CHAPTER 76 Patient Selection Criteria for Deep Brain Stimulation in Movement Disorders
Successful deep brain stimulation (DBS) therapy for movement disorders depends on a series of interrelated procedures that include precise lead placement and proficient electrode programming. However, the first and most important step toward consistent DBS outcomes remains careful patient selection because more than 30% of DBS failures can generally be ascribed to an incorrect initial diagnosis or inappropriate indication for surgery.1
General Selection Process
Neurological Evaluation
Preoperative evaluation for DBS normally begins with assessment by a neurologist with specific expertise in the management of movement disorders. The neurological evaluation, possibly performed by a movement disorders specialist, should be focused on establishing that one of the diagnoses amenable to DBS treatment has been made properly. The diagnoses currently approved in the United States and widely accepted for DBS therapy throughout the world are essential tremor (ET), Parkinson’s disease (PD), and dystonia. Other tremors (i.e., midbrain, cerebellar, and orthostatic tremor), tics, and choreas (Huntington’s chorea and neuroacanthocytosis) have also been targeted with DBS in more experimental settings. Table 76-1 summarizes movement disorders in which DBS is currently indicated.
TABLE 76-1 Movement Disorders for Which Deep Brain Stimulation Is Currently Indicated
FOOD AND DRUG ADMINISTRATION–APPROVED INDICATION FOR DBS |
Idiopathic Parkinson’s disease |
Essential tremor |
Primary dystonia |
Generalized |
Segmental |
Hemidystonia |
Cervical |
OTHER MOVEMENT DISORDERS POSSIBLY RESPONSIVE TO DBS |
Tardive dystonia |
Myoclonic dystonia |
Pantothenate kinase-associated neurodegeneration (PKAN) |
Huntington’s chorea |
Chorea acanthocytosis |
Tics |
Cerebellar tremor (multiple sclerosis) |
Midbrain tremor |
Orthostatic tremor |
Lesch-Nyhan syndrome |
MOVEMENT DISORDERS POORLY RESPONSIVE TO DBS |
Multiple system atrophy |
Progressive supranuclear palsy |
Corticobasal degeneration |
Vascular parkinsonism |
Secondary dystonias |
The value of the initial neurological visit does not end with the selection process. It also establishes a clinical baseline for the best postoperative management and provides an opportunity to educate patients and caregivers on the proper risks and expectations with respect to outcome. The initial programming and subsequent setting and medication adjustments may represent quite a challenge when the patient is unknown to the treating physician. Patient expectations must be realistic and discussed early in the process. False expectations by patients or family members are common reasons for “DBS failures.”1–3 DBS management represents a significant commitment of time, and consequently the patient and family must be motivated to undergo the challenges associated with the procedure.3 The role of the initial neurological evaluation extends to the surgical date in DBS centers that have the team neurologist present in the operating room; this person is an important source of clinical information to the surgeon and may be a calming influence on the patient during the implantation procedure.
Neurosurgical Evaluation
A fundamental task for the neurosurgeon is to define whether the risk-to-benefit ratio of the surgical procedure is acceptable to the patient. The most fearsome risk associated with a DBS procedure is the occurrence of intracerebral hemorrhage, which may cause contralateral weakness or other neurological deficits, including death in the most severe cases.4 The risk for hemorrhage may vary from center to center, based on the experience of the functional surgeon, but it is never null. In addition, there are device-related risks of system failure and infection, which can occur in 20% to 25% of patients in the best centers.5,6 Patients are also reminded that battery replacement, requiring minor surgery, will be necessary after 2 to 5 years, depending on the current drain associated with therapeutic stimulation.
In addition, general contraindications to surgery should be explored. Patients with uncontrolled hypertension or diabetes, coronary artery disease, cardiac pacemakers, liver or kidney failure, seizure disorders, or coagulopathies may be poor candidates, although the risk-benefit ratio of DBS surgery should be assessed individually in every case.7 If the patient is a good surgical candidate and agrees to surgery, a tentative date for surgery is scheduled and the remainder of the preoperative evaluation is completed. If there is disagreement about the proper surgical target or treatment modality, the patient’s case should be reviewed at a multidisciplinary conference to arrive at a consensus.
