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Guideline Summary
Guideline Title
EFNS guidelines for the diagnosis and management of Alzheimer's disease.
Bibliographic Source(s)
Hort J, O'Brien JT, Gainotti G, Pirttila T, Popescu BO, Rektorova I, Sorbi S, Scheltens P, EFNS Scientist Panel on Dementia. EFNS guidelines for the diagnosis and management of Alzheimer's disease. Eur J Neurol. 2010 Oct;17(10):1236-48. [100 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B, EFNS. Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol 2007 Jan;14(1):e1-26.

Scope

Disease/Condition(s)

Alzheimer's disease (AD)

Note: This guideline does not address diagnosis and management of mild cognitive impairment (MCI) or non-Alzheimer dementias. See the National Guideline Clearinghouse (NGC) summary: EFNS-ENS guidelines on the diagnosis and management of disorders associated with dementia.

Guideline Category
Counseling
Diagnosis
Evaluation
Management
Screening
Treatment
Clinical Specialty
Family Practice
Geriatrics
Internal Medicine
Medical Genetics
Neurology
Psychiatry
Intended Users
Occupational Therapists
Physicians
Guideline Objective(s)
  • To revise previous European Federation of Neurological Societies (EFNS) recommendations on the diagnosis and management of Alzheimer's disease (AD)
  • To present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with AD
Target Population

Patients with suspected or diagnosed Alzheimer's disease

Interventions and Practices Considered

Evaluation/Diagnosis

  1. Medical/clinical history with informant supplementation
  2. Neurological and physical examination
  3. Assessment of cognitive function
  4. Assessment of behavioral and psychological symptoms (BPSD)
  5. Assessment of activities of daily living
  6. Assessment of co-morbidities
  7. Blood tests
  8. Neuroimaging (e.g., computed tomography [CT], magnetic resonance imaging [MRI], single photon emission computed tomography [SPECT], and positron emission tomography [PET])
  9. Electroencephalography, cerebrospinal fluid analysis, genetic testing, and tissue biopsy if indicated
  10. Screening for pathogenic mutations (routine Apolipoprotein E genotyping is not recommended)
  11. Assessment of driving ability

Management/Treatment

  1. Individually tailored disclosure of diagnosis
  2. Cholinesterase inhibitors (ChEIs)
  3. Memantine (alone or in combination with ChEIs)
  4. Conventional and atypical antipsychotics
  5. Cognitive stimulation or rehabilitation; occupational therapy
  6. Non-pharmacological management of BPSD
  7. Selective serotonin reuptake inhibitors to treat depression
  8. Regular patient follow-up
  9. Counseling and support for patients and caregivers

Note: The following treatments were considered but not recommended due to insufficient or inconsistent evidence: any drugs, including anti-inflammatory drugs, nootropics (including piracetam, nicergoline), selegiline, oestrogens, pentoxifylline, statins, EGb 761 and Cerebrolysin in the treatment or prevention of Alzheimer's disease (AD); ChEIs, vitamin E, ginkgo and oestrogens to treat mild cognitive impairment; aspirin solely to treat AD

Major Outcomes Considered
  • Sensitivity, specificity, and accuracy of diagnostic tests
  • Efficacy of treatment (measured by rate of conversion to Alzheimer's disease, cognitive function, global outcome, activities of daily living, behavioral and psychiatric symptoms, timing of institutionalisation, and quality of life)
  • Adverse effects of treatments
  • Psychiatric symptoms in care-givers

Methodology

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

The evidence for this guideline was collected from Cochrane Library reviews, meta-analyses, and systematic reviews and original scientific papers published in peer-reviewed journals before May 2009 accessed using the MEDLINE database.

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)

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

Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review
Description of the Methods Used to Analyze the Evidence

In the revised guideline special attention was given to whether further evidence had become available for biomarkers of disease like magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) that have been proposed to increase the confidence of the clinical diagnosis. Special attention was given to results of recent clinical trials in Alzheimer's disease, both for cognitive and behavioral aspects of the disease.

The scientific evidence was evaluated according to pre-specified levels of certainty (classes of evidence I, II, III, and IV) by the expert group members.

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

In 2008 a task force was set up to develop a revision of the European Federation of the Neurological Societies (EFNS) guideline for the diagnosis and management of Alzheimer's disease (AD) and other disorders associated with dementia, published in early 2007. A proposed guideline with specific recommendation was drafted for circulation to task force members and displayed on EFNS web pages for comments from all panel members. Consensus was reached at three task force meetings during 2009.

The recommendations were graded according to the strength of evidence (grade A, B, or C), using the definitions given in the EFNS guidance (see the "Rating Scheme for the Strength of the Evidence" field). In addressing important clinical questions, for which no evidence was available, 'good practice points' were recommended based on the experience and consensus of the expert task force group.

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 (GPP) Where there was a lack of evidence, but clear consensus, good practice points are provided.

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 Points (GPP) Where there was a lack of evidence, but clear consensus, good practice points are provided.

