The Treatment of Dystonic Tremor: A Systematic Review
There are very few studies specifically addressing the treatment of the DTs and, more importantly, almost all of them are retrospective and not randomised. Moreover, in many studies the tremor outcome was poorly documented as were the assessment tools, which were very rarely based on objective measurements (electromyography (EMG) or kinematics). These limitations account for the lack of evidence-based guidelines in the treatment of these tremor disorders.
In addition, it is impossible to know whether the reviewed studies reliably distinguished TAD and DT. In order to clarify this issue, we also reviewed the literature on TAD but unfortunately we did not find any study specifically addressing its treatment. TAD is usually treated with the medications used for ET and believed to respond in a comparable fashion, although there is little available data to support this supposition. Consequently, the data on the effectiveness of β-blockers or primidone in DT are limited by these diagnostic difficulties. Indeed, sometimes it is very difficult to distinguish between different tremor conditions, particularly with writing tremor, and isolated head or voice tremor. Therefore, it is possible that some of the DT patients reported in the literature were actually affected by TAD or even ET. In order to limit this bias, we focused our recommendations on DT and PWT.
In this systematic review, we found that the outcome of all the possible interventions (drugs, BoNT, surgery and alternative approaches) is highly variable, depending on the specific type of intervention and tremor distribution. Figure 3 provides a possible algorithm for the treatment of DT/PWT, admittedly based on very limited evidence available to date. On the basis of tremor distribution, BoNT is the most useful strategy in the management of axial (head or vocal cord) tremors and has the largest amount of data in the literature confirming its efficacy. With respect to appendicular tremor, BoNT and surgery might be effective in PWT, whereas no data are available for DT of the upper limbs. Drugs are generally less efficacious but could be tried especially when tremor involves different body regions, thus allowing the use of BoNT in a stepwise approach (in order to further improve the regions not adequately controlled by drugs). Apart from tremor in DRD, which typically responds to levodopa, the first-line drugs should be anticholinergics, as their use has been described in large samples of patients. Second-line drugs have been less extensively investigated; trials might include tetrabenazine, due to the reported efficacy in dystonia and DT/PWT, and clonazepam, especially in the light of the description of "clonazepam-sensitive dystonic tremor". Third-line drugs could be β-blockers, primidone and many others occasionally found to improve DT. Drug tolerability is an important issue for clinical decision-making as most of adult patients experience unwanted effects at lower doses than those needed for yielding a benefit. Even though the available literature did not specifically address the side effects produced by medications, the choice to rely on medications (eg, increasing the dose or adding another compound) or to adopt other approaches (ie, BoNT and/or surgery) should be based on these aspects as well.
(Enlarge Image)
Figure 3.
A possible algorithm for the treatment of dystonic tremor (DT) or primary writing tremor (PWT) on the basis of the limited evidence available to date. Botulinum neurotoxin (BoNT) is the most useful strategy in the management of axial (head or vocal cord) tremors, whereas appendicular tremor—with the exception of PWT—should be firstly treated with drugs, thus allowing the use of BoNT in a stepwise approach (in order to further improve the regions not adequately improved). By contrast, BoNT might be first-choice therapy in PWT, followed by drugs or surgery. Surgery (DBS) should be considered only when the disability derived by tremor overcomes the risks of its invasiveness. Unilateral procedures can be tried in case of appendicular tremor, whereas bilateral surgery is indicated for head tremor. As for the target of DBS, Vim and Gpi are the most used ones, based on the predominance of tremor (Vim) or dystonic postures (Gpi). The combined approach Vim+Gpi might be considered in case of failure of the single target procedure. Other targets (VLp, STN and surrounding areas, ie, PSA or cZi) might be considered in very selected cases. cZi, caudal zona incerta; DBS, deep brain stimulation; Gpi, globus pallidus internus; PSA, posterior subthalamic area; STN, subthalamus; Vim, ventralis intermedius nucleus of thalamus; VLp, posterior part of the ventrolateral thalamus.
Finally, DBS could be considered only when the disability derived from tremor overcomes the risks of its invasiveness. For example, the disability caused by PWT can vary from mild to considerable, depending on the profession of the patient. The handicap that it produces in Western cultures has generally not been considered sufficient to merit the risks involved in stereotactic surgery. However, in Japan where calligraphy is an important occupation, neurosurgery has been successfully performed for this condition, as it can threaten the professional career of the patient. Taking into account the potential ameliorative effect on the other dystonic features, GPi should be viewed as the preferred target for either stimulation or ablation; thalamic stimulation may be added in cases in which the benefit is insufficient, because it can also alleviate the tremor but can occasionally lead to worsening of dystonia itself. Stimulation of thalamic VLp is considered as less efficacious in dystonia and tremor treatment than GPi DBS. Noteworthy, a recent study challenged this assumption, concluding that DT patients with a mild dystonia should be considered for Vim DBS while the coexistence of severe DT and dystonia may be successfully controlled by combined GPi and Vim DBS. Subthalamic area might be an interesting target for stimulation, given the early experiences with lesions and the hypothesis that many fibres can be modulated in this 'bottle-neck' anatomical region; however, the available data are too scanty to support its use beyond an experimental approach.
In conclusion, paradoxically the most important result of our systematic review is the demonstration of the lack of good-quality studies addressing the treatment of DT. For instance, although surgery seems to be a useful treatment for tremor refractory to drugs or BoNT, the outcomes of either DBS or ablations of different brain nuclei have been reported in only 37 patients (20 studies); even the recent GPi DBS trials did not focus on the outcome of tremor, although they were conducted according to the criteria of evidence-based medicine. Future randomised controlled trials are needed, particularly those with active comparators, thus allowing the comparison of different treatment approaches (eg, BoNT vs drugs or GPi vs thalamic DBS).
