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Guideline Summary
Guideline Title
EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke and dementias.
Bibliographic Source(s)
Burgunder JM, Finsterer J, Szolnoki Z, Fontaine B, Baets J, Van Broeckhoven C, Di Donato S, De Jonghe P, Lynch T, Mariotti C, Schols L, Spinazzola A, Tabrizi SJ, Tallaksen C, Zeviani M, Harbo HF, Gasser T, European Federation of Neurological Societies. EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias. Eur J Neurol. 2010 May;17(5):641-8. [28 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

Scope

Disease/Condition(s)
  • Channelopathies
  • Epilepsies
  • Cerebrovascular diseases (including stroke)
  • Migraine
  • Inherited dementias
Guideline Category
Counseling
Diagnosis
Evaluation
Screening
Clinical Specialty
Family Practice
Internal Medicine
Medical Genetics
Neurology
Intended Users
Physicians
Guideline Objective(s)

To summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated

Target Population

Patients with suspected genetic disorders including channelopathies, epilepsies, migraine, stroke and dementias

Interventions and Practices Considered
  1. Assessment of clinical symptoms
  2. Genetic counseling
  3. Molecular genetic testing and mutation screening
Major Outcomes Considered

Proportion of cases of a clinically defined group of patients that are explained by a specific molecular diagnostic test

Methodology

Methods Used to Collect/Select the Evidence
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

To collect data about planning, conditions, and performance of molecular diagnosis of channelopathies, epilepsies, migraine, stroke and dementias, a literature search in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST, or EMBASE was carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

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).

Methods Used to Analyze the Evidence
Systematic Review
Description of the Methods Used to Analyze the Evidence

The level of recommendations was based on the quality of available studies, and the proportion of cases of a clinically defined group of patients that are explained by a specific molecular diagnostic test was estimated. As nearly all of these studies have a retrospective design and look for a specific mutation in a previously ascertained and clinically diagnosed cohort of patients, the highest achievable recommendation level was B. If only small case-series studying genotype–phenotype correlations were available, the level of recommendation was C. If only case reports could be found, but experts still felt that they could give a recommendation, the level of recommendation was assessed as 'good practice point' (see the "Rating Scheme for the Strength of the Evidence" and the "Rating Scheme for the Strength of the Recommendations" fields).

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

Consensus about the recommendations was reached by a step-wise approach. First, task force members met at the European Federation of Neurological Societies (EFNS) congresses in 2007 and 2008 to discuss the preparations of the guidelines. In a second step, experts in genetics of the disorders wrote a guideline proposal. In a third step, these recommendations were distributed and discussed in detail among all task force members until a final consensus had been reached.

Rating Scheme for the Strength of the Recommendations

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.

Good Practice Points (GPPs) Where there was lack of evidence but consensus was clear the Task Force members have stated their opinion as good practice points.

Cost Analysis

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

Method of Guideline Validation
Peer Review
Description of Method of Guideline Validation

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

Recommendations

Major Recommendations

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

Channelopathies

Muscular Channelopathies, Neuronal Channelopathies

There is good evidence to suggest that a thorough clinical and electrophysiological investigation may lead to the choice of the gene to be tested in patients with periodic paralysis (Level B). In myotonic disorders, it is recommended to first search for myotonic dystrophy and use clinical and electrophysiological phenotype characterization to guide for molecular genetic testing (Level B).

Molecular investigations are possible and may help in some cases to diagnose the condition but cannot be considered as a routine procedure with regard to the large number of different mutations in different genes. Furthermore, diagnosis can be made more easily by clinical and physiological investigations (Good Practice Point). One exception of note is the diagnosis of severe myoclonic epilepsy of infancy (SMEI), in which mutations are found in SCN1A in 80% of the patients (Level B).

Cerebrovascular Diseases

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), Amyloid Angiopathies, Cavernous Malformations, Fabry's Disease, Homocystinuria, Ehlers-Danlos Syndrome

Direct sequencing of exons 3 and 4 in the Notch3 gene is suggested as a first step if clinical suspicion for CADASIL is high (Level B). Cerebral amyloid angiopathy (CAA) should be considered in patients with early-onset, recurrent cerebral hemorrhages in association with prominent white matter lesions without classic clinical risk factors. In such cases, the KRIT1 gene should be screened for causative mutations (Level B). Genetic tests for Fabry's disease are suggested in the case of neuropathic pain, hypohidrosis, acroparesthesia, corneal opacities, cataract, renal failure, cardiac failure, ischaemic stroke, or transient ischemic attacks (TIAs) (Level B). Mutation screening in Ehlers-Danlos syndrome can be performed in case of clinical implications (easy bruising, hyperextensibility of joints, thin skin with visible veins, rupture of arteries, uterus or intestines, and arterial dissection) (Good Practice Point). In the event of a stroke attack with elevated level of serum homocysteine (>15 µM), screening for mutations in cystatione beta-synthetase and methylenetetrahydrofolate reductase is suggested (Level B).

Migraine

Familial Hemiplegic Migraine (FHM)

The diagnosis of familial hemiplegic migraine can be confirmed with sequencing the hot spots of the most often affected gene (CACNA1A) (Good Practice Point).

