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Deep brain stimulation in the treatment of Parkinson's disease: a review and update
Clinical Neuroscience Research 1 (2001) 521–526 www.elsevier.com/locate/clires
Deep brain stimulation in the treatment of Parkinson’s disease: a review and update Patricia Dowsey-Limousin a, Pierre Pollak b,* a
Sobell Department of Neurophysiology, Institute of Neurology, Queen Square, WC1N 3BG London, UK Department of Neurosciences, University Hospital of Grenoble, INSERM 318, 38043 Grenoble, France
b
Received 3 August 2001; received in revised form 9 August 2001; accepted 20 August 2001
Abstract Deep brain stimulation (DBS) is a neurosurgical treatment of severe forms of Parkinson’s disease, already applied to three targets, the thalamus, the internal pallidum (GPi) and the subthalamic nucleus (STN). Thalamic DBS mainly improves contralateral tremor and is therefore restricted to a small group of patients with tremor dominant disease. STN and GPi DBS improve off-motor periods and dyskinesias. The magnitude of the improvement seems more constant with STN DBS than with GPi, but there is very little comparative data between these procedures. The DBS procedure has the unique advantage of reversibility and adjustability over time. Most authors agree that bilateral DBS is reasonably safe, which is not the case of ablation. In any event, surgery is restricted to patients disabled by their condition but still responding well at times to levodopa, who are generally fit with no behavioural, mood or cognitive impairment. DBS can have side effects. Side effects more specific to the DBS procedure are infection, disconnection and hardware failure. DBS, like ablative surgery can induce an intracranial lesion like a hematoma or a stroke. There are side effects more specific to the target like postural instability, dysarthria or paresthesia in the thalamus and dyskinesias or eyelid opening apraxia in the STN. The mechanism by which high frequency DBS mimics the effect of ablation is not fully understood. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Deep brain stimulation; Thalamus; Internal pallidum; Subthalamic nucleus; Parkinson’s disease; Surgical treatment
1. Introduction Following the discovery of levodopa in the 1960s, neurosurgical treatment of Parkinson’s disease (PD) was almost abandoned. The limits of drug therapy, intractable motor fluctuations or severe tremor and levodopa-induced dyskinesias have lead to a renewal of neurosurgery. This renewal was greatly supported by the advance in the understanding of the basal ganglia pathophysiology, which pointed out the association between akinesia and the subthalamic nucleus (STN) and internal pallidum (GPi) overactivity. The neurosurgery of today benefits from the development of brain imaging methods and new technology like chronic deep brain stimulation (DBS), which offers an alternative to lesions. The technique of DBS has been adapted from the treatment of chronic pain syndrome. In the field of movement disorders, it was first applied to the Ventral intermediate (Vim) nucleus of the thalamus in patients with severe * Corresponding author. Department of Clinical and Biological Neurosciences, Service de Neurologie, Centre Hospitalier Universitaire de Grenoble, BP 217, 38043 Grenoble Cedex 9, France. Tel.: 133-476765791; fax: 133-476765631. E-mail address: [email protected] (P. Pollak).
tremor, initially contralaterally to thalamotomies, to reduce the risks of bilateral procedures [1]. In the 1990s the same procedure was applied to two other targets, the STN [2] and GPi [3]. These two targets have the advantage to help motor fluctuations and dyskinesias, which are much more frequent than refractory tremor. STN surgery was based on the dramatic improvement of the parkinsonian syndrome of MPTP-treated monkeys by STN lesions [4]. GPi stimulation, like thalamic stimulation, was proposed as an alternative to ablation with the aim to reduce the morbidity of bilateral procedures, because most surgeons consider it unsafe to perform bilateral pallidotomy [5]. In the first part of this review, we will present the common characteristics of the 3 targets, patient selection, intraoperative and postoperative management. In the second part, we will describe the particular features of each target.
