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Surgical Treatment of Dystonia
SURGICAL TREATMENT OF DYSTONIA
John Yianni1, Alexander L. Green2 and Tipu Z. Aziz2 1
Department of Neurosurgery, Royal Hallamshire Hospital, Sheffield, UK 2 Nuffield Department of Surgery, University of Oxford, UK
I. Background A. History of Dystonia B. Prevalence Estimates II. Classification A. Aetiological Classification B. Descriptive Classification III. Medical Treatment of Dystonia IV. Surgical Treatment of Dystonia V. Deep Brain Stimulation (DBS) for Dystonia A. Development B. Preoperative Assessment C. Surgical Considerations and Techniques D. Postoperative DBS Programming and Patient Management VI. DBS for Dystonia—Clinical Overview A. Cervical Dystonia B. Generalized Dystonia C. Segmental and Focal Dystonia D. Secondary Dystonia VII. Conclusion References
Dystonia is a neurological condition characterised by abnormal muscle contractions, often causing repetitive twisting movements or abnormal postures. Varying forms of surgical intervention, for dystonia unresponsive to medical therapy, have evolved over the years and have often been associated with poor outcomes and high morbidity. The advent of stereotactic neurosurgery and the success of deep brain stimulation in treating a number of movement disorders have revolutionized the surgical treatment for dystonia. This chapter reviews the literature concerning the surgical treatment dystonic conditions, from historical origins to the current use of modern functional neurosurgical techniques.
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I. Background
A. HISTORY OF DYSTONIA One of the earliest descriptions of dystonia was recorded by Gowers in 1888 (Kandel et al., 1989), whilst Destarac in 1901 used the term “torticollis spasmodique” to describe the twisting neck movements observed in a 17-year girl. Dystonic conditions were identified as distinct from other hyperkinesias by Schwalbe in 1908; however, because of the bizarre nature of the movements, dystonias were originally considered a form of “hysterical neurosis.” The term “dystonia” was first coined by Oppenheim in 1911, who was the first to correctly identify the organic nature of dystonia (Goetz et al., 2001). Focal dystonias however, unlike the generalized condition, have been recognized for centuries. For example, the first recorded case of surgery for spasmodic torticollis was performed in 1641 by German physician Minnius who sectioned the sternocleidomastoid muscle (Kandel et al., 1989). In 1944 Herz revived the concept of dystonia being an organic disease; however because of failures to identify any specific brain lesions in dystonia, arguments for an organic basis to the condition were not recognized until the 1980s following Marsden’s work on cases of hemidystonia (Marsden et al., 1985). In the 1980s and 1990s investigation into generalized dystonia, particularly amongst Jews of Ashkenazi descent, led to the discovery of the DYTI gene mutation at the 9q34 locus. Since then continued research has led to the awareness of a complex array of aetiological causes underlying dystonia. B. PREVALENCE ESTIMATES Dystonic conditions are not rare. Epidemiological surveys estimate that dystonia is the third most common movement disorder after Parkinson’s disease and Essential Tremor (Fahn et al., 1998b), more prevalent than a number of better known neurological conditions such as myotonic dystrophy, myasthenia gravis, and motor neuron disease. In contrast to many other conditions, however, there have been few published epidemiological studies of dystonia. Differences in study design have further confused prevalence estimates, making it difficult to extrapolate data from certain studies to the general population.One of the most comprehensive examinations of prevalence estimates currently available was provided by the Epidemiological Study of Dystonia in Europe (ESDE) collaborative group (ESDE group, 2000). Data pooled from eight countries revealed a prevalence rate of 152 per million for primary dystonia. The highest subcategory prevalence was 117 per million for focal dystonia with segmental dystonia constituting 32 per million and multifocal dystonia 2.4 per million. The commonest form of focal
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dystonia was cervical dystonia (57 per million). However, true prevalence is unknown, with many authors suggesting that estimates in published reports are considerably lower than the actual prevalence (Jankovic et al., 2007) due to significant numbers of undiagnosed cases within the community.
II. Classification
The term dystonia is employed to describe a syndrome characterized by sustained muscle contractions, often causing repetitive twisting movements or abnormal postures. These involuntary movements are caused by co-contractions of agonist and antagonist muscles and are often exacerbated during action but improve with rest, sleep, or sensory tricks (geste antagoniste) such as touching the chin to improve cervical dystonia. Some dystonic movements (e.g., writer’s cramp) appear only with specific actions and are referred to as task-specific dystonias. Dystonic conditions are many and varied and can be described either aetiologically or descriptively. A. AETIOLOGICAL CLASSIFICATION An important aspect of the clinical evaluation of dystonia is the aetiological classification of the condition. This helps in formulating treatment strategies, deciding on the need for genetic counselling and may also aid our understanding of the underlying pathophysiology of the illness. In order to assist the aetiological classification of dystonic conditions, a similar system for the classification of parkinsonism has been adopted by many (Fahn et al., 1998a) to include the subcategories of primary dystonia, dystonia-plus syndromes, secondary dystonia, and heredodegenerative diseases in which dystonia is the prominent feature. The molecular classification of dystonia includes several genetic loci. Currently at least 19 gene loci have been described (Kamm, 2009; Schmidt and Klein, 2010); although it is likely that there are many more dystonia genes that have yet to be discovered. B. DESCRIPTIVE CLASSIFICATION 1. Age at Onset Dystonia can be subdivided into two groups on the basis of age at onset of symptoms. The term early-onset dystonia is often employed when symptoms begin before the age of 26 years, whereas after this age, they are classified as late-onset dystonia. The earlier dystonic symptoms appear, the more likely the condition will
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progress to become generalized, whilst in the older onset individuals, it is more likely to remain focal. 2. Distribution of Affected Body Regions When dystonia is classified according to body distribution, it can be described as focal, segmental, multifocal, or generalized. In focal dystonia, a single body region is affected, such as the arm in writer’s cramp, the eyes in blepharospasm, the neck in spasmodic torticollis, or the laryngeal muscles in spasmodic dysphonia. In segmental dystonia, two or more contiguous body regions are affected, for example cranial– cervical dystonia or crural dystonia (one leg plus trunk or both legs). If two or more noncontiguous body parts are affected, the disorder is termed multifocal dystonia. Generalized dystonia refers to crural dystonia with at least one other body part involved. When dystonia is confined to one side of the body, it is called hemidystonia. The site of the first dystonic symptom is also a valuable prognostic indicator. 90% of patients with onset in the lower limbs will develop symptoms in other parts of the body. Their symptoms are also more likely to become generalized (Greene et al., 1995), compared to those who present with cervical dystonia, of which only a minority will have disease spread to other body parts. Hemidystonia is almost always symptomatic regardless of its age of onset (Marsden et al., 1985).
