Botulinum toxin for the management of adult patients with upper motor neuron syndrome

The upper motor neuron (UMN) syndrome is a collection of interactive positive signs (associated with spastic hypertonia) and negative signs, such as muscle weakness and loss of voluntary control. In clinical practice, the distinction between active and passive functions allows identifying appropriate treatment objectives. During the last decades, many studies have evaluated the possibility to treat UMN syndromes with botulinum neurotoxin (BoNT). They have shown that BoNT is effective in controlling upper limb spasticity in adults. The clinical improvement is more consistent in the distal joints and the reduction of muscle hypertonia is dose-dependent. The functional efficacy of BoNT for lower limb spasticity has not been documented as well, as some series report efficacy in reducing muscle tone in the lower limb, but not in improving walking.The functional benefit arising from the reduction of spasticity is often difficult to judge in the context of the complex phenomenology of the UMN syndrome. Certain data indicate that some disabilities related to passive and active function in the upper limb can improve with treatment. However, to date, the functional improvement after BoNT treatment in patients with UMN symptoms remains a point of ambiguity in the literature.BoNT is overall well tolerated and must be regarded as a safe treatment intervention. Safety data are abundant in the literature for type-A toxin and scant for type-B toxin. There is no clear evidence to suggest the best time to introduce BoNT injections in the management of UMN syndromes. A common sense approach would be to introduce BoNT treatment as early as possible, in order to prevent further complications including contractures.     

Ergonomic Recommendations in Ultrasound-Guided Botulinum Neurotoxin Chemodenervation for Spasticity: An International Expert Group Opinion

Ultrasound (US)-guided botulinum neurotoxin (BoNT) injections are becoming a mainstay in the treatment of muscle spasticity in upper motor neuron syndromes. As a result, there has been a commensurate increase in US-guided BoNT injection for spasticity training courses. However, many of these courses do not emphasize the importance of ergonomics. This paper aims to highlight the importance of ultrasound ergonomics and presents ergonomic recommendations to optimize US-guided BoNT injection techniques in spasticity management. Expert consensus opinion of 11 physicians (4 different continents; representing 8 countries, with an average of 12.6 years of practice using US guidance for BoNT chemodenervation (range 3 to 22 years)). A search using PubMed, College of Physicians and Surgeons of British Columbia database, EMbase was conducted and found no publications relating the importance of ergonomics in US-guided chemodenervation. Therefore, recommendations and consensus discussions were generated from the distribution of a 20-question survey to a panel of 11 ultrasound experts. All 11 surveyed physicians considered ergonomics to be important in reducing physician injury. There was complete agreement that physician positioning was important; 91% agreement that patient positioning was important; and 82% that ultrasound machine positioning was important. Factors that did not reach our 80% threshold for consensus were further discussed. Four categories were identified as being important when implementing ultrasound ergonomics for BoNT chemodenervation for spasticity; workstation, physician, patient and visual ergonomics. Optimizing ergonomics is paramount when performing US-guided BoNT chemodenervation for spasticity management. This includes proper preparation of the workspace and allowing for sufficient pre-injection time to optimally position both the patient and the physician. Lack of awareness of ergonomics for US-guided BoNT chemodenervation for spasticity may lead to suboptimal patient outcomes, increase work-related injuries, and patient discomfort. We propose key elements for optimal positioning of physicians and patients, as well as the optimal setup of the workspace and provide clinical pearls in visual identification of spastic muscles for chemodenervation.     

Spasticity and drug therapy

An overview is presented of pathophysiology, classification and measurement of spasticity and of its treatment, especially with dantrolene and baclofen. In spasticity, the balance between excitatory and inhibitory neurotransmitters in the central nervous system is impaired by mechanisms that are for the greater part unknown. Spasticity includes various disorders of motor control, and classification is needed for a meaningful evaluation of antispastic therapy. Cerebral palsy is a specific disorder, sometimes also called spasticity. Measurement of spasticity is complicated and should include signs characteristic of spasticity and parameters for clinical improvement. Dantrolene and baclofen have established their place in the treatment of spastic disorders, but a preference for either drug is hard to give. For tizanidine it is still too early to determine its place in therapy. Dantrolene is a direct acting muscle relaxant which should be avoided in patients with pre-existing liver damage. Its mechanism of metabolism and excretion is for the greater part unknown. The GABA _b agonist baclofen is a centrally acting muscle relaxant. In patients with impaired renal function the dose should be reduced. Abrupt withdrawal carries the risk of unwanted reactions. TheR(–)-enantiomer has proved to be the active isomer. This means that human trials need reappraisal, especially those relating to the pharmacokinetics of the racemate.     