2. Common characteristics of all DBS procedures in PD 2.1. Patient selection The efficacy of DBS has been shown only for parkinson-
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ism related to idiopathic PD. There is very little data in the literature concerning other parkinsonian syndromes. STN stimulation has been reported to be ineffective in a case of post-ischemic parkinsonian syndrome [6]. The good predictive value of the pre-operative response to levodopa or apomorphine in the case of STN surgery makes it unlikely that a parkinsonian syndrome refractory to levodopa will respond well to DBS [7]. In the case of PD, the symptoms not responding to levodopa, like on-drug postural instability, freezing or dysarthria do not respond well to STN DBS either [8]. This does not necessarily apply for tremor, since tremor tends to respond to higher doses of medications. On the other hand, patients with Juvenile Autosomal Recessive Parkinsonism, whose phenotype looks like levodoparesponsive PD should benefit from DBS. Before considering surgery, patients should have tried all main medications, at least levodopa preparations at the highest tolerated dose, if possible 800 mg/d for 3 months, and dopamine agonists. The patients should be disabled by motor fluctuations and/or dyskinesias to the point that they can no longer cope with their professional obligation or need help for some daily living activities several hours a day to justify the risk of surgery. As we will detail further, there is a 2–3% risks of permanent morbidity after DBS in experienced teams. At the time of surgery, patients have to be in a good general condition, without major depression or cognitive impairment and with a brain imaging considered normal for the age. Patient expectations, cooperation and familial support are also important to consider. History of behavioural disorders is predictive of poor outcome because of the risk of psychiatric decompensation after surgery. 2.2. DBS surgery technique The surgery is done in stereotaxic conditions. Various techniques can be used to locate the target. Imaging methods (ventriculography, CT or MRI) are usually combined with electrophysiology methods (stimulation, recordings). MRI is becoming the imaging method of choice for many teams since it allows direct visualization of the target [9– 11], providing the distortion problem has been solved. The use of microelectrodes is still debated, mainly because of a possible increased risk of bleeding [12,13]. Intraoperative stimulation is mandatory. The implantation of the electrodes is carried out under local anaesthesia to allow assessment of the effect of the stimulation on parkinsonian features and the induction of side effects. In case of thalamic DBS, the efficacy is assessed on tremor. In case of STN DBS, rigidity is particularly useful since it does not depend on the patient effort, bradykinesia and tremor are also expected to improve. Induction of dyskinesias is a good predictive factor. In the case of GPi DBS, the acute effect of the stimulation is less reliable and side effects might be more useful like induction of visual flashes in particular to assess the depth of the electrode. When the best location is found, which means that the stimulation induces a good improve-
ment of parkinsonism without side effects, a quadripolar electrode for chronic stimulation is inserted and secured to the skull (Medtronic model 3387 or 3389; Minneapolis, MN, USA). This electrode is then connected by a subcutaneous lead to a pulse generator placed under the skin in the subclavicular area (Itrell II, Soletra or Kinetra, Medtronic, Minneapolis, USA). The Kinetra can be connected to two electrodes and allows independent setting of electrical parameters for each. It also has the advantage of not being sensitive to magnetic fields, and therefore does not switch off accidentally. The effect of DBS is mainly contralateral [14], which leads to bilateral surgery for most PD patients except those with unilateral tremor dominant PD. Both sides can be implanted in one session, or each side can be done separately in a staged procedure. 2.3. Postoperative management Electrical parameters of stimulation and polarities of the contacts of the electrode can be programmed by telemetry. This has to be done by an experienced physician. Electrical parameters are adjusted according to the clinical improvement and the side effects. The first screening of electrical parameters involves assessing the effect of a progressive increase in voltage on each contact of the quadripolar electrode. One can use a monopolar configuration with the active contact as the cathode, and the reference as the case of the stimulator, or a bipolar configuration with the reference as another contact. We tend to favour monopolar stimulation that is usually effective with a lower voltage than bipolar stimulation. Frequencies above 100 Hz, typically 130–185 Hz are mainly effective. Pulse widths of 60 or 90 ms are more commonly used, rarely above. The voltage is selected according to the symptoms, usually between 2.0 and 3.5 V. In case of STN DBS, the voltage is increased progressively over a few days, in parallel with the reduction of medications, because of the risks of inducing dyskinesias [15]. Stimulators have to be changed every 3–8 years depending on the voltage used. Patients with Vim DBS are often asked to switch off at night, whereas STN and GPi DBS are stimulated around the clock. Patients can switch on and off the stimulator using a magnet (for Itrell II) or a therapy controller (for Kinetra). The therapy controller can also allow the patient to increase or decrease the stimulation within the limits set by the physician. The electrical parameters need to be adjusted in the first 3 months, then once a year and occasionally in between depending on the patient. 2.4. Side effects common to all targets The major risks are intracranial vascular damage. The risk of haemorrhage leading to permanent neurological impairment is about 1% and stroke 2%, but these figures can vary according to the experience and the method used. The risk of infection is about 2%, which often leads to the removal of the implanted material in addition to antibiotics.
