Deep-Brain Stimulation for Generalized Dystonia
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《新英格兰医药杂志》
Dystonia is characterized by twisting postures, tremor, and pain resulting from sustained muscle contractions. Idiopathic dystonia, in which dystonia is the only neurologic symptom, follows a very different course, depending on whether it starts in childhood or adult life. In the more common adult-onset dystonia, symptoms of idiopathic dystonia are usually restricted to a single region of the body, such as the neck, arm, or face (focal dystonia), or to a limited number of contiguous regions (segmental dystonia). Childhood-onset dystonia often spreads beyond one or two segments, involving one leg, the second leg or the trunk, and at least one other part of the body (generalized dystonia) in over 50 percent of patients.1 Because it interferes with walking, generalized dystonia can be particularly devastating. The majority of children in the United States with idiopathic dystonia have the DYT1 mutation, which conveys a genetic predisposition to dystonia and is extremely common in the Ashkenazi Jewish population.2
Botulinum-toxin injections have proved to be an adequate treatment for many patients (generally adults) with focal and segmental dystonia3 but are not feasible for most patients with generalized dystonia, since in these patients, numerous muscles contribute to the disability. Medications, especially high doses of anticholinergic agents combined with baclofen and sometimes other drugs, have a dramatic, sustained benefit in over half of children with idiopathic dystonia.4,5 However, symptoms are not adequately controlled in many patients.
The exact cause of dystonia is not known, but there are complex links to the dopaminergic system. A defect in the metabolism of the essential tyrosine hydroxylase cofactor tetrahydrobiopterin causes dopa-responsive dystonia, a condition of dopamine deficiency, dystonia, and parkinsonism.2 Patients with juvenile-onset parkinsonism have a profound deficiency of dopamine and also frequently have dystonic symptoms. On the other hand, dystonia cannot routinely be attributed to dopamine deficiency, since it is also a side effect of levodopa therapy in some patients with Parkinson's disease. However, another treatment for Parkinson's disease — high-frequency stimulation of the medial globus pallidus — typically decreases dyskinesias and dystonia in affected patients. This observation motivated investigators to evaluate this approach in patients with idiopathic dystonia.
Since 1999, almost 100 patients with generalized, segmental, or focal dystonia have been reported to have a response, which is sometimes quite dramatic, to bilateral pallidal deep-brain stimulation.6 However, these reports have almost exclusively been isolated case reports or have involved small, uncontrolled case series. A single report described a benefit of neurostimulation in a patient who underwent double-blind examination with neurostimulators off and at various frequencies.7
In this issue of the Journal, Vidailhet et al. report the results of bilateral pallidal deep-brain stimulation in 22 patients with generalized dystonia and severe impairment despite optimal medical therapy.8 Rather than expose a control group to sham surgery, they performed a controlled assessment by evaluating the patients three months after implantation while the neurostimulator was off and while it was on in a randomized, double-blind fashion. Pallidal deep-brain stimulation produced substantial improvement in patients with generalized dystonia, as compared with both baseline values and results obtained with the neurostimulator off. There were serious adverse events in 3 of the 22 patients; all were reversible. During open-assignment follow-up, improvement was sustained for at least one year. At the time of surgery, the median age of the patients was 30 years, yet 17 of the patients had begun to have symptoms before the age of 18 years. These results indicate that improvement is possible in patients with childhood-onset dystonia who have had symptoms for decades.
With such extensive successful experience with open assignment, was a controlled study really necessary? The experience with fetal-tissue transplantation in patients with Parkinson's disease tells us that it was. More than 100 such patients underwent open-label fetal-tissue transplantation, and most were described as having moderate-to-marked improvement after the procedure. However, two prospective, controlled studies showed no significant benefit in patients thought to be good candidates for the procedure.9,10 If the open-assignment results of a surgical procedure for Parkinson's disease, a relentlessly progressive condition, can be misleading, then controlled studies are essential to evaluate surgical procedures for dystonia.
