3-26.6 years, median 12.7 years) were treated with dronabinol by our specialized pediatric palliative care team between 01.12.2010 and 30.04.2015 in a home-care setting. Therapeutic efficacy and side effects were closely monitored.
Results:
Drops of the 2.5% oily tetrahydrocannabinol solution (dronabinol) were administered. A promising therapeutic effect was seen, mostly due to abolishment or marked improvement of severe, treatment resistant spasticity (n = 12). In two cases the effect could not be determined, two patients did not benefit. The median duration of treatment was 181 days (range 23-1429 days). Dosages to obtain a therapeutic effect varied from 0.08 to 1.0 mg/kg/d with a median of 0.33 mg/kg/d in patients with a documented therapeutic effect. When administered as an escalating dosage scheme, side effects were rare and only consisted in vomiting and restlessness (one patient each). No serious and enduring side effects occurred even in young children and/or over a longer period of time.
Conclusions:
In the majority of pediatric palliative patients the treatment with dronabinol showed promising effects in treatment resistant spasticity.
Movement disorders in children are causally and clinically heterogeneous and present in a challenging developmental context. Treatment options are broad ranging, from pharmacotherapy to invasive neuromodulation and experimental gene and stem cell therapies. The clinical effects of these therapies are variable and often poorly sustained, and only a few of the management strategies used in paediatric populations have been tested in randomised controlled studies with age-appropriate cohorts. Identification of the most appropriate treatment is uniquely challenging in children because of the incomplete knowledge about the pathophysiology of movement disorders and their influence on normal motor development; thus, effective therapeutic options for these children remain an unmet need. It is vital to transfer the expanding knowledge of the movement disorders into the development of novel symptomatic or, ideally, disease-modifying treatments, and to assess these therapeutic strategies in appropriately designed and well done trials.
An "unintended consequence" of marijuana legalization is the impact on the pediatric population. From prenatal exposure to unintentional childhood exposures, through concerns of adolescence abuse and marijuana use for medicinal indications in children, marijuana exposure can affect pediatric patients at every stage in childhood. Regardless of the stage or reason of exposure, concerns exist about short-term and long-term consequences in a child's physical and mental health. The use of cannabidiol (CBD) may have some benefit for the treatment of epilepsy, but emphasis needs to be on rigorous clinical trials to evaluate efficacy and safety. As more states allow both medical and recreational marijuana, availability and prevalence of use will likely increase and more surveillance and research is needed to evaluate the consequences on the pediatric population.
Background:
Data around current prescription practices in childhood dystonia is limited. Medication use may be limited by side effects, the incidence of which is uncertain. For a large cohort assessed by our supra-regional service we aimed to: i) Review medications used at the point of referral. ii) Determine the prevalence of adverse drug responses (ADR) resulting in discontinuation of drug use. iii) Identify clinical risk factors for ADR.
Methods:
Case note review of 278 children with dystonia referred to our service. Data collected on medications, ADR, dystonia aetiology, Gross Motor Function Classification System (GMFCS) level and motor phenotype (pure dystonia/mixed dystonia-spasticity). Logistic regression analysis was used to identify risk factors for ADR.
Results:
At referral 82/278 (29.4%) children were taking no anti-dystonic medication. In the remainder the median number of anti-dystonic medications was 2 (range 1-5). Medications use increased with worsening GMFCS level. The commonest drugs used were baclofen (118/278: 42.4%), trihexyphenidyl (98/278: 35.2%), l-Dopa (57/278: 20.5%) and diazepam (53/278: 19%). Choice of medication appeared to be influenced by dystonia aetiology. ADR had been experienced by 171/278 (61.5%) of children. The commonest drugs responsible for ADR were trihexyphenidyl (90/171: 52.3%), baclofen (43/171: 25.1%) and l-Dopa (26/171: 15.2%). Binary logistic regression demonstrated no clinical risk factors for ADR.
Conclusions:
ADR is commonly experienced by children with dystonia, regardless of dystonia severity or aetiology. A wide variation in drug management of dystonia was identified. Collectively these findings highlight the need for a rational approach to the pharmacological management of dystonia in childhood.
Public interest in the use of "medical marijuana" for the treatment of childhood epilepsy has burgeoned in the last few years. This has occurred in parallel with a growing interest in "medical marijuana" in general. Physicians and pediatricians must balance their patients' desire for immediate access to these products with the tenets of evidence-based medicine. This review discusses the biochemistry of cannabis products (the phytocannabinoids) setting this in the context of the endogenous endocannabinoid system. The differing and potentially modulating effects of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are reviewed. The evidence-base supporting or not the use of cannabis products for the treatment of neurological disease and specifically epilepsy is explored. The potential for adverse effects and particularly of neurotoxicity is addressed. Finally, public health and sociocultural implications are touched upon. Specific recommendations for interested physicians are provided including advocacy for patients and for a change in the "scheduling" of cannabis in order to better foster much-needed high-quality scientific research in this important area.
