Guideline:A systematic review on the diagnosis and treatment of primary (idiopathic) dystonia and dystonia plus syndromes: report of an EFNS/MDS-ES Task Force. Measure Summary

Primary (idiopathic) dystonia and dystonia plus syndromes

To review the literature on diagnosis and treatment of primary dystonia and dystonia plus to provide evidence-based recommendations for diagnosis and treatment

Patients with primary (idiopathic) dystonia and dystonia plus syndromes

Diagnosis

1. Expert observation and neurological examination
2. Classification of dystonia (by cause, age at onset, and distribution)
3. Diagnostic testing (for DYT-1 and DYT-11 genes) and genetic counseling
4. Neurophysiological tests in selected cases
5. Diagnostic levodopa trial
6. Magnetic resonance imaging (MRI) for screening of secondary dystonia (or computed tomography when brain calcifications are suspected)

Treatment

1. Botulinum toxin (BoNT)
2. Levodopa
3. Neurosurgical procedures
   • Pallidal deep brain stimulation (DBS)
   • Selective peripheral denervation and myectomy
   • Intrathecal baclofen

Note: The following interventions were considered but not recommended because of lack of evidence or inefficacy:

• Diagnostic testing in selected patients (see the "Major Recommendations" field for details)
• Routine neurophysiological tests
• Routine structural brain imaging
• Anticholinergic, antiepileptic, and anti-dopaminergic drugs
• Radiofrequency ablations
• Intradural rhizotomy
• Microvascular decompression

Computerized MEDLINE and EMBASE searches (1966 to February 2005) were conducted using a combination of text words and MeSH terms 'dystonia', 'blepharospasm', 'torticollis', 'writer's cramp', 'Meige Syndrome', 'dysphonia' and 'sensitivity and specificity' or 'diagnosis', and 'clinical trial' or 'random allocation' or 'therapeutic use' limited to human studies. The Cochrane Library and the reference lists of all known primary and review articles were searched for relevant citations. No language restrictions were applied.

Evidence Classification Scheme for a Diagnostic Measure

Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a "gold standard" for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy

Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by "gold standard") compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy

Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation

Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls)

Evidence Classification Scheme for a Therapeutic Intervention

Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:

1. Randomization concealment
2. Primary outcome(s) is/are clearly defined
3. Exclusion/inclusion criteria are clearly defined
4. Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
5. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences

Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment

Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion

Studies of diagnosis, diagnostic test, and various treatments for patients suffering from dystonia were considered and rated as level A to C according to the recommendations for European Federation of Neurological Societies (EFNS) scientific task forces (See the "Rating Scheme for the Strength of the Recommendations" field and "Availability of Companion Documents" field in this summary).

The results of the literature searches were circulated by email to the task force members for comments. The task force chairman prepared a first draft of the manuscript based on the results of the literature review, data synthesis and comments from the task force members. The draft and the recommendations were discussed during a conference held in Milan on 11–12 February 2005, until consensus was reached within the task force.

Rating of Recommendations for a Diagnostic Measure

Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.

Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.

Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.

Rating of Recommendations for a Therapeutic Intervention

Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.

Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.

Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.

Good practice point Where only class IV evidence was available but consensus could be achieved the Task Force has proposed good practice points.

A formal cost analysis was not performed and published cost analyses were not reviewed.

The guidelines were validated according to the European Federation of Neurological Societies (EFNS) criteria (See "Availability of Companion Documents" field in this summary).

Note: This guideline has been updated. The National Guideline Clearinghouse (NGC) is working to update this summary. The recommendations that follow are based on the previous version of the guideline.

The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C, Good practice point) are defined at the end of the "Major Recommendations" field.

Diagnosis and Classification

1. Diagnosis and classification of dystonia are highly relevant for providing appropriate management, prognostic information, genetic counseling and treatment (good practice point). (Refer to Table 1 in the original guideline documentation)
2. Based on the lack of specific diagnostic tests, expert observation is recommended. Referral to a movement disorder's expert increases the diagnostic accuracy (good practice point).
3. Neurological examination alone allows the clinical identification of primary dystonia and dystonia plus, but not the distinction amongst different aetiological forms of heredo-degenerative and secondary dystonias (good practice point).

