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Deep Brain Stimulation Which Patients and When?

Published Online: June 4th 2011
Authors: Tipu Z Aziz, Erlick AC Pereira
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Abstract:
Overview

Deep brain stimulation (DBS) is neurosurgery that enables deep brain structures to be stimulated electrically by a pacemaker implanted under the skin. It has been popularized for those sufferers of Parkinson’s disease who have been unresponsive to drugs or have shown side effects from them. Its efficacy has been demonstrated robustly by clinical trials with multiple novel brain targets having been discovered recently. Many other indications for deep brain stimulation now exist, such as:

  • tremor and dystonia in movement disorders;
  • psychiatric disorders such as obsessive-compulsive disorder (OCD), depression, and Tourette’s syndrome;
  • cluster headache;
  • epilepsy; and
  • chronic pain including amputation, stroke, trigeminal neuralgia, and multiple sclerosis.

Novel indications of orthostatic hypotension and hypertension also show experimental promise. Here, we review the evidence for which patients are treated and when.

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Parkinson’s Disease
Parkinson’s disease (PD) is a slowly progressive neurodegenerative disease characterized by tremor, rigidity, bradykinesia, and postural instability. It is common in middle or late life with prevalence rising to 1% in people over 60 years of age. Established basal ganglia brain structures currently targeted for PD DBS include the globus pallidus interna (GPi), ventralis intermedius nucleus of the thalamus (VIm), and subthalamic nucleus (STN). Over 30,000 patients have been implanted to date.1

The GPi has traditionally been targeted mainly for dyskinesia symptoms, STN for levodopa-refractory patients, and VIm for tremor. Despite its smaller size, the STN recently gained dominance over the GPi as the surgical target of choice for PD due to reports of favorable motor outcomes.2 A 156-patient, randomized, controlled, multicenter trial of STN DBS versus medical treatment alone showed a 25% benefit in motor function and 22% improvement in quality of life outcomes at six months after surgery.3 Sustained benefit with STN DBS has also been described after five years of follow-up.4,5 GPi and STN have been compared at four year follow-up;6 however, long-term, back-to-back, randomized, blinded, controlled trials of the two surgical targets are yet to be completed.7

The pedunculopontine nucleus (PPN) has been discovered in the last decade as a deep brain target, stimulation of which reduces gait abnormalities and postural instability.8 Like the STN, its clinical utility has been realized by nonhuman primate research.9,10 Initial results favor its use in PD patients blighted most by postural instability, in PD-plus syndromes of multiple system atrophy and progressive supranuclear palsy, and in those with symptoms not ameliorated by STN stimulation alone.11

Tremor
Tremor is the involuntary, rhythmic oscillation of a body part. Essential tremor prevalence varies greatly throughout the world and can be up to 2%. DBS can alleviate contralateral limb tremor in essential tremor, Holmes’ tremor, cerebellar tremor, tremulous multiple sclerosis, and tremor after head injury.12 For trunk, head, and voice tremors, bilateral DBS is considered.13 Brain targets considered in patients refractory to medication are the VIm and the zona incerta (ZI).

Sustained and consistent motor improvements with VIm DBS have been shown six years after surgery in 19 patients with essential tremor.14 Quality of life improvements have also been demonstrated in 40 patients one year after surgery.15 In multiple sclerosis, patient selection is paramount.16 Distal limb tremor responds best to VIm DBS and proximal limb tremor to ZI DBS.17 Post-operative benefits in motor function for 88% of patients and in daily functioning for 76% have been shown in a systematic review of 75 multiple sclerosis patients.18 Brain targets in DBS for head injury depend upon the prevailing movement disorder, with excellent results described in the small numbers of cases reported.19 Dystonia
Dystonias are disorders of involuntary sustained muscle contractions that can affect certain body regions or be generalized. They may begin in childhood or young adulthood, often progressing from focal limb involvement to a severe generalized form, or manifest in later adulthood, when they are usually focal or segmental and frequently craniocervical (spasmodic torticollis). Prevalence of early-onset dystonias is up to 50 per million with a greater—up to 0.01%—prevalence of the late-onset type. DBS is considered for children refractory to medical therapy, usually by anticholinergic, dopaminergic, or benzodiazepine treatments, and adults refractory to botulinum toxin injections. Stimulation of the posteroventral GPi is performed for primary dystonias.20 GPi DBS is particularly effective in childhood dystonias21 and in those patients carrying a mutation in the DYT1 gene.22 Secondary dystonias are less responsive.23 Moderate benefits have also been observed with VIm but not with STN DB.24 Motor improvements are often not fully realized until weeks or months later.26 Sustained motor and quality of life improvements without cognitive impairment have been shown three months after surgery in a prospective, multicenter trial of 40 patients,26 and three years after surgery in 58% of patients in a trial of 22 patients.27

Depression

Depression is extremely common. Lifetime prevalence for major depressive disorder has been estimated at 16%, with half of all patients having reduced function and role impairment. Patients with major depressive disorder are twice as likely to die as those who are not depressed. One trial of DBS in drug-refractory depression targeted the subgenual cingulate cortex bilaterally, with four out of six patients showing improvement.28 Another targeted the anterior limb of the internal capsule as for OCD in five patients,29 with three patients showing a greater than 50% symptom improvement. Both studies were uncontrolled and had less than one year of follow-up. While DBS for severe depression appears promising, further studies are required to confirm efficacious targets and successful outcomes.