III. Medical Treatment of Dystonia
One of the first general considerations in approaching the treatment of a patient with dystonia is to differentiate between the primary and secondary dystonias. In a minority of patients with secondary dystonia, for example Wilson’s disease, drug-induced dystonia or dopa-responsive dystonia (DRD), benefit can be gained from specific treatments (Jankovic, 1998). For example, all patients with childhood onset dystonias should receive a trial of L-Dopa, as this may bring about dramatic improvement after a short period of time in those with DRD. For other patients, therapy is directed at controlling the symptoms rather than the cause, with different management strategies employed for generalized as opposed to focal conditions. As a general rule, in patients with generalized and multifocal diseases, oral pharmacotherapy constitutes the mainstay of treatment. Unfortunately the treatment of dystonia with oral agents is often unsatisfactory. In addition to L-Dopa, other established medications include anticholinergics, benzodiazepines, and baclofen. Except in the case of DRD, anticholinergic medications such as trihexyphenidyl are arguably the most effective pharmacotherapy for dystonia (Bressman and Greene, 2000); although effective treatment is sometimes limited by the development of side effects. Although considered less effective than
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anticholinergics, baclofen has proved efficacious in children (Greene, 1992; Greene and Fahn, 1992). Benzodiazepines are also often employed, such as clonazepam, and are particularly useful in the treatment of myoclonic dystonia (Das and Choudhary, 2000). The dopamine depleting drug tetrabenazine is considered to be effective in the treatment of some patients with tardive dystonia. Other antidopaminergics such as haloperidol, may be effective but may also worsen symptoms or induce tardive dyskinesia and hence are not recommended. Although atypical neuroleptics such as clozapine have been suggested for the treatment of tardive dystonia, their effectiveness in treating other forms of dystonia remains questionable. Several other forms of pharmacological therapy have been reported to be beneficial in individual cases of dystonia; however their role in treating dystonia has yet to be fully established.In contrast, patients with focal dystonia tend to benefit most from treatment with botulinum toxin (BTX) injection. BTX is often the treatment of choice for the majority of focal dystonias, particularly cervical dystonia, and has been the most comprehensively investigated therapy for treatment of this patient group. Injections in the most severely affected muscle groups can also be employed in association with other treatments. BTX produces chemodenervation and hence local muscle paralysis at the neuromuscular junction and also appears to improve reciprocal inhibition by altering sensory inflow through muscle afferent fibres (Priori et al., 1995). There are several serotypes of BTX although currently only types A and B are available for use in clinical practice. The duration of effect for BTX is variable but on average lasts for two to three months. Lack of response to BTX injection may occur if there is long-standing disease with contractures or the development of antibodies. Resistance associated with neutralizing antibodies may occur after repeated injections in 5–10% of cases (Hanna and Jankovic, 1998). Both BTX A and B have been shown to be efficacious in placebo-controlled trials (Comella et al., 2000; Sycha et al., 2004) with improvements of 80–90% observed in cervical dystonia (Adler, 2000). There are various injection strategies that have been used including the use of EMGs to guide selection of the appropriate muscle groups requiring treatment (Childers, 2003). It is usually a safe treatment that can be performed repeatedly; however side effects including dysphagia, pain at the injection site, dry mouth, flu-like symptoms, and dysphonia have been reported (Dauer et al., 1998). The majority of patients report satisfactory benefit from BTX treatment, however if this and other conservative measures fail, patients should then be considered for surgical intervention. IV. Surgical Treatment of Dystonia
More than two centuries after Minnius’ operation for torticollis, the Russian surgeon Buyalsky (1850) performed the first spinal accessory nerve section for
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spasmodic torticollis, followed by Morgan in 1867 and Collier in 1890 (Kandel et al., 1989). Spinal cord root section to treat spasmodic torticollis was first proposed over a century ago by Keen (Keen, 1891) who suggested unilateral section of the first three anterior cervical roots. Cervical rhizotomy procedures were further refined by surgeons such as Dandy in 1928, who combined cervical root and accessory nerve sectioning. Bertrand provided extensive data based upon experience with a wide range of procedures derived from Keen’s original operation (Bertrand et al., 1978; Bertrand and Molina-Negro, 1988). By 1979 variations of this procedure were still considered the operation of choice for cervical dystonia refractory to medical therapy, although long-term follow-up disputed the effectiveness of these techniques (Meares, 1971). The issue of long-term efficacy, together with the high incidence of denervation related complications, has led to the virtual abandonment of these techniques. Microvascular decompression of the accessory nerve, peripheral facial neurectomy, and cervical cord stimulation are further examples of procedures employed that have also fallen out of favor. Although satisfactory results have been reported for extensive muscle resections performed in patients with cervical dystonia, the extreme nature of this surgery has prevented it from being widely used (Chen et al., 1991; Xinkang, 1981).
V. Deep Brain Stimulation (DBS) for Dystonia
A. DEVELOPMENT The development of DBS treatment for dystonia dates back to the 1950s, when Hess and Hassler constructed an elaborate animal model to explain both the physiology and pathophysiology of cervical dystonia (Hassler and Dieckmann, 1970). In clinical practice, however, ablative thalamic surgery for dystonia was used almost exclusively for decades (Ondo et al., 2001; Tasker, 1998). Reported results were very variable with about 50% of patients experiencing some degree of benefit. In 1977 when Mundinger reported his early results with thalamic DBS for dystonia, there was little initial interest in his studies (Mundinger, 1977). The globus pallidus internus (GPi) was suggested to be a suitable target for dystonia based upon the discovery that ablative pallidal surgery brought about marked improvement in the dystonic dyskinesias of Parkinson’s disease. Since then, pallidotomy has been reported to be effective in various dystonic disorders (Hutchison et al., 2003; Lozano et al., 1997; Ondo et al., 1998; Yoshor et al., 2001); although it has carried with it the risks of speech and cognitive impairment, as well as a partial recurrence of dystonic symptoms over time. Since its introduction, DBS has replaced ablative surgery for the treatment of dystonia in many neurosurgical centers throughout the world. Initial studies of DBS in dystonia targeted nuclei within the
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thalamus with variable outcome. GPi DBS, inspired initially by the success obtained with pallidotomy, is currently the most popular surgical target for dystonia. Thalamic targets can still be considered in patients with secondary dystonias with pathological changes in the pallidum or where GPi stimulation has been unsuccessful. More recently Subthalamic nucleus stimulation has been reported to be effective in focal and segmental dystonia (Kleiner-Fisman et al., 2007). B. PREOPERATIVE ASSESSMENT Prior to consideration for surgery all patients should be evaluated to assess the severity of dystonia, the level of disability and to screen for secondary causes of dystonia. As well as a thorough neurological assessment, a cognitive and psychiatric assessment is often undertaken to evaluate for cognition and mood disorders that may affect the outcome. A preoperative MRI is required to rule out any structural lesions in the basal ganglia that may interfere with surgical treatment. A preoperative MRI of the cervical spine may also be indicated in order to assess the contribution of degenerative cervical spine disease in those with cervical dystonia. A valid rating scale should also be employed for evaluating the clinical state of a patient with dystonia and should accurately represent the extent of the disease severity as well as the disability caused in relation to activities of daily living. Burke, Fahn and Marsden produced a rating scale, initially for the therapeutic trial of trihexyphenidyl in the treatment of dystonia. This clinical assessment scale, the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) (Burke et al., 1985), was later developed further for the assessment of primary torsion dystonia. By documenting serial scores, the BFMDRS has been used extensively for following the clinical course and response to therapy of dystonia patients. It is arguably the most widely accepted rating scale for generalized dystonia and hence has improved comparison of dystonia patient data amongst clinicians by providing comparable quantitative information. Although originally designed for assessment of primary generalized dystonias, the scale has also been used to assess secondary and focal dystonias. There is probably less consensus, compared with other dystonias, as to which outcome measure best monitors response to treatment in patients with cervical dystonia. Several different rating scales have been proposed, including the Columbia rating scale (Greene et al., 1990), Tsui rating scale (Tsui et al., 1986), and Jankovic rating scale (Jankovic, 1982). These scales however have not been validated as extensively as the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), a scoring system employing a video protocol, which has been used in many clinical reports. Although TWSTRS has its limitations, the presence of a specific videotape protocol helps ensure that patients are assessed in a more consistent manner, hence why TWSTRS has been chosen by most as the rating scale to evaluate patients with cervical dystonia.
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FIG. 1. Fused axial CT and MRI scans following insertion of DBS leads. Stimulator electrodes traversing the GPi are displayed. (For color version of this figure, the reader is referred to the web version of this book.).