Spasticity associated with cerebral palsy in children: guidelines for the use of botulinum A toxin

Botulinum A toxin produces selective and reversible chemodenervation that can be employed to balance muscle forces across joints in children with cerebral palsy (CP). Currently, there are two commercially available botulinum A toxin formulations (BOTOX) and Dysport). The amount of botulinum A toxin required depends upon the number of muscles that are targeted, and the size of the patient. In order to achieve adequate chemodenervation with botulinum A toxin, the following conditions must be met: (i) a sufficient number of units of toxin must be injected in order to neutralize neuromuscular junction (NMJ) activity; (ii) an appropriate drug volume is required in order to optimize the delivery of the toxin to the NMJs; and (iii) localization of the injecting needle through the fascia of the target muscle is necessary. Localization of the injection may be facilitated by active electromyography, ultrasonography, palpation of the muscle belly, and/or use of anatomic landmarks. Botulinum A toxin injections are indicated for use in pediatric patients with CP to: (i) improve motor function by balancing muscle forces across joints; (ii) improve health-related quality of life by decreasing spasticity and/or decreasing caregiver burden; (iii) decrease pain from spasticity; (iv) enhance self-esteem by diminishing inappropriate motor responses; and (v) provide a presurgical diagnostic tool. Following intramuscular injections of botulinum A toxin, short-term benefits of reduced spasticity are observed in approximately 70-82% of children. The intermediate term (1-2 years) efficacy rate is approximately 50%. The most common deformity treated with toxin injections in pediatric patients with CP is equinus foot deformity. However, efficacy of toxin injections for the management of crouched gait, pelvic flexion contracture, cervical spasticity, seating difficulties, and upper extremity deformity also has been documented. In addition, toxin injections have been shown to manage painful muscle spasticity associated with surgery or application of casts and painful cervical spasticity with or without dystonia. Toxin injections can also be used as a diagnostic tool to determine the appropriateness of other interventions by observing the muscle response to the injection in order to gain additional information for the development of a treatment plan. Botulinum A toxin, when used in appropriate doses, is well tolerated.     

Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity

Dantrolene sodium acts primarily by affecting calcium flux across the sarcoplasmic reticulum of skeletal muscle. Recently, dantrolene has been used very successfully in the treatment of several rare hypercatabolic syndromes which have previously been associated with high mortality rates. In malignant hyperthermia, where early diagnosis and treatment usually with intravenous dantrolene in association with other supportive measures (and often subsequent dantrolene therapy) is performed, recovery is seen in virtually 100% of patients. There is a rapid resolution of hyperthermia, dysrhythmias, muscle rigidity, tachycardia, hypercapnia, mottled or cyanotic skin, and metabolic acidosis, and a slower normalisation of myoglobinuria and elevated serum creatine phosphokinase levels. In patients with family history or previous episodes of malignant hyperthermia, prophylactic treatment with dantrolene prior to anaesthesia prevents the syndrome occurring in most cases. Where malignant hyperthermia has developed patients have been successfully treated with further dantrolene therapy. Dantrolene has also been used successfully in the treatment of a few cases of heat stroke and the neuroleptic malignant syndrome--both of which have many similarities to malignant hyperthermia. Dantrolene is well established in the treatment of patients with muscle spasticity where it generally improves at least some of the components of spasticity (i.e. hyper/hypotonia, clonus, muscle cramps and spasms, resistance to stretch and flexor reflexes, articular movement, neurological and motor functions and urinary control). However, in some patients, particularly those with multiple sclerosis, dantrolene may not be effective, and in many cases muscular strength may diminish. Long term dantrolene therapy has been associated with hepatic toxicity and may cause problems in patients treated for disorders of muscle spasticity. Thus, dantrolene offers a unique advance in the therapy available for the treatment of hypercatabolic disorders and is also useful in the treatment of muscle spasticity of various aetiology.     