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Dislocation, migration and breaking of leads are rare in our experience. But a careful method of fixation of the electrode to the skull and connection to the pulse generator is mandatory. 3. Specific targets 3.1. Thalamus Thalamic DBS is mainly effective on contralateral tremor [16]. Upper limb tremor tends to respond better than lower limb. Daily life activities and quality of life scales are improved [16,17]. However, only a very small group of patients with disability related only to severe tremor can benefit from it. Sixty-five percent of patients after 4 years of thalamic stimulation complain from motor fluctuations or dyskinesias [18]. Therefore other targets, like GPi and STN should be considered even in patients with tremor. On average, drug dosages are unchanged after thalamic DBS [16]. A particular problem encountered with this procedure is the development of rebound and tolerance in some patients. To try to limit this occurrence, patients are asked to stop the stimulator at night. Dysarthria, dystonia and postural instability can occur, usually dependent on the electrical parameters [16]. Transient paresthesias when switching on the stimulators are frequent [19]. 3.2. Internal pallidum The improvement of off-phases is variable among series in the literature, from 0 to 56% of the motor part of the UPDRS [20–25]. The improvement in dyskinesias is more marked and more constant. On average there is no change in drug dosage after surgery, even in the series with a good improvement [25]. Side effects are relatively mild in most series, even in case of bilateral stimulation. No major change in cognitive function has been reported in these studies and other studies more oriented towards cognitive function assessment [26–29], although older patients seem to be more vulnerable to cognitive decline after DBS [30]. The GPi is a complex structure containing many fibres. Several studies have shown that very different effects can be obtained according to the exact location of the stimulated contact or the ablation in case of pallidotomy [31–33]. This could explain at least in part the variable results between patients and between studies. The morbidity of GPi stimulation tends to be very low. Owing to the adaptability of the procedure, visual fields problems described after pallidotomy do not occur with DBS. 3.3. Subthalamic nucleus STN stimulation has a dramatic effect on off-drug parkinsonian symptoms, UPDRS motor score improves from 41 to 66% in some recent series from the literature [8,34–38]. Most patients become unaware of any fluctuations. Limb
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bradykinesia, rigidity and tremor are reduced. Gait and balance are improved, if they are sensitive to levodopa [39,40]. The preoperative response to levodopa and apomorphine is a good predictive factor of the post-operative response to STN stimulation [7]. The effect on speech is more variable [8,41,42]. In the initial postoperative period of adaptation of the drug dosage and electrical parameters, dyskinesias can be increased transiently, but are greatly reduced in the long term [8,34–37]. Off-dystonia greatly improves [8,43]. Drug dosage is reduced in most studies and some patients can even stop medications [8,34–38]. Although dopaminergic drug dosage can be slowly reduced, stopping medications should not be the main aim, since the lack of levodopa can induce some behavioural problems like apathy [23]. Daily living activities and quality of life scales show significant improvement. Reversible dyskinesias can be induced by the stimulation in most patients [15]. Apraxia of eyelid opening, speech disturbances, weight gain, have been described [8,25]. More recently, behavioural problems have been identified like worsening of depression, suicide attempts, mania/hypomania and acute aggressive behaviour, mainly in patients with presurgical personality disorders or psychiatric history. Transient confusion is frequent immediately after surgery and probably not specific of the target. Studies of cognitive functions show only some subtle changes on average [27–29], but patients with cognitive impairment before surgery or older than 69 are at risk of worsening after [8,44,45].