Neurocognitive and Psychiatric Evaluation
A neuropsychologist and a psychiatrist are essential members of a good DBS program because proper cognitive assessment and psychiatric screening are fundamental steps in patient selection, in particular for subthalamic nucleus (STN) DBS for PD. Little or no data are available on patients with premorbid psychiatric or cognitive symptoms undergoing DBS of the globus pallidus (pars) interna (GPi) or ventral intermediate (VIM) nucleus of the thalamus.8
The prevalence of dementia is high in patients with PD,9 and preoperative dementia is a risk factor for permanent cognitive decline after DBS.10,11 Because of insufficient evidence on the predictive validity of any given neuropsychological assessment, interview, or cognitive test,8 several test batteries are used for the selection of surgical candidates, with the goal of excluding those with dementia or severe deficits in executive function.12 No consensus guidelines or “gold standards” are available, and detailed comparative data have not been published. In designing a neuropsychological battery for DBS candidates, it is important to cover the major neurocognitive domains for both patient selection and follow-up (Table 76-2); at the same time, the battery should not be excessively long because patients with PD fatigue easily. Moreover, many PD patients who are DBS candidates have severe medication-related “on-off fluctuations” and can sometimes experience significant cognitive disturbance during the “off” cycle and yet perform relatively normally during the “on period.”8,13,14 Unfortunately, neuropsychological testing is not universally performed before DBS, potentially leading to negative postsurgical outcomes.1
TABLE 76-2 Neuropsychological Evaluation of Patients with Parkinson’s Disease for Deep Brain Stimulation Surgery
CRITERIA EVALUATED | EVALUATION TOOL |
---|---|
General |
A full psychiatric evaluation is essential for patients who pass cognitive screening but have signs of untreated depression or psychosis, including dopaminergic dysregulation syndrome, medication-induced hypomania/mania, and suicide risk.8
The need for systematic neuropsychological and neuropsychiatric evaluation is less established for other DBS indications, including ET and dystonia. These conditions are not usually characterized by progressive neurodegeneration and dementia. In addition, patients with dystonia who are DBS candidates are normally young and less prone to suffer cognitive abnormalities after surgery.15
Neuroimaging
Preoperative imaging, preferably magnetic resonance imaging (MRI), is considered mandatory in patients being evaluated for DBS.8 In general, screening with MRI should rule out the presence of structural lesions or anatomic distortions16 that may either interfere with proper targeting (e.g., areas of encephalomalacia) or represent an increased risk for hemorrhage (e.g., abnormally enlarged lateral ventricles, severe brain atrophy). In addition, when the diagnosis of idiopathic PD is under scrutiny, MRI can show abnormalities typical of multiple system atrophy (MSA) or progressive supranuclear palsy (PSP),17 which would be a contraindication to DBS surgery (see Table 76-1).
Nuclear imaging studies (single-photon emission computed tomography/positron emission tomography) can occasionally be helpful in differentiating atypical parkinsonism from idiopathic PD.18 Although performed in the past to predict pallidotomy outcomes,19 the use of metabolic imaging modalities for screening patients undergoing DBS therapy is currently not part of routine DBS screening.
Specific Indications for Deep Brain Stimulation
Parkinson’s Disease
Selection Criteria
Among the many elements involved in successful DBS surgery for PD, patient selection has proved to be the most significant factor in determining postoperative benefit. Several good outcome predictors have been established, including a diagnosis of advanced idiopathic PD, response to levodopa, and absence of cognitive deterioration.8 The role of other variables, such as age and concurrent non–motor-associated symptoms, is less well defined (Table 76-3).
TABLE 76-3 Specific Deep Brain Stimulation Selection Criteria for Parkinson’s Disease
SELECTION CRITERIA | COMMENTS |
---|---|
Diagnosis | A diagnosis of idiopathic PD should be carefully established according to available criteria because atypical parkinsonism (e.g., MSA, PSP, CBD) is generally poorly responsive to DBS |
Disease severity |
The most important factors leading to performance of DBS are marked motor fluctuations in the response to dopaminergic therapy, including levodopa-induced dyskinesia and frequent and sudden wearing off with a prominent freezing responsive to levodopa
|
CBD, corticobasal degeneration; DBS, deep brain stimulation; MSA, multiple system atrophy; PD, Parkinson’s disease; PSP, progressive supranuclear palsy; UPDRS, Unified Parkinson’s Disease Rating Scale.
