Deep brain stimulation for the treatment of Parkinson's disease.

Deep brain stimulation (DBS) is increasingly accepted as an adjunct therapy for Parkinson's disease (PD). It is considered a surgical treatment alternative for patients with intractable tremor or for those patients who are affected by long-term complications of levodopa therapy such as motor fluctuations and severe dyskinesias. Thalamic stimulation in the ventral intermediate nucleus (Vim) leads to a marked reduction of contralateral tremor but has no beneficial effect on other symptoms of Parkinson's disease. The subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi) are targeted for the treatment of advanced Parkinson's disease. Several studies have proven the efficacy of STN-DBS and GPi-DBS in alleviating off motor symptoms and dyskinesias. Sub-thalamic nucleus deep brain stimulation is currently considered superior to GPi-DBS because the antiakinetic effect seems to be more pronounced, allows a more marked reduction of antiparkinsonian medication, and requires less stimulation energy. More recently, however, a number of reports on possible psychiatric and behavioral side effects of STN-DBS have been a matter of concern. Given the chronic nature of PD and the noncurative approach of DBS, both targets will need to be reevaluated on the basis of their long-term efficacy and their impact on quality of life. Despite the rapidly increasing numbers of DBS procedures, surprisingly few controlled clinical trials are available that address important clinical issues such as: When should DBS be applied during the course of disease? Which patients should be selected? Which target should be considered? Which guidelines should be followed during postoperative care? Here is summarized the available evidence on DBS as a therapeutic tool for the treatment of Parkinson's disease and the current state of debate on open issues.     

Deep brain stimulation in dystonia

Renewed interest in stereotaxy for dystonia followed the introduction of deep brain stimulation (DBS) in Parkinson's disease and essential tremor in the 1990s. DBS evolved from ablative surgery, which was applied with varying results in the 1950s in patients with movement disorders such as Parkinson's disease, essential tremor and dystonia. The present review summarizes the current knowledge on clinical aspects of DBS in dystonia (Dec. 2002). Excellent results have been achieved in dystonic patients carrying a mutation in the DYT1 gene with improvements up to 90 %. Similar results may also be obtained in patients with idiopathic generalized dystonia, myoclonus-dystonia syndrome, and tardive dystonia. Substantial improvement has been observed in patients with focal dystonia (for instance cervical dystonia). Patients with secondary dystonia often display a lesser and more variable degree of improvement. Long-term studies are warranted to assess both motor and neuropsychological sequelae of DBS in dystonia. Furthermore, the optimal target for different dystonic disorders remains to be determined, although the globus pallidus internus has currently emerged as the most promising target for dystonia.     

Deep brain stimulation in the treatment of dystonia

Dystonia refers to movement disorders characterized by sustained muscle contractions that produce abnormal postures and twisting movements. First-line therapy for dystonia includes several classes of pharmacologic agents. Botulinum toxin injections are the treatment of choice for several forms of focal dystonia. Many patients with dystonia do not benefit from these treatments, and for those patients whose symptoms are sufficiently troublesome, surgical treatment can be used to reduce symptoms and to improve function. Formerly the ablative procedures of thalamotomy and pallidotomy were used. More recently, deep brain stimulation (DBS) has emerged not only as the preferred surgical treatment for advanced idiopathic form of Parkinson's disease and severe forms of essential tremor but also for dystonia. For dystonia, stimulation directed at the globus pallidus internus has been the most thoroughly studied to date. Advantages of DBS include its relatively non-destructive nature, its adjustability and reversibility, and its capacity to be used bilaterally in a single surgical session. Use of DBS to treat dystonia is a rapidly evolving area, and preliminary evidence suggests that primary dystonia linked to genetic mutation, especially DYT-1 positive generalized dystonia, and other primary dystonias respond most dramatically to treatment with DBS, whereas secondary dystonia tends to be less responsive.     

Surgery insight: Deep brain stimulation for movement disorders

Over the past two decades, deep brain stimulation (DBS) has supplanted lesioning techniques for the treatment of movement disorders, and has been shown to be safe and efficacious. The primary therapeutic indications for DBS are essential tremor, dystonia and Parkinson's disease. In the case of Parkinson's disease, DBS is effective for treating the primary symptoms--tremor, bradykinesia and rigidity--as well as the motor complications of drug treatment. Progress has been made in understanding the effects of stimulation at the neuronal level, and this knowledge should eventually improve the effectiveness of this therapy. Preliminary studies also indicate that DBS might be used to treat Tourette's syndrome, obsessive-compulsive disorder, depression and epilepsy. As we will discuss in this review, the success of DBS depends on an appropriate rationale for the procedure, and on collaborations between neurologists and neurosurgeons in defining outcomes.     