Discussion and Recommendations
There are very few studies specifically addressing the treatment of the DTs and, more importantly, almost all of them are retrospective and not randomised. Moreover, in many studies the tremor outcome was poorly documented as were the assessment tools, which were very rarely based on objective measurements (electromyography (EMG) or kinematics). These limitations account for the lack of evidence-based guidelines in the treatment of these tremor disorders.
In addition, it is impossible to know whether the reviewed studies reliably distinguished TAD and DT. In order to clarify this issue, we also reviewed the literature on TAD but unfortunately we did not find any study specifically addressing its treatment. TAD is usually treated with the medications used for ET and believed to respond in a comparable fashion, although there is little available data to support this supposition. Consequently, the data on the effectiveness of β-blockers or primidone in DT are limited by these diagnostic difficulties. Indeed, sometimes it is very difficult to distinguish between different tremor conditions, particularly with writing tremor, and isolated head or voice tremor. Therefore, it is possible that some of the DT patients reported in the literature were actually affected by TAD or even ET. In order to limit this bias, we focused our recommendations on DT and PWT.
In this systematic review, we found that the outcome of all the possible interventions (drugs, BoNT, surgery and alternative approaches) is highly variable, depending on the specific type of intervention and tremor distribution. Figure 3 provides a possible algorithm for the treatment of DT/PWT, admittedly based on very limited evidence available to date. On the basis of tremor distribution, BoNT is the most useful strategy in the management of axial (head or vocal cord) tremors and has the largest amount of data in the literature confirming its efficacy. With respect to appendicular tremor, BoNT and surgery might be effective in PWT, whereas no data are available for DT of the upper limbs. Drugs are generally less efficacious but could be tried especially when tremor involves different body regions, thus allowing the use of BoNT in a stepwise approach (in order to further improve the regions not adequately controlled by drugs). Apart from tremor in DRD, which typically responds to levodopa, the first-line drugs should be anticholinergics, as their use has been described in large samples of patients. Second-line drugs have been less extensively investigated; trials might include tetrabenazine, due to the reported efficacy in dystonia and DT/PWT, and clonazepam, especially in the light of the description of "clonazepam-sensitive dystonic tremor". Third-line drugs could be β-blockers, primidone and many others occasionally found to improve DT. Drug tolerability is an important issue for clinical decision-making as most of adult patients experience unwanted effects at lower doses than those needed for yielding a benefit. Even though the available literature did not specifically address the side effects produced by medications, the choice to rely on medications (eg, increasing the dose or adding another compound) or to adopt other approaches (ie, BoNT and/or surgery) should be based on these aspects as well.
(Enlarge Image)
Figure 3.
A possible algorithm for the treatment of dystonic tremor (DT) or primary writing tremor (PWT) on the basis of the limited evidence available to date. Botulinum neurotoxin (BoNT) is the most useful strategy in the management of axial (head or vocal cord) tremors, whereas appendicular tremor—with the exception of PWT—should be firstly treated with drugs, thus allowing the use of BoNT in a stepwise approach (in order to further improve the regions not adequately improved). By contrast, BoNT might be first-choice therapy in PWT, followed by drugs or surgery. Surgery (DBS) should be considered only when the disability derived by tremor overcomes the risks of its invasiveness. Unilateral procedures can be tried in case of appendicular tremor, whereas bilateral surgery is indicated for head tremor. As for the target of DBS, Vim and Gpi are the most used ones, based on the predominance of tremor (Vim) or dystonic postures (Gpi). The combined approach Vim+Gpi might be considered in case of failure of the single target procedure. Other targets (VLp, STN and surrounding areas, ie, PSA or cZi) might be considered in very selected cases. cZi, caudal zona incerta; DBS, deep brain stimulation; Gpi, globus pallidus internus; PSA, posterior subthalamic area; STN, subthalamus; Vim, ventralis intermedius nucleus of thalamus; VLp, posterior part of the ventrolateral thalamus.
Finally, DBS could be considered only when the disability derived from tremor overcomes the risks of its invasiveness. For example, the disability caused by PWT can vary from mild to considerable, depending on the profession of the patient. The handicap that it produces in Western cultures has generally not been considered sufficient to merit the risks involved in stereotactic surgery. However, in Japan where calligraphy is an important occupation, neurosurgery has been successfully performed for this condition, as it can threaten the professional career of the patient. Taking into account the potential ameliorative effect on the other dystonic features, GPi should be viewed as the preferred target for either stimulation or ablation; thalamic stimulation may be added in cases in which the benefit is insufficient, because it can also alleviate the tremor but can occasionally lead to worsening of dystonia itself. Stimulation of thalamic VLp is considered as less efficacious in dystonia and tremor treatment than GPi DBS. Noteworthy, a recent study challenged this assumption, concluding that DT patients with a mild dystonia should be considered for Vim DBS while the coexistence of severe DT and dystonia may be successfully controlled by combined GPi and Vim DBS. Subthalamic area might be an interesting target for stimulation, given the early experiences with lesions and the hypothesis that many fibres can be modulated in this 'bottle-neck' anatomical region; however, the available data are too scanty to support its use beyond an experimental approach.
In conclusion, paradoxically the most important result of our systematic review is the demonstration of the lack of good-quality studies addressing the treatment of DT. For instance, although surgery seems to be a useful treatment for tremor refractory to drugs or BoNT, the outcomes of either DBS or ablations of different brain nuclei have been reported in only 37 patients (20 studies); even the recent GPi DBS trials did not focus on the outcome of tremor, although they were conducted according to the criteria of evidence-based medicine. Future randomised controlled trials are needed, particularly those with active comparators, thus allowing the comparison of different treatment approaches (eg, BoNT vs drugs or GPi vs thalamic DBS).
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