Obsessive Compulsive Disorder
OCD can manifest at any age, but first onset is usually in a person s third decade. Prevalence is 0.8% in adults and lower in children. About 10% of patients are refractory to pharmacotherapy, usually selective serotonin reuptake inhibitors, and frequently become housebound.

The anatomical target for DBS derives from the success of the lesional procedure of anterior capsulotomy, which improves symptoms in approximately half of patients treated.30 Long-term outcomes for bilateral DBS of the anterior limb of the internal capsule and adjacent ventral striatum have been reported by two groups. In one study, blinded assessment of four patients followed up for at least 21 months after surgery revealed significant improvements in three patients.31 In another study, of 10 patients evaluated three years after surgery, seven showed a one-third or greater percentage reduction in symptoms and six had an improvement in activities of daily living.32

Tourette s Syndrome
Tourette s syndrome has 0.1 1% prevalence, usually affecting children and adolescents. It is more common in people with autistic spectrum disorders and is characterized by motor and vocal tics. Simple tics typically involve one muscle group and complex tics may mimic a purposeful movement such as an obscene gesture. Simple vocal tics are sounds or noises like grunting, and complex vocalizations include echolalia and coprolalia, the latter affecting 10% of patients. For most sufferers, symptoms decline in adulthood, but DBS may be considered for those with debilitating tics refractory to drugs such as neuroleptics and anticonvulsants.

Brain regions targeted for DBS have included the medial intralaminar thalamic centromedian and parafascicular nuclei (three patients)33 and case reports of stimulation of the anterior limb of the internal capsule,34 and GPi.35-37 With this initial experience and experience of ablative surgery for Tourette s syndrome,38 criteria for DBS suitability have been proposed.39 Alongside clarifying the quality and duration of failed medical and behavioral treatments, the criteria suggest a minimum age of 25 years. A lower age limit for the procedure lies juxtaposed against the benefits seen from early treatment of medically refractory childhood dystonias, yet may be appropriate while numbers of patients treated remain small and long-term outcomes are yet to be determined.

Epilepsy
Epilepsy is a debilitating neurological condition affecting 50 in every 100,000 people, with higher prevalence in children and the elderly. Symptomatic epilepsy is estimated to reduce life expectancy by up to two decades. Sudden death in medically refractory epilepsy is 0.5% and highest in adolescents and young adults. Neurosurgical treatment is considered after poor seizure control despite trial of at least three antiepileptic medications. DBS of the anterior thalamic nuclei has been undertaken by several groups. In one study, five of six patients had improvements in their seizures over an average follow-up period of five years.40 In another study, four of five patients showed significant reductions in frequency and severity of seizures after 6 – 36 months without adverse complications.41 A third study showed significantly reduced seizures in all four patients over an average 44-month follow-up period.42 Putative targets of stimulation may depend upon seizure localization and also include the STN, caudate, hippocampus, cerebellum, hypothalamus, and medial intralaminar thalamic nuclei,43 but further controlled trials underway with long-term follow-up are required before DBS in epilepsy can be considered appropriate for patients as an alternative to resective surgery.44

Cluster Headache
Cluster headache is characterized by severe unilateral peri-orbital pain with concomitant autonomic sequelae of vasodilatation and peri-orbital edema. Prevalence is less than 1%, with men more commonly affected. DBS can be performed for cluster headache refractory to medical treatments, targeting the ipsilateral posterior hypothalamus. After mean follow-up of almost two years, 13 out of 16 patients were reported symptom-free or almost headache-free in the largest study to date.45 Another group has reported three of six patients considerably improved.46 The procedure appears to be extremely successful,47 but risks of hemorrhage remain a pervading concern in targeting such a deep brain structure bilaterally.

Chronic Pain
Chronic pain presents a considerable burden to society, occurring in cancer, stroke, trauma, and failed surgery. It may affect as many as one in five people. DBS has been undertaken for almost four decades. Targets have included the internal capsule and medial intralaminar thalamic nuclei, but most current treatments target the ventral posterolateral and ventral posteromedial thalamic nuclei (VPL/VPM) and periaqueductal and periventricular gray matter (PAG/PVG).

To date, 1,300 recipients of DBS for pain have been reported.48,49 Chronic pain etiologies with good outcomes in contemporary series are stroke,50 amputation,51 anesthesia dolorosa,52,53 and plexopathies, with success also seen in multiple sclerosis54 and malignancy.55

Blood Pressure
The promising but still experimental indication of DBS for disorders of blood pressure includes malignant hypertension and medically refractory orthostatic hypotension as putative indications. Suggestive findings from PAG/PVG DBS in 16 patients with chronic pain augur well for autonomic applications of DBS.56-58

At present, surgeon experience and clinical evidence point toward those patients who should be offered DBS, when, and which targets to select; and also, tentatively, toward prognostication for many emerging and some enduring indications. For all DBS targets, the relative contributions of local interactions and wider functional neuroanatomical circuitry are yet to be fully elucidated. In addition, research attention should turn to focus upon improving patient selection. When successful, results are frequently spectacular and life-transforming. DBS is brain surgery and is thus often regarded as a last-resort treatment. The questions of which patients and when remain hotly debated. However, as evidence of efficacy and our mechanistic knowledge improve and the number of indications increases, interest in the technique will continue to yield insights and answers.

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