Psychogenic dystonia and peripheral trauma

Dystonia in association with peripheral trauma is a well-described clinical syndrome. The syndrome goes by many names--"traumatic" dystonia, "fixed" dystonia, peripherally induced dystonia, or complex region pain syndrome (CRPS) dystonia. We reviewed the role of peripheral trauma in the development of dystonia, focusing on 4 subtypes--cervical dystonia, focal limb dystonia, CRPS dystonia, and psychogenic dystonia. We show that peripheral trauma inducing, provoking, or precipitating structural changes within the CNS leading to dystonia is not an accepted concept, and current evidence supporting a pathophysiologic mechanism is virtually nonexistent. A better approach to this clinical syndrome is to define it as fixed abnormal posturing that is most commonly psychogenic. While symptomatic treatment of pain and spasms with medication can be beneficial, early psychological evaluation and patient-specific treatment is important. Modalities such as physical and occupational therapy should be utilized early. Finally, it should be emphasized that like many psychogenic movement disorders, it remains a highly disabling and distressing disorder.     

Prevalence and diagnostic challenge of dystonia in Thailand: a service-based study in a tertiary university referral centre

Although the subspeciality of movement disorders was established in neurology more than 20 years ago, it is relatively new in Thailand, and while most physicians are generally aware of Parkinson's disease, they often are not familiar with dystonia. As one of the common movement disorders seen in general practice, a number of family and population studies have suggested that as many as two-thirds of patients with dystonia may be underdiagnosed and it is likely that misdiagnosis occurs frequently. Moreover, there is little information on the prevalence of dystonia in Thailand. The purpose of this study was to determine the prevalence and clinical profile of dystonia among Thai patients who came from the southern part of Bangkok, which is in the catchment area of Chulalongkorn University Hospital. In addition, the diagnostic accuracy of dystonia among referred patients was assessed. The medical records of 207 patients were reviewed and it was determined that a large proportion of them (71.9%) had focal dystonia with cervical dystonia being the most common form. Primary dystonia (68.1%) accounted for the majority of the cases. The prevalence of all forms of dystonia, primary dystonia and focal dystonia was 19.9, 13.6 and 14.3 per 100,000 persons, respectively. The diagnostic accuracy of dystonia among referred patients was 85.5%. The most common misdiagnosis was cervical spondylosis, followed by myofascial pain syndrome. Most patients had an average disease duration of 4 years before dystonia was finally diagnosed. Most patients with focal dystonia responded well to botulinum toxin therapy, with 13.3% suffering only mild transient adverse events. In spite of the limitations of this study, this data will initiate a process of increasing both patient and professional awareness of dystonia in Thailand.     

Deep brain stimulation in movement disorders

Deep brain stimulation (DBS) is used for advanced and medically intractable patients with Parkinson's disease (PD), essential tremor (ET), and dystonia who meet strict criteria after a detailed motor, cognitive, and psychiatric evaluation. The potential targets are the ventral intermediate nucleus (VIM) of the thalamus for tremor, the globus pallidus interna (GPI) and the subthalamic nucleus (STN) for PD, and GPI for dystonia. The optimal target for PD has not been determined yet, although STN DBS has been performed more frequently in recent years. The mechanism of DBS effect is believed to be associated with disruption of pathological network activity in the cortico-basal ganglia-thalamic circuits by affecting the firing rates and bursting patterns of neurons and synchronized oscillatory activity of neuronal networks. Good candidates should be free of dementia, major psychiatric disorders, structural brain lesions, and important general medical problems. Although the risk for complications with DBS is less than with lesioning techniques, there is still a small risk for major complications associated with surgery. Bilateral procedures are more likely to cause problems with speech, cognition, and gait.     

Current status and prospects of medical therapy for dystonia]

The goal of medical therapy for primary dystonia is conservative. While botulinum toxin (BTX) therapy is a first choice for blepharospasm and cervical dystonia, medical therapy is selected as such for other types of dystonia. As oral medications, trihexyphenidyl and benzodiazepines are most frequently used. Muscle relaxants are also commonly used, but dopamine antagonists are not recommended because of the risk of inducing tardive dyskinesia. For childhood-onset generalized dystonia, levodopa should be considered to rule out levodopa-responsive dystonia. Mexiletine is reported to be effective not only for bleharospasm and cervical dystonia but for focal limb dystonia. To improve the therapeutic performance of BTX therapy for blepharospasm, it is recommended that corrugator supercilii and procerus muscles, as well as orbicularis oculi muscle, be added as target muscles. To improve the therapeutic performance of BTX therapy for cervical dystonia, it is recommended that this therapy be started as early as possible, especially within one year of illness, and that levator scapulae muscle be added as target if necessary. To improve usefulness of medical therapy for dystonia, its strategy must be standardized, and more useful therapies must be positively adopted. Algorithm for treatment of dystonia must also be established and generalized.     