Cannabis has been used for many medicinal purposes, including management of spasms, dystonia, and dyskinesias, with variable success. Its use for tetanus was described in the second century BCE, but the literature continues to include more case reports and surveys of its beneficial effects in managing symptoms of hyperkinetic movement disorders than randomized controlled trials, making evidence-based recommendations difficult. This paper reviews clinical research using various formulations of cannabis (botanical products, oral preparations containing ∆(9)-tetrahydrocannabinol and/or cannabidiol) and currently available preparations in the USA (nabilone and dronabinol). This has been expanded from a recent systematic review of cannabis use in several neurologic conditions to include case reports and case series and results of anonymous surveys of patients using cannabis outside of medical settings, with the original evidence classifications marked for those papers that followed research protocols. Despite overlap in some patients, dyskinesias will be treated separately from dystonia and chorea; benefit was not established beyond individual patients for these conditions. Tics, usually due to Tourettes, did respond to cannabis preparations. Side effects reported in the trials will be reviewed but those due to recreational use, including the dystonia that can be secondary to synthetic marijuana preparations, are outside the scope of this paper.
The endocannabinoid system is currently defined as the ensemble of the two 7-transmembrane-domain and G protein-coupled receptors for Δ(9)-tetrahydrocannabinol (but not for most other plant cannabinoids or phytocannabinoids)-cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R); their two most studied endogenous ligands, the "endocannabinoids" N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG); and the enzymes responsible for endocannabinoid metabolism. However, anandamide and 2-AG, and also the phytocannabinoids, have more molecular targets than just CB1R and CB2R. Furthermore, the endocannabinoids, like most other lipid mediators, have more than just one set of biosynthetic and degrading pathways and enzymes, which they often share with "endocannabinoid-like" mediators that may or may not interact with the same proteins as Δ(9)-tetrahydrocannabinol and other phytocannabinoids. In some cases, these degrading pathways and enzymes lead to molecules that are not inactive and instead interact with other receptors. Finally, some of the metabolic enzymes may also participate in the chemical modification of molecules that have very little to do with endocannabinoid and cannabinoid targets. Here, we review the whole world of ligands, receptors, and enzymes, a true "endocannabinoidome", discovered after the cloning of CB1R and CB2R and the identification of anandamide and 2-AG, and its interactions with phytocannabinoids.
: Marijuana policy is rapidly evolving in the United States and elsewhere, with cannabis sales fully legalized and regulated in some jurisdictions and use of the drug for medicinal purposes permitted in many others. Amidst this political change, patients and families are increasingly asking whether cannabis and its derivatives may have therapeutic utility for a number of conditions, including developmental and behavioral disorders in children and adolescents. This review examines the epidemiology of cannabis use among children and adolescents, including those with developmental and behavioral diagnoses. It then outlines the increasingly well-recognized neurocognitive changes shown to occur in adolescents who use cannabis regularly, highlighting the unique susceptibility of the developing adolescent brain and describing the role of the endocannabinoid system in normal neurodevelopment. The review then discusses some of the proposed uses of cannabis in developmental and behavioral conditions, including attention-deficit hyperactivity disorder and autism spectrum disorder. Throughout, the review outlines gaps in current knowledge and highlights directions for future research, especially in light of a dearth of studies specifically examining neurocognitive and psychiatric outcomes among children and adolescents with developmental and behavioral concerns exposed to cannabis.
There is growing interest in the therapeutic potential of marijuana (cannabis) and cannabinoid-based chemicals within the medical community and, particularly, for neurological conditions. This interest is driven both by changes in the legal status of cannabis in many areas and increasing research into the roles of endocannabinoids within the central nervous system and their potential as symptomatic and/or neuroprotective therapies. We review basic science as well as preclinical and clinical studies on the therapeutic potential of cannabinoids specifically as it relates to movement disorders. The pharmacology of cannabis is complex, with over 60 neuroactive chemicals identified to date. The endocannabinoid system modulates neurotransmission involved in motor function, particularly within the basal ganglia. Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits, but more consistently suggest potential neuroprotective effects in several animal models of Parkinson's (PD) and Huntington's disease (HD). Clinical observations and clinical trials of cannabinoid-based therapies suggests a possible benefit of cannabinoids for tics and probably no benefit for tremor in multiple sclerosis or dyskinesias or motor symptoms in PD. Data are insufficient to draw conclusions regarding HD, dystonia, or ataxia and nonexistent for myoclonus or RLS. Despite the widespread publicity about the medical benefits of cannabinoids, further preclinical and clinical research is needed to better characterize the pharmacological, physiological, and therapeutic effects of this class of drugs in movement disorders. © 2015 International Parkinson and Movement Disorder Society.