Use of Genetic Test in Diagnosis and Counseling

1. Diagnostic DYT-1 testing in conjunction with genetic counseling is recommended for patients with primary dystonia with onset before age 30 years (level B; Klein et al., 1999).
2. Diagnostic DYT-1 testing in patients with onset after age 30 years may also be warranted in those having an affected relative with early onset (level B; Klein et al., 1999; Bressman et al., 2000).
3. Diagnostic DYT-1 testing is not recommended in patients with onset of symptoms after age 30 years who either have focal cranial-cervical dystonia or have no affected relative with early onset dystonia (level B: Klein et al., 1999; Bressman et al., 2000).
4. Diagnostic DYT-1 testing is not recommended in asymptomatic individuals, including those under the age of 18, who are relatives of familial dystonia patients. Positive genetic testing for dystonia (e.g. DYT-1) is not sufficient to make a diagnosis of dystonia unless clinical features show dystonia (level B; Klein et al., 1999; "Points to consider: ethical, legal, and psychosocial," 1995).
5. A diagnostic levodopa trial is warranted in every patient with early onset dystonia without an alternative diagnosis (good practice point; Robinson et al., 1999).
6. Individuals with myoclonus affecting the arms or neck, particularly if positive for autosomal dominant inheritance, should be tested for the DYT-11 gene (good practice point; Valente et al., 2005).
7. Diagnostic testing for the paroxysmal non-kinesigenic form of dystonia (PNKD) gene (DYT- 8) is not widely available, but this may become possible in the near future (good practice point).

Use of Neurophysiology in the Diagnosis and Classification of Dystonia

1. Neurophysiological tests are not routinely recommended for the diagnosis or classification of dystonia; however, the observation of abnormalities typical of dystonia is an additional diagnostic tool in cases where the clinical features are considered insufficient to the diagnosis (good practice point; Hughes & McLellan, 1985; Deuschl et al., 1992).

Use of Brain Imaging in the Diagnosis of Dystonia

1. Structural brain imaging is not routinely required when there is a confident diagnosis of primary dystonia in adult patients, because a normal study is expected in primary dystonia (good practice point; Rutledge et al., 1988).
2. Structural brain imaging is necessary for screening of secondary forms of dystonia, particularly in the paediatric population due to the more widespread spectrum of dystonia at this age (good practice point; Meunier et al., 2003).
3. Magnetic resonance imaging (MRI) is preferable to computed tomography (CT), except when brain calcifications are suspected (good practice point).
4. There is no evidence that more sophisticated imaging techniques (e.g. voxel-based morphometry, diffusion-weighted imaging, functional MRI [fMRI]) are currently of any value in either the diagnosis or the classification of dystonia (good practice point).

Treatment

Botulinum Toxins (BoNT)

1. BoNT-A (or type B if there is resistance to type A) can be regarded as first line treatment for primary cranial (excluding oromandibular) or cervical dystonia (level A; Costa et al., 2005; American Academy of Ophthalmology, 1989).
2. Due to the large number of patients who require BoNT injections, the burden of performing treatment could be shared with properly trained nurse specialists, except in complex dystonia or where electromyography (EMG) guidance is required (level B; Whitaker et al., 2001).
3. BoNT-A may be considered in patients with writing dystonia (level C; Balash & Giladi, 2004).

Anticholinergic Drugs

The absolute and comparative efficacy and tolerability of anticholinergic agents in dystonia is poorly documented in children and there is no proof of efficacy in adults; therefore, no recommendations can be made to guide prescribing (good practice point).

Antiepileptic Drugs

There is lack of evidence to give recommendations for this type of treatment (good practice point).

Anti-dopaminergic Drugs

There is lack of evidence to give recommendations for this type of treatment (good practice point).

Dopaminergic Drugs

Following a positive diagnostic trial with levodopa, chronic treatment with levodopa should be initiated and adjusted according to the clinical response (good practice point; Hwang et al., 2001).

Neurosurgical Procedures

Deep Brain Stimulation (DBS)

Pallidal DBS is considered a good option, particularly for generalized or cervical dystonia, after medication or BoNT have failed to provide adequate improvement. Whilst it can be considered second-line treatment in patients with generalized dystonia, this is not the case in cervical dystonia since there are other surgical options available (see below). This procedure requires a specialized expertise, and is not without side effects (good practice point; Vidailhet et al., 2005; Eltahawy et al., 2004).

Selective Peripheral Denervation and Myectomy

Selective peripheral denervation is a safe procedure with infrequent and minimal side effects that is indicated exclusively in cervical dystonia. This procedure requires a specialized expertise (level C; The National Institute for Clinical Excellence, 2004).

Intrathecal Baclofen

There is insufficient evidence to use this treatment in primary dystonia; the procedure can be indicated in patients where secondary dystonia is combined with spasticity (good practice point; Albright et al., 2001).

Radiofrequency Lesions

Radiofrequency ablations are currently discouraged for bilateral surgery because of the relatively high risk of side effects (good practice point). The focus of treatment has currently shifted to DBS because of its lower risk for bilateral procedures.

Rare, Uncommon or Obsolete Procedures

1. Intradural rhizotomy has been replaced by selective ramisectomy and peripheral denervation or myotomy. These procedures are no longer recommended.
2. Microvascular decompression is not recommended for treatment of cervical dystonia.