Forms of dystonia in patients with Parkinson's disease

We studied various forms of dystonia associated with Parkinson's disease (PD) in 207 patients who were on levodopa therapy for more than 1 year. Dystonia, sometimes more than one type, occurred in 63 (30%). In five patients, dystonia preceded initiation of treatment. Fifteen patients had peak-dose dystonia, 33 had early-morning dystonia, and 20 had "off-period" dystonia. The different clinical features of the dystonias are presented and compared. Findings indicate that dystonia is a frequent feature of levodopa-treated PD patients.     

Deep brain stimulation in neurologic disorders

Deep brain stimulation (DBS) is an effective surgical therapy for well-selected patients with medically intractable Parkinson's disease (PD) and essential tremor (ET). The purpose of this review is to describe the success of DBS in these two disorders and its promising application in dystonia, Tourette Syndrome (TS) and epilepsy. In the last 10 years, numerous short- and intermediate-term outcome studies have demonstrated significant relief to patients with PD and ET. A few long-term follow-up studies have also reported sustained benefits. When successful, DBS greatly reduces most of parkinsonian motor symptoms and drug-induced dyskinesia, and it frequently improves patients' ability to perform activities of daily living with less encumbrance from motor fluctuations. Quality of life is enhanced and many patients are able to significantly reduce the amount of antiparkinsonian medications required to still get good pharmacological benefit. Overall, adverse effects associated with DBS tend to be transient, although device-related and other postoperative complications do occur. DBS should be considered the surgical procedure of choice for patients who meet strict criteria with medically intractable PD, ET and selected cases of dystonia.     

脑深部电刺激治疗运动障碍性疾病

目的探讨脑深部电刺激(DBS)对帕金森病(PD)和肌张力障碍(dystonia)等运动障碍性疾病的治疗作用及手术方法。方法应用3.0TMRI和微电极导向技术及手术计划系统进行靶点定位,对40例PD病人和3例继发性肌张力障碍病人进行双侧丘脑底核(STN)电极植入。结果PD病人的主要症状有显著改善,服药量也明显减少,术前和术后UPDRS评分有显著差异;3例继发性肌张力障碍病人症状均有不同程度的改善,如以UDRS和BFMS作为评价指标,其中1例药物引起的迟发性肌张力障碍病人症状改善达90%以上;术后无严重及永久并发症。结论首次证实STN-DBS对继发性肌张力障碍是一种有效的治疗方法,双侧STN-DBS是外科治疗PD的首选方法,DBS对运动障碍性疾病的治疗已显示出良好的前景。     

Long-term care of Parkinson patients with deep brain stimulation

For more than 15 years deep brain stimulation of the subthalamic nucleus and globus pallidus internus have become therapeutic options in advanced Parkinson's disease. The number of patients with long-term treatment is increasing steadily. This review focuses on issues of the long-term care of these Parkinson's patients, including differences of the available deep brain stimulation systems, recommendations for follow-up examinations, implications for medical diagnostics and therapies and an algorithm for symptom deterioration. Today, there is no profound evidence that deep brain stimulation prevents disease progression. However, symptomatic relief from motor symptoms is maintained during long-term follow-up and interruption of the therapy remains an exception.     

Pallidal deep brain stimulation in patients with cervical dystonia and severe cervical dyskinesias with cervical myelopathy