Diagnosis
DBS therapy should be considered only for patients with a confirmed diagnosis of advanced idiopathic PD, as defined by the presence of bradykinesia associated with at least one of the three following conditions: rigidity, resting tremor, and postural instability.21 It is important to differentiate idiopathic PD from the atypical parkinsonian disorders, which generally have an earlier onset and a more rapidly progressive course, including early dysautonomia, bulbar dysfunction, respiratory compromise, spasticity, ataxia, and apraxia.22 The most frequent atypical parkinsonian syndromes that can be misdiagnosed for idiopathic PD are PSP, MSA, Lewy body dementia (LBD), and corticobasal ganglionic degeneration (CBGD).21
Patients with atypical parkinsonian syndromes should not be selected for DBS therapy. Several case reports have demonstrated the ineffectiveness of DBS for MSA using either STN23–26 or GPi targets,27 even when the patient is responsive to levodopa. Although patients with levodopa-responsive bradykinesia, rigidity, or dystonia may show transient improvement,24 speech, swallowing, and gait usually deteriorate, motor fluctuations do not improve, and the levodopa dose remains unchanged.23,25 Clinical experience with DBS for other types of atypical parkinsonism, including CBGD and PSP, is extremely limited.28
Disease Severity and Duration
Although it is not considered a predictor of DBS outcome, the duration of PD should be taken into consideration when ruling out atypical parkinsonism.8,29 Typically, PD motor disability progresses slowly, so patients with advanced symptoms less than 5 years after onset should be evaluated further for atypical parkinsonism before being considered for DBS. At the same time, DBS should not be offered too late, when severe motor complications have resulted in marked loss of quality of life. Currently, DBS is performed after an average PD duration of 11 to 14 years. However, investigational studies offering DBS therapy at an early stage of the disease (7 years after initial motor symptoms) have yielded positive results, thus suggesting that DBS should be considered a therapeutic option earlier in the course of PD, when quality of life is still maintained.30 Indeed, there is little consensus on what defines advanced, medication-refractory PD and therefore candidacy for DBS. Severe PD disability generally coincides with Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores of around 30 (out of a maximum of 108), and this would be a reasonable severity cutoff.7 Available experience with STN or GPi DBS has mostly been with levodopa-responsive patients having off-period UPDRS motor scores higher than 40 or 50.8 An ideal PD surgical candidate should be severely disabled when off levodopa while doing well, often with associated dyskinesias, on medications.
Response to Levodopa
A sustained preoperative response to levodopa not only provides support for the diagnosis of idiopathic PD but is also considered the best predictor of outcome after DBS.8,29 Levodopa responsiveness should ideally be assessed in each patient being considered for DBS8 with a dose sufficient to reproduce the patient’s best on response after a medication-free interval of 12 hours (usually overnight). It is particularly important to assess whether gait difficulties (in particular, freezing and imbalance) are sensitive to levodopa before offering DBS.
Levodopa response is normally defined as a 30% improvement in UPDRS motor scores (part III) over the off state,8,29 although there is no consensus on what constitutes an appropriate challenge dose of levodopa. A suprathreshold dose has been defined variably: use of the normal first dose of the day,31 a fixed 200-mg test dose,32 or even apomorphine33 has been proposed. In the experience of our group and others, however, patients with well-defined idiopathic PD can benefit from DBS even when their motor response is indeterminate because of intolerance to levodopa34 or when the most disabling symptom is a dopa-refractory tremor.2
Age
The role of age as an outcome predictor for DBS is somewhat controversial.28,35 Some authors consider advanced age (in particular, age older than 70 years) a poor outcome predictor if not a contraindication to DBS surgery20,29 because it has been correlated with negative outcomes such as cognitive decline11 and gait instability.35 Nonetheless, given that the average age at the onset of PD is 60 years and that the mean duration of illness is 10 to 15 years at the time of surgery, a large proportion of potential DBS candidates are 70 years or older. In reality, no specific age cutoff has been defined for DBS candidates with advanced PD.8 Decisions for or against DBS in the elderly population should be individualized by taking into account the grade of disability, risk factors for complications, general life expectancy, and the patient’s motivation. Unilateral procedures could be an option in some patients who are otherwise at too high a risk for a bilateral procedure. Alternative targets, such as thalamic and pallidal implants, may be considered in an older PD candidate when deteriorating cognition is an issue.36,37
Cognitive Status
Normal cognitive status should be established with an appropriate battery of neuropsychological testing.12 Preoperative dementia is considered a risk factor for permanent cognitive decline after DBS, independent of the target, even though the risk for cognitive decline after GPi DBS may be less than that after STN DBS.36,38 Older age and severe preoperative cognitive impairment might be associated with poorer neurobehavioral outcomes.39–44
Cognitive decline in PD is characterized by impaired executive function, visuospatial abnormalities, impaired memory, and language deficits.45 An appropriate scale that reliably incorporates executive function (e.g., frontal assessment battery and other practical tests of executive function) should be included in screening tests for PD dementia. However, in PD patients it may be difficult to assess impairment in domains other than memory.8 No studies have yet evaluated the sensitivity, specificity, and negative or positive predictive value of any disease, demographic, or test score variable in predicting which patients might experience such clinically meaningful cognitive declines.
Psychiatric Comorbid Conditions
A psychiatric evaluation should be performed to assess the presence of untreated depression, anxiety, apathy, dopaminergic dysregulation syndrome, medication-induced hypomania/mania, psychotic symptoms, and suicide risk because all have been related to some extent to STN DBS.8 Postoperative depression has been reported in 1% to 25% of patients,36,41,42,46–48 but preoperative assessment for depression is not always documented. Two studies focusing on whether preoperative depression was a risk factor for postoperative depression found conflicting results.42,47 In particular, neither study differentiated between postoperative depression and dopaminergic withdrawal symptoms.
