Treatment of dystonia refractory to oral medications or botulinum toxin injections includes the use of deep brain stimulation (DBS). Expectations should be established based on patient-related factors, including type of dystonia, genetic cause, target symptoms, age at the time of surgery, disease duration, or the presence of fixed skeletal deformities. Premorbid conditions such as psychiatric illness and cognitive impairment should be considered. Target selection is an emerging issue in DBS for dystonia. Although efficacy has been established for targeting the globus pallidus internus for dystonia, other brain targets such as the subthalamic nucleus, thalamus, or cortex may be promising alternatives.
Key points
- •
Greater understanding of the influence of patients’ baseline characteristics on therapeutic response to deep brain stimulation (DBS) helps to more accurately counsel patients on expected outcome.
- •
Primary generalized dystonia has good evidence for a robust improvement in movement and disability after globus pallidus internus (Gpi) DBS.
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Specific types of secondary dystonia (tardive, cerebral palsy, neurodegeneration with brain iron accumulation) have reasonable outcomes after GPi DBS, whereas other secondary dystonias deserve more study.
- •
GPi has the strongest evidence in primary and secondary dystonia, but alternative brain targets such as the subthalamic nucleus or thalamus are being explored.
Introduction
Dystonia is a clinical syndrome of sustained muscle contractions producing twisting and repetitive movements or abnormal postures, often resulting in simultaneous contraction of agonist and antagonist muscles. Medical therapies with anticholinergic and GABAergic medications are helpful in some cases, but often limited by side effects. Pallidotomy and thalamotomy were used extensively for the treatment of dystonia after it was observed that pallidotomy for Parkinson disease (PD) improved PD-related dystonia. Deep brain stimulation (DBS) therapy has shown significant and sustained success in the treatment of dystonia (especially in primary dystonia) when medical therapy fails to improve symptoms and there is disability.
Most patients with dystonia over the last decade have been treated with globus pallidus internus (GPi) DBS. In recent years, DBS has been applied to treat a broader range of patients with dystonia (focal and secondary) and new brain targets for stimulation have been explored. In this article, the current status of DBS for treating patients with various types of dystonia is reviewed. Predictors of outcome and alternative brain targets are also discussed to help guide patient selection and target choice.
Classification
Three parallel classification schemes are used to describe dystonia, including categorization by age at onset, distribution, and cause ( Table 1 ). Age at onset is divided into early and late onset and can be helpful in understanding the underlying cause and likelihood of spread (eg, early-onset primary dystonia is more likely to become generalized than late onset). Distribution refers to the extent to which the dystonia occurs across the body. Cause is an attempt to classify the dystonia by underlying cause. Classification can provide prognostic information and is essential when predicting potential benefit from therapies such as DBS. When no cause (with the exception of known genetic mutations) can be determined, then the dystonia is considered primary, which also implies the absence of other neurologic symptoms (with the exception of tremor). Familial early-onset dystonia are often caused by mutations in TOR1A (DYT1) or THAP1 (DYT6), whereas late-onset sporadic and familial dystonia typically presenting with cranial or cervical dystonia (CD) have been associated with THAP1 (DYT6), CIZ1, and GNAL, although these are more commonly without a known mutation.
| Age at Onset (y) | Distribution | Cause |
|---|---|---|
| Early (≤26) | Focal | Primary |
| Late (>26) | Segmental | Dystonia-plus |
| Multifocal | Secondary | |
| Generalized | Heredodegenerative | |
| Hemidystonia | Feature of another disease (eg, tics, PD, corticobasal syndrome, progressive supranuclear palsy) |
Dystonia-plus syndromes are nonneurodegenerative conditions associated with other neurologic features such as myoclonus, parkinsonism, or autonomic dysfunction and include dopa-responsive dystonia, myoclonus-dystonia, and rapid-onset dystonia-parkinsonism. Secondary dystonia is diagnosed when symptoms can be related to acquired insults such as central nervous system (CNS) structural lesions, hypoxic injury, metabolic disease, or medication exposure (tardive). Heredodegenerative dystonias have a neurodegenerative cause, follow a progressive course, and may include other findings on examination but have dystonia as a prominent feature. A separate category has also been considered to capture dystonia associated with other neurodegenerative diseases that may not always be a central symptom (eg, corticobasal syndrome [CBS], progressive supranuclear palsy [PSP], PD, paroxysmal dyskinesia).