Regulatory authorities admit clinical studies with an initial enrichment phase to select patients that respond to treatment before randomization (Enriched Design Studies; EDSs). The trial period aims to prevent long-term drug exposure risks in patients with limited chances of improvement while optimizing costs. In EDSs for symptom control therapies providing early improvements and without a wash-out period, it is difficult to show further improvements and thus large therapeutic gains versus placebo. Moreover, in trials with cannabinoids, the therapeutic gains can be further biased in the postenrichment randomized phase because of carryover and other effects. The aims of the present review article are to examine the placebo effects in the enrichment and postenrichment phases of an EDS with Δ(9) -tetrahydrocannabinol and cannabidiol (THC/CBD) oromucosal spray in patients with multiple sclerosis (MS) spasticity and to discuss the possible causes of maintained efficacy after randomization in the placebo-allocated patients. The overall mean therapeutic gain of THC/CBD spray over placebo in resistant MS spasticity after 16 weeks can be estimated as a ~1.27-point improvement on the spasticity 0-10 Numerical Rating Scale (NRS; ~-20.1% of the baseline NRS score). We conclude that careful interpretation of the results of EDSs is required, especially when cannabinoid-based medications are being investigated.
© 2014 John Wiley & Sons Ltd.
Methylphenidate (MPH) is commonly prescribed for the treatment of Attention Deficit Hyperactivity Disorder (ADHD), and is often used illicitly by young adults. Illicit users often coadminister MPH with marijuana. Little is known about physiologic and subjective effects of these substances used in combination. In this double-blind, cross-over experiment, sixteen healthy adult subjects free from psychiatric illness (including ADHD) and reporting modest levels of marijuana use participated in 6 experimental sessions wherein all combinations of placebo or 10 mg oral doses of delta-9-tetrahydocannibinol (THC); and 0 mg, 10 mg and 40 mg of MPH were administered. Sessions were separated by at least 48 hours. Vital signs, subjective effects, and performance measure were collected. THC and MPH showed additive effects on heart rate and rate pressure product (e.g., peak heart rate for 10 mg THC + 0 mg, 10 mg, and 40 mg MPH = 89.1, 95.9, 102.0 beats/min, respectively). Main effects of THC and MPH were also observed on a range of subjective measures of drug effects, and significant THC dose x MPH dose interactions were found on measures of “Feel Drug,” “Good Effects,” and “Take Drug Again.” THC increased commission errors on a continuous performance test (CPT) and MPH reduced reaction time variability on this measure. Effects of THC, MPH, and their combination were variable on a measure of working memory (n-back task), though in general, MPH decreased reaction times and THC mitigated these effects. These results suggest that the combination of low to moderate doses of MPH and THC produces unique effects on cardiovascular function, subjective effects and performance measures.
Purpose of review:
Despite widespread marijuana use among adolescents, accurate information on known health effects is poorly disseminated to clinicians and their patients. Amidst rapidly evolving drug policy in the United States and elsewhere, it is imperative that providers understand the short-term and long-term consequences of marijuana use.
Recent findings:
Research on regular marijuana use highlights a unique susceptibility of the developing adolescent brain to adverse neurocognitive and psychiatric outcomes. Although studies have not firmly established causality, onset of regular marijuana use in adolescence is associated with later decline in cognitive function, as well as with adult onset of psychosis and anxiety. Educational and employment outcomes may be poorer among regular marijuana-using adolescents. A number of other adverse respiratory, cardiovascular, endocrine and gastrointestinal associations with regular marijuana use have also been established. Good screening tools and promising brief intervention and behavioral treatment programs are available to clinicians, who are in a position to identify problematic marijuana use among adolescents.
Summary:
A common misperception among youth is that marijuana use is without harm. However, adolescent marijuana use may have measurable, durable, and potentially irreversible effects on later cognitive function and mental health.
To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Δ9-Tetrahydrocannabinol (Δ9-THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Δ9-THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Δ9-THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 and α1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Δ9-THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted.A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.
Object:
This single-center study investigated adverse events that occurred in children and adolescent patients treated with intrathecal baclofen (ITB) therapy for spasticity and/or dystonia.
Methods:
In a 14-year period, 430 consecutive patients with a mean age of 13.3 ± 5.9 years received ITB over a mean follow-up period of 8.6 ± 3.8 years (range 12 months to 14 years). Eighty-nine percent of these patients had cerebral palsy. Major complications, defined as those that required a surgical intervention, were infections, CSF leaks, and device problems related to the catheter or pump. Assessing infections, the authors compared the 2 groups of patients implanted with an ITB system by either the subcutaneous or subfascial technique. The temporal distribution of events related to the catheter was also considered.