The relationships among postoperative depression and preoperative depression, stimulation, medication changes, disease factors, and psychosocial factors has not been completely elucidated. A number of tools can be used, including the Beck Depression Inventory,49 Hamilton Depression Rating Scale,50 and Montgomery-Asberg Depression Rating Scale.51 Other scales, such as the Geriatric Depression Scale52 and Zung Self-Rating Depression Scale,53 have not been formally validated in patients with PD. Further research is required to determine the best (i.e., sensitive, specific, but also practical for clinicians to administer rapidly) depression screening tool for PD patients.
In a study focusing on behavioral symptoms, postoperative hypomania developed in one of two patients with preoperative hypomania.42 No associations between postoperative mania and preoperative mania have otherwise been reported; however, the adequacy of the preoperative assessment for behavioral disorders is not always known.
Psychosis in PD patients is characterized by visual hallucinations and delusions (often paranoid).54 Screening tools for psychosis should be sensitive to hallucinations, as well as other psychotic features such as delusions. Only one study evaluated the Parkinson Psychosis Rating Scale (PPRS), which may be appropriate for patients with PD.55 However, to determine its specificity, the PPRS needs to be evaluated in both nonpsychotic and psychotic PD patients. Criteria for psychosis from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) have not been validated in PD. Likewise, there are insufficient data to draw conclusions about whether a preoperative history of medication-induced psychiatric symptoms or features of dopamine dysregulation syndrome worsen after surgery.
In uncontrolled series, suicide attempts and suicides have been documented in 0.5% to 2.9% of patients.42,56–58 A multicenter study of 450 STN DBS patients reported a postoperative suicide rate of 0.5%.57 In contrast, a study of 120 patients who underwent DBS (including patients with PD, dystonia, and ET) documented a postoperative suicide rate of 2.9% in PD patients who had undergone STN DBS.58 The authors suggested that young male patients with a history of multiple surgeries may be at greater risk for such outcomes. However, given the nature of the study as a small uncontrolled retrospective cohort from a single center, conclusions from this study are limited.
Target Selection
Ventral Intermediate Thalamus
The first reports of DBS for the treatment of PD used thalamic stimulation. In a series of 80 PD patients treated by either unilateral or bilateral VIM DBS, 88% achieved complete or nearly complete relief of tremor on the Fahn-Tolosa-Marín scale at 6 months to 8 years postoperatively.59 The effects of VIM DBS on other symptoms of PD, however, such as rigidity, bradykinesia, or drug-induced dyskinesias, were either short lasting or nonexistent. Currently, the role of VIM DBS for PD is limited to patients with tremor-predominant symptoms.
Globus Pallidus Interna
A number of studies have shown that bilateral GPi stimulation is safe and effective for the management of PD symptoms.60–62 Based on previous experience with pallidotomy,63 the ideal target for DBS is thought to be the most ventral-posterolateral area of the pallidum. In PD patients, GPi DBS improves tremor, rigidity, and bradykinesia in the off-medication state, as well as drug-induced dyskinesia, and results in overall improvement in UPDRS motor scores.64–66 The most pronounced and long-lasting effect is a reduction in on-medication dyskinesias,67 and PD patients suffering mainly from motor fluctuations and dyskinesias might be good candidates for GPi DBS. Unlike STN DBS, however, GPi DBS does not lead to a reduction in the patient’s levodopa requirement.68
Subthalamic Nucleus
The clinical efficacy of STN DBS in reducing PD symptoms has been reported by numerous investigators and validated in prospective, randomized trials.69–71 Long-term follow-up results show sustained improvement in tremor, rigidity, and akinesia in the off-medication state and a reduction in dopaminergic medication requirements 5 years after implantation.56,72–77 A reduction in levodopa dosage is usually achieved and leads indirectly to improvement in levodopa-induced dyskinesias.78,79 Initial improvements in gait, however, are not always sustained in the long term.56,69,80
Dystonia
Selection Criteria
Dystonia is a movement disorder characterized by sustained, involuntary muscle contractions generating twisting and repetitive movements or abnormal postures.81 Different muscle groups can be involved to a variable extent and severity can range from intermittent contractions limited to a single body region (focal dystonia) to generalized dystonia involving the axial and limb muscles. Dystonia may be classified by age at onset (early versus late), anatomic distribution (focal, segmental, multifocal, and generalized), and etiology. Etiologic classification of dystonia includes two broad categories: primary, or idiopathic, and secondary, or symptomatic.81 There is a bimodal distribution in the age at onset of primary dystonia, with modes at 9 years (early onset) and 45 years (late onset).82 The majority of early-onset cases begin with leg or arm dystonia that progresses to involve more than one limb, and in about 50% the dystonia eventually generalizes. Late-onset primary dystonia commonly affects the neck or cranial muscles and tends to remain localized as focal or segmental dystonia. With cloning of the DYT1 gene,83 it is now possible to diagnose a leading cause of generalized primary dystonia.