Adverse effects secondary to baclofen withdrawal

Drug therapy is now the preferred method of treatment for spasticity, and several effective agents have been developed. The safety and efficacy of these drugs has been established in short-term studies. Overall, due to its low incidence of sedation and serious side effects, baclofen appears to be the drug of choice in the treatment of spinal cord-related spasticity. It is, however, not without its side effects due to both its administration and abrupt withdrawal. This case illustrates some significant problems associated with the abrupt withdrawal of long-term baclofen therapy in a patient with multiple sclerosis.     

Management of spasticity in stroke

Spasticity treatment must be considered in relation to other impairments with functional goals defined prior to intervention. The effects of muscle co-contraction and involuntary limb movement associated with exaggerated cutaneous reflexes or effort as well as stretch reflex hyperexcitability need to be considered. Exacerbating factors such as pain must be identified. Physical therapy and conventional orthoses are the mainstays of spasticity management during acute rehabilitation. Botulinum toxin shows promise but needs further evaluation in the context of acute rehabilitation. Phenol chemodenervation can produce good results in spasticity refractory to standard treatments. Muscle strengthening exercises may be appropriate in chronic hemiparesis without adversely affecting tone. Electrical stimulation may be a useful adjunct to other spasticity treatments. Difficulty demonstrating functional benefit from antispasticity treatment may imply that interventions directed at single motor impairments whether weakness or spasticity are not likely to result in functional benefit, but it is their combination that is important.     

Spasticity and drug therapy

An overview is presented of pathophysiology, classification and measurement of spasticity and of its treatment, especially with dantrolene and baclofen. In spasticity, the balance between excitatory and inhibitory neurotransmitters in the central nervous system is impaired by mechanisms that are for the greater part unknown. Spasticity includes various disorders of motor control, and classification is needed for a meaningful evaluation of antispastic therapy. Cerebral palsy is a specific disorder, sometimes also called spasticity. Measurement of spasticity is complicated and should include signs characteristic of spasticity and parameters for clinical improvement. Dantrolene and baclofen have established their place in the treatment of spastic disorders, but a preference for either drug is hard to give. For tizanidine it is still too early to determine its place in therapy. Dantrolene is a direct acting muscle relaxant which should be avoided in patients with pre-existing liver damage. Its mechanism of metabolism and excretion is for the greater part unknown. The GABA _b agonist baclofen is a centrally acting muscle relaxant. In patients with impaired renal function the dose should be reduced. Abrupt withdrawal carries the risk of unwanted reactions. TheR(?)-enantiomer has proved to be the active isomer. This means that human trials need reappraisal, especially those relating to the pharmacokinetics of the racemate.     

AbobotulinumtoxinA Doses in Upper and Lower Limb Spasticity: A Systematic Literature Review

Disabling limb spasticity can result from stroke, traumatic brain injury or other disorders causing upper motor neuron lesions such as multiple sclerosis. Clinical studies have shown that abobotulinumtoxinA (AboBoNT-A) therapy reduces upper and lower limb spasticity in adults. However, physicians may administer potentially inadequate doses, given the lack of consensus on adjusting dose according to muscle volume, the wide dose ranges in the summary of product characteristics or cited in the published literature, and/or the high quantity of toxin available for injection. Against this background, a systematic literature review based on searches of MEDLINE and Embase (via Ovid SP) and three relevant conferences (2018 to 2020) was conducted in November 2020 to examine AboBoNT-A doses given to adults for upper or lower limb muscles affected by spasticity of any etiology in clinical and real-world evidence studies. From the 1781 unique records identified from the electronic databases and conference proceedings screened, 49 unique studies represented across 56 publications (53 full-text articles, 3 conference abstracts) were eligible for inclusion. Evidence from these studies suggested that AboBoNT-A dose given per muscle in clinical practice varies considerably, with only a slight trend toward a relationship between dose and muscle volume. Expert-based consensus is needed to inform recommendations for standardizing AboBoNT-A treatment initiation doses based on muscle volume.     

