Stereotactic Surgery in Parkinson Disease Overview of Stereotactic Surgery

For patients who have motor fluctuations and dyskinesia that cannot be adequately managed with medication manipulation, surgery is considered. The principal surgical option is deep brain stimulation (DBS), which has largely replaced neuroablative lesion surgeries. Experimental surgical approaches include transplantation and gene therapy.

During stereotactic surgery, imaging data are correlated to 3-dimensional space, permitting a target deep within the brain to be reached blindly and with minimal trauma. With frame-based techniques, the application of a reference coordinate system to the skull permits any point within the brain to be described with Cartesian (ie, x, y, z) coordinates. Ventriculography, an important method for target localization before the development of CT scan and MRI, is used uncommonly now.

Stereotactic surgery has made a resurgence in the treatment of Parkinson disease, largely due to long-term complications of levodopa therapy resulting in significant disability despite optimal medical management. A better understanding of basal ganglia physiology and circuitry and improvements in surgical techniques, neuroimaging, and electrophysiologic recording have allowed surgical procedures to be performed more accurately and with lower morbidity.

CT-guided stereotaxis provides direct imaging of brain parenchyma without image distortion; however, its gray-white resolution is inferior to that of MRI and only axial imaging is possible. MRI provides superior target resolution and triplanar imaging; however, some smaller targets cannot always be visualized, and MRI is prone to image distortion. Although usually small, these distortions can affect targeting for functional neurosurgery.

The possibility of targeting errors due to image distortion necessitates the use of some form of intraoperative neurophysiologic monitoring to confirm the correct targeting during surgery for movement disorders.

Intraoperative physiological monitoring equipment is shown in the image below.

See Parkinson Disease for a complete discussion of this disease.

Deep brain stimulation (DBS) has become the surgical procedure of choice for Parkinson disease because it does not involve destruction of brain tissue; it is reversible; it can be adjusted as the disease progresses or adverse events occur; and bilateral procedures can be performed without a significant increase in adverse events.

Deep brain stimulation, a form of stereotactic surgery, has made a resurgence in the treatment of Parkinson disease largely because of long-term complications of levodopa therapy resulting in significant disability despite optimal medical management. A better understanding of basal ganglia physiology and circuitry and improvements in surgical techniques, neuroimaging, and electrophysiologic recording have allowed surgical procedures to be performed more accurately and with lower morbidity.

Until recently, surgery for movement disorders involved predominantly destructive lesioning of abnormally hyperactive deep brain nuclei; however, the observation that high-frequency electrostimulation in the ventral lateral nucleus (VL) of the thalamus eliminates tremors in patients undergoing thalamotomy led to investigation of long-term DBS as a reversible alternative to lesioning procedures.

Continued refinement of the knowledge of basal ganglia circuitry and Parkinson disease pathophysiology has narrowed the focus of movement disorder surgery to 3 key gray-matter structures: the thalamus, the globus pallidus, and the subthalamic nucleus (STN). (See the image below.)

A randomized controlled trial in 255 patients with advanced Parkinson disease found that bilateral DBS was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months; however, DBS was associated with an increased risk of serious adverse events.^[1]

In Australia, guidelines have been developed to help neurologists and general physicians identify Parkinson disease patients who may benefit from referral to a specialized DBS team; these teams assess the likely benefits and risks of DBS for each referred patient.^[2]

See Deep Brain Stimulation in Parkinson Disease for a more extensive discussion of deep brain stimulation in this setting, including mechanisms of action, advantages and disadvantages, and stages of the procedure,

Lesion surgeries involve the destruction of targeted areas of the brain to control the symptoms of Parkinson disease. Lesion surgeries for Parkinson disease have largely been replaced by deep brain stimulation (DBS). During neuroablation, a specific deep brain target is destroyed by thermocoagulation. A radiofrequency generator is used most commonly to heat the lesioning electrode tip to the prescribed temperature in a controlled fashion.

The 2 most commonly performed neuroablative procedures are thalamotomy and pallidotomy, in which lesions are created in the ventral lateral nucleus (VL) thalamus and the globus pallidus pars interna (GPi), respectively.

Ventrolateral thalamotomy

The VL thalamus receives afferent innervation from 2 primary sources: the GPi via the ansa lenticularis and thalamic fasciculus and the contralateral cerebellum via the superior cerebellar peduncle. These cerebellar fibers synapse primarily in the ventral intermediate (VIM) and ventral oral posterior (VOP), the most posterior segments of the VL. Oscillating excitatory input from the cerebellum may be responsible for the tremor observed in Parkinson disease, as cellular activity synchronous with the frequency of parkinsonian tremor can be recorded in the VL. These data support the clinical observation that lesions placed within the VL (and specifically within the VIM/VOP) arrest parkinsonian and essential tremors.