For the great majority of patients with dystonia, treatment is aimed at controlling symptoms rather than addressing the underlying cause. Pharmacologic therapies can be further subdivided into focal therapies such as intramuscular injections of botulinum toxin and systemic administration of medications that affect the central nervous system. Many medications have been reported to be of some benefit to selected dystonia patients, including anticholinergic, dopaminergic, and GABAergic (γ-aminobutyric acid agonists) agents, but no single therapy has been found to consistently produce improvement. Botulinum toxin is considered the treatment of choice for many focal dystonias.84
With the notable exception of DRD, pharmacologic treatment of primary generalized dystonia is mostly unsatisfactory. As a consequence, surgical attempts to relieve dystonic spasm have become progressively more relevant for the treatment of dystonia. Chronic stimulation of the GPi is currently considered a safe and effective treatment of advanced, disabling dystonia.85,86 Selection of appropriate patients for DBS is a prominent issue for neurologists and neurosurgeons who treat patients with movement disorders (Table 76-4). In determining an individual patient’s risk-benefit ratio, several variables need to be taken into consideration, including the patient’s motor, cognitive, overall medical, and psychological status.87 The best candidates are patients with primary generalized, segmental, or cervical dystonia or hemidystonia who have not responded to medications or botulinum toxin injections and have progressed to profound disability as a result of motor impairment or pain.87
TABLE 76-4 Specific Deep Brain Stimulation Selection Criteria for Dystonia
SELECTION CRITERIA | COMMENT |
---|---|
Diagnosis |
A trial of levodopa therapy should always be performed to rule out patients with DRD. It is important to determine whether the target symptom or symptoms for surgery are the major source of disability and the likelihood that the symptom or symptoms will improve with DBS. Other sources of disability must be identified, and the patient’s individual risk of encountering complications should be considered. Ideally, surgery should be performed before secondary orthopedic complications (i.e., contractures) compromise the neurological rehabilitation.87
In general, patients with primary dystonia are better candidates for DBS than those with secondary dystonia.88 Short disease duration appears to be a positive outcome predictor.89 DYT1+ patients seem to respond better than others in some, but not all series, and their advantage may be attributable to their young age at onset and relatively quick progression warranting DBS surgery after a short duration of disease.85,89,90
DBS results in patients with secondary dystonia have generally been disappointing,88,91–93 with some notable exceptions, including those with tardive dystonia,94,95 myoclonic dystonia,96 and pantothenate kinase–associated neurodegeneration (PKAN).97–99
Target Selection
Although thalamic and subthalamic targets have occasionally been used as DBS targets, in particular for secondary dystonias, the vast majority of procedures for dystonia target the globus pallidum; indeed, DBS of the GPi proved to be a safe and effective treatment of advanced, disabling primary85,86 and some types of secondary dystonia.94,95,100,101
Thalamic DBS may be an option for some patients with secondary dystonia, including posttraumatic hemidystonia, postanoxic dystonia and bilateral basal ganglia necrosis, myoclonic dystonia, and dystonic paroxysmal nonkinesigenic dyskinesia.88 The thalamic structures targeted in these cases are the VIM nucleus,102–104 the ventro-oralis anterior (VOA) nucleus,105,106 and the ventroposterolateral nucleus.107 Combined implants of thalamic and pallidal targets in the same patients have also been successfully attempted.106,108
STN DBS is currently the procedure of choice for the treatment of medically refractory PD, for which it is effective in treating both “off”- and “on”-state dystonias.109 These results have prompted speculation on the potential of this target for the treatment of idiopathic torsion dystonia. Potential advantages of targeting the STN instead of the GPi include more rapid response to stimulation and the ability to achieve identical or enhanced clinical effects with less energy, thereby prolonging battery life. These ideas are supported by encouraging preliminary results.110,111
Essential Tremor
Selection Criteria
ET is a progressive neurological disease characterized by a postural or kinetic tremor affecting mainly the arms, but also the head, jaw, and voice, as well as other body regions.112 Tremor usually begins in the arms and then spreads to other regions in some patients. Essential head tremor is more likely to develop in women than in men.113 Other types of tremor may also occur, including occasionally rest tremor in the arms.114 In some patients, gait and balance difficulties, anxiety and depressive symptoms, and cognitive difficulty may also develop.115,116
ET is a common neurological disease, with a prevalence of approximately 4% in persons 40 years and older and considerably higher in the elderly population.114 ET is often mild and is occasionally defined as “benign essential tremor” or “familial tremor” because of the fact that approximately half the cases are transmitted with a pattern of inheritance most consistent with autosomal dominant transmission. However, no genes have as yet been identified.