Inherited Dementias

Alzheimer's Disease (AD), Frontotemporal Lobar Degeneration (FTLD), Prion Diseases

In the setting of a clinical diagnosis of AD, mutational screening first in PSEN1, then in APP, and finally (if negative) in PSEN2 can be useful for genetic counseling in cases of early-onset autosomal dominant AD (Level B). Genetic screening in sporadic cases with early onset can be considered (Good Practice Point). If the clinical diagnosis is that of a frontotemporal dementia, genetic testing for mutations in PGRN and MAPT is clearly indicated and useful for genetic counseling in patients with autosomal dominant FTLD (Level B), regardless of the presence or severity of extrapyramidal features. Testing can also be considered in familial and sporadic cases, although mutations are found only in <5% (Good Practice Point).

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).

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.

Good Practice Points (GPPs) Where there was lack of evidence but consensus was clear the Task Force members have stated their opinion as good practice points.

Clinical Algorithm(s)

None provided

Evidence Supporting the Recommendations

Type of Evidence Supporting the Recommendations

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

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate use of molecular genetics in diagnosing neurogenetic disorders

Potential Harms

Not stated

Qualifying Statements

Qualifying Statements
  • These guidelines are provisional, and the future availability of molecular genetic epidemiological data about the neurogenetic disorders under discussion in this article will allow improved recommendation with an increased level of evidence.
  • This guideline provides the view of an expert task force appointed by the Scientific Committee of the European Federation of Neurological Societies (EFNS). It represents a peer-reviewed statement of minimum desirable standards for the guidance of practice based on the best available evidence. It is not intended to have legally binding implications in individual cases.

Implementation of the Guideline

Description of Implementation Strategy

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.

Implementation Tools
Staff Training/Competency Material
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Living with Illness
IOM Domain
Effectiveness

Identifying Information and Availability

Bibliographic Source(s)
Burgunder JM, Finsterer J, Szolnoki Z, Fontaine B, Baets J, Van Broeckhoven C, Di Donato S, De Jonghe P, Lynch T, Mariotti C, Schols L, Spinazzola A, Tabrizi SJ, Tallaksen C, Zeviani M, Harbo HF, Gasser T, European Federation of Neurological Societies. EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias. Eur J Neurol. 2010 May;17(5):641-8. [28 references] PubMed External Web Site Policy
Adaptation

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

Date Released
2010 May
Guideline Developer(s)
European Federation of Neurological Societies - Medical Specialty Society
Source(s) of Funding

European Federation of Neurological Societies

Guideline Committee

European Federation of Neurological Societies Task Force on the Molecular Diagnosis of Channelopathies, Epilepsies, Migraine, Stroke and Dementias

Composition of Group That Authored the Guideline

Task Force Members: J-M. Burgunder, Department of Neurology, University of Bern, Bern, Switzerland; J. Finsterer, KA Rudolfstiftung, Vienna and Danube University, Krems, Austria; Z. Szolnoki, Department of Neurology and Cerebrovascular Diseases, Pandy County Hospital, Gyula, Hungary; B. Fontaine, Assistance Publique-Hôpitaux de Paris, Centre de référence des canalopathies musculaires, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; J. Baets, Department of Neurology, University Hospital of Antwerp, Department of Molecular Genetics, VIB, and Laboratory of Neurogenetics, Institute Born-Bunge, and University of Antwerp, Antwerpen, Belgium; C. Van Broeckhoven, Department of Molecular Genetics, VIB, and Laboratory of Neurogenetics, Institute Born-Bunge, and University of Antwerp, Antwerpen, Belgium; S. Di Donato, Fondazione-IRCCS, Istituto Neurologico Carlo Besta, Milan, Italy; P. De Jonghe, Department of Neurology, University Hospital of Antwerp, Department of Molecular Genetics, VIB, and Laboratory of Neurogenetics, Institute Born-Bunge, and University of Antwerp, Antwerpen, Belgium; T. Lynch, The Dublin Neurological Institute, Mater Misericordiae University, Beaumont & Mater Private Hospitals, Dublin, Ireland; C. Mariotti, Unit of Genetic of Neurodegenerative and Metabolic Diseases, IRCCS Foundation, Neurological Institute Carlo Besta, Milan, Italy; L. Schöls, Clinical Neurogenetics, Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; A. Spinazzola, Division of Molecular Neurogenetics, IRCCS Foundation Neurological Institute Carlo Besta, Milan, Italy; S. J. Tabrizi, Department of Neurodegenerative Disease, Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK; C. Tallaksen, Department of Neurology, Ullevål University Hospital and Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway; M. Zeviani, Division of Molecular Neurogenetics, IRCCS Foundation Neurological Institute Carlo Besta, Milan, Italy; H. F. Harbo, Department of Neurology, Oslo University Hospital, Ulleval, Oslo, Norway; and T. Gasser, Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen and German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany

Financial Disclosures/Conflicts of Interest

Not stated

Guideline Status

This is the current release of the guideline.

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from the European Federation of Neurological Societies Web site External Web Site Policy.

Print copies: Available from J.-M. Burgunder MD, Department of Neurology, University of Bern, Inselspital, CH-3010 Bern, Switzerland; Phone: +41 31 352 20 70; Fax: +41 31 351 80 70; E-mail: Jean-marc.burgunder@dkf.unibe.ch.

Availability of Companion Documents

The following are 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 (EFNS) Web site External Web Site Policy.
  • Continuing Medical Education questions available from the EFNS Web site External Web Site Policy.
Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on August 8, 2011.

Copyright Statement

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

Disclaimer

NGC Disclaimer

The National Guideline Clearinghouseâ„¢ (NGC) does not develop, produce, approve, or endorse the guidelines represented on this site.

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