VL thalamotomy was the most frequently performed procedure for movement disorders in the prelevodopa era because tremor responds best to thalamotomy and can be monitored more easily in the operating room than gait abnormalities, rigidity, and akinesia.

Thalamotomy involves destruction of a part of the thalamus, generally the VIM, to relieve tremor. VIM almost unanimously is considered the best target for tremor suppression, with excellent short- and long-term results in 80-90% of patients with Parkinson disease. Thalamotomy has little effect on bradykinesia, rigidity, motor fluctuations, or dyskinesia. When rigidity and akinesia are prominent, other targets, including the GPi and subthalamic nucleus (STN), are preferred.

Thalamotomy is indicated in patients with Parkinson disease who are disabled by medically refractory tremor. The anticipated benefit of tremor reduction or elimination must be considered carefully. Rest tremor alone is rarely disabling, and bradykinesia and rigidity can reduce dexterity irrespective of tremor. Most patients with Parkinson disease who undergo thalamotomy have significant improvement in tremor of the limbs contralateral to the side of the lesion. Bilateral thalamotomy is generally avoided because complications, especially speech and cognitive impairment, are common.

The reported morbidity rate for thalamotomy ranges from 9-23%. The predominant complication is speech impairment with dysarthria and hypophonia. The risk of speech abnormalities is 30% for unilateral thalamotomy and greater than 60% following bilateral thalamotomy. Other complications include memory loss, contralateral hemiparesis, and, more rarely, hemineglect, dystonia, hemiballismus, athetosis, and dyspraxia.

Preoperative memory and language evaluation can help identify patients who are at greatest risk for postoperative cognitive and language dysfunction. In the largest series, the mortality rate for thalamotomy ranged from 0.5-1%. Death results almost exclusively from intraparenchymal hemorrhage.

Pallidotomy

Svenillson and Leksell described ventral posterior pallidotomy in the 1960s^[3] ; however, their report was largely overlooked. The original pallidotomy target was in the medial and anterodorsal part of the nucleus. This so-called medial pallidotomy effectively relieved rigidity but inconsistently improved tremor. Leksell subsequently moved the target to the posteroventral and lateral GPi, resulting in sustained improvement in as many as 96% of patients. In 1992, Laitinen et al reported reduced tremor, rigidity, akinesia, and levodopa-induced dyskinesia in 38 patients treated with pallidotomy, prompting a reappraisal of the procedure performed with more modern techniques.^[4]

The negative symptoms of Parkinson disease (ie, rigidity, bradykinesia) are caused, in part, by excessive inhibitory output from the GPi to the VL thalamus. Lesioning of the sensorimotor region of the GPi, which lies ventral and posterior in the nucleus, decreases this hyperinhibition of motor thalamus. Pallidotomy involves destruction of a part of the GPi. Pallidotomy studies have demonstrated significant improvements in each of the cardinal symptoms of Parkinson disease (tremor, rigidity, bradykinesia), as well as a significant reduction in dyskinesia. Tremor improvement is less consistent than with thalamotomy.

The most serious and frequent (3.6%) adverse effect of pallidotomy is a scotoma in the contralateral lower-central visual field. This complication occurs when the GPi lesion extends into the optic tract, which lies immediately below the GPi. The risk of visual-field deficit is reduced greatly by accurate delineation of the ventral GPi border by microelectrode recording. Less frequent complications (< 5%) include injury to the internal capsule, facial paresis, and intracerebral hemorrhage (1-2%). Abnormalities of speech, swallowing, and cognition may also be observed.

Bilateral pallidotomy is not recommended because complications are relatively common and include speech difficulties, dysphagia, and cognitive impairment.

Hyperactivity of the excitatory subthalamic nucleus (STN) projections to the globus pallidus pars interna (GPi) is a crucial physiologic feature of Parkinson disease. Subthalamotomy involves destruction of a part of the STN. Although lesioning the STN usually has been avoided out of concern of producing hemiballismus, results obtained by experimental lesions of the STN in animals and humans suggest that subthalamotomy may be performed safely and may reverse parkinsonism dramatically. Subthalamotomy studies have shown significant improvements in the cardinal features of Parkinson disease, as well as the reduction of motor fluctuations and dyskinesia.

Good surgical outcomes begin with careful patient selection and end with attentive, detail-oriented postoperative care. The authors believe that this level of care is best provided by a multidisciplinary team comprising a movement disorder neurologist, a neurosurgeon who is well-versed in stereotactic technique, a neurophysiologist, a psychiatrist, and a neuropsychologist. Additional support from neuroradiology and rehabilitation medicine is essential.