Patients with severe tremor have difficulty performing many of their routine activities of daily living and require pharmacologic or surgical therapy.114,117 Before considering surgery, patients should undergo an adequate trial of first-line drugs alone and in combination, including propranolol (60 to 320 mg/day) and primidone (300 to 750 mg/day). If patients fail first-line therapy, trials of second-line (clonazepam, alprazolam, and topiramate) and third-line (clonidine, acetazolamide, flunarizine, and theophylline) drugs may be administered; however, these medications rarely result in marked improvement, and surgery should not be delayed unnecessarily.114 In general, oral medications tend to be more helpful for limb tremor than for head or voice tremor, which may benefit from botulinum toxin injections.
DBS is indicated for ET patients refractory to medications when tremor severity and distribution cause unacceptable impairment of activities of daily living.59,118–129 Table 76-5 summarizes current DBS selection criteria for ET. The most widely accepted scale for evaluating the severity of ET is the Fahn-Tolosa-Marín rating scale for tremor.130
TABLE 76-5 Specific Deep Brain Stimulation Selection Criteria for Essential Tremor
SELECTION CRITERIA | COMMENT |
---|---|
Diagnosis | The symptom tremor is generally well responsive to thalamic DBS |
Disease severity | Tremor must significantly interfere with the patient’s quality of life |
Disease duration | No limitation |
Age at surgery | Older age is not a specific exclusion criterion if the patient is cognitively intact and in good general health |
Response to medications | Patients with ET must have medication-refractory symptoms, defined as having failed maximal titrations and preferably combinations of a beta blocker, primidone, and possibly a benzodiazepine |
Cognitive status |
DBS, deep brain stimulation; ET, essential tremor; VIM, ventral intermediate nucleus of the thalamus.
Few reports have addressed cognitive function in patients with ET to document abnormalities that would suggest systematic neuropsychological testing before DBS surgery.131–136 However, no standardized cognitive screening has consistently been advocated to test ET patients before DBS implants. Quality of life can be investigated with the Quality of Life in Essential Tremor Questionnaire (QUEST); although still partially validated, this scale is the only one available to assess impairment of daily living activities in patients with ET.137
Target Selection
At present, the VIM nucleus of the thalamus is the most commonly targeted site for DBS in patients with ET.120,138–141 In addition, there is limited yet positive evidence that stimulation of the STN can also produce satisfactory tremor control in ET patents.142 Unilateral VIM stimulation results in marked short- and long-term improvement in contralateral action and postural tremor and in some cases may have a mild ipsilateral effect.122,141,143 There is, however, a decreasing effect over time, most noticeable with tremor of action.144
Because voice tremor is not reliably improved by unilateral VIM stimulation,125,145,146 it should not be a primary indication for DBS. Head tremor has also shown inconsistent or unpredictable improvement with unilateral and bilateral stimulation.3,122,125,139,147
Complex Tremor Syndromes
Selection Criteria
Cerebellar Tremor
Cerebellar tremor is characterized by a coarse action tremor, generally less than 5 Hz, and is occasionally associated with postural tremor. Typically, cerebellar tremor affects the upper extremities unilaterally or bilaterally, although head and trunk titubation is also common and may be the most disabling feature. A simple observation of the frequency and regularity of movements when performing typical activities (e.g., drinking from a cup) may give clues to the diagnosis.148 Cerebellar tremor is most commonly problematic in patients with MS, after head injury, following brainstem cerebrovascular events, and occasionally in those with spinocerebellar ataxia or the cerebellar subtype of MSA.
Disabling tremor that impairs a patient’s quality of life is seen in approximately 10% to 15% of MS clinic patients.149 Drug therapy with agents such as carbamazepine, clonazepam, l,5-hydroxytryptophan, and buspirone is rarely successful; occasional patients may have mild improvement with high-dose propranolol.149 Appropriate patients for stereotactic surgery should have tremor that significantly interferes with activities of daily living. Only two disease severity scales have been proposed, and both take into account tremor severity and distribution for evaluation of MS tremor.150,151 No validation studies are available.