Results:
At least 1 complication was present in 25% of the patients: 9.3% experienced an infection, 4.9% a CSF leak, 15.1% a problem with the catheter, and 1% a problem related to the pump. Five percent of the assessed patients suffered more than 1 complication. The rate of infections was significantly lower (p < 0.001) in patients with the pump placed subfascially compared with those with the pump placed subcutaneously. A higher rate of infection was found after pump replacement compared with the first pump implantation (10.6% vs 6%, respectively). Catheter problems were the most common complication and occurred more frequently during the 1st year after the implant.
Conclusions:
While ITB is an effective treatment to manage spasticity of different origins, adverse events may occur and need to be managed. The surgical procedure should be meticulous and different techniques may have a diverse impact on the infection rate, which is the most critical complication. Despite the adverse events that occurred in this study, the majority of patients were satisfied with the treatment received.
The reliability and responsiveness of the Barry-Albright Dystonia (BAD) Scale, a 5-point ordinal severity scale for secondary dystonia, was assessed. For interrater reliability, 13 raters scored 10 videotaped patients; for intrarater reliability, two raters rated the videotape again. For test-retest reliability, patients were rated on two occasions. Four inexperienced raters scored patients, received training, then scored additional patients. To assess responsiveness, we compared patient and physician global ratings of change (better, same, and worse) with BAD Scale score changes for 18 patients on intrathecal baclofen (ITB) trials. We assessed reliability with the intraclass correlation coefficient (ICC). The mean ICC for total BAD Scale scores were as follows: interrater reliability 0.866, intrarater reliability 0.967 and 0.978, test-retest reliability 0.978 (before training) and 0.967 (after training). We found the BAD Scale responsive to change, with most improved scores in patients rated by the patient, family, and neurosurgeon as 'better'. The total scores were reliable for experienced raters. We recommend training for clinicians interested in using the scale.
An initial report on the therapeutic application of delta 9-THC (THC) (Dronabinol, Marinol) in 8 children resp. adolescents suffering from the following conditions, is given: neurodegenerative disease, mitochondriopathy, posthypoxic state, epilepsy, posttraumatic reaction. THC effected reduced spasticity, improved dystonia, increased initiative (with low dose), increased interest in the surroundings, and anticonvulsive action. The doses ranged from 0.04 to 0.12 mg/kg body weight a day. The medication was given as an oily solution orally in 7 patients, via percutaneous gastroenterostomy tube in one patient. At higher doses disinhibition and increased restlessness were observed. In several cases treatment was discontinued and in none of them discontinuing resulted in any problems. The possibility that THC-induced effects on ion channels and transmitters may explain its therapeutic activity seen in epileptic patients is discussed.
The measurement of spasticity as a symptom of neurologic disease is an area of growing interest. Clinician-rated measures of spasticity purport to be objective but do not measure the patient's experience and may not be sensitive to changes that are meaningful to the patient. In a patient with clinical spasticity, the best judge of the perceived severity of the symptom is the patient.
The aim of this study was to assess the validity and reliability, and determine the clinical importance, of change on a 0-10 numeric rating scale (NRS) as a patient-rated measure of the perceived severity of spasticity.
Using data from a large,randomized, doubleblind, placebo-controlled study of an endocannabinoid system modulator in patients with multiple sclerosis-related spasticity, we evaluated the test-retest reliability and comparison-based validity of a patient-reported 0-10 NRS measure of spasticity severity with the Ashworth Scale and Spasm Frequency Scale. We estimated the level of change from baseline on the 0-10 NRS spasticity scale that constituted a clinically important difference (CID) and a minimal CID (MCID) as anchored to the patient's global impression of change (PGIC).
Data from a total of 189 patients were included in this assessment (114 women, 75 men; mean age, 49.1 years). The test-retest reliability analysis found an interclass correlation coefficient of 0.83 (P < 0.001) between 2 measures of the 0-10 NRS spasticity scores recorded over a 7- to 14-day period before randomization. A significant correlation was found between change on 0-10 NRS and change in the Spasm Frequency Scale (r = 0.63; P < 0.001), and a moderate correlation was found between the change on 0-10 NRS and the PGIC (r = 0.47; P < 0.001). A reduction of approximately 30% in the spasticity 0-10 NRS score best represented the CID and a change of 18% the MCID.
The measurement of the symptom of spasticity using a patient-rated 0-10 NRS was found to be both reliable and valid. The definitions of CID and MCID will facilitate the use of appropriate responder analyses and help clinicians interpret the significance of future results.
Cannabiniods for epilepsy. Cochrane Database Syst Rev
- D Gloss
- B Vickrey
Gloss D, Vickrey B. Cannabiniods for epilepsy. Cochrane Database Syst Rev. 2014;5:CD009270.