Poststroke motor dysfunction and spasticity: novel pharmacological and physical treatment strategies

Following stroke, approximately 90% of patients experience persistent neurological motor deficits that lead to disability and handicap. Both pharmacological and physical treatment strategies for motor rehabilitation may be considered. In terms of pharmacological treatment, drugs that may potentially promote motor recovery when added to a regimen of physical therapy include the stimulants amphetamine and methylphenidate, as well as levodopa and fluoxetine. Botulinum toxin A has proven effective and well tolerated in several placebo-controlled trials for the treatment of focal upper and lower limb spasticity, although it has not been shown to improve motor function. The focal injection of botulinum toxin A inhibits the release of acetylcholine into the synaptic cleft, resulting in a reversible paresis of the muscles relevant for the spastic deformity. Other drugs, such as benzodiazepines, antiepileptic drugs and antipsychotics, may have detrimental effects on motor function and should be avoided, if possible. With respect to physical strategies, modern concepts of motor learning favour a task-specific repetitive approach that induces skill-acquisition relevant to the patient's daily life. Constrained-induced movement therapy based on the concept of learned non-use, electromyography-triggered electrical stimulation of the wrist muscles, robot-assisted motor rehabilitation to increase therapy intensity and bilateral practice to facilitate the movement of the paretic extremity are examples in upper limb rehabilitation. Lower limb rehabilitation has been enriched by treadmill training with partial bodyweight support, enabling the practice of up to 1000 steps per session; automated gait rehabilitation to relieve the strenuous effort required of the therapist; and rhythmic auditory stimulation, applying individually adjusted music to improve walking speed and symmetry.     

Botulinum toxin as an effective treatment of clozapine-induced hypersalivation

Hypersalivation is a common and frequently disabling side effect of atypical neuroleptics such as clozapine. Current treatment options of this adverse advent are limited by lack of efficacy or additional side effects. Botulinum toxin (BTX) injections into the parotid glands have been shown to be very effective in treating sialorrhea in the context of various neurological disorders, such as Parkinsons and motor neuron disease. Surprisingly, BTX treatment of drug-induced sialorrhea has not yet been described. We here report a patient with clozapine-induced hypersalivation and a good response to BTX injections lasting for more than 12 weeks, resulting in a marked reduction of the hypersalivation and consequently of his social withdrawal. Our patient serves to alert clinicians to the frequent problem of drug-induced sialorrhea and suggests that BTX injections should be considered as an effective and safe treatment for hypersalivation in psychiatric patients treated with clozapine.The first two authors contributed equally to this work.     

杜仲提取物及有效成分防治肌萎缩性侧索硬化症的可行性分析

肌萎缩性侧索硬化症（Amyotrophic lateral sclerosis,ALS）是运动神经元病变相关疾患中最常见的类型之一,致残致死率高,严重影响患者生活质量,给家庭带来了沉重的负担。其主要病理机制为多种因素导致运动神经元损伤变性,保护神经元乃行之有效的治疗方法。补益类中药杜仲来源于杜仲Eucommia ulmoides的干燥树皮,现代药理研究证实其有效成分具有神经保护、抗氧化应激等作用而被广泛运用于临床神经退行性疾患的防治。以当前对ALS发病机制的主流认识为出发点,探讨杜仲提取物及有效成分防治ALS的可行性,以期为杜仲防治ALS方面的开发应用有所裨益。     