MS patients have multiple other nervous system lesions that result in neurological deficits, and it is important to distinguish between tremor-related disability and disability caused by other deficits. In fact, studies of the effects of DBS on MS tremor consistently show some improvement in the majority of patients, but the improvement is often overshadowed by progression of the other symptoms of MS.141 Patients with marked sensory impairment in the target limb, excessive arm weakness, or marked truncal weakness resulting in a bed-bound state should not be offered surgery because significant functional improvement is unlikely to be achieved even if the tremor were eliminated.149
Holmes’ Tremor
Also known as “rubral tremor” or midbrain tremor, HT is an irregular, low-frequency rest and intention tremor that is enhanced by posture in most cases. The Movement Disorder Society has established three criteria for the diagnosis of HT, including (1) the presence of both resting and intentional tremor, (2) a slow frequency, usually less than 4.5 Hz, and (3) a variable delay (usually months) after occurrence of the lesion.152 HT has been reported in association with trauma, cerebrovascular events, neuroleptic agents, infections, MS, neoplasm, Wilson’s disease, cavernoma, and radiation toxicity.153 The pathogenesis of HT has been attributed to combined destruction of the pallidothalamic and cerebellothalamic pathways, with involvement of the rubro-olivo-cerebello-rubral loops and possibly the nigrostriatal system.154
Thalamic Tremor
TT is characterized by variable degrees of dystonia, athetosis, chorea, and action tremor and occasionally associated with myoclonic components after lateral posterior thalamic stroke, most frequently hemorrhagic in nature.155,156 Dystonia, athetosis, and chorea are usually associated with position sensory loss after thalamic lesions, whereas tremor and myoclonic movements are most frequently related to cerebellar ataxia.155 The pathogenesis of TT is unclear, but it has been related to defective motor-sensory integrative processes because of persistent failure of proprioceptive sensory and cerebellar input after recovery of motor dysfunction, with severe lateral-posterior thalamic strokes simultaneously damaging the lemniscal sensory pathway, the cerebellar-rubrothalamic tract, and, less severely, the pyramidal tract.155 TT generally starts gradually and progressively worsens for weeks or months before stabilizing. Involuntary movements usually remain persistent and only rarely show spontaneous improvement.155
Orthostatic Tremor
Described as a quivering tremor of the legs and trunk during standing accompanied by a sensation of unsteadiness, OT is usually relieved by walking or leaning against objects.157 It is characterized by distinctive 14- to 16-Hz lower extremity electromyographic activity that is evoked on standing but not while walking or supine. OT is believed to be a variant of ET despite lack of response to alcohol, beta blockers, and primidone and the absence of a family history.158,159 OT usually responds to clonazepam but shows a progressive reduction in the latency between standing and the onset of unsteadiness, with an increase in tremor severity that may result in an inability to stand still without support. Although patients may not fall, the sensation of unsteadiness can markedly interfere with their quality of life.160
Tremor severity, consequent disability, and lack of response to common antitremor medications are the criteria generally used to select patients with atypical tremor syndromes for DBS surgery. No specific neuropsychological selection criteria have been described in the literature, but it is probably good practice to test any DBS candidate older than 50 years. Physiologic assessment of patients with complex tremor and ataxia may help predict those who will most likely benefit from surgery. Thalamotomy has resulted in complete resolution of upper extremity postural tremor with frequencies greater than 3 Hz as assessed by an accelerometer, whereas tremor of less than 3 Hz did not improve postoperatively.149 Furthermore, frequency analysis during a wrist-tracking task may also be predictive of the response of action tremor to thalamotomy, with an 80% reduction in tremor in patients with just one frequency peak in the spectra and only a 30% reduction in those with multiple frequency peaks.161
MS patients who are being considered for thalamic DBS surgery to control intention tremor should undergo brain MRI within 3 months of surgery because their disease can progress without obvious clinical sequelae. We were surprised in one instance when the targeting MRI of an MS patient revealed a new plaque in the internal capsule that extended into the ventrolateral thalamus, the preferred target for tremor control. Stimulation within the ventrolateral thalamus in this patient yielded unwanted side effects at very low currents, most probably caused by aberrant conduction through this new plaque. Consequently, a DBS lead could not be implanted.16
Target Selection
DBS has been shown to be beneficial for several atypical tremor syndromes, although fewer cases have been reported and the benefit is less remarkable and less consistent than that reported for ET.141 Most studies of DBS for MS tremor targeted the thalamus and the VIM nucleus in particular.162,163 Other successful targets include the ventralis oralis posterior (VOP) nucleus of the thalamus and the zona incerta. Stimulation of these alternative targets produced a 64% improvement in postural tremor and a 36% improvement in intention tremor.164 Dual-electrode stimulation to simultaneously target the VIM/VOP border and the VOA/VOP border also provided significant reduction of tremor in one MS patient.165 Because DBS of the thalamic VIM nucleus produces often inconsistent and short-term benefits, further research is necessary to determine the most effective target for MS-associated tremor.
