EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives

ene_1351 921..938EFNS TASK FORCE/CME ARTICLE
EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives
An evidence-based review with good practice points
The EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis:
P. M. Andersena, G. D. Borasiob, R. Denglerc, O. Hardimand, K. Kollewec, P. N. Leighe,
P.-F. Pradatf, V. Silanig and B. Tomikh aDepartment of Neurology, Umea University Hospital, Umea, Sweden; bInterdisciplinary Center for Palliative Medicine and Department of
Neurology, Munich University Hospital, Grosshadern, Munich, Germany; cDepartment of Neurology, Medizinische Hochschule Hannover,
Hannover, Germany; dDepartment of Neurology, Beaumont Hospital, Dublin, Ireland; eDepartment of Clinical Neuroscience, King’s College
London, Institute of Psychiatry, De Crespigny Park, London, UK; fFederation des Maladies du Systeme Nerveux, Hopital de la Salpetriere,
Paris, France; gDepartment of Neurology and Laboratory of Neuroscience, Dino Ferrari Center – IRCCS Istituto Auxologico Italiano –
University of Milan Medical School, Milan, Italy; and hDepartment of Neurology, Institute of Neurology, Collegium Medicum, Jagiellonian
University, Krakow, Poland
Received 1 August 2005
Accepted 3 August 2005
Despite being one of the most devastating diseases known, there is little evidence for
diagnosing and managing patients with amyotrophic lateral sclerosis (ALS). Although
specific therapy is lacking, correct early diagnosis and introduction of symptomatic and
specific therapy can have a profound influence on the care and quality of life of the
patient and may increase survival time. This document addresses the optimal clinical
approach to ALS. The final literature search was performed in the spring of 2005.
Consensus recommendations are given graded according to the EFNS guidance regu-
lations. Where there was lack of evidence but consensus was clear we have stated our
opinion as good practice points. People affected with possible ALS should be examined
as soon as possible by an experienced neurologist. Early diagnosis should be pursued and
anumber of investigations should be performedwith highpriority. The patient should be
informed of the diagnosis by a consultant with a good knowledge of the patient and the
disease. Following diagnosis, the patient and relatives should receive regular support
from amultidisciplinary care team.Medication with riluzole should be initiated as early
as possible. PEG is associated with improved nutrition and should be inserted early. The
operation is hazardous in patients with vital capacity <50%. Non-invasive positive
pressure ventilation improves survival and quality of life but is underused. Maintaining
the patients ability to communicate is essential. During the entire course of the disease,
every effort should be made to maintain patient autonomy. Advance directives for
palliative end of life care are important and should be fully discussed early with the
patient and relatives respecting the patients social and cultural background.
Introduction
motor neuron disease (MND), sclerose laterale
amyotrophique (SLA) is a fatal syndrome character-
ized by onset of symptoms and signs of degeneration
of primarily upper (UMN) and lower (LMN) motor
neurons, leading to progressive weakness of bulbar,
limb, thoracic and abdominal muscles. Other brain
functions, including oculomotor and sphincter func-
tions, are relatively spared, although these may be
involved in some cases. Cognitive dysfunction is seen
in 20–50%, and 3–5% develop dementia that is usu-
ally of frontotemporal type (Abrahams et al., 1996).
Death due to respiratory failure follows on average 2–
4 years after onset, but a small group may survive for
a decade or more (Forsgren et al., 1983). The mean
age of onset is 47–52 years in familial cases (FALS)
and 58–63 years in sporadic (SALS) cases (Haverkamp
et al., 1995). The lifetime risk of developing ALS is
about 1:1000 [approximately half the risk of getting
Correspondence: Peter M. Andersen, MD DMSc, Associate professor
of Neurology, Department of Neurology, Umea Universityhospital,
SE-901 85 Umea, Sweden (tel.: +46 (0)90 785 2372; fax:
+46 (0)90 143 107; e-mail: [email protected]).
This is a Continuing Medical Education paper and can be found
with corresponding questions on the Internet at: http://www.
blackwellpublishing.com/products/journals/ene/mcqs. Certificates for
correctly answering the questions will be issued by the EFNS.