Current management of pain associated with multiple sclerosis

While pain is a common problem in patients with multiple sclerosis (MS), it is not frequently mentioned by patients and a more direct approach is required in order to obtain information about pain from patients. Many patients with MS experience more than one pain syndrome; combinations of dysaesthesia, headaches and/or back or muscle and joint pain are frequent. For each pain syndrome a clear diagnosis and therapeutic concept needs to be established. Pain in MS can be classified into four diagnostically and therapeutically relevant categories: (i) neuropathic pain due to MS (pain directly related to MS); (ii) pain indirectly related to MS; (iii) MS treatment-related pain; and (iv) pain unrelated to MS. Painful paroxysmal symptoms such as trigeminal neuralgia (TN), or painful tonic spasms are treated with antiepileptics as first choice, e.g. carbamazepine, oxcarbazepine, lamotrigine, gabapentin, pregabalin, etc. Painful 'burning' dysaesthesias, the most frequent chronic pain syndrome, are treated with TCAs such as amitriptyline, or antiepileptics such as gabapentin, pregabalin, lamotrigine, etc. Combinations of drugs with different modes of action can be particularly useful for reducing adverse effects. While escalation therapy may require opioids, there are encouraging results from studies regarding cannabinoids, but their future role in the treatment of MS-related pain has still to be determined. Pain related to spasticity often improves with adequate physiotherapy. Drug treatment includes antispastic agents such as baclofen or tizanidine and in patients with phasic spasticity, gabapentin or levetiracetam are administered. In patients with severe spasticity, botulinum toxin injections or intrathecal baclofen merit consideration. While physiotherapy may ameliorate malposition-induced joint and muscle pain, additional drug treatment with paracetamol (acetaminophen) or NSAIDs may be useful. Moreover, painful pressure lesions should be avoided by using optimally adjusted aids. Treatment-related pain associated with MS can occur with subcutaneous injections of interferon-beta or glatiramer acetate, and may be reduced by optimizing the injection technique and by local cooling. Systemic (particularly 'flu-like') adverse effects of interferons, e.g. myalgias, can be reduced by administering paracetamol, ibuprofen or naproxen. A potential increase in the frequency of pre-existing headaches after starting treatment with interferons may require optimization of headache attack therapy or even prophylactic treatment. Pain unrelated to MS, such as back pain or headache, is common in patients with MS and may deteriorate as a result of the disease. In summary, a careful analysis of each pain syndrome will allow the design of the appropriate treatment plan using various medical and nonmedical options (multimodal therapy), and will thus help to improve the quality of life (QOL) of the patients.     

痉挛肌治疗仪联合康复训练治疗脑卒中后肢体痉挛的效果观察

目的探讨痉挛肌治疗仪联合康复训练治疗脑卒中患者痉挛肢体的临床效果。方法采用随机数字表法将66例脑卒中患者分为治疗组和对照组,每组33例。两组均给予传统康复训练,治疗组在此基础上辅以痉挛肌治疗仪治疗,治疗前及治疗8周后,分别采用改良Ashworth分级法、简式Fugl—Meyer运动功能评定量表（FMA）、改良Barthel指数（MBU,对患者的上下肢肌痉挛情况、肢体运动功能、生活自理能力分别进行评定。结果两组治疗后上下肢的改良Ashwonh分级较治疗前均显著改善,且治疗组较对照组改善明显,差异有统计学意义（P〈0．05）。两组治疗后的FMA及MBI评分较治疗前均明显提高,且治疗组较对照组提高更明显,差异有统计学意义（P〈0．05）。结论在常规康复训练的基础上配合痉挛肌治疗仪治疗可起到协同作用,可显著降低痉挛肢体肌张力,提高脑卒中患者的运动功能水平,改善ADL能力,值得临床推广应用。     

低频神经肌治疗加运动功能训练对痉挛型脑瘫的疗效观察

目的：研究低频神经肌治疗配合运动功能训练对痉挛型脑瘫患儿的治疗效果。方法：60例痉挛型脑瘫患儿随机分为两组,治疗组采用低频神经肌治疗加运动功能训练;对照组采用单纯运动功能训练,同时治疗半年,观察低频神经肌治疗配合运动功能训练对痉挛型脑瘫患儿的治疗效果。结果：治疗组的肌张力显效率为33.3％。总有效率为90．0％,对照组显效率为13．3％,总有效率为83．3％,两组在肌张力的缓解上差异有统计学意义,治疗后较治疗前GMFM评分有所提高,其差异有统计学意义（p〈0．05）,低频神经肌治疗加运动功能训练较单纯运动功能训练组大运动评分高,其差异有统计学意义（P〈0．05）。结论：低频神经肌治疗加运动功能训练疗效优于单纯运动功能训练。     

Depression and anxiety in individuals with amyotrophic lateral sclerosis: epidemiology and management