OBJECTIVES: Surgical treatment of complex cervical dystonia and of cervical dyskinesias associated with cervical myelopathy is challenging. In this prospective study, the long term effect of chronic pallidal stimulation in cervical dystonia and on combining the technique with spinal surgery in patients with severe cervical dyskinesias and secondary cervical myelopathy is described. METHODS: Eight patients with a history of chronic dystonia who did not achieve adequate benefit from medical treatment or botulinum toxin injection participated in the study. Five patients had complex cervical dystonia with tonic postures and phasic movements. Three patients had rapidly progressive cervical myelopathy secondary to severe cervical dyskinesias and dystonia in the context of a generalised movement disorder. Quadripolar electrodes were implanted in the posteroventral lateral globus pallidus internus with stereotactic CT and microelectrode guidance. In the three patients with secondary cervical myelopathy, spinal surgery was performed within a few weeks and included multilevel laminectomies and a four level cervical corporectomy with spinal stabilisation. RESULTS: Improvement of the movement disorder was noted early after pallidal surgery, but the full benefit could be appreciated only with a delay of several months during chronic stimulation. Three months after surgery, patients with cervical dystonia had improved by 38% in the severity score, by 54% in the disability score, and by 38% in the pain score of a modified version of the Toronto western spasmodic torticollis rating scale. At a mean follow up of 20 months, the severity score had improved by 63%, the disability score by 69%, and the pain score by 50% compared with preoperatively. There was also sustained amelioration of cervical dyskinesias in the three patients who underwent spinal surgery. Lead fractures occurred in two patients. The mean amplitude needed for chronic deep brain stimulation was 3.8 V at a mean pulse width of 210 micros, which is higher than that used for pallidal stimulation in Parkinson's disease. CONCLUSIONS: Chronic pallidal stimulation is effective for complex cervical dystonia and it is a useful adjunct in patients with cervical dyskinesias and secondary cervical myelopathy who undergo spinal surgery.     

Dystonia and parkinsonism

Parkinsonism and dystonia may coexist in a number of neurodegenerative, genetic, toxic, and metabolic disorders and as a result of structural lesions in the basal ganglia. Parkinson's disease (PD) and the 'Parkinson-plus' syndromes (PPS) account for the majority of patients with the parkinsonism-dystonia combination. Dystonia, particularly when it involves the foot, may be the presenting sign of PD or PPS and these disorders should be suspected when adults present with isolated foot dystonia. Young age, female gender, and long disease duration are risk factors for PD-related dystonia, but dystonia in patients with PD is usually related to levodopa therapy. The mechanism of dystonia in PD is not well understood and the management is often challenging because levodopa and other dopaminergic agents may either improve or worsen dystonia. Other therapeutic strategies include oral medications (baclofen, anticholinergics and benzodiazepines), local injections of botulinum toxin, intrathecal baclofen, and surgical lesions or high frequency stimulation of the thalamus, globus pallidus, or subthalamus.     

The diagnostic and therapeutic application of transcranial magnetic stimulation

The functional abnormalities of the central motor structures and its contribution of rigidity, tremor and bradykinesia in Parkinson's disease seem mainly due to the degeneration of the nigro-striatal pathway. Transcranial magnetic stimulation (TMS) of the motor cortex may provide useful data on the pathophysiology of motor dysfunction in Parkinson's disease. Recent reviews on the basic mechanisms of TMS in Parkinson's disease show reduced inhibitory motor network at the cortical and spinal level. The observed changes are thought to be in relation with a dysfunction of subcortico-cortical and subcortico-spinal pathways. The abnormalities of the central motor function seem to be modified by several clinical related factors as prevalence of cardinal Parkinson's disease signs (e.g. rigidity versus tremor or bradykinesia), L-dopa therapy ('on/off' states) and laterality of the Parkinson's disease signs. Observations made using TMS give new pathophysiological insights in functioning of the central motor structures in Parkinson's disease and started new form of TMS - repetitive TMS (rTMS) as a treatment of the Parkinson's disease motor signs. A few studies using rTMS with repetition rate of 0.2, 1, and 5 Hz showed improvement of motor signs in the Parkinson's disease patients. Although these results support the beneficial effects of rTMS on parkinsonian symptoms, long-term studies with large numbers of subjects should be conducted to assess the efficacy of the rTMS on Parkinson's disease in future.     

Deep brain stimulation and the role of the neuropsychologist

Deep brain stimulation (DBS) now plays an important role in the treatment of Parkinson's disease, tremor, and dystonia. DBS may also have a role in the treatment of other disorders such as obsessive-compulsive disorder, Tourette's syndrome, and depression. The neuropsychologist plays a crucial role in patient selection, follow-up, and management of intra-operative and post-operative effects (Pillon, 2002; Saint-Cyr & Trepanier, 2000). There is now emerging evidence that DBS can induce mood, cognitive, and behavioral changes. These changes can have dramatic effects on patient outcome. There have been methodological problems with many of the studies of DBS on mood, cognition, and behavior. The neuropsychologist needs to be aware of these issues when following up patients, and constructing future studies. Additionally, this article will review all aspects of the DBS procedure that can result in mood, cognitive, and behavioral effects and what role(s) the neuropsychologist should play in screening and follow-up.     

Deep brain stimulation for dystonia.