Introduction
Dystonia is a clinical syndrome of sustained muscle contractions producing twisting and repetitive movements or abnormal postures, often resulting in simultaneous contraction of agonist and antagonist muscles. Medical therapies with anticholinergic and GABAergic medications are helpful in some cases, but often limited by side effects. Pallidotomy and thalamotomy were used extensively for the treatment of dystonia after it was observed that pallidotomy for Parkinson disease (PD) improved PD-related dystonia. Deep brain stimulation (DBS) therapy has shown significant and sustained success in the treatment of dystonia (especially in primary dystonia) when medical therapy fails to improve symptoms and there is disability.
Most patients with dystonia over the last decade have been treated with globus pallidus internus (GPi) DBS. In recent years, DBS has been applied to treat a broader range of patients with dystonia (focal and secondary) and new brain targets for stimulation have been explored. In this article, the current status of DBS for treating patients with various types of dystonia is reviewed. Predictors of outcome and alternative brain targets are also discussed to help guide patient selection and target choice.
Classification
Three parallel classification schemes are used to describe dystonia, including categorization by age at onset, distribution, and cause ( Table 1 ). Age at onset is divided into early and late onset and can be helpful in understanding the underlying cause and likelihood of spread (eg, early-onset primary dystonia is more likely to become generalized than late onset). Distribution refers to the extent to which the dystonia occurs across the body. Cause is an attempt to classify the dystonia by underlying cause. Classification can provide prognostic information and is essential when predicting potential benefit from therapies such as DBS. When no cause (with the exception of known genetic mutations) can be determined, then the dystonia is considered primary, which also implies the absence of other neurologic symptoms (with the exception of tremor). Familial early-onset dystonia are often caused by mutations in TOR1A (DYT1) or THAP1 (DYT6), whereas late-onset sporadic and familial dystonia typically presenting with cranial or cervical dystonia (CD) have been associated with THAP1 (DYT6), CIZ1, and GNAL, although these are more commonly without a known mutation.
| Age at Onset (y) | Distribution | Cause |
|---|---|---|
| Early (≤26) | Focal | Primary |
| Late (>26) | Segmental | Dystonia-plus |
| Multifocal | Secondary | |
| Generalized | Heredodegenerative | |
| Hemidystonia | Feature of another disease (eg, tics, PD, corticobasal syndrome, progressive supranuclear palsy) |
Dystonia-plus syndromes are nonneurodegenerative conditions associated with other neurologic features such as myoclonus, parkinsonism, or autonomic dysfunction and include dopa-responsive dystonia, myoclonus-dystonia, and rapid-onset dystonia-parkinsonism. Secondary dystonia is diagnosed when symptoms can be related to acquired insults such as central nervous system (CNS) structural lesions, hypoxic injury, metabolic disease, or medication exposure (tardive). Heredodegenerative dystonias have a neurodegenerative cause, follow a progressive course, and may include other findings on examination but have dystonia as a prominent feature. A separate category has also been considered to capture dystonia associated with other neurodegenerative diseases that may not always be a central symptom (eg, corticobasal syndrome [CBS], progressive supranuclear palsy [PSP], PD, paroxysmal dyskinesia).
Patient selection
Although each patient’s surgical candidacy should be evaluated individually considering their level of disability from dystonia, inclusion and exclusion criteria are helpful in patient selection ( Table 2 ). The degree of disability required to warrant DBS may be dependent on the patient’s expected baseline level of function, caregiver burden, and the degree of potential improvement in the disabling symptom. There are also several prognostic indicators to consider when accurately describing the risk/benefit ratio in any given case ( Box 1 ).
| Inclusion Criteria | Exclusion Criteria |
|---|---|
| Unequivocal diagnosis of dystonia | Young age (generally <7 y) |
| Failure of previous medical treatment | Low weight |
| Disability to patient or caregivers sufficient to warrant surgery | High infection risk |
| Inability to follow-up | |
| Actively suicidal | |
| Unrealistic expectations |
Dystonia classification
Prominent involuntary movement type
Prominent pain
Age at the time of surgery
Disease duration
Psychiatric disease/depression
Cognitive function
Fixed skeletal deformities
Influence of Dystonia Type on Outcome
The quality of information predicting response to DBS in a specific type of dystonia is variable, with class 1 data for primary generalized dystonia (PGD) to class IV data for several types of secondary and heredodegenerative dystonia. The expected surgical outcome is discussed based on evidence available for the various etiologic classifications.