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease with no curative treatment. Considering the devastating nature of the disease, a high prevalence of depression and anxiety in affected patients would be expected. A review of the literature shows prevalence rates for depression in ALS patients ranging from 0% to 44%, but studies using the structured interview according to DSM-IV criteria find highly consistent rates of 9-11%. Prevalence rates for anxiety in ALS range from 0% to 30%. Depression and anxiety appear to be not always properly addressed aspects of ALS, as there are only a few references in the literature about psychological and pharmacological interventions. Additionally, pharmacological antidepressant therapy is often not continuously monitored and its effectiveness remains unevaluated. A review of the literature and our own experiences show that there is a lack of psychological care and, to our knowledge, there is no specific psychological intervention method for ALS patients. Concerning pharmacological treatment of depression in patients with ALS, there is broad consensus among clinical experts that SSRIs and TCAs are helpful, but there have been no controlled clinical studies of these medications in ALS patients. TCAs can be prescribed if anticholinergic effects are desired simultaneously for treating pseudohypersalivation or insomnia. Anxiety is usually treated with anxiolytics, but again there have been no systematic studies of these drugs in patients with ALS. For psychological intervention we suggest a cognitive behavioural approach, which has to be integrated into an intervention programme that includes teaching of appropriate coping strategies and reappraisal skills and encourages engagement in activities that are still practicable and pleasant. We propose that the treatment of depression and anxiety should involve both cognitive behavioural therapy and pharmacological intervention. Pharmacological treatment should be strictly monitored for effectiveness. To date, no clinical trials are available that would allow us to recommend pharmacotherapy over psychotherapy or vice versa; however, evidence from other patient groups, such as elderly patients diagnosed with major depressive disorder, suggests that a combination of both therapies has the potential to also improve depression and anxiety in patients with ALS.     

伴周围神经病变的副肿瘤性僵人综合征一例报道

目的 探究僵人综合征(SPS)的临床特点、免疫学化验、肌电图等辅助检查的特征及治疗方法.方法 对1例僵人综合征患者的临床资料进行整理,分析其发病过程、临床症状、实验室结果、辅助检查及诊断.结果 本病例临床表现为左肩背肌肉发作性僵硬疼痛,进行性加重.免疫学检查脑脊液蛋白0.81 g/L;副肿瘤抗体谱:GAD65阳性(+)...     

A benefit-risk assessment of baclofen in severe spinal spasticity.

Baclofen is used for treatment of the spasticity of spinal origin that is a common sequela of spinal cord injury and multiple sclerosis; spasticity occurs in about 50% of patients affected by these disorders. In open-label studies of oral baclofen, the drug improved spasticity in 70-87% of patients; additionally, improvement in spasms was reported in 75-96% of patients. In double-blind, crossover, placebo-controlled trials, baclofen was reported to be effective, producing statistically significant improvements in spasticity. Tizanidine is the antispasticity drug that has been most widely compared with oral baclofen; studies have generally found the two drugs to have equivalent efficacy. However, tizanidine has better tolerability, in particular weakness was reported to be occur less frequently with tizanidine than with baclofen. The main adverse effects of oral baclofen include: sedation or somnolence, excessive weakness, vertigo and psychological disturbances. The incidence of adverse effects is reported to range from 10% to 75%. The majority of adverse effects are not severe; most are dose related, transient and/or reversible. The main risks of oral baclofen administration are related to withdrawal: seizures, psychic symptoms and hyperthermia can occur. These symptoms improve after the reintroduction of baclofen, usually without sequelae. When not related to withdrawal; these symptoms mainly present in patients with brain damage and in the elderly. The limited data on baclofen toxicity in patients with renal disease suggest that administration of the drug in these persons may carry an unnecessarily high risk. Intrathecal baclofen is indicated for use in patients with spasticity of spinal origin unresponsive to treatment with maximum doses of oral baclofen, tizanidine and/or dantrolene. The benefits of continuous intrathecal baclofen infusion have been demonstrated: >80% and >65% of patients have improvement in tone and spasms, respectively. The main risks of intrathecal baclofen infusion are symptoms related to overdose or withdrawal; the latter is more important because of the associated severe effects on clinical status and the possibility of death, but it is responsive to rapid treatment. Overdose primarily arises from drug test doses or human error during refill and programming of the pump, and withdrawal most commonly occurs as a result of a problem with the delivery system. Since the adverse consequences do not exceed the benefits of oral and intrathecal baclofen for patients with spinal spasticity, the benefit/risk assessment is favourable.     