Within the past few years, there has been a renaissance of functional neurosurgery for the treatment of dystonic movement disorders. In particular, deep brain stimulation (DBS) has widened the spectrum of therapeutical options for patients with otherwise intractable dystonia. It has been introduced only with a delay after DBS became an accepted treatment for advanced Parkinson' disease (PD). In this overview, the authors summarize the current status of its clinical application in dystonia. Deep brain stimulation for dystonia has been developed from radiofrequency lesioning, but it has replaced the latter largely in most centers. The main target used for primary dystonia is the posteroventral globus pallidus internus (GPi), and its efficacy has been shown in generalized dystonia, segmental dystonia, and complex cervical dystonia. The optimal target for secondary dystonias is still unclear, but some patients appear to benefit more from thalamic stimulation. The improvement of dystonia with chronic DBS frequently is delayed, in particular concerning tonic dystonic postures. Because more energy is needed for stimulation than in other movement disorders such as PD, more frequent battery replacements are necessary, which results in relatively higher costs for chronic DBS. The study of intraoperative microelectrode recordings and of local field potentials by the implanted DBS electrodes has yielded new insights in the pathophysiology of dystonia. Larger studies are underway presently to validate the observations being made.     

Nocturnal subcutaneous apomorphine infusion in Parkinson's disease and restless legs syndrome

OBJECTIVES: Nocturnal disabilities leading to fragmented sleep arising from parkinsonian off period related complications are common, under-reported and are difficult to treat. In this study, we evaluate the use of nocturnal continuous subcutaneous overnight apomorphine infusion in Parkinson's disease and restless legs syndrome. METHODS: Six parkinsonian patients and 2 patients with restless legs syndrome with nocturnal disabilities refractory to conventional oral therapy were assessed using a sleep diary while on standard treatment and during nocturnal apomorphine infusion. Three patients agreed to assessments during placebo infusion with normal saline. RESULTS: Apomorphine led to a dramatic reduction of nocturnal awakenings, nocturnal off periods, pain, dystonia and nocturia in parkinsonian patients. In patients with restless legs syndrome, apomorphine reduced nocturnal discomfort, reduced leg movements and improved pain and spasm scores significantly. Placebo infusion reproduced pain, nocturnal spasms and sleep disruption. CONCLUSION: This study suggests that overnight apomorphine infusion may be effective in overcoming refractory nocturnal disabilities in selected patients with Parkinson's disease and restless legs syndrome.     

Cabergoline in the treatment of Parkinson's disease

Cabergoline (1-[(6-allelylergolin-8 beta-yl)carbonyl]-1-[3-(dimethylamino)propyl]-3-ethyl-urea) is a new agonist of the D2 dopaminergic receptors used in the treatment of Parkinson's disease. Cabergoline is characterized by unique pharmacologic properties, such as its long plasma half-life (about 68 hours), which allows for once a day administration. Cabergoline is well tolerated, as has been shown in several clinical trials. Based on the information available, we suggest that cabergoline produces an improvement in the symptoms of Parkinson's disease similar to those produced by other dopaminergic agonists. Cabergoline monotherapy, when used in previously untreated patients, is an appropriate option for the symptomatic treatment of Parkinson's disease. Cabergoline improves motor symptoms, delays the presentation of levodopa-induced motor complications, and diminishes the amount of levodopa required for the control of the symptoms. We suggest that cabergoline is an adequate adjuvant treatment for Parkinson' disease. There is improvement in motor symptoms (without substantially increased dyskinesias), reduced severity and duration of the wearing-off period, and diminished need for levodopa. Cabergoline can also be useful in the treatment of sleep disturbances associated with advanced Parkinson's disease such as nocturnal akinesia and dystonia. However, additional studies on cabergoline's effects in nocturnal disturbances associated with Parkinson's disease are still required. Cabergoline is a well tolerated drug. Its side effects are seen mainly in the digestive and nervous system (central and peripheral). The efficacy of cabergoline in comparison to other dopaminergic agonists should be tested in future clinical studies.     

Deep brain stimulation for Parkinson's disease

Deep brain stimulation (DBS) is making a major impact in patients with advanced Parkinson's disease who continue to be disabled despite the best available medical therapy. Stimulation of the internal segment of the globus pallidus (GPi) or the subthalamic nucleus (STN) can improve tremor, rigidity, bradykinesia and gait disturbances in Parkinson's disease and improve the day-to-day activities of patients with these disabling symptoms. While the mechanism of action of DBS remains poorly understood, the success of technique in the treatment of movement disorders is bringing into question traditional concepts of the organization and of the basal ganglia and spearheading a re-examination of the nature and function of brain areas involved in the control of movement. Future developments in this rapidly advancing area will include the elucidation of the mechanism of action of DBS and technical advances in surgical techniques, in electrode design and in choosing better stimulation parameters. These advances will improve the scope and effectiveness of DBS and expand its clinical indications.