Primary generalized dystonia
The most rigorously studied group of patients with dystonia receiving DBS are those with PGD ( Tables 3 and 4 ) and includes many patients who have tested positive for the TOR1A (DTY1) mutation. Early work suggested a 59% to 86% improvement in the Burk-Fahn-Marsden Dystonia Rating Scale Movement Score (BFMDRS-m) in open-label trials of patients with PGD receiving bilateral GPi DBS, although more moderate effects were also reported in several other studies. In 2005, Vidailhet and colleagues reported a randomized, prospective multicenter trial in patients with PGD in which patients underwent double-blind video assessment 3 months after surgery and showed a 29% improvement in the BFMDRS-m score with DBS on compared with DBS off. After 12 months, these patients showed a 51% reduction in BFMDRS-m and a 44% improvement in the disability score.
| Type of Dystonia | N | Scale (Subscale) | Baseline Score | Follow-Up Time (mo) | Follow-Up Score | Percent Improvement |
|---|---|---|---|---|---|---|
| Vercueil et al, 2001 | ||||||
| PGD a | 1 | BFMDRS (m/d) | — | 12 | — | 67/81 |
| PGD a | 1 | BFMDRS (m/d) | — | 6 | — | 70/50 |
| PGD DYT1+ | 1 | BFMDRS (m/d) | — | 12 | — | 86/86 |
| PGD DYT1− | 1 | BFMDRS (m/d) | — | 24 | — | 41/43 |
| Craniocervical | 1 | BFMDRS (m/d) | — | 6 | — | 66/66 |
| Krauss et al, 2002 | ||||||
| Cervical | 5 | TWSTRS (s/d/p) | 20.5/40.5/6 | 20 | 7.5/12.7/3 | 62/69/50 |
| Yianni et al, 2003 | ||||||
| PGD DYT1+ | 2 | BFMDRS (m) | — | 12 | — | 85 b |
| PGD DYT1− | 11 | BFMDRS (m) | — | 12 | — | 46 b |
| Cervical | 7 | TWSTRS (s/d/p) | 21.3/21.7/15.1 | 12 | 10/14/8.3 | 50/38/43 |
| Cif et al, 2003 | ||||||
| PGD DYT1+ | 15 | BFMDRS (m/d) | 60.8/16.7 | 24–36+ | 14.2/5.7 | 71/63 |
| PGD DYT1− | 17 | BFMDRS (m/d) | 56.5/16.4 | 24–36 | 15.1/9.5 | 74/49 |
| Kupsch et al, 2003 | ||||||
| PGD DYT1+ | 1 | BFMDRS (m) | 34.5 | 3–12 | 27 | 22 |
| PGD DYT1− | 3 | BFMDRS (m) | 40 | 3–13 | 20 | 50 |
| Segmental | 1 | BFMDRS (m) | 32 | 3–14 | 19 | 41 |
| Katayama et al, 2003 | ||||||
| PGD | 5 | BFMDRS (m) | 18–62 | 6 | 4–23 | 51–92 |
| Coubes et al, 2004 | ||||||
| PGD DYT1+ | 17 | BFMDRS (m) | 62.5 | 24 | 12.4 | 83 |
| PGD DYT1− | 14 | BFMDRS (m) | 56.3 | 24 | 13.4 | 75 |
| Eltahawy et al, 2004 | ||||||
| PGD DYT1+ | 1 | BFMDRS (m) | 88 | 6 | 66 | 25 |
| PGD DYT1− | 1 | BFMDRS (m) | 48 | 6 | 16 | 21 |
| Cervical | 3 | TWSTRS (t) | 37.7 | 6 | 16 | 57 |
| Krause et al, 2004 | ||||||
| PGD DYT1+ | 4 | BFMDRS (m) | 72 | 12–66 | 34 | 53 |
| PGD DYT1− | 6 | BFMDRS (m) | 73.9 | 12–67 | 50 | 32 |
| Cervical | 1 | BFMDRS (m) | 6 | 12–68 | 6 | 0 |
| Vidailhet et al, 2005 | ||||||
| PGD DYT1+ | 7 | BFMDRS (m/d) | 55.1/14.72 | 12 | 26.1/85 | 53/45.6 |
| PGD DYT1− | 15 | BFMDRS (m/d) | 41.96/10.2 | 12 | 18.7/5.5 | 55.4/45 |
| Bittar et al, 2005 | ||||||
| PGD DYT1+ | 2 | BFMDRS (t) | 103.8 c | 24 | 55.8 | 46 c |