Towards cannabis and cannabinoid treatment of multiple sclerosis

Multiple sclerosis is a common human demyelinating disease of the central nervous system (CNS), and it is thought to involve autoimmune responses to CNS myelin antigens. Current symptomatic therapies for multiple sclerosis are in some cases ineffective and may have a high risk of serious side effects. This has led some multiple sclerosis patients to self-medicate with cannabis, which anecdotal evidence suggests may be beneficial in controlling symptoms such as spasticity, pain, tremor and bladder dysfunction. In support of these claims, results from experimental studies have suggested that cannabinoid-based treatments may be beneficial in a wide number of diseases. Furthermore, recent research in animal models of multiple sclerosis has demonstrated the efficacy of cannabinoids in controlling disease-induced symptoms such as spasticity and tremor, as well as in ameliorating the severity of clinical disease. However, these initially promising results have not yet been fully translated into the clinic. Although cannabinoid treatment of multiple sclerosis symptoms has been shown to be both well tolerated and effective in a number of subjective tests in several small-scale clinical trials, objective measures demonstrating the efficacy of cannabinoids are still lacking. Currently, a number of large-scale phase III clinical trials are under way to further elucidate the use of cannabinoids in the symptomatic treatment of multiple sclerosis. This review highlights the recent advances in our understanding of the endocannabinoid system, discusses both the experimental and clinical evidence for the use of cannabinoids to treat multiple sclerosis and explores possible future strategies of cannabinoid therapy in multiple sclerosis.     

Treatment of psychosis in Parkinson's disease: safety considerations

Psychosis only rarely occurs in patients with untreated Parkinson's disease. Much more commonly, psychosis is induced by drug therapy for Parkinson's disease and is the strongest known risk factor for nursing home placement. Delusions are less frequent than hallucinations, but are more concerning as they are often paranoid in nature. Treatment begins with a search for correctable infectious, toxic, and metabolic aetiologies. If symptoms persist, anti-Parkinson's disease medications are slowly reduced. However, withdrawal of these drugs usually worsens parkinsonism and is often not tolerated. Certain atypical antipsychotics can be used to treat psychosis without compromising motor function. The choice of atypical antipsychotic is largely based on ease of use and adverse effect profile as most have comparable efficacy in improving psychosis. Currently, there are five marketed atypical drugs - clozapine, risperidone, olanzapine, quetiapine and ziprasidone. Ziprasidone is the only agent whose adverse effect profile has not been reported in Parkinson's disease. The most common adverse effects of clozapine in Parkinson's disease are sedation, orthostatic hypotension and sialorrhoea. Sedation is generally helpful since these patients are frequently awake at night and tend to have worse behavioural problems then. Clozapine does not induce deterioration of motor function, but it has the potential to cause agranulocytosis, which is idiosyncratic and not dose-related. In risperidone-treated Parkinson's disease patients, reported adverse effects include somnolence, sialorrhoea, dizziness, palpitations, constipation, delirium, fatigue, leg cramps, depression, urinary incontinence and hypotension. Although in some Parkinson's disease studies, risperidone has been well tolerated, others have shown that many patients are unable to tolerate the drug due to deterioration of motor function. While an initial study of olanzapine in Parkinson's disease psychosis showed the drug to be effective without deterioration of motor function, succeeding reports demonstrated a deleterious effect of the drug on motor functioning. The most common adverse effects of quetiapine in Parkinson's disease patients are sedation and orthostatic hypotension. There is a lack of double-blind trials; however, cumulative reports involving >200 Parkinson's disease patients strongly suggest that quetiapine is well tolerated and effective. Unlike clozapine, it does not improve tremor and may induce mild deterioration of motor function. Recently, cholinesterase inhibitors have been reported to alleviate psychosis in Parkinson's disease. Although ondansetron, an antiemetic with antiserotonergic properties, has been reported to relieve psychosis in Parkinson's disease, its prohibitive cost has prevented further study in this population. Electroconvulsive treatment is generally reserved for the patient with psychotic depression who is unable to tolerate any pharmacological therapy.