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) are defined at the end of the "Major Recommendations" field.

Recommendations for Diagnosis

Clinical history should be supplemented by an informant (Level A). A neurological and physical examination should be performed in all patients with dementia (Good Practice Point). Activities of daily living (ADL) impairment due to cognitive decline is an essential part of the diagnostic criteria for dementia and should be assessed in the diagnostic evaluation (Level A).

Several informant-based questionnaires are available and should be used where possible (Good Practice Point).

Cognitive assessment should be performed in all patients (Level A). Quantitative neuropsychological testing should be made in patients with questionable or very early Alzheimer's disease (AD) (Level B). The assessment of cognitive functions should include a general cognitive measure and more detailed testing of the main cognitive domains, and in particular an assessment of delayed recall (Level A). In patients with moderate memory impairment cued recall could be more appropriate than free recall (Level B).

Assessment of behavioral and psychological symptoms of dementia (BPSD) should be performed in each patient (Level A). Information should be gathered from an informant using an appropriate rating scale (Good Practice Point).

Assessment of co-morbidity is important in AD patients, both at the time of diagnosis and throughout the course of the illness (Good Practice Point) and should always be considered as a possible cause of BPSD (Level C). Blood levels of folate, vitamin B12, thyroid stimulating hormone, calcium, glucose, complete blood cell count, renal and liver function tests should be evaluated at the time of diagnosis and serological tests for syphilis, Borrelia, and human immunodeficiency virus (HIV) might also be needed in cases with atypical presentation or clinical features suggestive of these disorders (Good Practice Point).

Computed tomography (CT) and magnetic resonance imaging (MRI) may be used to exclude treatable causes of dementia. Multislice CT and coronal MRI may be used to assess hippocampal atrophy to support a clinical diagnosis of AD (Level B). Fluorodeoxy-glucose-positron emission tomography (FDG-PET) and perfusion single photon emission computed tomography (SPECT) are useful adjuncts when diagnosis remains in doubt (Level B). Dopaminergic SPECT is useful to differentiate AD from dementia with Lewy bodies (DLB) (Level A). Follow up with serial MRI is useful in a clinical setting to document disease progression (Good Practice Point).

Electroencephalography (EEG) is recommended in differential diagnosis of atypical clinical presentations of AD (Good Practice Point) and when Creutzfeldt–Jacob disease (CJD) or transient epileptic amnesia is suspected (Level B).

Routine cerebrospinal fluid (CSF) analysis is recommended in differential diagnosis for atypical clinical presentations of AD (Good Practice Point). CSF 14-3-3 or total tau measurement are recommended for the identification of CJD in patients with rapidly progressive dementia (Level B). Alterations in CSF total tau, phospho-tau, and Aβ42 support diagnosis of AD (Level B).

Screening for known pathogenic mutations can be undertaken in patients with appropriate phenotype or a family history of an autosomal dominant dementia. Routine apolipoprotein E (Apo E) genotyping is not recommended.

Recommendations on Management

Diagnosis of AD should be disclosed to patient (and caregivers as appropriate) (Level B). Disclosure of diagnosis should be individually tailored. It should be accompanied by information and counseling, as well as useful contacts such as Alzheimer's patient organizations. Patients and caregivers should be provided with education and support (Level A). Driving, medico-legal issues, and the need for other support services should be considered (Good Practice Point). If possible physicians may encourage patients to draw up advance directives containing future treatment and care preferences (Good Practice Point).

There is insufficient evidence to support the use of any drugs purely for the primary prevention of dementia. Cholinesterase inhibitors (ChEIs), vitamin E, ginkgo, and oestrogens should not be used as treatments for those with mild cognitive impairment (MCI) (Level A).

In patients with AD, treatment with ChEIs (donepezil, galantamine, or rivastigmine) should be considered at the time of diagnosis, taking into account expected therapeutic benefits and potential safety issues (Level A). Benefits on cognitive and non-cognitive symptoms have been demonstrated in those with mild, moderate, and severe disease (Level A). Realistic expectations for treatment effects and potential side effects should be discussed with the patient and caregivers (Good Practice Point).

In patients with moderate to severe AD, treatment with memantine should be considered taking into account expected therapeutic benefits and potential safety issues (Level A). Benefits on cognitive and noncognitive symptoms are apparent, some non-cognitive symptoms (agitation, delusions) may respond better than others (Level B). Realistic expectations for treatment effects and potential side effects should be discussed with the patient and caregivers (Good Practice Point).

Regular patient follow-up, which should include scales like the Mini-Mental State Examination (MMSE) to monitor response to treatment and disease progression, should be an integral part of management (Good Practice Point).

Aspirin should not be used as a treatment for AD (Level A), though it can be used in those with AD who also have other indications for its use (e.g., to prevent cardiovascular events). Vitamin E should not be used as a treatment for AD (Level A).