| PGD DYT1− | 4 | BFMDRS (t) | — | 24 | — | — |
| Cervical | 6 | TWSTRS (t) | 6 | 24 | 23.7 | 59 |
| Zorzi et al, 2005 | ||||||
| PGD DYT1+ | 1 | BFMDRS (m/d) | 47/11 | 4 | 14/6 | 70/45 |
| PGD DYT1− | 8 | BFMDRS (m/d) | 68.9/17.9 | 19.1 | 46.5/12.6 | 32/37 |
| Diamond et al, 2006 | ||||||
| PGD DYT1+ | 5 | UDRS | 44.6 | 27.5 | 4.8 | 89 c |
| PGD DYT1− | 5 | — | — | — | — | — |
| Kupsch et al, 2006 | ||||||
| PGD DYT1+ | 6 | BFMDRS (m/d) | 36.4/10.0 | 6 | 20.2/5.9 | 45/41 d |
| PGD DYT1− | 4 | BFMDRS (m/d) | — | — | — | — |
| Primary a | 14 | BFMDRS (m/d) | — | — | — | — |
| Cervical | 16 | BFMDRS (m/d) | — | — | — | — |
| Starr et al, 2006 | ||||||
| PGD DYT1+ | 6 | BFMDRS (m) | 59.6 | 13.2 | 24.2 | 59 c |
| PGD DYT1− | 1 | BFMDRS (m) | 94 | — | — | — |
| Segmental | 3 | BFMDRS (m) | 22.6 | 21.7 | 12 | 47 |
| Craniocervical | 1 | BFMDRS (m) | 30 | 9 | 3 | 90 |
| Generalized a | 2 | BFMDRS (m) | 83 | 10.5 | 72.8 | 12 |
| Hung et al, 2007 | ||||||
| Cervical | 10 | TWSTRS (s/d/p) | 21.9/18/11.7 | 12–67 | 9.9/7.4/5.8 | 54.8/52.1/50.5 |
| Alterman et al, 2007 | ||||||
| PGD DYT1+ | 12 | BFMDRS (m/d) | 35/8 | 38.9/9.0 | 4/2 | 89/75 c |
| PGD DYT1− | 3 | BFMDRS (m/d) | — | — | — | — |
| Tisch et al, 2007 | ||||||
| PGD DYT1+ | 7 | BFMDRS (m/d) | 38.9/9.0 | 6 | 11.9/4.1 | 69.5/58 c |
| PGD DYT1− | 8 | — | — | — | — | — |
| Ostrem et al, 2007 | ||||||
| Craniocervical | 6 | BFMDRS (m/d) | 22/6 | 6 | 6.1/3.7 | 72/38 |
| — | TSWSTRS (t) | 39 | — | 17 | 54 | |
| Kiss et al, 2007 | ||||||
| Cervical | 10 | TWSTRS (s/d/p) | 14.7/14.9/26.6 | 12 | 8.4/5.4/9.2 | 43/64/65 |
| Cersosimo et al, 2008 | ||||||
| PGD bilateral DBS | 3 | BFMDRS (m/d) | 42.8/12.6 | 33–84 | 23.7/8.7 | 44.7/31 |
| PGD DBS + lesion | 5 | BFMDRS (m/d) | 60.2/19 | 15–94 | 28.4/10.8 | 52.8/43.2 |
| Isaias et al, 2009 | ||||||
| PGD DYT1+ | 17 | BFMDRS (m) | 44 | 84 | 13.6 | 82 c |
| PGD DYT1− | 7 | — | — | — | — | — |
| PGD DYT1+ FSD | 3 | BFMDRS (m) | 10.6 | 84 | 5.6 | 62 c |
| PGD DYT1− FSD | 3 | — | — | — | — | — |
| Valldeoriola et al, 2010 | ||||||
| PGD DYT1+ | 6 | BFMDRS (m/d) | 46.4/12.4 | 6 – 12 | 26.1/7.64 | 43/38 c , d |
| PGD DYT1− | 16 | BFMDRS (m/d) | — | 6 – 13 | — | — |
| Cervical | 2 | BFMDRS (m/d) | — | 6 – 14 | — | — |
| Cacciola et al, 2010 | ||||||
| Cervical | 10 | TWSTRS (t) | 55.7 | 37.6 | 17.6 | 68 |
| Groen et al, 2010 | ||||||
| PGD DYT6+ | 5 | BFMDRS (m) | 38.9 | 6 | 25.6 | 34 |
| Yamada et al, 2012 | ||||||
| Cervical | 8 | TWSTRS (s/d/p) | — | 24–36 | — | 70.2/76.1/87.1 |
| Borggraefe et al, 2010 | ||||||
| PGD DYT1+ | 3 | BFMDRS (m) | 52 | 13 | 8.7 | 83 |
| PGD DYT1− | 3 | BFMDRS (m) | 51 | 16.7 | 19 | 63 |
| Panov et al, 2012 | ||||||
| PGD DYT6+ | 3 | BFMDRS (m) | — | 24 | — | 61 |
| PGD DYT1+ | 23 | — | — | 24 | — | 87 |
| Skogseid et al, 2012 | ||||||
| Cervical | 8 | TWSTRS (s/d/p) | 28/15/22 | 30 | 7/2/2002 | 73/92/91 |
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