At the authors' movement disorder center, patients are evaluated for surgery as follows:

1. Neurologist evaluation
2. Neurosurgeon evaluation to identify potential surgical candidates
3. Psychiatrist evaluation
4. Medical evaluation

First, a neurologist with expertise in movement disorders evaluates the patient. Patient selection is particularly important for successful subthalamic nucleus deep brain stimulation (STN DBS) because a number of factors concur to determine positive surgical outcome.^{[5, 6]} These can be summarized as follows:

• A diagnosis of idiopathic Parkinson disease
• Positive response to levodopa
• Absence of atypical parkinsonian features
• Advanced disease, virtually unmanageable with dopaminergic medications
• Relatively young age; however, advanced age (>75 y) is not an absolute contraindication to surgery (if a patient otherwise meets the selection criteria for a procedure and the quality of life is predicted to improve substantially, surgery should be offered)
• Normal cognition
• Absence of active psychiatric disease
• Good social support and access to programming

Potential surgical candidates then are evaluated by the neurosurgeon, who determines whether the patient is indeed a surgical candidate and decides which procedure(s) would benefit the patient most. Close collaboration between the neurologist and the neurosurgeon aids the decision-making process, minimizing patient confusion and stress. If the neurologist and neurosurgeon agree that the patient is a good surgical candidate, further workup includes the following:

• Brain MRI to rule out comorbid conditions and to assess the degree of brain atrophy; significant atrophy may increase the risk of perioperative hemorrhage
• Detailed neuropsychological testing to rule out subtle cognitive impairment, which can be worsened by the surgical procedure

A psychiatrist with expertise in psychiatric complications of movement disorders may be consulted to rule out active psychiatric disease and screen for relevant past psychiatric history that may pose a contraindication to surgery (eg, major depression, suicidality).

A fluorodopa positron emission tomography (PET) scan may be performed in the unusual circumstance that an alternative diagnosis of multiple system atrophy cannot be ruled out clinically. A medical evaluation is performed to determine the patient's general fitness for surgery.

Surgery is reserved for patients with medically refractory Parkinson disease with disabling problems. Currently, the authors' center adopts the following surgical recommendations for patients with medically refractory Parkinson disease:

• Unilateral pallidotomy is offered to patients with asymmetric Parkinson disease who develop fluctuations in their response to levodopa, including disabling dyskinesias and off-state dystonia
• Bilateral pallidotomy is avoided, although investigations are under way to evaluate contralateral globus pallidus pars interna deep brain stimulation (GPi DBS) in patients who have undergone a successful pallidotomy and are experiencing disease progression in the untreated side
• Thalamotomy or thalamic DBS is offered to the minority of patients with Parkinson disease who have predominant and disabling tremor (more commonly, this procedure is performed on patients with disabling essential tremors)
• Thalamic DBS is preferred over thalamotomy, particularly in young patients with Parkinson disease who are disabled solely by tremor early in the course of their disease, because it gives the option of removing the stimulator if more effective therapies are developed or if symptom progression necessitates DBS at another target such as the STN
• Bilateral STN DBS is offered to patients with advanced Parkinson disease with bilateral levodopa-induced dyskinesia, significant gait disturbances and axial symptoms, or medically refractory rigidity and akinesia. The effect of STN DBS on speech varies, but it ultimately results in the deterioration of speech intelligibility.^[7]
• Prior to surgery, the patient should be informed that these procedures do not cure Parkinson disease and that progression is expected

Neural transplantation is a potential treatment for Parkinson disease because the neuronal degeneration is site and type specific (ie, dopaminergic), the target area is well defined (ie, striatum), postsynaptic receptors are relatively intact, and the neurons provide tonic stimulation of the receptors and appear to serve a modulatory function.

Transplantation of autologous adrenal medullary cells and transplantation of fetal porcine cells have not been found to be effective in double-blind studies and have been abandoned. Although open-label studies of fetal dopaminergic cell transplantation yielded promising results, 3 randomized, double-blind, sham-surgery–controlled studies found no net benefit. In addition, some patients receiving these transplants developed a potentially disabling form of dyskinesia that persisted even after withdrawal of levodopa. Features such as gait dysfunction, freezing, falling, and dementia are likely due to nondopaminergic pathology and hence are unlikely to respond to dopaminergic grafts.^[8]

Lewy body–like inclusions have been found in grafted nigral neurons in long-term transplant recipients; these inclusions stained positively for alpha-synuclein and ubiquitin and had reduced immunostaining for dopamine transporter, suggesting that Parkinson disease may affect grafted cells.^[9]

Human retinal pigment epithelial cells produce levodopa, and retinal pigment epithelial cells in gelatin microcarriers have been implanted into the putamen in preliminary studies. A phase II double-blind, randomized, multicenter, sham-surgery–controlled study of this technique is under way.^[10] In one case study, however, postmortem examination in a patient who died 6 months after surgical implantation of 325,000 retinal pigment epithelial cells found only 118 surviving cells.^[11]