Exactly why this procedure works is not known. Current models of basal-ganglia circuitry are not adequate to account for the improvement in dystonia after pallidal deep-brain stimulation. Neurons in the medial globus pallidus have an increased firing rate in patients with Parkinson's disease, resulting in increased inhibition in the thalamus and, ultimately, decreased excitation in the motor cortex — effects that are consistent with the key symptom of bradykinesia.11 Although the mechanism of deep-brain stimulation has not been established, it is generally believed that the output of the globus pallidus is reduced by the inhibitory effects of high-frequency stimulation of either the medial globus pallidus or the subthalamic nucleus, explaining the benefit in Parkinson's disease. In dystonia, neurons in the medial globus pallidus fire in irregular bursts at a reduced overall frequency.12 Although it is hard to understand how a further reduction of neuronal activity in the globus pallidus could improve dystonia, it may be that no neuronal activity is better than irregular activity.12
Successful medical treatment of dystonia requires high doses of medications and slow adjustment of the doses to avoid side effects; achieving the optimal benefit may take months. As a result, there may be pressure to bypass this cumbersome process in favor of a surgical solution. Yet the study by Vidailhet et al. also illustrates some limitations of pallidal deep-brain stimulation. Although the condition of most patients improved, the procedure was far from a cure. Despite the significant improvement in scores on a disease-specific disability scale at one year, a more general indicator of the quality of life showed no significant improvement in scores on most subscales. Medication doses were frequently reduced after the procedure, but 17 of 20 patients who had received medical therapy preoperatively continued to receive some medication throughout the trial. Two of the 22 patients had minimal improvement after the procedure and 2 had worsening dystonia, and Vidailhet et al. were unable to predict the magnitude of the benefit on the basis of the presence or absence of the DYT1 mutation or the initial severity or duration of disease. There were few serious adverse events in this study. However, intracranial hemorrhage and infection of the deep-brain–stimulation hardware are serious potential problems. Complications can also result from breakdown of the skin surrounding the stimulator or leads, lead fracture, and other lead malfunctions.6 Sudden loss of the electrical signal (from battery depletion or inadvertent turning off of one or both stimulators) can exacerbate dystonic symptoms in a rebound phenomenon. A benefit from deep-brain stimulation may appear in days or weeks, but programming the neurostimulators may take considerable time, thus delaying the maximal benefit from stimulation by many months.6
Although the results of the study reported by Vidailhet et al. are encouraging, more data are needed before the widespread adoption of this approach can be recommended. On the basis of the available literature, we cannot predict which patients will have a response to deep-brain stimulation, nor do we know the long-term outcomes of this procedure. At this time, pallidal deep-brain stimulation can be recommended only for patients with severe dystonia despite optimal medical therapy.
Source Information
From the Department of Neurology, Columbia College of Physicians and Surgeons, New York.
References
Greene P, Kang UJ, Fahn S. Spread of symptoms in idiopathic torsion dystonia. Mov Disord 1995;10:143-152.
Bressman SB. Dystonia: phenotypes and genotypes. Rev Neurol (Paris) 2003;159:849-856.
Comella CL, Pullman SL. Botulinum toxins in neurological disease. Muscle Nerve 2004;29:628-644.
Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl. Neurology 1986;36:160-164.
Greene P, Shale H, Fahn S. Analysis of open-label trials in torsion dystonia using high dosages of anticholinergics and other drugs. Mov Disord 1988;3:46-60.
Krauss JK, Yianni J, Loher TJ, Aziz TZ. Deep brain stimulation for dystonia. J Clin Neurophysiol 2004;21:18-30.
Kumar R, Dagher A, Hutchison WD, Land AE, Lozano AM. Globus pallidus deep brain stimulation for generalized dystonia: clinical and PET investigation. Neurology 1999;53:871-874.
Vidailhet M, Vercueil L, Houeto J-L, et al. Bilateral pallidal deep-brain stimulation in primary generalized dystonia. N Engl J Med 2005;352:459-467.
Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 2001;344:710-719.
Olanow CW, Goetz CG, Kordower JH, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol 2003;54:403-414.
Lang AE. Subthalamic stimulation for Parkinson's disease -- living better electrically? N Engl J Med 2003;349:1888-1891.
Vitek JL, Chockkan V, Zhang JY, et al. Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol 1999;46:22-35.(Paul Greene, M.D.)
Botulinum-toxin injections have proved to be an adequate treatment for many patients (generally adults) with focal and segmental dystonia3 but are not feasible for most patients with generalized dystonia, since in these patients, numerous muscles contribute to the disability. Medications, especially high doses of anticholinergic agents combined with baclofen and sometimes other drugs, have a dramatic, sustained benefit in over half of children with idiopathic dystonia.4,5 However, symptoms are not adequately controlled in many patients.
The exact cause of dystonia is not known, but there are complex links to the dopaminergic system. A defect in the metabolism of the essential tyrosine hydroxylase cofactor tetrahydrobiopterin causes dopa-responsive dystonia, a condition of dopamine deficiency, dystonia, and parkinsonism.2 Patients with juvenile-onset parkinsonism have a profound deficiency of dopamine and also frequently have dystonic symptoms. On the other hand, dystonia cannot routinely be attributed to dopamine deficiency, since it is also a side effect of levodopa therapy in some patients with Parkinson's disease. However, another treatment for Parkinson's disease — high-frequency stimulation of the medial globus pallidus — typically decreases dyskinesias and dystonia in affected patients. This observation motivated investigators to evaluate this approach in patients with idiopathic dystonia.
Since 1999, almost 100 patients with generalized, segmental, or focal dystonia have been reported to have a response, which is sometimes quite dramatic, to bilateral pallidal deep-brain stimulation.6 However, these reports have almost exclusively been isolated case reports or have involved small, uncontrolled case series. A single report described a benefit of neurostimulation in a patient who underwent double-blind examination with neurostimulators off and at various frequencies.7
In this issue of the Journal, Vidailhet et al. report the results of bilateral pallidal deep-brain stimulation in 22 patients with generalized dystonia and severe impairment despite optimal medical therapy.8 Rather than expose a control group to sham surgery, they performed a controlled assessment by evaluating the patients three months after implantation while the neurostimulator was off and while it was on in a randomized, double-blind fashion. Pallidal deep-brain stimulation produced substantial improvement in patients with generalized dystonia, as compared with both baseline values and results obtained with the neurostimulator off. There were serious adverse events in 3 of the 22 patients; all were reversible. During open-assignment follow-up, improvement was sustained for at least one year. At the time of surgery, the median age of the patients was 30 years, yet 17 of the patients had begun to have symptoms before the age of 18 years. These results indicate that improvement is possible in patients with childhood-onset dystonia who have had symptoms for decades.
With such extensive successful experience with open assignment, was a controlled study really necessary? The experience with fetal-tissue transplantation in patients with Parkinson's disease tells us that it was. More than 100 such patients underwent open-label fetal-tissue transplantation, and most were described as having moderate-to-marked improvement after the procedure. However, two prospective, controlled studies showed no significant benefit in patients thought to be good candidates for the procedure.9,10 If the open-assignment results of a surgical procedure for Parkinson's disease, a relentlessly progressive condition, can be misleading, then controlled studies are essential to evaluate surgical procedures for dystonia.