C. SURGICAL CONSIDERATIONS AND TECHNIQUES The target we employ for dystonia is located in the posteroventral lateral GPi and is the same as that used for pallidal DBS in PD. Our operative technique has been published elsewhere in more detail (Joint et al., 2002). Most patients with dystonic conditions have bilateral stimulation, and the two electrodes are usually implanted in the same surgical session under general anaesthesia (Fig. 1). These electrodes are then connected to a subcutaneous programmable pulse generator usually implanted in the subclavicular tissue. An alternative surgical method employs the use of microelectrode recordings; however this is not routinely applied for stereotactic operations in our centers. D. POSTOPERATIVE DBS PROGRAMMING AND PATIENT MANAGEMENT Improvements following pallidal stimulation may be delayed, and it can take several months before the full benefit is evident (Yianni et al., 2003). The initial stimulation settings are based on a bipolar stimulation mode in accordance with the standard practice at the authors units. Initial stimulator parameters aim for
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settings in the region of: 2.0–4.0 V, 130–180 Hz, and 90–240 ms as tolerated by the individual patient with progressive adjustment of electrical parameters at each follow-up visit. Beneficial results have also been achieved with differing parameter settings, particularly with lower frequency stimulation at 60 Hz (Alterman, Miravite et al. 2007). This strategy differs slightly to methods employed by other groups who advocate the use of monopolar electrode settings with a maximum of two electrodes (Coubes, Roubertie et al. 2000). During the next few months, the intensity of stimulation is gradually increased, although usually only modest adjustments are required. Side effects of stimulation are reversible upon adjustment of DBS settings. The threshold for undesired effects, such as perioral tightness, dysarthria, dizziness, and paraesthesias, tends to change during progressive adjustments of stimulation amplitude. Weight gain is observed in some patients, but is nonspecific and has also been observed in pallidal surgery for other movement disorders (Krauss, Yianni et al. 2004). DBS has the advantages over lesional surgery of being reversible and adaptable. It avoids concern about the effects of lesioning on the developing brain in children and allows bilateral surgery to be undertaken more safely because of the reduced level of morbidity involved when compared to lesioning. However, DBS is not without its problems, which include hardware failure, high costs, time-consuming follow-up as well as the peri-operative risks of infection and possible intracranial hemorrhage (Joint et al., 2002; Rowe et al., 1999). The overall rate of hardware-related problems reported is very variable ranging from 8–65%, and perhaps reflects differences in surgical technique (Hariz, 2002; Joint et al., 2002; Lyons et al., 2001). Failure of chronic GPi stimulation may result in a medical emergency such as the rapid and potentially serious reappearance of dystonic symptoms known as “status dystonicus” (Manji et al., 1998; Teive et al., 2005). More often in our groups’ experience, hardware failure caused by unilateral lead dysfunction results in a more gradual and progressive recurrence of symptoms, perhaps accounted for by the presence of the retained contralateral stimulation. So far most studies suggest that GPi DBS does not have a significant adverse effect on cognition or mood although, although to date two suicides have been reported after GPi DBS for dystonia (Foncke et al., 2006).
VI. DBS for Dystonia—Clinical Overview
Several studies have now shown that DBS, in particularly pallidal DBS, is reasonably safe and efficacious in a variety of dystonic disorders. However, until recently the majority of evidence supporting GPi DBS as an effective treatment
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was provided by pilot data comprising a number of case series or case reports. The evidence from these studies has now more recently been strengthened following the results of a number of trials detailing improvements in segmental, generalized and cervical dystonia (Kupsch et al., 2006; Morgan and Sethi, 2008; Mueller et al., 2008). A number of studies with blinded outcome assessments have also been performed which have further added to the evidence base (Diamond et al., 2006; Kiss et al., 2007; Pretto et al., 2008; Vidailhet et al., 2007). Verification of the continued benefit of this treatment has also been provided by recent long-term studies conveying the sustained improvements experienced by patients several years after their initial surgery (Cersosimo et al., 2008; Hung et al., 2007; Isaias et al., 2009; Loher et al., 2008). Age is generally not a contraindication to dystonia surgery as patients from ages of 8 to 75 years of age have been successfully operated on. Whilst it is still debatable as to whether age of onset of dystonia influences outcome (Vasques et al., 2009a), the overall duration of dystonia has been reported to negatively correlate with poorer post-operative outcomes in a few studies (Isaias et al., 2008). Thus DBS should be considered earlier rather than later in the disease course, in order to prevent secondary fixed deformity that may compromise rehabilitation. The overall costs of chronic pallidal stimulation are relatively high for patients with dystonia (Yianni et al., 2005). This is partly due to the relatively younger age of patients treated for dystonia compared to those with Parkinson’s disease but also due to the comparatively higher energy required for chronic stimulation. Strategies to help address this cost issue have included the development of rechargeable pulse generator batteries. A. CERVICAL DYSTONIA Since cervical dystonia is the most frequent dystonic movement disorder DBS might be of considerable interest particularly to those patients who do not respond satisfactorily to conservative interventions. Since the first patients with cervical dystonia have been treated by GPi DBS in the late 1990s, beneficial results have been reported by a number of centers. Bilateral pallidal stimulation produces both symptomatic and functional improvement including marked and sustained relief of pain in patients with cervical dystonia (Krauss et al., 1999). The gradual amelioration of symptoms over months was reflected in our data by improvement of a modified TWSTRS scale on subsequent follow-up examinations, and the mean scores were better at 1 year after surgery than at 3 months postoperatively (Fig. 2). In the patients from our unit, formal follow-up evaluation has demonstrated sustained improvements in the region of 60–65% in overall patient TWSTRS scores. In some patients, relief of pain preceded
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FIG. 2. Effect of GPi DBS on TWSTRS scores of patients with cervical dystonia. Regression curve displays overall change in TWSTRS total scores.
improvements observed in the other aspects of the TWSTRS scale. The literature also reports patients in whom relief of pain was the most prominent feature (Kulisevsky et al., 2000). A further benefit of GPi DBS in this patient group has been its use as an adjunct in patients with cervical dyskinesias and secondary cervical myelopathy prior to performing spinal surgery or spinal stabilization (Krauss et al., 2002). B. GENERALIZED DYSTONIA The most beneficial results with pallidal DBS were reported in children with genetic DYT1-positive generalized dystonia. In their first publication on this subject, Coubes and colleagues described a mean improvement of 90% in the BFMDRS at a follow-up of at least 1 year after surgery in seven patients (mean age of 14 years at operation) (Coubes et al., 2000). Improvement was gradual occurring months after implantation of the electrodes. Six children managed to walk without assistance after surgery and became functionally normal. Drugs were reduced in all patients resulting in improvement of alertness. All children returned to school. More recently, beneficial long-term results for a larger number of patients have also been reported by the Montpellier group (Vasques et al., 2009b). Adverse effects have been minimal and several other groups have reported similarly favorable results. Nevertheless, single cases have been reported of patients who did not achieve this expected dramatic postoperative benefit.
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FIG. 3. Regression curve displaying reduction in BFMDRS total scores following pallidal stimulation in patients with generalized dystonia.
It also appears that in adult patients with primary generalized dystonia remarkable benefit is also achieved with bilateral pallidal DBS. Meta-analysed data indicates that a greater than 50% mean improvement in dystonia severity following DBS would be expected in patients with primary dystonias, myoclonus dystonia, certain types of heredo-degenerative dystonia and tardive dystonia (Andrews et al., 2010). In two adult patients with a positive family history of dystonia, BFMDRS motor scores improved by 74% after 2 years and disability scores by 67% (Krauss et al., 2003). In our group 12 patients with generalized dystonia achieved a mean improvement of 48% in the BFMDRS severity scores, and 38% in the disability scores (Yianni et al., 2003) (Fig. 3). The lesser improvement in our group was most likely the consequence of several factors including greater variability in clinical background, the effect of treatment duration, and the duration of disease onset to treatment, which was on average more than 12 years. It is important to treat generalized dystonia at an early stage (Andrews et al., 2010), particularly before improvement is limited by permanent neurological deficits due to cervical myelopathy, spine deformities or musculoskeletal injury. The response of generalized dystonia to pallidal DBS also relates to the underlying aetiology of the dystonic condition. In general, patients with primary dystonia, particularly DYT1 dystonia appear to respond well (Andrews et al., 2010). Patients with secondary dystonia respond less well (see below), and poorer results are expected in patients with secondary dystonia with structural lesions (Alkhani and Lozano, 2001).