4. DBS versus ablation The main disadvantage of DBS is that it is an expensive procedure, because of the equipment and also the manpower necessary to manage the patients. However, since STN DBS allows a dramatic decrease in dopaminergic drugs and medical and social care, the cost to effectiveness ratio of this procedure could be favourable. Some types of stimulators, like the Itrell II can be accidentally switched-off. The stimulator or extension lead can give some discomfort. More severe risks are related to complications with the implanted material. Permanent morbidity specifically related to DBS technique is rare. Tolerance and rebound have been described, particularly with tremor, mainly with thalamic DBS, but could also happen in other targets. DBS has many advantages [46]. The risks of bleeding or stroke are reduced. A misplaced electrode might not be very effective but is less dangerous than a misplaced ablation. The risk of excessively large ablation does not exist. Owing to the adaptability of electrical parameters, there is less risk of recurrence of symptoms in the long-term. Bilateral surgery is possible with only moderate risks. Most surgeons have stopped doing bilateral ablations because of cognitive, speech and balance problems. However, there are only few comparative data in the
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literature. The Amsterdam group has published a prospective randomized study of uni- or bilateral thalamic DBS versus unilateral thalamotomy [47]. Both procedures are equally effective, but there are fewer adverse effects with DBS and the possibility to do bilateral procedures allows a better functional improvement. Several surgeons have also published their own experience with both techniques. Siegfried et al. report 25% of cases with dysarthria and dysphagia with ablation and none with stimulation [48]. According to Tasker, the adaptability of DBS prevents the re-operation often necessary with ablation procedures [49]. STN DBS can be applied after an unsuccessful or partly successful ablation or DBS of another target [50–52]. Bilateral implantation might be necessary. 5. STN versus GPi Both STN and GPi DBS can be used to treat patients suffering from motor fluctuations and dyskinesias. Little comparative data between both targets are available. In the best cases the percentage of improvement of UPDRS motor score is relatively similar but nevertheless medications are generally reduced only in the STN group. Preliminary results on a blinded randomized study of STN versus GPi DBS show a 40% improvement of the UPDRS motor score in both groups, and dyskinesias are reduced in both groups, but drug dosage is decreased only in the STN group [53]. A retrospective open study on 13 patients shows a 71% improvement of motor UPDRS in the STN group and 39% in the GPi group [23]. As in the Burchiel et al. study [53], dyskinesias were reduced in both groups, but levodopa dosage was reduced only in the STN group and electrical parameters were higher in the GPi group. A more recent retrospective study on 27 patients shows no significant difference between the two targets in the improvement of off-period motor score (67% STN, 54% GPi) and dyskinesias [25]. Nevertheless, medications were reduced only in the STN group, and electrical parameters were threefold lower in the STN group than in the Gpi. Adverse events were more frequent in the STN group, in particular depression/anhedonia and hypophonia/dysarthria [25].
tion. It has a more constant effect against off-motor phases, it permits a reduction of medication, and lower amplitude of stimulation is required. The adaptability of electrical parameters makes DBS safer than ablation, particularly bilaterally. There is nevertheless some morbidity and only patients with disability despite all drug trials should be operated on. There are still many unknown issues, like the effect in the very long term, particularly for STN and GPi. There are some theoretical reasons to believe, and some animal studies to suggest, a neuroprotective role of STN DBS, but this remains to be studied in patients [54,55]. The mechanisms of action of DBS are not fully understood, but are definitely related to high frequency. DBS mimics the effect of a lesion in each target, but it does not work through a lesion since it is reversible when the stimulators are switched off and pathological studies show only very small gliosis at the tip of the electrode which cannot explain the benefit [56–58]. The efficacy of narrow pulse width might be an argument for stimulation of fibres and not cells [59,60]. The stimulation could excite GABAergic fibres or work less specifically, by disrupting an electric message going through the basal ganglia. In contrast to this latter proposed mechanism, the effect of high-frequency STN stimulation was analyzed with patchclamp techniques in vitro and produced a blockade of the spontaneous activities of STN neurons as a result of a strong depression of intrinsic voltage-gated currents underlying single-spike and bursting modes of discharge [61]. The effect of STN DBS shares many aspects of the effect of dopaminergic drugs. Even PET studies have shown that like apomorphine, STN DBS allows a better activation of non primary motor areas like SMA, cingulate and dorsolateral prefrontal cortex [62,63]. Acknowledgements DBS studies in the Grenoble group were supported by the Rhoˆ ne-Alpes Government and the INSERM (Institut National de la Sante´ Et de la Recherche Me´ dicale). References
