Deep brain stimulation for the treatment of Parkinsons disease C Hamani J Neimat and A M Lozano

All About Parkinson's Disease

All About Parkinson's Disease By Lianna Marie

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Division of Neurosurgery, University of Toronto, Toronto Western Hospital, Toronto, Canada

Summary. Approximately 30,000 patients have been treated throughout the world with deep brain stimulation for Parkinson's disease and other conditions. With accumulating experience, there has been an appreciation of the important benefits of this procedure, including the alleviation of disability and improvement in the quality of life. We have also become aware of some limitations of DBS surgery. Among the important issues that remain to be resolved are the timing of surgery, whether early or late in the course of the disease, and the best target for the individual patient, including a reassessment of the relative merits of globus pallidus versus subthalamic nucleus surgery. A better understanding of the symptoms that are resistant to both levodopa therapy and DBS surgery is also required.

Introduction

The introduction of deep brain stimulation (DBS) as a therapeutic alternative for the treatment of advanced Parkinson's disease (PD) has revolutionized the clinical management of this condition. In the last decade, the treatment has matured from one of ''last resort'' to a valuable therapeutic modality that is now offered routinely to patients. It has become an important contributor to helping these patients live an active and functional life. In this review we will discuss the anatomical targets, technical aspects, clinical results and adverse effects of DBS for the treatment of PD.

Anatomical target

Targets for DBS treatment of PD are the thalamus, globus pallidus internus (GPi), and the subthalamic nucleus (STN). There is still debate regarding target selection.

Thalamic DBS significantly improves contralateral arm tremor, but it is not effective for the treatment of other parkinsonian motor symptoms (Benabid et al., 1996; Pollak et al., 2002). As a result, thalamic surgery for PD has virtually been replaced by GPi and particularly STN DBS surgery.

The GPi is a large structure, which can lead to significant variation in the site of DBS implantation. This may be one of the factors responsible for the variability in outcome reported in different surgical series (30-55% improvement with bilateral stimulation) (Deep-Brain Stimulation for Parkinson's Disease Study Group, 2001; Brown et al., 1999; Burchiel et al., 1999; Durif et al., 2002; Ghika et al., 1998; Rodriguez-Oroz et al., 2005). The reduction in tremor with GPi surgery is in the order of 70-80%, while rigidity and akinesia improve by approximately 40-60% (Deep-Brain Stimulation for Parkinson's Disease Study Group, 2001; Brown et al., 1999; Burchiel et al., 1999; Durif et al., 2002; Ghika et al., 1998; Rodriguez-Oroz et al., 2005). Gait and posture have a smaller degree of improvement that significantly declines over time (approximately 40% at 1 year and 25% at 3-4 years). There is a striking decrease in the involuntary movements induced by levodopa, in the order of 70-90% (Deep-Brain Stimulation for Parkinson's Disease Study Group, 2001; Brown et al., 1999; Burchiel et al., 1999; Durif et al., 2002; Ghika et al., 1998; Krack et al., 1998; Rodriguez-Oroz et al., 2005).

The compact size of the subthalamic nucleus and the reproducibility of surgical results (Hamani et al., 2004, 2005) has made the STN the most popular surgical target to treat patients with PD. STN DBS not only improves the cardinal manifestations of the disease and levodopa-induced dyskinesias, but also postural instability and gait to a certain extent (Hamani et al., 2005; Kleiner-Fisman et al., 2003; Krack et al., 2003; Rodriguez-Oroz et al., 2005). Although not entirely clear, it has been suggested that DBS in the STN might pose a higher risk of cognitive and psychiatric side effects compared to GPi stimulation. A final comparison of GPi and STN as the proper target for the treatment of advanced Parkinson's disease will only be properly addressed in future prospective randomized trials. Details on the surgical technique, clinical outcome and adverse effects of STN DBS are presented below.