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C. SEGMENTAL AND FOCAL DYSTONIA Similar to the results for generalized dystonia substantial benefit has been described in patients with primary segmental dystonia. Improvement of cranial dystonias has also been reported in patients with segmental or generalized dystonia (Bereznai et al., 2002; Muta et al., 2001; Vercueil et al., 2001). In a pilot study, bilateral pallidal DBS was performed in a 60-year-old woman with medicallyrefractory Meige syndrome. At two year follow-up BFMDRS subscores had improved by 92% for eyes, by 75% for mouth, and by 33% for speech and swallowing (Capelle et al., 2003). A further exploration of the use of Pallidal DBS for Meige syndrome and other focal dystonias might be of future interest. D. SECONDARY DYSTONIA The outcomes of DBS for the treatment of secondary dystonia appear to be more complex and less predictable than those for primary dystonia (Andrews et al., 2010). Although overall it appears to be less effective in secondary dystonia, pallidal stimulation has been reported as successful in some individual cases (Vercueil et al., 2001). Thalamic DBS has been suggested to be more useful in such cases. Before the routine use of GPi DBS for dystonia, patients with medically-intractable dystonia who were treated in Grenoble underwent thalamic DBS. Approximately half of the patients treated achieved a good functional result, with some improvements also noted in patients with post-traumatic hemidystonia, and postanoxic dystonia with basal ganglia necrosis. Treatment of choreoathetosis secondary to cerebral palsy is problematic. Bilateral pallidotomies have yielded limited benefit in such patients with objective improvement of up to 42%, but with a high rate of persistent complications (Lin et al., 1999). More promising results have been described in two case reports using GPi DBS (Angelini et al., 2000; Gill et al., 2001). In a 13-year-old boy with cerebral palsy, who presented with a life-threatening “dystonic storm” requiring artificial respiration and continuous sedation, bilateral pallidal DBS resulted in dramatic improvement with restoration of the ability to walk and a less severe degree of residual dystonia seven months after the operation. Hemidystonia is a typical manifestation of secondary dystonia. In the past, hemidystonia was shown to respond well to thalamotomies, while pallidotomies yielded less consistent improvement (Alkhani and Lozano, 2001; Krauss and Jankovic, 2002). The results with pallidal DBS are rather heterogeneous. While little or no improvement has been reported in some studies (Yianni et al., 2003), unilateral DBS contralateral to the hemidystonia has resulted in improvement of dystonia-associated pain, movements, posture and functional benefit in other patients (Loher et al., 2000).
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VII. Conclusion
GPi DBS is becoming the mainstay of surgical treatment for disabling and medically refractory dystonia. The outcomes following this treatment are often impressive, however cost and availability have been limiting factors for the more widespread use of this technology. Future developments may include the creation of new technologies and the development of carefully conducted studies exploring differing and new surgical targets.
References
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Das, S.K. and Choudhary, S.S. (2000). A spectrum of dystonias-clinical features and update on management. J. Assoc. Physicians India 48(6); 622–630. Dauer, W.T. and Burke, R.E et al., (1998). Current concepts on the clinical features, aetiology and management of idiopathic cervical dystonia. Brain 121(Pt 4); 547–560. Diamond, A. and Shahed, J et al., (2006). Globus pallidus deep brain stimulation in dystonia. Mov. Disord. 21(5); 692–695. Fahn, S. and Bressman, S.B et al., (1998 a) Classification of dystonia. Adv. Neurol. 78, 1–10. Fahn, S. and Greene, P et al., (1998 b) Handbook of Movement Disorders. Current Medicine Inc, New York. Foncke, E.M. and Schuurman, P.R et al., (2006). Suicide after deep brain stimulation of the internal globus pallidus for dystonia. Neurology 66(1); 142–143. Gill, S. and Curran, A et al., (2001). Hyperkinetic movement disorder in an 11-year-old child treated with bilateral pallidal stimulators. Dev. Med. Child Neurol. 43(5); 350–353. Goetz, C.G. and Chmura, T.A et al., (2001). History of dystonia: part 4 of the MDS-sponsored history of movement disorders exhibit, Barcelona, June, 2000. Mov. Disord. 16(2); 339–345. Greene, P. (1992). Baclofen in the treatment of dystonia. Clin. Neuropharmacol. 15(4); 276–288. Greene, P. and Kang, U et al., (1990). Double-blind, placebo-controlled trial of botulinum toxin injections for the treatment of spasmodic torticollis. Neurology 40(8); 1213–1218. Greene, P. and Kang, U.J et al., (1995). Spread of symptoms in idiopathic torsion dystonia. Mov. Disord. 10(2); 143–152. Greene, P.E. and Fahn, S. (1992). Baclofen in the treatment of idiopathic dystonia in children. Mov. Disord. 7(1); 48–52. Group, ESDE. c. (2000), A prevalence study of primary dystonia in eight European countries, J Neurol 247(10): 787–92. Hanna, P.A. and Jankovic, J. (1998). Mouse bioassay versus Western blot assay for botulinum toxin antibodies: correlation with clinical response. Neurology 50(6); 1624–1629. Hariz, M.I. (2002). Complications of deep brain stimulation surgery. Mov. Disord. 17(Suppl 3); S162–S166. Hassler, R. and Dieckmann, G. (1970). Stereotactic treatment of different kinds of spasmodic torticollis. Confin. Neurol. 32(2); 135–143. Hung, S.W. and Hamani, C et al., (2007). Long-term outcome of bilateral pallidal deep brain stimulation for primary cervical dystonia. Neurology 68(6); 457–459. Hutchison, W.D. and Lang, A.E et al., (2003). Pallidal neuronal activity: implications for models of dystonia. Ann. Neurol. 53(4); 480–488. Isaias, I.U. and Alterman, R.L et al., (2008). Outcome predictors of pallidal stimulation in patients with primary dystonia: the role of disease duration. Brain 131(Pt 7); 1895–1902. Isaias, I.U. and Alterman, R.L et al., (2009). Deep brain stimulation for primary generalized dystonia: long-term outcomes. Arch. Neurol. 66(4); 465–470. Jankovic, J. (1982). Treatment of hyperkinetic movement disorders with tetrabenazine: a double-blind crossover study. Ann. Neurol. 11(1); 41–47. Jankovic, J. (1998). Medical therapy and botulinum toxin in dystonia. Adv. Neurol. 78, 169–183. Jankovic, J. and Tsui, J et al., (2007). Prevalence of cervical dystonia and spasmodic torticollis in the United States general population. Parkinsonism Relat. Disord. 13(7); 411–416. Joint, C. and Nandi, D et al., (2002). Hardware-related problems of deep brain stimulation. Mov. Disord. 17(Suppl 3); S175–S180. Kamm, C. (2009). Genetics of dystonia. Fortschr. Neurol. Psychiatr. 77(Suppl 1); S32–S36. Kandel, E.I. and Watts, G et al., (1989). Functional and stereotactic neurosurgery. Plenum Medical, New York, London. Kiss, Z.H. and Doig-Beyaert, K et al., (2007). The Canadian multicentre study of deep brain stimulation for cervical dystonia. Brain 130(Pt 11); 2879–2886.