6. Discussion Thalamic, STN and GPi DBS have clearly established their efficacy in the treatment of PD. Thalamic DBS is useful only for the few patients with severe isolated tremor and alternative targets should be considered also for those. STN and GPi can be applied to the larger group of patients with motor fluctuations and dyskinesias. Only a small proportion of patients with motor fluctuations and dyskinesias are eligible because of the risks and contraindications. The lack of randomized study in a large group of patients makes difficult the comparison of the effect between different targets, but data in the literature favours STN stimula-
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Deep brain stimulation in the treatment of Parkinson’s disease: a review and update Patricia Dowsey-Limousin a, Pierre Pollak b,* a
Sobell Department of Neurophysiology, Institute of Neurology, Queen Square, WC1N 3BG London, UK Department of Neurosciences, University Hospital of Grenoble, INSERM 318, 38043 Grenoble, France
b
Received 3 August 2001; received in revised form 9 August 2001; accepted 20 August 2001
Abstract Deep brain stimulation (DBS) is a neurosurgical treatment of severe forms of Parkinson’s disease, already applied to three targets, the thalamus, the internal pallidum (GPi) and the subthalamic nucleus (STN). Thalamic DBS mainly improves contralateral tremor and is therefore restricted to a small group of patients with tremor dominant disease. STN and GPi DBS improve off-motor periods and dyskinesias. The magnitude of the improvement seems more constant with STN DBS than with GPi, but there is very little comparative data between these procedures. The DBS procedure has the unique advantage of reversibility and adjustability over time. Most authors agree that bilateral DBS is reasonably safe, which is not the case of ablation. In any event, surgery is restricted to patients disabled by their condition but still responding well at times to levodopa, who are generally fit with no behavioural, mood or cognitive impairment. DBS can have side effects. Side effects more specific to the DBS procedure are infection, disconnection and hardware failure. DBS, like ablative surgery can induce an intracranial lesion like a hematoma or a stroke. There are side effects more specific to the target like postural instability, dysarthria or paresthesia in the thalamus and dyskinesias or eyelid opening apraxia in the STN. The mechanism by which high frequency DBS mimics the effect of ablation is not fully understood. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Deep brain stimulation; Thalamus; Internal pallidum; Subthalamic nucleus; Parkinson’s disease; Surgical treatment
1. Introduction Following the discovery of levodopa in the 1960s, neurosurgical treatment of Parkinson’s disease (PD) was almost abandoned. The limits of drug therapy, intractable motor fluctuations or severe tremor and levodopa-induced dyskinesias have lead to a renewal of neurosurgery. This renewal was greatly supported by the advance in the understanding of the basal ganglia pathophysiology, which pointed out the association between akinesia and the subthalamic nucleus (STN) and internal pallidum (GPi) overactivity. The neurosurgery of today benefits from the development of brain imaging methods and new technology like chronic deep brain stimulation (DBS), which offers an alternative to lesions. The technique of DBS has been adapted from the treatment of chronic pain syndrome. In the field of movement disorders, it was first applied to the Ventral intermediate (Vim) nucleus of the thalamus in patients with severe * Corresponding author. Department of Clinical and Biological Neurosciences, Service de Neurologie, Centre Hospitalier Universitaire de Grenoble, BP 217, 38043 Grenoble Cedex 9, France. Tel.: 133-476765791; fax: 133-476765631. E-mail address: [email protected] (P. Pollak).
tremor, initially contralaterally to thalamotomies, to reduce the risks of bilateral procedures [1]. In the 1990s the same procedure was applied to two other targets, the STN [2] and GPi [3]. These two targets have the advantage to help motor fluctuations and dyskinesias, which are much more frequent than refractory tremor. STN surgery was based on the dramatic improvement of the parkinsonian syndrome of MPTP-treated monkeys by STN lesions [4]. GPi stimulation, like thalamic stimulation, was proposed as an alternative to ablation with the aim to reduce the morbidity of bilateral procedures, because most surgeons consider it unsafe to perform bilateral pallidotomy [5]. In the first part of this review, we will present the common characteristics of the 3 targets, patient selection, intraoperative and postoperative management. In the second part, we will describe the particular features of each target.