Subthalamic nucleus stimulation

Selection criteria

Perhaps the most critical factor in determining surgical outcome in DBS surgery is the selection of appropriate surgical candidates. To be considered an optimal candidate, patients have to be diagnosed with PD, present disabling motor fluctuations with a prolonged ''off'' state, significant dyskinesias, and demonstrate a good clinical response to L-DOPA (Chen et al., 2003; Daniele et al., 2003; Herzog et al., 2003; Nasser et al., 2002; Pahwa et al., 2003; Patel et al., 2003; Simuni et al., 2002; Thobois et al., 2002; Welter et al., 2002). The last item is worth stressing, as the response to L-DOPA during the L-DOPA challenge test seems to predict surgical outcome (Charles et al., 2002). During this test, a patient's United Parkinson's Disease Rating Scale (UPDRS) motor scores are evaluated before and after receiving a large standardized dose of L-DOPA. The improvement measured in this challenge is what a patient might expect from DBS therapy if a good surgical outcome is attained.

The main exclusion criteria for STN DBS are the presence of a significant cognitive dysfunction, concomitant neurological disorders, and medical problems that might pose a risk for the patient during the procedure (i.e. coagulopathies) (Daniele et al., 2003; Herzog et al., 2003; Nasser et al., 2002; Pahwa et al., 2003; Patel et al., 2003; Simuni et al., 2002; Thobois et al., 2002; Vingerhoets et al., 2002; Welter et al., 2002). There is no consistent age limit for the operation but several centers do not offer surgery to patients older than 70 years.

Surgical technique and parameters of stimulation

As the STN and surrounding structures can be directly visualized with magnetic resonance imaging (MRI), this has been the most commonly employed imaging technique for targeting the nucleus (Barichella et al., 2003; Daniele et al., 2003; Dujardin et al., 2001; Figueiras-Mendez et al., 2002; Gomez et al., 2003; Herzog et al., 2003; Kleiner-Fisman et al., 2003; Krack et al., 2003; Lopiano et al., 2001; Nasser et al., 2002; Ostergaard et al., 2002; Pahwa et al., 2003; Patel et al., 2003; Pinter et al., 1999; Simuni et al., 2002; Starr et al., 2002; Thobois et al., 2002; Vesper et al., 2002; Vingerhoets et al., 2002; Volkmann et al., 2001; Welter et al., 2002). Ventriculography and/or computed tomography scans (CT) are also used to precisely target the anterior and posterior commissures (the former technique) and correct possible imaging distortions related to the MRI

(Daniele et al., 2003; Dujardin et al., 2001; Figueiras-Mendez et al., 2002; Krack et al., 2003; Pinter et al., 1999; Thobois et al., 2002). To date however, the use of neuro-navigation planning stations for surgical targeting has also been able to correct MRI distortions and several centers are using only this imaging modality to target the STN.

Although there remains some controversy over the benefits of microelectrode recording (MER) to map the correct DBS target, most centers that have reported their experience in the literature do use MER to target the STN (Dujardin et al., 2001; Figueiras-Mendez et al., 2002; Gomez et al., 2003; Herzog et al., 2003; Kleiner-Fisman et al., 2003; Krack et al., 2003; Lopiano et al., 2001; Pahwa et al., 2003; Simuni et al., 2002; Starr et al., 2002; Thobois et al., 2002; Vesper et al., 2002; Vingerhoets et al., 2002; Welter et al., 2002). The objectives of this technique are to identify the sensorimotor territory of the subthalamic nucleus (characterized by the presence of movement-related cells) and the transition between the STN and the sub-stantia nigra (Abosch et al., 2002; Hutchison et al., 1998). Once the surgical target is mapped, the DBS electrode is implanted at the established coordinates and each contact is tested for efficacy and stimulation-induced adverse effects. Such stimulation-induced effects are

often caused by the electrical stimulation of structures that are adjacent to the STN. Typical findings include stimulation of oc-culomotor fibers (medial to the STN), the corticospinal tract (anterior and lateral), and fibers of the medial lemniscus (posterior). If adverse effects are noticed when low voltages are applied, the electrodes may have to be repositioned.

Implantation of the pulse generator and battery constitutes the second step of the procedure. The pulse generator is most commonly implanted in the subcutaneous tissue of the infraclavicular region. This can be done on the day the electrodes are implanted or after a brief period of time (days to weeks). Programming of the device often starts a few weeks after surgery. Most centers are currently using monopolar stimulation (one of the electrode contacts is used as the cathode and the pulse generator as the anode). Stimulation parameters typically vary between 2.5 to 3.5 V, 60 or 90 microseconds of pulse width, and 130185 Hz of frequency (Hamani et al., 2005).