With the exception of one patient treated by GPi DBS,166 the thalamic VIM nucleus is also the most frequent target for successful DBS treatment of atypical tremors (mostly TT and HT) resulting from posttraumatic and vascular lesions.165,167–176 The youngest patient who underwent implantation, a 14-year-old girl, showed remarkable improvement (90%) with VIM DBS up to 2.5 years.153 Successful VIM DBS has also been reported in three patients suffering from OT.160,177
The caudal (motor) zona incerta has also been used as an alternative target for DBS treatment of atypical tremor, with reported improvement in all components of tremor affecting both the distal and proximal ends of limbs, as well as the axial musculature.178 Two patients with dystonic tremor and one with neuropathic-related tremor responded well to unilateral stimulation of the posterior subthalamic area.179 Subthalamic-thalamic stimulation achieved suppression of tremor related to spinocerebellar ataxia type 2.180
Multiple targets have also been used to improve HT symptoms. Simultaneous placement of two DBS electrodes at the VIM/VOP border and at the VOA/VOP border resulted in excellent reduction of symptoms in three patients.165 In one patient, combined STN-VIM stimulation but not stimulation of the STN or VIM nucleus alone produced global relief of tremor without adverse events.170
Tourette’s Syndrome
Selection Criteria
Tourette’s syndrome (TS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics that wax and wane over time, often associated with behavioral disorders.181 The motor tics are stereotyped repetitive and involuntary movements that generally affect the face, head, and upper part of the body, whereas vocal tics are sounds usually represented by shouting, barking, sniffing, or grunting. Comorbid conditions include attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, anxiety, and self-injurious behavior. Symptoms often disappear before or during early adulthood or may be controlled with medication.181 Some patients, however, may have medically resistant severe and disabling tics that persist or worsen in adulthood.
To be considered a surgical candidate, TS patients need to be refractory to medical treatment and be severely disabled by the condition.182 A multidisciplinary approach that includes neurological and psychiatric evaluation is strongly recommended. The main scale used to evaluate the severity of symptoms is the Yale Global Tic Severity Scale.183
The Dutch-Flemish Tourette Surgery Study Group has established guidelines for DBS in patients with TS,184 and the Movement Disorders Society has published the recommendations of the Tourette Syndrome Association.182 The proposed selection criteria include the following:
Target Selection
The choice of target in TS is still controversial inasmuch as good outcomes have been reported with both thalamic and GPi DBS. To date, five targets have been used for DBS in patients with TS: (1) the medial portion of the thalamus at the cross point of the centromedian nucleus/substantia periventricularis/VOA nucleus,187–190 (2) the medial portion of the thalamus at the centromedian nucleus and parafascicular nucleus,183 (3) the posteroventrolateral GPi,191 (4) the anteromedial GPi,183 and (5) the nucleus accumbens and anterior limb of the internal capsule.192,193
Huntington’s Disease and Other Choreas
Selection Criteria
Two types of chorea have been considered for treatment with DBS: Huntington’s disease (HD) and neuroacanthocytosis (NA). HD is a progressive hereditary neurodegenerative disease manifested by chorea and other hyperkinetic (dystonia, myoclonus, tics) and hypokinetic (parkinsonism) movement disorders. In addition, a variety of psychiatric and behavioral symptoms, along with cognitive decline, contribute significantly to the patient’s disability. No effective neuroprotective or disease-modifying therapy for HD is available.194 NA includes combined features of chorea, orofacial tics, dystonia, amyotrophy, and elevated serum creatine kinase levels, with a peculiar finding of spiked red blood cells (acanthocytosis) in the blood smear. NA has been described most commonly as an autosomal recessive hereditary gene defect located on chromosome 9, but it also occurs as an autosomal dominant disorder and as part of an X-linked disorder called McLeod’s syndrome.195 In most cases, the neurological disability caused by chorea is progressive.
Clinical assessment of patients with chorea can be standardized with the UHDRS196 or the Abnormal Involuntary Movement Scale.197 The functional status of HD patients is commonly assessed with the Total Functional Capacity Scale and the Independence Scale, both of which are incorporated into the UHDRS.
Medical therapy for chorea is fairly limited and restricted to symptomatic relief. Numerous medications have been used to improve chorea, including typical and atypical neuroleptics, dopamine depleters, antidepressants, antiglutamatergic drugs, GABA agonists, antiepileptic medications, acetylcholinesterase inhibitors, and botulinum toxin.196
Target Selection
Thalamic and pallidal targets have been used for DBS therapy in patients with chorea. Bilateral GPi DBS in HD was first used for the treatment of a 43-year-old patient who had genetically confirmed HD, rapidly progressive disabling chorea despite medical treatment (tetrabenazine, haloperidol, amantadine), and no psychiatric symptoms.198
Positive results of bilateral GPi DBS were reported in a second HD patient with debilitating choreoathetoid movements refractory to medical management (tetrabenazine, neuroleptics, minocycline) but no psychiatric comorbid conditions.199 The effects were maintained at 1 year, but progressive hypokinetic symptoms eventually developed. Combined thalamic (VOP) and pallidal (GPi) stimulation proved effective in controlling abnormal movements in one case of intractable senile chorea.200
A slightly larger experience is available for NA. Bilateral high-frequency stimulation (160 Hz) of the VOP nucleus of the thalamus improved trunk spasms in one patient with NA, with stable clinical benefit for 1 year, although no clear effect on dysarthria was observed.201 Interestingly, high-frequency stimulation of the GPi failed to improve202 or even worsened NA-related chorea,203 whereas the best results were obtained with low-frequency (40 Hz) bilateral pallidal DBS using monopolar stimulation on two adjacent contacts.203
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