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Kleiner-Fisman, G. and Liang, G.S et al., (2007). Subthalamic nucleus deep brain stimulation for severe idiopathic dystonia: impact on severity, neuropsychological status, and quality of life. J. Neurosurg. 107(1); 29–36. Krauss, J.K. and Jankovic, J. (2002). Head injury and posttraumatic movement disorders. Neurosurgery 50(5); 927–939 discussion 939-40. Krauss, J.K. and Loher, T.J et al., (2002). Pallidal deep brain stimulation in patients with cervical dystonia and severe cervical dyskinesias with cervical myelopathy. J. Neurol. Neurosurg. Psychiatry 72 (2); 249–256. Krauss, J.K. and Loher, T.J et al., (2003). Chronic stimulation of the globus pallidus internus for treatment of non-dYT1 generalized dystonia and choreoathetosis: 2-year follow up. J. Neurosurg. 98 (4); 785–792. Krauss, J.K. and Pohle, T et al., (1999). Bilateral stimulation of globus pallidus internus for treatment of cervical dystonia. Lancet 354(9181); 837–838. Krauss, J.K. and Yianni, J et al., (2004). Deep brain stimulation for dystonia. J. Clin. Neurophysiol. 21(1); 18–30. Kulisevsky, J. and Lleo, A et al., (2000). Bilateral pallidal stimulation for cervical dystonia: dissociated pain and motor improvement. Neurology 55(11); 1754–1755. Kupsch, A. and Benecke, R et al., (2006). Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N. Engl. J. Med. 355(19); 1978–1990. Lin, J.J. and Lin, S.Z et al., (1999). Pallidotomy and generalized dystonia. Mov. Disord. 14(6); 1057–1059. Loher, T.J. and Capelle, H.H et al., (2008). Deep brain stimulation for dystonia: outcome at long-term follow-up. J. Neurol. 255(6); 881–884. Loher, T.J. and Hasdemir, M.G et al., (2000). Long-term follow-up study of chronic globus pallidus internus stimulation for posttraumatic hemidystonia. J. Neurosurg. 92(3); 457–460. Lozano, A.M. and Kumar, R et al., (1997). Globus pallidus internus pallidotomy for generalized dystonia. Mov. Disord. 12(6); 865–870. Lyons, K.E., W.C. Koller, et al. (2001), “Surgical and device-related events with deep brain stimulation.” Neurology 56(April): A147 (Suppl). Manji, H. and Howard, R.S et al., (1998). Status dystonicus: the syndrome and its management. Brain 121(Pt 2); 243–252. Marsden, C.D. and Obeso, J.A et al., (1985). The anatomical basis of symptomatic hemidystonia. Brain 108(Pt 2); 463–483. Meares, R. (1971). Natural history of spasmodic torticollis, and effect of surgery. Lancet 2(7716); 149–150. Morgan, J.C. and Sethi, K.D. (2008). A single-blind trial of bilateral globus pallidus internus deep brain stimulation in medically refractory cervical dystonia. Curr. Neurol. Neurosci. Rep. 8(4); 279–280. Mueller, J. and Skogseid, I.M et al., (2008). Pallidal deep brain stimulation improves quality of life in segmental and generalized dystonia: results from a prospective, randomized sham-controlled trial. Mov. Disord. 23(1); 131–134. Mundinger, F. (1977). New stereotactic treatment of spasmodic torticollis with a brain stimulation system (author’s transl). Med. Klin. 72(46); 1982–1986. Muta, D. and Goto, S et al., (2001). Bilateral pallidal stimulation for idiopathic segmental axial dystonia advanced from Meige syndrome refractory to bilateral thalamotomy. Mov. Disord. 16(4); 774–777. Ondo, W. and Almaguer, M et al., (2001). Thalamic deep brain stimulation: comparison between unilateral and bilateral placement. Arch. Neurol. 58(2); 218–222. Ondo, W.G. and Desaloms, J.M et al., (1998). Pallidotomy for generalized dystonia. Mov. Disord. 13(4); 693–698. Pretto, T.E. and Dalvi, A et al., (2008). A prospective blinded evaluation of deep brain stimulation for the treatment of secondary dystonia and primary torticollis syndromes. J. Neurosurg. 109(3); 405–409.
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Priori, A. and Berardelli, A et al., (1995). Physiological effects produced by botulinum toxin treatment of upper limb dystonia. Changes in reciprocal inhibition between forearm muscles. Brain 118(Pt 3); 801–807. Rowe, J.G. and Davies, L.E et al., (1999). Surgical complications of functional neurosurgery treating movement disorders: results with anatomical localisation. J. Clin. Neurosci. 6(1); 36–37. Schmidt, A. and Klein, C. (2010). The role of genes in causing dystonia. Eur. J. Neurol. 17(Suppl 1); 65–70. Sycha, T. and Kranz, G et al., (2004). Botulinum toxin in the treatment of rare head and neck pain syndromes: a systematic review of the literature. J. Neurol. 251(Suppl 1); I19–I30. Tasker, R.R. (1998). Deep brain stimulation is preferable to thalamotomy for tremor suppression. Surg. Neurol. 49(2); 145–153 discussion 153-4. Teive, H.A. and Munhoz, R.P et al., (2005). Status Dystonicus: study of five cases. Arq. Neuropsiquiatr. 63 (1); 26–29. Tsui, J.K. and Eisen, A et al., (1986). Double-blind study of botulinum toxin in spasmodic torticollis. Lancet 2(8501); 245–247. Vasques, X. and Cif, L et al., (2009 a) Factors predicting improvement in primary generalized dystonia treated by pallidal deep brain stimulation. Mov. Disord. 24(6); 846–853. Vasques, X. and Cif, L et al., (2009 b) Prognostic value of globus pallidus internus volume in primary dystonia treated by deep brain stimulation. J. Neurosurg. 110(2); 220–228. Vercueil, L. and Pollak, P et al., (2001). Deep brain stimulation in the treatment of severe dystonia. J. Neurol. 248(8); 695–700. Vidailhet, M. and Vercueil, L et al., (2007). Bilateral, pallidal, deep-brain stimulation in primary generalised dystonia: a prospective 3 year follow-up study. Lancet. Neurol. 6(3); 223–229. Xinkang, C. (1981). Selective resection and denervation of cervical muscles in the treatment of spasmodic torticollis: results in 60 cases. Neurosurgery 8(6); 680–688. Yianni, J. and Bain, P et al., (2003 a) Globus pallidus internus deep brain stimulation for dystonic conditions: a prospective audit. Mov. Disord. 18(4); 436–442. Yianni, J. and Bain, P.G et al., (2003 b) Post-operative progress of dystonia patients following globus pallidus internus deep brain stimulation. Eur. J. Neurol. 10(3); 239–247. Yianni, J. and Green, A.L et al., (2005). The costs and benefits of deep brain stimulation surgery for patients with dystonia: An initial exploration. Neuromodulation 8(3); 155–161. Yoshor, D. and Hamilton, W.J et al., (2001). Comparison of thalamotomy and pallidotomy for the treatment of dystonia. Neurosurgery 48(4); 818–824 discussion 824-6.
John Yianni1, Alexander L. Green2 and Tipu Z. Aziz2 1
Department of Neurosurgery, Royal Hallamshire Hospital, Sheffield, UK 2 Nuffield Department of Surgery, University of Oxford, UK
I. Background A. History of Dystonia B. Prevalence Estimates II. Classification A. Aetiological Classification B. Descriptive Classification III. Medical Treatment of Dystonia IV. Surgical Treatment of Dystonia V. Deep Brain Stimulation (DBS) for Dystonia A. Development B. Preoperative Assessment C. Surgical Considerations and Techniques D. Postoperative DBS Programming and Patient Management VI. DBS for Dystonia—Clinical Overview A. Cervical Dystonia B. Generalized Dystonia C. Segmental and Focal Dystonia D. Secondary Dystonia VII. Conclusion References
Dystonia is a neurological condition characterised by abnormal muscle contractions, often causing repetitive twisting movements or abnormal postures. Varying forms of surgical intervention, for dystonia unresponsive to medical therapy, have evolved over the years and have often been associated with poor outcomes and high morbidity. The advent of stereotactic neurosurgery and the success of deep brain stimulation in treating a number of movement disorders have revolutionized the surgical treatment for dystonia. This chapter reviews the literature concerning the surgical treatment dystonic conditions, from historical origins to the current use of modern functional neurosurgical techniques.