2. Common characteristics of all DBS procedures in PD 2.1. Patient selection The efficacy of DBS has been shown only for parkinson-
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ism related to idiopathic PD. There is very little data in the literature concerning other parkinsonian syndromes. STN stimulation has been reported to be ineffective in a case of post-ischemic parkinsonian syndrome [6]. The good predictive value of the pre-operative response to levodopa or apomorphine in the case of STN surgery makes it unlikely that a parkinsonian syndrome refractory to levodopa will respond well to DBS [7]. In the case of PD, the symptoms not responding to levodopa, like on-drug postural instability, freezing or dysarthria do not respond well to STN DBS either [8]. This does not necessarily apply for tremor, since tremor tends to respond to higher doses of medications. On the other hand, patients with Juvenile Autosomal Recessive Parkinsonism, whose phenotype looks like levodoparesponsive PD should benefit from DBS. Before considering surgery, patients should have tried all main medications, at least levodopa preparations at the highest tolerated dose, if possible 800 mg/d for 3 months, and dopamine agonists. The patients should be disabled by motor fluctuations and/or dyskinesias to the point that they can no longer cope with their professional obligation or need help for some daily living activities several hours a day to justify the risk of surgery. As we will detail further, there is a 2–3% risks of permanent morbidity after DBS in experienced teams. At the time of surgery, patients have to be in a good general condition, without major depression or cognitive impairment and with a brain imaging considered normal for the age. Patient expectations, cooperation and familial support are also important to consider. History of behavioural disorders is predictive of poor outcome because of the risk of psychiatric decompensation after surgery. 2.2. DBS surgery technique The surgery is done in stereotaxic conditions. Various techniques can be used to locate the target. Imaging methods (ventriculography, CT or MRI) are usually combined with electrophysiology methods (stimulation, recordings). MRI is becoming the imaging method of choice for many teams since it allows direct visualization of the target [9– 11], providing the distortion problem has been solved. The use of microelectrodes is still debated, mainly because of a possible increased risk of bleeding [12,13]. Intraoperative stimulation is mandatory. The implantation of the electrodes is carried out under local anaesthesia to allow assessment of the effect of the stimulation on parkinsonian features and the induction of side effects. In case of thalamic DBS, the efficacy is assessed on tremor. In case of STN DBS, rigidity is particularly useful since it does not depend on the patient effort, bradykinesia and tremor are also expected to improve. Induction of dyskinesias is a good predictive factor. In the case of GPi DBS, the acute effect of the stimulation is less reliable and side effects might be more useful like induction of visual flashes in particular to assess the depth of the electrode. When the best location is found, which means that the stimulation induces a good improve-
ment of parkinsonism without side effects, a quadripolar electrode for chronic stimulation is inserted and secured to the skull (Medtronic model 3387 or 3389; Minneapolis, MN, USA). This electrode is then connected by a subcutaneous lead to a pulse generator placed under the skin in the subclavicular area (Itrell II, Soletra or Kinetra, Medtronic, Minneapolis, USA). The Kinetra can be connected to two electrodes and allows independent setting of electrical parameters for each. It also has the advantage of not being sensitive to magnetic fields, and therefore does not switch off accidentally. The effect of DBS is mainly contralateral [14], which leads to bilateral surgery for most PD patients except those with unilateral tremor dominant PD. Both sides can be implanted in one session, or each side can be done separately in a staged procedure. 2.3. Postoperative management Electrical parameters of stimulation and polarities of the contacts of the electrode can be programmed by telemetry. This has to be done by an experienced physician. Electrical parameters are adjusted according to the clinical improvement and the side effects. The first screening of electrical parameters involves assessing the effect of a progressive increase in voltage on each contact of the quadripolar electrode. One can use a monopolar configuration with the active contact as the cathode, and the reference as the case of the stimulator, or a bipolar configuration with the reference as another contact. We tend to favour monopolar stimulation that is usually effective with a lower voltage than bipolar stimulation. Frequencies above 100 Hz, typically 130–185 Hz are mainly effective. Pulse widths of 60 or 90 ms are more commonly used, rarely above. The voltage is selected according to the symptoms, usually between 2.0 and 3.5 V. In case of STN DBS, the voltage is increased progressively over a few days, in parallel with the reduction of medications, because of the risks of inducing dyskinesias [15]. Stimulators have to be changed every 3–8 years depending on the voltage used. Patients with Vim DBS are often asked to switch off at night, whereas STN and GPi DBS are stimulated around the clock. Patients can switch on and off the stimulator using a magnet (for Itrell II) or a therapy controller (for Kinetra). The therapy controller can also allow the patient to increase or decrease the stimulation within the limits set by the physician. The electrical parameters need to be adjusted in the first 3 months, then once a year and occasionally in between depending on the patient. 2.4. Side effects common to all targets The major risks are intracranial vascular damage. The risk of haemorrhage leading to permanent neurological impairment is about 1% and stroke 2%, but these figures can vary according to the experience and the method used. The risk of infection is about 2%, which often leads to the removal of the implanted material in addition to antibiotics.