Exactly why this procedure works is not known. Current models of basal-ganglia circuitry are not adequate to account for the improvement in dystonia after pallidal deep-brain stimulation. Neurons in the medial globus pallidus have an increased firing rate in patients with Parkinson's disease, resulting in increased inhibition in the thalamus and, ultimately, decreased excitation in the motor cortex — effects that are consistent with the key symptom of bradykinesia.11 Although the mechanism of deep-brain stimulation has not been established, it is generally believed that the output of the globus pallidus is reduced by the inhibitory effects of high-frequency stimulation of either the medial globus pallidus or the subthalamic nucleus, explaining the benefit in Parkinson's disease. In dystonia, neurons in the medial globus pallidus fire in irregular bursts at a reduced overall frequency.12 Although it is hard to understand how a further reduction of neuronal activity in the globus pallidus could improve dystonia, it may be that no neuronal activity is better than irregular activity.12
Successful medical treatment of dystonia requires high doses of medications and slow adjustment of the doses to avoid side effects; achieving the optimal benefit may take months. As a result, there may be pressure to bypass this cumbersome process in favor of a surgical solution. Yet the study by Vidailhet et al. also illustrates some limitations of pallidal deep-brain stimulation. Although the condition of most patients improved, the procedure was far from a cure. Despite the significant improvement in scores on a disease-specific disability scale at one year, a more general indicator of the quality of life showed no significant improvement in scores on most subscales. Medication doses were frequently reduced after the procedure, but 17 of 20 patients who had received medical therapy preoperatively continued to receive some medication throughout the trial. Two of the 22 patients had minimal improvement after the procedure and 2 had worsening dystonia, and Vidailhet et al. were unable to predict the magnitude of the benefit on the basis of the presence or absence of the DYT1 mutation or the initial severity or duration of disease. There were few serious adverse events in this study. However, intracranial hemorrhage and infection of the deep-brain–stimulation hardware are serious potential problems. Complications can also result from breakdown of the skin surrounding the stimulator or leads, lead fracture, and other lead malfunctions.6 Sudden loss of the electrical signal (from battery depletion or inadvertent turning off of one or both stimulators) can exacerbate dystonic symptoms in a rebound phenomenon. A benefit from deep-brain stimulation may appear in days or weeks, but programming the neurostimulators may take considerable time, thus delaying the maximal benefit from stimulation by many months.6
Although the results of the study reported by Vidailhet et al. are encouraging, more data are needed before the widespread adoption of this approach can be recommended. On the basis of the available literature, we cannot predict which patients will have a response to deep-brain stimulation, nor do we know the long-term outcomes of this procedure. At this time, pallidal deep-brain stimulation can be recommended only for patients with severe dystonia despite optimal medical therapy.
Source Information
From the Department of Neurology, Columbia College of Physicians and Surgeons, New York.
References
Greene P, Kang UJ, Fahn S. Spread of symptoms in idiopathic torsion dystonia. Mov Disord 1995;10:143-152.
Bressman SB. Dystonia: phenotypes and genotypes. Rev Neurol (Paris) 2003;159:849-856.
Comella CL, Pullman SL. Botulinum toxins in neurological disease. Muscle Nerve 2004;29:628-644.
Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double-blind, prospective trial of high-dosage trihexyphenidyl. Neurology 1986;36:160-164.
Greene P, Shale H, Fahn S. Analysis of open-label trials in torsion dystonia using high dosages of anticholinergics and other drugs. Mov Disord 1988;3:46-60.
Krauss JK, Yianni J, Loher TJ, Aziz TZ. Deep brain stimulation for dystonia. J Clin Neurophysiol 2004;21:18-30.
Kumar R, Dagher A, Hutchison WD, Land AE, Lozano AM. Globus pallidus deep brain stimulation for generalized dystonia: clinical and PET investigation. Neurology 1999;53:871-874.
Vidailhet M, Vercueil L, Houeto J-L, et al. Bilateral pallidal deep-brain stimulation in primary generalized dystonia. N Engl J Med 2005;352:459-467.
Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 2001;344:710-719.
Olanow CW, Goetz CG, Kordower JH, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol 2003;54:403-414.
Lang AE. Subthalamic stimulation for Parkinson's disease -- living better electrically? N Engl J Med 2003;349:1888-1891.
Vitek JL, Chockkan V, Zhang JY, et al. Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol 1999;46:22-35.(Paul Greene, M.D.)