2005 EFNS 921
hereditary disposition being the main risk factors
(Bobowick and Brody, 1973). When diagnosing and
managing a patient with ALS it is important to
recognize that ALS is a heterogeneous syndrome that
overlaps with a number of other conditions (Fig. 1;
Ince et al., 1998; Brugman et al., 2005). This system-
atic review comprises of an objective appraisal of the
evidence in regard to the diagnosis and clinical man-
agement of patients with ALS. The primary aim has
been to establish evidence-based and patient and carer
centered guidelines, with secondary aims of identifying
areas where further research is needed.
Methods
Register of Controlled Trials (CENTRAL) (The Coch-
rane Library to date); MEDLINE-OVID (January 1966
to date); MEDLINE-ProQuest; MEDLINE-EIFL;
tion Index (ISI); The National Research Register; Ox-
ford Centre for Evidenced-based Medicine; American
Speech Language Hearing Association (ASHA); the
world Federation of Neurology ALS Page of reviews of
published research; the Oxford Textbook of Palliative
Medicine, and the UK Department of Health National
Research Register (http://www.update-software.com/
databases (e.g. http://www.alsa.org and http://www.
alsod.org) and personal collections of references and
reference lists of articles. There were no constraints
based on language or publication status. Any differences
at any stage of the review were resolved by discussion.
Results
Ten central issues in the management of ALS were ad-
dressed by the Task Force. The following is an abbre-
viated report, the full report with all tables, figures and
references is available at http://www.efns.org. Supple-
mentary material presented on http://www.efns.org only
is listed as tables S1–S7. The guidelines were prepared
following the EFNS criteria (Brainin et al., 2004) and the
level of evidence and grade of recommendation are ex-
pressed in accordance with this reference. Where there
was lack of evidence but consensus was clear we have
stated our opinion as good practice points.
1 Diagnosing ALS/MND
Diagnosing ALS is usually considered straight forward
if the patient has been ill for some time and has gener-
alized symptoms (Table 1; Li et al., 1986). Diagnosing
the disease early in the disease when the patient has only
limited focal symptoms from one or two regions (bulbar,
upper limb, truncal, lower limb) may be difficult and
depends on the presence of signs in other affected regions
and a number of investigations (Wilbourn, 1998; Mei-
ninger, 1999). The mean time from onset of symptoms to
confirmation of diagnosis of ALS is 13–18 months
(Chio, 1999). Delays may arise from a complex referral
pathway, and early symptoms are often intermittent and
non-specific and may be denied or go unrecognized by
the patient. However, three studies have shown that the
longest delay occurs after the patient actually has seen
the neurologist (Chio, 1999). There are four cogent
reasons for making the diagnosis as early as possible:
For psychological reasons, as the progressive loss of
motor symptoms causes anxiety and discomfort,
Figure 1 Schematic illustration of the relationship between ALS and some other motor neuron syndromes and motor neuronopathies. On
the far left are syndromes affecting lower motor neurons (LMN) and/or the peripheral motor axons, on the right syndromes affecting the
upper motor neurons and/or the corticospinal and corticobulbar tractsystems. The approximate clinical spectrum associated with
mutations in some genes is shown below the bar. At present, 44 genes have been associated with motor neuron disease or neuronopathy.
CMT, Charcot-Marie-Tooth; HMN, distal hereditary motor neuronopathies; PMA, progressive spinal muscular atrophies; PLS, primary
lateral sclerosis syndrome; HSP, hereditary spastic paraplegias.
922 P. M. Andersen et al.
2005 EFNS European Journal of Neurology 12, 921–938
impairing the patient’s social and professional life; for
ethical reasons, so that the patient can better plan the
remaining part of her or his life; for economic reasons, as
many patients go on a tour of the health care system
undergoing series of (expensive) unnecessary tests; for
neurological reasons to be able to initiate neuroprotec-
tive medication before too many neuronal cells become
dysfunctional and lost. Although no hard evidence exists
on the kinetics of cell loss in ALS, it is reasonable to
assume that the earlier medication is started the greater
the neuroprotective effect will be (Bromberg, 1999).
Studies in experimental animal models and humans with
SOD1 gene mutations indicate that loss of motor neu-
rons is preceded by a period of cellular dysfunction
(Aggarwal and Nicholson, 2002). Both in humans and
animal models the life prolonging effect of riluzole is
greater the earlier medication is initiated. Also, early
administration of medication can have a profound
positive psychological effect on the patient and carers.