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Dislocation, migration and breaking of leads are rare in our experience. But a careful method of fixation of the electrode to the skull and connection to the pulse generator is mandatory. 3. Specific targets 3.1. Thalamus Thalamic DBS is mainly effective on contralateral tremor [16]. Upper limb tremor tends to respond better than lower limb. Daily life activities and quality of life scales are improved [16,17]. However, only a very small group of patients with disability related only to severe tremor can benefit from it. Sixty-five percent of patients after 4 years of thalamic stimulation complain from motor fluctuations or dyskinesias [18]. Therefore other targets, like GPi and STN should be considered even in patients with tremor. On average, drug dosages are unchanged after thalamic DBS [16]. A particular problem encountered with this procedure is the development of rebound and tolerance in some patients. To try to limit this occurrence, patients are asked to stop the stimulator at night. Dysarthria, dystonia and postural instability can occur, usually dependent on the electrical parameters [16]. Transient paresthesias when switching on the stimulators are frequent [19]. 3.2. Internal pallidum The improvement of off-phases is variable among series in the literature, from 0 to 56% of the motor part of the UPDRS [20–25]. The improvement in dyskinesias is more marked and more constant. On average there is no change in drug dosage after surgery, even in the series with a good improvement [25]. Side effects are relatively mild in most series, even in case of bilateral stimulation. No major change in cognitive function has been reported in these studies and other studies more oriented towards cognitive function assessment [26–29], although older patients seem to be more vulnerable to cognitive decline after DBS [30]. The GPi is a complex structure containing many fibres. Several studies have shown that very different effects can be obtained according to the exact location of the stimulated contact or the ablation in case of pallidotomy [31–33]. This could explain at least in part the variable results between patients and between studies. The morbidity of GPi stimulation tends to be very low. Owing to the adaptability of the procedure, visual fields problems described after pallidotomy do not occur with DBS. 3.3. Subthalamic nucleus STN stimulation has a dramatic effect on off-drug parkinsonian symptoms, UPDRS motor score improves from 41 to 66% in some recent series from the literature [8,34–38]. Most patients become unaware of any fluctuations. Limb
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bradykinesia, rigidity and tremor are reduced. Gait and balance are improved, if they are sensitive to levodopa [39,40]. The preoperative response to levodopa and apomorphine is a good predictive factor of the post-operative response to STN stimulation [7]. The effect on speech is more variable [8,41,42]. In the initial postoperative period of adaptation of the drug dosage and electrical parameters, dyskinesias can be increased transiently, but are greatly reduced in the long term [8,34–37]. Off-dystonia greatly improves [8,43]. Drug dosage is reduced in most studies and some patients can even stop medications [8,34–38]. Although dopaminergic drug dosage can be slowly reduced, stopping medications should not be the main aim, since the lack of levodopa can induce some behavioural problems like apathy [23]. Daily living activities and quality of life scales show significant improvement. Reversible dyskinesias can be induced by the stimulation in most patients [15]. Apraxia of eyelid opening, speech disturbances, weight gain, have been described [8,25]. More recently, behavioural problems have been identified like worsening of depression, suicide attempts, mania/hypomania and acute aggressive behaviour, mainly in patients with presurgical personality disorders or psychiatric history. Transient confusion is frequent immediately after surgery and probably not specific of the target. Studies of cognitive functions show only some subtle changes on average [27–29], but patients with cognitive impairment before surgery or older than 69 are at risk of worsening after [8,44,45].