Definitions:

Evidence Classification Scheme for a Diagnostic Measure

Class I: A prospective study in a broad spectrum of persons with the suspected condition, using a "gold standard" for case definition, where the test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy

Class II: A prospective study of a narrow spectrum of persons with the suspected condition, or a well-designed retrospective study of a broad spectrum of persons with an established condition (by "gold standard") compared to a broad spectrum of controls, where test is applied in a blinded evaluation, and enabling the assessment of appropriate tests of diagnostic accuracy

Class III: Evidence provided by a retrospective study where either persons with the established condition or controls are of a narrow spectrum, and where test is applied in a blinded evaluation

Class IV: Any design where test is not applied in blinded evaluation OR evidence provided by expert opinion alone or in descriptive case series (without controls)

Evidence Classification Scheme for a Therapeutic Intervention

Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:

1. Randomization concealment
2. Primary outcome(s) is/are clearly defined
3. Exclusion/inclusion criteria are clearly defined
4. Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
5. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences

Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment

Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion

Rating of Recommendations for a Diagnostic Measure

Level A rating (established as useful/predictive or not useful/predictive) requires at least one convincing class I study or at least two consistent, convincing class II studies.

Level B rating (established as probably useful/predictive or not useful/predictive) requires at least one convincing class II study or overwhelming class III evidence.

Level C rating (established as possibly useful/predictive or not useful/predictive) requires at least two convincing class III studies.

Rating of Recommendations for a Therapeutic Intervention

Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.

Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.

Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.

Good practice point Where only class IV evidence was available but consensus could be achieved the Task Force has proposed good practice points.

None provided

The type of supporting evidence is identified and graded for selected recommendations (see "Major Recommendations").

Appropriate diagnosis and treatment of primary (idiopathic) dystonia and dystonia plus syndromes

The European Federation of Neurological Societies has a mailing list and all guideline papers go to national societies, national ministries of health, World Health Organisation, European Union, and a number of other destinations. Corporate support is recruited to buy large numbers of reprints of the guideline papers and permission is given to sponsoring companies to distribute the guideline papers from their commercial channels, provided there is no advertising attached.

Not applicable: The guideline was not adapted from another source.

European Federation of Neurological Societies

European Federation of Neurological Societies Task Force/ MDS-ES Task Force

Task Force Members: A. Albanese (Chairman), Istituto Nazionale Neurologico Carlo Besta, Milan, Italy; M. P. Barnes, Hunters Moor Regional Rehabilitation Centre, Newcastle Upon Tyne, UK; K. P. Bhatia, Institute of Neurology, University College London, Queen Square, London, UK; E. Fernandez-Alvarez, Neuropediatric Department, Hospital San Joan de Dieu, Barcelona, Spain; G. Filippinia, T. Gasser, Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tubingen, Germany; J. K. Krauss, Department of Neurosurgery, Medical University of Hanover, MHH, Hannover, Germany; A. Newton, European Dystonia Federation, Brussels, Belgium; I. Rektor, First Department of Neurology, Masaryk University, St. Anne's Teaching Hospital, Brno, Czech Republic; M. Savoiardo, Istituto Nazionale Neurologico Carlo Besta, Milan, Italy; J. Valls-Sole`, Neurology Department, Hospital Clınic, Barcelona, Spain

Not stated

Note: This guideline has been updated. The National Guideline Clearinghouse (NGC) is working to update this summary.

Electronic copies of the updated guideline: Available in portable document format (PDF) from the European Federation of Neurological Societies (EFNS) Web site .

Print copies: Available from Alberto Albanese, Istituto Neurologica Besta, Milano, Italy; Phone: +39 02 2394 2552; Fax: +39 02 2394 2539; E-mail: alberto.albanese@unicatt.it

The following is available:

• Brainin M, Barnes M, Baron JC, Gilhus NE, Hughes R, Selmaj K, Waldemar G; Guideline Standards Subcommittee of the EFNS Scientific Committee. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces – revised recommendations 2004. Eur J Neurol. 2004 Sep;11(9):577-81. Electronic copies: Available in Portable Document Format (PDF) from the European Federation of Neurological Societies Web site .

None available

This NGC summary was completed by ECRI on March 26, 2007. The information was verified by the guideline developer on May 3, 2007. This summary was updated by ECRI Institute on May 26, 2009, following the U.S. Food and Drug Administration advisory on Botox, Botox Cosmetic (Botulinum toxin Type A), and Myobloc (Botulinum toxin Type B). This summary was updated by ECRI Institute on August 17, 2009, following the updated FDA advisory on Botox and Botox Cosmetic (Botulinum toxin Type A), and Myobloc (Botulinum toxin Type B).

This NGC summary is based on the original guideline, which is subject to the Blackwell-Synergy copyright restrictions.