Clinical outcome

A summary of the clinical outcome with STN DBS may be found in Table 1.

With STN DBS, UPDRS part II scores (activities of daily living) improve by 50-66%

Table 1. Clinical outcome following subthalamic nucleus stimulation in Parkinson's disease

1 year follow-up

"off" meds "on" meds

3-5 years follow-up

"off" meds "on" meds

UPDRS II

UPDRS III

Tremor

Rigidity

Bradykinesia

Gait

Postural Inst.

''on'' stim; ''off'' meds: Patients evaluated with stimulation and no drugs. ''on'' stim; ''on'' meds: Patients evaluated with stimulation and drugs. UPDRS Unified Parkinson's disease rating scale. Postural Inst. Postural instability after 1 year (Hamani et al., 2005; Krack et al., 2003; Rodriguez-Oroz et al., 2005), and by 40-45% after 3-5 years (Krack et al., 2003; Rodriguez-Oroz et al., 2005). When both stimulation and medications are used, UPDRS II scores improve by 60-76% after 12 months (Hamani et al., 2005; Krack et al., 2003; Rodriguez-Oroz et al., 2005), and 45-65% after 3-5 years (Krack et al., 2003; Rodriguez-Oroz et al., 2005).

Improvement in UPDRS motor scores with stimulation alone is 50-66% after 1 year (Hamani et al., 2005; Krack et al., 2003; Rodriguez-Oroz et al., 2005), and 45-60% after 3-5 years (Krack et al., 2003; Rodriguez-Oroz et al., 2005). When both stimulation and medications are used, UPDRS motor scores improve by 65-80% after 1 year (Hamani et al., 2005; Krack et al., 2003; Rodriguez-Oroz et al., 2005), and 55-75% after 3-5 years (Krack et al., 2003; Rodriguez-Oroz et al., 2005). Improvements in tremor and rigidity using only DBS at 1 year (without medications) are 75-95% and 60-75%, respectively (Hamani et al., 2005; Krack et al., 2003; Rodriguez-Oroz et al., 2005). Benefits of stimulation to treat these symptoms are sustained at long-term (Krack et al., 2003; Rodriguez-Oroz et al., 2005).

In contrast, the efficacy of STN DBS to control gait, postural instability, and to a certain extent bradykinesia declines over time (45-70% improvement at 1 year with DBS alone vs. 30-61% at 3-5 years) (Hamani et al., 2005; Krack et al., 2003; Rodriguez-Oroz et al., 2005).

The deterioration that has been reported at long term in the quality of life and overall motor scores in PD patients treated with STN DBS (Krack et al., 2003; Rodriguez-Oroz et al., 2005) is partly the result of worsening of gait, posture, and akinesia that occurs at long-term. In addition however, non-dopami-nergic symptoms begin to play a significant role in the morbidity of the condition. Symptoms that are resistant to levodopa, such as speech problems, cognitive and psycho logical difficulties, bladder, bowel and sexual dysfunction, among others, are also resistant to surgery and lead to a major disability in patients with advanced PD. At this time there is no effective treatment to address these symptoms.

Dyskinesias

The ability of STN DBS to improve dyskine-sias is likely related to two mechanisms: The reduction in patients' levodopa intake after surgery or a direct antidyskinetic effect. The mean levodopa-equivalent dose used pre-operatively is reduced by approximately 50-60% with STN DBS at 1 year (Hamani et al., 2005; Krack et al., 2003), results are sustained at long-term (Krack et al., 2003; Rodriguez-Oroz et al., 2005). At 1 year, the mean reduction in dyskinesias is around 70-80% and seems to be sustained at long term (Hamani et al., 2005; Krack et al., 2003; Rodriguez-Oroz et al., 2005). This feature of reducing levodopa requirement is not usually seen with GPi DBS surgery.

Adverse effects

There are several types of complications and adverse effects that can occur with DBS surgery. These include 1) surgical and hardware-related complications, 2) adverse effects related to stimulation, and 3) neurological complications.