Currently, there is insufficient evidence to support the use of other agents, including anti-inflammatory drugs, nootropics (including piracetam, nicergoline), selegiline, oestrogens, pentoxifylline, or statins and inconsistent evidence for EGb 761 and Cerebrolysin in the treatment or prevention of AD (Level A).

Cognitive stimulation or rehabilitation may be considered in patients with mild to moderate AD (Good Practice Point). Occupational therapy can improve patients' functioning and reduce need for informal care (Level B).

Management of BPSD should begin with a careful search for triggers and causative factors (i.e., physical illness). Where possible, initial treatment should be non-pharmacological (Level C).

Antipsychotics should only be used for moderate or severe BPSD symptoms causing significant distress which have either not responded to other treatments (like non-pharmacological measures or ChEIs) or when other treatments are not appropriate (Level A). Low dose of atypical agents should be used only after assessment of risk benefit and full discussion with patient (when capacity allows) and caregiver (Good Practice Point).

Atypical agents have fewer side effects and do not confer a greater risk of stroke or mortality than conventional drugs (Level B).

Selective serotonin reuptake inhibitors rather than tricyclic antidepressants should be used to treat depression in AD (Level B).

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.

Good Practice Points (GPP) Where there was a lack of evidence, but clear consensus, good practice points are provided.

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 Points (GPP) Where there was a lack of evidence, but clear consensus, good practice points are provided.

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 most recommendations (see the "Major Recommendations" field).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate diagnosis and management of Alzheimer's disease

Potential Harms
  • Cholinesterase inhibitors (ChEIs) are generally well tolerated, although common gastrointestinal adverse effects such as nausea, diarrhea, and vomiting may sometimes lead to discontinuation of treatment in some patients. One of the ChEIs, rivastigmine, is now available in a transdermal (patch) formulation which appears to have lower incidence of side effects than oral administration but equal efficacy.
  • Antipsychotics have important and potentially serious side effects, most especially increased stroke risk, increased mortality, parkinsonism, and cognitive impairment. They should be used with caution, at low dose, and for the shortest period needed only for those with moderate to severe symptoms causing distress and after careful assessment of risk and benefit and after discussion with caregiver and, where possible, patient. There is no evidence that conventional agents are any safer in regard to risk of stroke or mortality than atypical agents and they have a less established evidence base and greater side effects. Low doses of antipsychotics should be used with careful monitoring, and drugs prescribed for the minimum period required.

Qualifying Statements

Qualifying Statements
  • 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.
  • This guideline represents desirable standards to guide practice, but may not be appropriate in all circumstances as clinical presentation of the individual patient and available resources should be taken into account.

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
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Hort J, O'Brien JT, Gainotti G, Pirttila T, Popescu BO, Rektorova I, Sorbi S, Scheltens P, EFNS Scientist Panel on Dementia. EFNS guidelines for the diagnosis and management of Alzheimer's disease. Eur J Neurol. 2010 Oct;17(10):1236-48. [100 references] PubMed External Web Site Policy
Adaptation

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

Date Released
2007 Jan (revised 2010 Oct)
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 Scientist Panel on Dementia

Composition of Group That Authored the Guideline

Primary Authors: J. Hort, Memory Disorders Clinic, Department of Neurology, Charles University in Prague, Second Faculty of Medicine and Motol Hospital, Prague, Czech Republic; J. T. O'Brien, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK; G. Gainotti, Neuropsychology Service, Policlinico Gemelli/Catholic University, Rome, Italy; T. Pirttila, Department of Neurology, Kuopio University Hospital, Kuopio, Finland; B. O. Popescu, Department of Neurology, University Hospital, 'Carol Davila' University of Medicine and Pharmacy, Bucharest, Romania; I. Rektorova, First Department of Neurology, Masaryk University and St. Anne's Hospital, Brno, Czech Republic; S. Sorbi, Department of Neurological and Psychiatric Sciences University of Florence, Italy; and P. Scheltens, Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands

Financial Disclosures/Conflicts of Interest

Authors have received speaker's and/or consultancy honoraria from Eisai, GE Healthcare, Janssen-Cilag, Lundbeck, Mertz, Shire, Novartis, Elan, Zentiva, Pfizer, Wyeth and Elan. For the conception and writing of this guideline no honoraria or any other compensation were received by any of the authors.

Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Waldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B, EFNS. Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline. Eur J Neurol 2007 Jan;14(1):e1-26.

Guideline Availability

Electronic copies: Available to registered users from the European Federation of Neurological Societies Web site External Web Site Policy.

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 are available to registered users from the EFNS Web site External Web Site Policy.
Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on April 23, 2009. The information was verified by the guideline developer on June 12, 2009. This summary was updated by ECRI Institute on May 20, 2011 following the U.S. Food and Drug Administration advisory on antipsychotic drugs. This NGC summary was updated by ECRI Institute on November 20, 2012. The updated information was verified by the guideline developer on January 30, 2013.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the Wiley Online Library copyright restrictions.

Disclaimer

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