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I. Background
A. HISTORY OF DYSTONIA One of the earliest descriptions of dystonia was recorded by Gowers in 1888 (Kandel et al., 1989), whilst Destarac in 1901 used the term “torticollis spasmodique” to describe the twisting neck movements observed in a 17-year girl. Dystonic conditions were identified as distinct from other hyperkinesias by Schwalbe in 1908; however, because of the bizarre nature of the movements, dystonias were originally considered a form of “hysterical neurosis.” The term “dystonia” was first coined by Oppenheim in 1911, who was the first to correctly identify the organic nature of dystonia (Goetz et al., 2001). Focal dystonias however, unlike the generalized condition, have been recognized for centuries. For example, the first recorded case of surgery for spasmodic torticollis was performed in 1641 by German physician Minnius who sectioned the sternocleidomastoid muscle (Kandel et al., 1989). In 1944 Herz revived the concept of dystonia being an organic disease; however because of failures to identify any specific brain lesions in dystonia, arguments for an organic basis to the condition were not recognized until the 1980s following Marsden’s work on cases of hemidystonia (Marsden et al., 1985). In the 1980s and 1990s investigation into generalized dystonia, particularly amongst Jews of Ashkenazi descent, led to the discovery of the DYTI gene mutation at the 9q34 locus. Since then continued research has led to the awareness of a complex array of aetiological causes underlying dystonia. B. PREVALENCE ESTIMATES Dystonic conditions are not rare. Epidemiological surveys estimate that dystonia is the third most common movement disorder after Parkinson’s disease and Essential Tremor (Fahn et al., 1998b), more prevalent than a number of better known neurological conditions such as myotonic dystrophy, myasthenia gravis, and motor neuron disease. In contrast to many other conditions, however, there have been few published epidemiological studies of dystonia. Differences in study design have further confused prevalence estimates, making it difficult to extrapolate data from certain studies to the general population.One of the most comprehensive examinations of prevalence estimates currently available was provided by the Epidemiological Study of Dystonia in Europe (ESDE) collaborative group (ESDE group, 2000). Data pooled from eight countries revealed a prevalence rate of 152 per million for primary dystonia. The highest subcategory prevalence was 117 per million for focal dystonia with segmental dystonia constituting 32 per million and multifocal dystonia 2.4 per million. The commonest form of focal
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dystonia was cervical dystonia (57 per million). However, true prevalence is unknown, with many authors suggesting that estimates in published reports are considerably lower than the actual prevalence (Jankovic et al., 2007) due to significant numbers of undiagnosed cases within the community.
II. Classification
The term dystonia is employed to describe a syndrome characterized by sustained muscle contractions, often causing repetitive twisting movements or abnormal postures. These involuntary movements are caused by co-contractions of agonist and antagonist muscles and are often exacerbated during action but improve with rest, sleep, or sensory tricks (geste antagoniste) such as touching the chin to improve cervical dystonia. Some dystonic movements (e.g., writer’s cramp) appear only with specific actions and are referred to as task-specific dystonias. Dystonic conditions are many and varied and can be described either aetiologically or descriptively. A. AETIOLOGICAL CLASSIFICATION An important aspect of the clinical evaluation of dystonia is the aetiological classification of the condition. This helps in formulating treatment strategies, deciding on the need for genetic counselling and may also aid our understanding of the underlying pathophysiology of the illness. In order to assist the aetiological classification of dystonic conditions, a similar system for the classification of parkinsonism has been adopted by many (Fahn et al., 1998a) to include the subcategories of primary dystonia, dystonia-plus syndromes, secondary dystonia, and heredodegenerative diseases in which dystonia is the prominent feature. The molecular classification of dystonia includes several genetic loci. Currently at least 19 gene loci have been described (Kamm, 2009; Schmidt and Klein, 2010); although it is likely that there are many more dystonia genes that have yet to be discovered. B. DESCRIPTIVE CLASSIFICATION 1. Age at Onset Dystonia can be subdivided into two groups on the basis of age at onset of symptoms. The term early-onset dystonia is often employed when symptoms begin before the age of 26 years, whereas after this age, they are classified as late-onset dystonia. The earlier dystonic symptoms appear, the more likely the condition will
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progress to become generalized, whilst in the older onset individuals, it is more likely to remain focal. 2. Distribution of Affected Body Regions When dystonia is classified according to body distribution, it can be described as focal, segmental, multifocal, or generalized. In focal dystonia, a single body region is affected, such as the arm in writer’s cramp, the eyes in blepharospasm, the neck in spasmodic torticollis, or the laryngeal muscles in spasmodic dysphonia. In segmental dystonia, two or more contiguous body regions are affected, for example cranial– cervical dystonia or crural dystonia (one leg plus trunk or both legs). If two or more noncontiguous body parts are affected, the disorder is termed multifocal dystonia. Generalized dystonia refers to crural dystonia with at least one other body part involved. When dystonia is confined to one side of the body, it is called hemidystonia. The site of the first dystonic symptom is also a valuable prognostic indicator. 90% of patients with onset in the lower limbs will develop symptoms in other parts of the body. Their symptoms are also more likely to become generalized (Greene et al., 1995), compared to those who present with cervical dystonia, of which only a minority will have disease spread to other body parts. Hemidystonia is almost always symptomatic regardless of its age of onset (Marsden et al., 1985).
III. Medical Treatment of Dystonia
One of the first general considerations in approaching the treatment of a patient with dystonia is to differentiate between the primary and secondary dystonias. In a minority of patients with secondary dystonia, for example Wilson’s disease, drug-induced dystonia or dopa-responsive dystonia (DRD), benefit can be gained from specific treatments (Jankovic, 1998). For example, all patients with childhood onset dystonias should receive a trial of L-Dopa, as this may bring about dramatic improvement after a short period of time in those with DRD. For other patients, therapy is directed at controlling the symptoms rather than the cause, with different management strategies employed for generalized as opposed to focal conditions. As a general rule, in patients with generalized and multifocal diseases, oral pharmacotherapy constitutes the mainstay of treatment. Unfortunately the treatment of dystonia with oral agents is often unsatisfactory. In addition to L-Dopa, other established medications include anticholinergics, benzodiazepines, and baclofen. Except in the case of DRD, anticholinergic medications such as trihexyphenidyl are arguably the most effective pharmacotherapy for dystonia (Bressman and Greene, 2000); although effective treatment is sometimes limited by the development of side effects. Although considered less effective than
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anticholinergics, baclofen has proved efficacious in children (Greene, 1992; Greene and Fahn, 1992). Benzodiazepines are also often employed, such as clonazepam, and are particularly useful in the treatment of myoclonic dystonia (Das and Choudhary, 2000). The dopamine depleting drug tetrabenazine is considered to be effective in the treatment of some patients with tardive dystonia. Other antidopaminergics such as haloperidol, may be effective but may also worsen symptoms or induce tardive dyskinesia and hence are not recommended. Although atypical neuroleptics such as clozapine have been suggested for the treatment of tardive dystonia, their effectiveness in treating other forms of dystonia remains questionable. Several other forms of pharmacological therapy have been reported to be beneficial in individual cases of dystonia; however their role in treating dystonia has yet to be fully established.In contrast, patients with focal dystonia tend to benefit most from treatment with botulinum toxin (BTX) injection. BTX is often the treatment of choice for the majority of focal dystonias, particularly cervical dystonia, and has been the most comprehensively investigated therapy for treatment of this patient group. Injections in the most severely affected muscle groups can also be employed in association with other treatments. BTX produces chemodenervation and hence local muscle paralysis at the neuromuscular junction and also appears to improve reciprocal inhibition by altering sensory inflow through muscle afferent fibres (Priori et al., 1995). There are several serotypes of BTX although currently only types A and B are available for use in clinical practice. The duration of effect for BTX is variable but on average lasts for two to three months. Lack of response to BTX injection may occur if there is long-standing disease with contractures or the development of antibodies. Resistance associated with neutralizing antibodies may occur after repeated injections in 5–10% of cases (Hanna and Jankovic, 1998). Both BTX A and B have been shown to be efficacious in placebo-controlled trials (Comella et al., 2000; Sycha et al., 2004) with improvements of 80–90% observed in cervical dystonia (Adler, 2000). There are various injection strategies that have been used including the use of EMGs to guide selection of the appropriate muscle groups requiring treatment (Childers, 2003). It is usually a safe treatment that can be performed repeatedly; however side effects including dysphagia, pain at the injection site, dry mouth, flu-like symptoms, and dysphonia have been reported (Dauer et al., 1998). The majority of patients report satisfactory benefit from BTX treatment, however if this and other conservative measures fail, patients should then be considered for surgical intervention. IV. Surgical Treatment of Dystonia
More than two centuries after Minnius’ operation for torticollis, the Russian surgeon Buyalsky (1850) performed the first spinal accessory nerve section for
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spasmodic torticollis, followed by Morgan in 1867 and Collier in 1890 (Kandel et al., 1989). Spinal cord root section to treat spasmodic torticollis was first proposed over a century ago by Keen (Keen, 1891) who suggested unilateral section of the first three anterior cervical roots. Cervical rhizotomy procedures were further refined by surgeons such as Dandy in 1928, who combined cervical root and accessory nerve sectioning. Bertrand provided extensive data based upon experience with a wide range of procedures derived from Keen’s original operation (Bertrand et al., 1978; Bertrand and Molina-Negro, 1988). By 1979 variations of this procedure were still considered the operation of choice for cervical dystonia refractory to medical therapy, although long-term follow-up disputed the effectiveness of these techniques (Meares, 1971). The issue of long-term efficacy, together with the high incidence of denervation related complications, has led to the virtual abandonment of these techniques. Microvascular decompression of the accessory nerve, peripheral facial neurectomy, and cervical cord stimulation are further examples of procedures employed that have also fallen out of favor. Although satisfactory results have been reported for extensive muscle resections performed in patients with cervical dystonia, the extreme nature of this surgery has prevented it from being widely used (Chen et al., 1991; Xinkang, 1981).