Surgical and hardware-related complications

The most fearsome complications of STN DBS are intracranial hemorrhages produced by the electrode penetration. The incidence of hemorrhages is approximately 2-3%. These are most commonly located in the brain parenchyma but can also be subdural or in-traventricular (Hamani et al., 2005). Most hemorrhages are asymptomatic, and are identified only by post-operative scanning (Terao et al., 2003). However, in some patients the effects of a bleeding can be serious, leading to transient or permanent sequelae. There is some suggestion in the literature that multiple passes of microelectrodes for mapping may increase the risk of hemorrhage. In addition, some feel that the increased operative time for microelectrode mapping may increase the infection risk. In contrast, the use of MER is presumed to decrease the adverse effects associated with targeting inaccuracy. A definitive study weighing benefits and risks of MER has not yet been conducted.

Infections occur in 3-4% of the patients treated with STN DBS (Hamani et al., 2005). This infection rate is roughly equal to that of other neurosurgical procedures. Though controversial, it has been estimated that approximately half of these wound infections can be treated with antibiotics alone, while the other half require the removal of parts or the entire DBS system.

Lead replacement or repositioning is required in approximately 5% of the patients treated with STN DBS (Hamani et al., 2005). Half of these are leads that need to be reposi-tioned due to an initially poor clinical effect. One-quarter are replaced after lead migration from an initially effective position. The remaining 1 /4 are replaced after breakage of the wires. Postoperative swelling in the region of the internal pulse generator or extension cables occurs in less than 1% of patients.

Current battery technology has developed compact and long-lived batteries. Still the constant stimulation required to treat PD eventually exhausts the batteries and several replacements may be needed. The estimated time for the batteries to fail in patients with PD is 4-5 years (Bin-Mahfoodh et al., 2003). Emerging technologies should produce batteries that can periodically be recharged, obviating the need for replacement.

Other miscellaneous complications include CSF leaks, meningitis, venous phlebitis, pneumonia, urinary infections, pulmonary embolism, and perioperative seizures. These complications totaled an additional 3.1% of patients (Hamani et al., 2005).

Stimulation-induced adverse effects and neurological complications

Dyskinesias, paresthesias, diplopia, dystonia, and motor contractions are relatively common stimulation-induced side effects (particularly when higher voltages are used during the programming of the patients). In addition, hypophonia, eyelid apraxia, increased libido, sialorrhea, and decreased memory have also been reported, mostly unrelated to stimulation.

Weight gain is a common feature following STN surgery and may be attributed to several changes, including the control of dys-kinesias (Barichella et al., 2003), the increased motility experienced by the patients, and the greater social engagement that often occurs after surgery. Perioperative confusion occurs is approximately 15% of the patients (Hamani et al., 2005). It is usually transient and may be related to reductions in levodopa periopera-tively (Berney et al., 2002; Lang et al., 2003). Depression has been reported in 5-25% of the patients treated with STN DBS (Berney et al., 2002; Hamani et al., 2005; Houeto et al., 2002). However, these numbers are likely underestimated if one acknowledges that the general incidence of depression in patients with PD is in the order of 40-50% (McDonald et al., 2003; Murray, 1996). As suicide attempts have been described in PD patients that underwent STN DBS (Burkhard et al., 2004; Doshi et al., 2002), careful attention must be paid to patients that develop psychiatric complications in the post-operative period. Future studies are still needed to identify predictive factors of these complications before the procedures.

Conclusion

Bilateral subthalamic nucleus stimulation improves motor outcomes, activities of daily living and dyskinesias in patients with PD. Despite of the impact of this potent therapy, symptoms that are resistant to levo-dopa do not respond very well to surgery. The better understanding of the mechanisms of the disease and the identification of new surgical targets are current objects of study and may help to treat patients with PD in the future.

Acknowledgements

C. H. was supported by the Safra Foundation for Parkinson's disease. A. M. L. is a Canada Research Chair in Neuroscience.

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Author's address: A. M. Lozano, MD, PhD, Division of Neurosurgery, Toronto Western Hospital, West Wing 4-447, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada, e-mail: [email protected]

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