4. DBS versus ablation The main disadvantage of DBS is that it is an expensive procedure, because of the equipment and also the manpower necessary to manage the patients. However, since STN DBS allows a dramatic decrease in dopaminergic drugs and medical and social care, the cost to effectiveness ratio of this procedure could be favourable. Some types of stimulators, like the Itrell II can be accidentally switched-off. The stimulator or extension lead can give some discomfort. More severe risks are related to complications with the implanted material. Permanent morbidity specifically related to DBS technique is rare. Tolerance and rebound have been described, particularly with tremor, mainly with thalamic DBS, but could also happen in other targets. DBS has many advantages [46]. The risks of bleeding or stroke are reduced. A misplaced electrode might not be very effective but is less dangerous than a misplaced ablation. The risk of excessively large ablation does not exist. Owing to the adaptability of electrical parameters, there is less risk of recurrence of symptoms in the long-term. Bilateral surgery is possible with only moderate risks. Most surgeons have stopped doing bilateral ablations because of cognitive, speech and balance problems. However, there are only few comparative data in the
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literature. The Amsterdam group has published a prospective randomized study of uni- or bilateral thalamic DBS versus unilateral thalamotomy [47]. Both procedures are equally effective, but there are fewer adverse effects with DBS and the possibility to do bilateral procedures allows a better functional improvement. Several surgeons have also published their own experience with both techniques. Siegfried et al. report 25% of cases with dysarthria and dysphagia with ablation and none with stimulation [48]. According to Tasker, the adaptability of DBS prevents the re-operation often necessary with ablation procedures [49]. STN DBS can be applied after an unsuccessful or partly successful ablation or DBS of another target [50–52]. Bilateral implantation might be necessary. 5. STN versus GPi Both STN and GPi DBS can be used to treat patients suffering from motor fluctuations and dyskinesias. Little comparative data between both targets are available. In the best cases the percentage of improvement of UPDRS motor score is relatively similar but nevertheless medications are generally reduced only in the STN group. Preliminary results on a blinded randomized study of STN versus GPi DBS show a 40% improvement of the UPDRS motor score in both groups, and dyskinesias are reduced in both groups, but drug dosage is decreased only in the STN group [53]. A retrospective open study on 13 patients shows a 71% improvement of motor UPDRS in the STN group and 39% in the GPi group [23]. As in the Burchiel et al. study [53], dyskinesias were reduced in both groups, but levodopa dosage was reduced only in the STN group and electrical parameters were higher in the GPi group. A more recent retrospective study on 27 patients shows no significant difference between the two targets in the improvement of off-period motor score (67% STN, 54% GPi) and dyskinesias [25]. Nevertheless, medications were reduced only in the STN group, and electrical parameters were threefold lower in the STN group than in the Gpi. Adverse events were more frequent in the STN group, in particular depression/anhedonia and hypophonia/dysarthria [25].
tion. It has a more constant effect against off-motor phases, it permits a reduction of medication, and lower amplitude of stimulation is required. The adaptability of electrical parameters makes DBS safer than ablation, particularly bilaterally. There is nevertheless some morbidity and only patients with disability despite all drug trials should be operated on. There are still many unknown issues, like the effect in the very long term, particularly for STN and GPi. There are some theoretical reasons to believe, and some animal studies to suggest, a neuroprotective role of STN DBS, but this remains to be studied in patients [54,55]. The mechanisms of action of DBS are not fully understood, but are definitely related to high frequency. DBS mimics the effect of a lesion in each target, but it does not work through a lesion since it is reversible when the stimulators are switched off and pathological studies show only very small gliosis at the tip of the electrode which cannot explain the benefit [56–58]. The efficacy of narrow pulse width might be an argument for stimulation of fibres and not cells [59,60]. The stimulation could excite GABAergic fibres or work less specifically, by disrupting an electric message going through the basal ganglia. In contrast to this latter proposed mechanism, the effect of high-frequency STN stimulation was analyzed with patchclamp techniques in vitro and produced a blockade of the spontaneous activities of STN neurons as a result of a strong depression of intrinsic voltage-gated currents underlying single-spike and bursting modes of discharge [61]. The effect of STN DBS shares many aspects of the effect of dopaminergic drugs. Even PET studies have shown that like apomorphine, STN DBS allows a better activation of non primary motor areas like SMA, cingulate and dorsolateral prefrontal cortex [62,63]. Acknowledgements DBS studies in the Grenoble group were supported by the Rhoˆ ne-Alpes Government and the INSERM (Institut National de la Sante´ Et de la Recherche Me´ dicale). References
6. Discussion Thalamic, STN and GPi DBS have clearly established their efficacy in the treatment of PD. Thalamic DBS is useful only for the few patients with severe isolated tremor and alternative targets should be considered also for those. STN and GPi can be applied to the larger group of patients with motor fluctuations and dyskinesias. Only a small proportion of patients with motor fluctuations and dyskinesias are eligible because of the risks and contraindications. The lack of randomized study in a large group of patients makes difficult the comparison of the effect between different targets, but data in the literature favours STN stimula-
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