V. Deep Brain Stimulation (DBS) for Dystonia
A. DEVELOPMENT The development of DBS treatment for dystonia dates back to the 1950s, when Hess and Hassler constructed an elaborate animal model to explain both the physiology and pathophysiology of cervical dystonia (Hassler and Dieckmann, 1970). In clinical practice, however, ablative thalamic surgery for dystonia was used almost exclusively for decades (Ondo et al., 2001; Tasker, 1998). Reported results were very variable with about 50% of patients experiencing some degree of benefit. In 1977 when Mundinger reported his early results with thalamic DBS for dystonia, there was little initial interest in his studies (Mundinger, 1977). The globus pallidus internus (GPi) was suggested to be a suitable target for dystonia based upon the discovery that ablative pallidal surgery brought about marked improvement in the dystonic dyskinesias of Parkinson’s disease. Since then, pallidotomy has been reported to be effective in various dystonic disorders (Hutchison et al., 2003; Lozano et al., 1997; Ondo et al., 1998; Yoshor et al., 2001); although it has carried with it the risks of speech and cognitive impairment, as well as a partial recurrence of dystonic symptoms over time. Since its introduction, DBS has replaced ablative surgery for the treatment of dystonia in many neurosurgical centers throughout the world. Initial studies of DBS in dystonia targeted nuclei within the
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thalamus with variable outcome. GPi DBS, inspired initially by the success obtained with pallidotomy, is currently the most popular surgical target for dystonia. Thalamic targets can still be considered in patients with secondary dystonias with pathological changes in the pallidum or where GPi stimulation has been unsuccessful. More recently Subthalamic nucleus stimulation has been reported to be effective in focal and segmental dystonia (Kleiner-Fisman et al., 2007). B. PREOPERATIVE ASSESSMENT Prior to consideration for surgery all patients should be evaluated to assess the severity of dystonia, the level of disability and to screen for secondary causes of dystonia. As well as a thorough neurological assessment, a cognitive and psychiatric assessment is often undertaken to evaluate for cognition and mood disorders that may affect the outcome. A preoperative MRI is required to rule out any structural lesions in the basal ganglia that may interfere with surgical treatment. A preoperative MRI of the cervical spine may also be indicated in order to assess the contribution of degenerative cervical spine disease in those with cervical dystonia. A valid rating scale should also be employed for evaluating the clinical state of a patient with dystonia and should accurately represent the extent of the disease severity as well as the disability caused in relation to activities of daily living. Burke, Fahn and Marsden produced a rating scale, initially for the therapeutic trial of trihexyphenidyl in the treatment of dystonia. This clinical assessment scale, the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) (Burke et al., 1985), was later developed further for the assessment of primary torsion dystonia. By documenting serial scores, the BFMDRS has been used extensively for following the clinical course and response to therapy of dystonia patients. It is arguably the most widely accepted rating scale for generalized dystonia and hence has improved comparison of dystonia patient data amongst clinicians by providing comparable quantitative information. Although originally designed for assessment of primary generalized dystonias, the scale has also been used to assess secondary and focal dystonias. There is probably less consensus, compared with other dystonias, as to which outcome measure best monitors response to treatment in patients with cervical dystonia. Several different rating scales have been proposed, including the Columbia rating scale (Greene et al., 1990), Tsui rating scale (Tsui et al., 1986), and Jankovic rating scale (Jankovic, 1982). These scales however have not been validated as extensively as the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), a scoring system employing a video protocol, which has been used in many clinical reports. Although TWSTRS has its limitations, the presence of a specific videotape protocol helps ensure that patients are assessed in a more consistent manner, hence why TWSTRS has been chosen by most as the rating scale to evaluate patients with cervical dystonia.
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FIG. 1. Fused axial CT and MRI scans following insertion of DBS leads. Stimulator electrodes traversing the GPi are displayed. (For color version of this figure, the reader is referred to the web version of this book.).
C. SURGICAL CONSIDERATIONS AND TECHNIQUES The target we employ for dystonia is located in the posteroventral lateral GPi and is the same as that used for pallidal DBS in PD. Our operative technique has been published elsewhere in more detail (Joint et al., 2002). Most patients with dystonic conditions have bilateral stimulation, and the two electrodes are usually implanted in the same surgical session under general anaesthesia (Fig. 1). These electrodes are then connected to a subcutaneous programmable pulse generator usually implanted in the subclavicular tissue. An alternative surgical method employs the use of microelectrode recordings; however this is not routinely applied for stereotactic operations in our centers. D. POSTOPERATIVE DBS PROGRAMMING AND PATIENT MANAGEMENT Improvements following pallidal stimulation may be delayed, and it can take several months before the full benefit is evident (Yianni et al., 2003). The initial stimulation settings are based on a bipolar stimulation mode in accordance with the standard practice at the authors units. Initial stimulator parameters aim for
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settings in the region of: 2.0–4.0 V, 130–180 Hz, and 90–240 ms as tolerated by the individual patient with progressive adjustment of electrical parameters at each follow-up visit. Beneficial results have also been achieved with differing parameter settings, particularly with lower frequency stimulation at 60 Hz (Alterman, Miravite et al. 2007). This strategy differs slightly to methods employed by other groups who advocate the use of monopolar electrode settings with a maximum of two electrodes (Coubes, Roubertie et al. 2000). During the next few months, the intensity of stimulation is gradually increased, although usually only modest adjustments are required. Side effects of stimulation are reversible upon adjustment of DBS settings. The threshold for undesired effects, such as perioral tightness, dysarthria, dizziness, and paraesthesias, tends to change during progressive adjustments of stimulation amplitude. Weight gain is observed in some patients, but is nonspecific and has also been observed in pallidal surgery for other movement disorders (Krauss, Yianni et al. 2004). DBS has the advantages over lesional surgery of being reversible and adaptable. It avoids concern about the effects of lesioning on the developing brain in children and allows bilateral surgery to be undertaken more safely because of the reduced level of morbidity involved when compared to lesioning. However, DBS is not without its problems, which include hardware failure, high costs, time-consuming follow-up as well as the peri-operative risks of infection and possible intracranial hemorrhage (Joint et al., 2002; Rowe et al., 1999). The overall rate of hardware-related problems reported is very variable ranging from 8–65%, and perhaps reflects differences in surgical technique (Hariz, 2002; Joint et al., 2002; Lyons et al., 2001). Failure of chronic GPi stimulation may result in a medical emergency such as the rapid and potentially serious reappearance of dystonic symptoms known as “status dystonicus” (Manji et al., 1998; Teive et al., 2005). More often in our groups’ experience, hardware failure caused by unilateral lead dysfunction results in a more gradual and progressive recurrence of symptoms, perhaps accounted for by the presence of the retained contralateral stimulation. So far most studies suggest that GPi DBS does not have a significant adverse effect on cognition or mood although, although to date two suicides have been reported after GPi DBS for dystonia (Foncke et al., 2006).
VI. DBS for Dystonia—Clinical Overview
Several studies have now shown that DBS, in particularly pallidal DBS, is reasonably safe and efficacious in a variety of dystonic disorders. However, until recently the majority of evidence supporting GPi DBS as an effective treatment
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was provided by pilot data comprising a number of case series or case reports. The evidence from these studies has now more recently been strengthened following the results of a number of trials detailing improvements in segmental, generalized and cervical dystonia (Kupsch et al., 2006; Morgan and Sethi, 2008; Mueller et al., 2008). A number of studies with blinded outcome assessments have also been performed which have further added to the evidence base (Diamond et al., 2006; Kiss et al., 2007; Pretto et al., 2008; Vidailhet et al., 2007). Verification of the continued benefit of this treatment has also been provided by recent long-term studies conveying the sustained improvements experienced by patients several years after their initial surgery (Cersosimo et al., 2008; Hung et al., 2007; Isaias et al., 2009; Loher et al., 2008). Age is generally not a contraindication to dystonia surgery as patients from ages of 8 to 75 years of age have been successfully operated on. Whilst it is still debatable as to whether age of onset of dystonia influences outcome (Vasques et al., 2009a), the overall duration of dystonia has been reported to negatively correlate with poorer post-operative outcomes in a few studies (Isaias et al., 2008). Thus DBS should be considered earlier rather than later in the disease course, in order to prevent secondary fixed deformity that may compromise rehabilitation. The overall costs of chronic pallidal stimulation are relatively high for patients with dystonia (Yianni et al., 2005). This is partly due to the relatively younger age of patients treated for dystonia compared to those with Parkinson’s disease but also due to the comparatively higher energy required for chronic stimulation. Strategies to help address this cost issue have included the development of rechargeable pulse generator batteries. A. CERVICAL DYSTONIA Since cervical dystonia is the most frequent dystonic movement disorder DBS might be of considerable interest particularly to those patients who do not respond satisfactorily to conservative interventions. Since the first patients with cervical dystonia have been treated by GPi DBS in the late 1990s, beneficial results have been reported by a number of centers. Bilateral pallidal stimulation produces both symptomatic and functional improvement including marked and sustained relief of pain in patients with cervical dystonia (Krauss et al., 1999). The gradual amelioration of symptoms over months was reflected in our data by improvement of a modified TWSTRS scale on subsequent follow-up examinations, and the mean scores were better at 1 year after surgery than at 3 months postoperatively (Fig. 2). In the patients from our unit, formal follow-up evaluation has demonstrated sustained improvements in the region of 60–65% in overall patient TWSTRS scores. In some patients, relief of pain preceded
[(Fig._2)TD$IG]
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FIG. 2. Effect of GPi DBS on TWSTRS scores of patients with cervical dystonia. Regression curve displays overall change in TWSTRS total scores.
improvements observed in the other aspects of the TWSTRS scale. The literature also reports patients in whom relief of pain was the most prominent feature (Kulisevsky et al., 2000). A further benefit of GPi DBS in this patient group has been its use as an adjunct in patients with cervical dyskinesias and secondary cervical myelopathy prior to performing spinal surgery or spinal stabilization (Krauss et al., 2002). B. GENERALIZED DYSTONIA The most beneficial results with pallidal DBS were reported in children with genetic DYT1-positive generalized dystonia. In their first publication on this subject, Coubes and colleagues described a mean improvement of 90% in the BFMDRS at a follow-up of at least 1 year after surgery in seven patients (mean age of 14 years at operation) (Coubes et al., 2000). Improvement was gradual occurring months after implantation of the electrodes. Six children managed to walk without assistance after surgery and became functionally normal. Drugs were reduced in all patients resulting in improvement of alertness. All children returned to school. More recently, beneficial long-term results for a larger number of patients have also been reported by the Montpellier group (Vasques et al., 2009b). Adverse effects have been minimal and several other groups have reported similarly favorable results. Nevertheless, single cases have been reported of patients who did not achieve this expected dramatic postoperative benefit.
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FIG. 3. Regression curve displaying reduction in BFMDRS total scores following pallidal stimulation in patients with generalized dystonia.
It also appears that in adult patients with primary generalized dystonia remarkable benefit is also achieved with bilateral pallidal DBS. Meta-analysed data indicates that a greater than 50% mean improvement in dystonia severity following DBS would be expected in patients with primary dystonias, myoclonus dystonia, certain types of heredo-degenerative dystonia and tardive dystonia (Andrews et al., 2010). In two adult patients with a positive family history of dystonia, BFMDRS motor scores improved by 74% after 2 years and disability scores by 67% (Krauss et al., 2003). In our group 12 patients with generalized dystonia achieved a mean improvement of 48% in the BFMDRS severity scores, and 38% in the disability scores (Yianni et al., 2003) (Fig. 3). The lesser improvement in our group was most likely the consequence of several factors including greater variability in clinical background, the effect of treatment duration, and the duration of disease onset to treatment, which was on average more than 12 years. It is important to treat generalized dystonia at an early stage (Andrews et al., 2010), particularly before improvement is limited by permanent neurological deficits due to cervical myelopathy, spine deformities or musculoskeletal injury. The response of generalized dystonia to pallidal DBS also relates to the underlying aetiology of the dystonic condition. In general, patients with primary dystonia, particularly DYT1 dystonia appear to respond well (Andrews et al., 2010). Patients with secondary dystonia respond less well (see below), and poorer results are expected in patients with secondary dystonia with structural lesions (Alkhani and Lozano, 2001).
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C. SEGMENTAL AND FOCAL DYSTONIA Similar to the results for generalized dystonia substantial benefit has been described in patients with primary segmental dystonia. Improvement of cranial dystonias has also been reported in patients with segmental or generalized dystonia (Bereznai et al., 2002; Muta et al., 2001; Vercueil et al., 2001). In a pilot study, bilateral pallidal DBS was performed in a 60-year-old woman with medicallyrefractory Meige syndrome. At two year follow-up BFMDRS subscores had improved by 92% for eyes, by 75% for mouth, and by 33% for speech and swallowing (Capelle et al., 2003). A further exploration of the use of Pallidal DBS for Meige syndrome and other focal dystonias might be of future interest. D. SECONDARY DYSTONIA The outcomes of DBS for the treatment of secondary dystonia appear to be more complex and less predictable than those for primary dystonia (Andrews et al., 2010). Although overall it appears to be less effective in secondary dystonia, pallidal stimulation has been reported as successful in some individual cases (Vercueil et al., 2001). Thalamic DBS has been suggested to be more useful in such cases. Before the routine use of GPi DBS for dystonia, patients with medically-intractable dystonia who were treated in Grenoble underwent thalamic DBS. Approximately half of the patients treated achieved a good functional result, with some improvements also noted in patients with post-traumatic hemidystonia, and postanoxic dystonia with basal ganglia necrosis. Treatment of choreoathetosis secondary to cerebral palsy is problematic. Bilateral pallidotomies have yielded limited benefit in such patients with objective improvement of up to 42%, but with a high rate of persistent complications (Lin et al., 1999). More promising results have been described in two case reports using GPi DBS (Angelini et al., 2000; Gill et al., 2001). In a 13-year-old boy with cerebral palsy, who presented with a life-threatening “dystonic storm” requiring artificial respiration and continuous sedation, bilateral pallidal DBS resulted in dramatic improvement with restoration of the ability to walk and a less severe degree of residual dystonia seven months after the operation. Hemidystonia is a typical manifestation of secondary dystonia. In the past, hemidystonia was shown to respond well to thalamotomies, while pallidotomies yielded less consistent improvement (Alkhani and Lozano, 2001; Krauss and Jankovic, 2002). The results with pallidal DBS are rather heterogeneous. While little or no improvement has been reported in some studies (Yianni et al., 2003), unilateral DBS contralateral to the hemidystonia has resulted in improvement of dystonia-associated pain, movements, posture and functional benefit in other patients (Loher et al., 2000).
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VII. Conclusion
GPi DBS is becoming the mainstay of surgical treatment for disabling and medically refractory dystonia. The outcomes following this treatment are often impressive, however cost and availability have been limiting factors for the more widespread use of this technology. Future developments may include the creation of new technologies and the development of carefully conducted studies exploring differing and new surgical targets.
References
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