The objective is to present guidelines for making the
correct diagnosis and doing this as early as possible. As
no single investigation is specific for the diagnosis, car-
rying out the diagnosis should be based on symptoms, a
thorough clinical examination, electrodiagnostic stud-
ies, neuroimaging and laboratory studies (Tables 1 and
2; Lima et al., 2003). Great care should be taken to rule
out diseases that can masquerade as ALS (Table S1;
Evangelista et al., 1996; Traynor et al., 2000). In spe-
cialist practice, 5–8% of apparent ALS cases have an
alternative diagnosis, which may be treatable in about
half the cases (Belsh and Schiffman, 1990; Davenport
et al., 1996; Traynor et al., 2000). Evolution of atypical
symptoms or failure of the patient to show progress are
the most important red flags suggesting that the diag-
nosis may be wrong (Traynor et al., 2000). The revised
El Escorial criteria are research diagnostic criteria for
clinical trials (Table 3, adapted from Brooks et al.,
2000). The criteria are too restrictive for use in routine
clinical practice and are not suitable if the objective is to
establish the diagnosis as early as possible (Ross et al.,
1998). In practice, we do not recommend that patients
are told they have definite, probable or possible ALS.
The clinician must decide, on the balance of probability,
whether or not the patient has ALS, even in the absence
of unequivocal UMN and LMN signs (Leigh et al.,
2003).
1 The diagnosis should be pursued as early as possible.
Patients with whom ALS is suspected should be
referred with high priority to an experienced neuro-
logist.
detailed clinical and paraclinical examinations
(Tables 1 and 2).
ded (Table 2).
4 Repetition of the investigations may be needed if the
initial series of tests do not result in a diagnosis.
5 Review of the diagnosis is advisable if there is no
evidence of progression or if the patient develops
atypical features (Table 1).
Telling the patient and the family that the diagnosis is
ALS is a daunting task for the physician. If not per-
formed appropriately, the effect can be devastating,
leaving the patient with a sense of abandonment and
destroying the patient–physician relationship (Lind
et al., 1989). Studies of other fatal illnesses (Damian
and Tattersall, 1991; Doyle, 1996; Davies and Hopkins,
1997) clearly demonstrated the advantages of utilizing
specific techniques (Table 4). Surveys in ALS patients
and caregivers have demonstrated that the way the
diagnosis is communicated is less than satisfactory in
half of the cases (Borasio et al., 1998; McCluskey et al.,
2004). Better performance on all attributes of effective
communication as well as greater time spent discussing
the diagnosis was correlated with higher patient/care-
giver satisfaction (McCluskey et al., 2004). A survey in
ALS centers has shown that physicians in 44% of center
usually spend 30 min or less discussing the diagnosis
(Borasio et al., 2001a). Callous delivery of the diagnosis
may affect the psychological adjustment to bereavement
(Ackerman and Oliver, 1997).
sultant with a good knowledge of the patient.
Table 1 Diagnostic criteria for ALS
The diagnosis of ALS requires the presence of: (positive criteria)
LMN signs (including EMG features in clinically unaffected
muscles)
Progression of symptoms and signs
The diagnosis of ALS requires the absence of: (diagnosis by exclusion)
Sensory signs
Sphincter disturbances
Visual disturbances
Autonomic features
Basalganglia dysfunction
Alzheimer-type dementia
The diagnosis of ALS is supported by:
Fasciculations in one or more regions
Neurogenic changes in EMG
Absence of conduction block
what the patient already knows or suspects.
3 Respect the cultural and social background of the
patient by asking whether the patient wishes to re-
ceive information or prefers that the information be
communicated to a family member.
4 The physician should give the diagnosis to the patient
and discuss its implications in a stepwise fashion,
checking repeatedly if the patient understands what is
said, and reacting appropriately to the verbal and
non-verbal cues of the patient.
5 The diagnosis should always be given in person and
never bymail or telephone, with enough time available
(at least 45–60 min) on the part of the physician.
6 Provide printed materials about the disease, about
support and advocacy organizations, and about
informative websites on the internet. Optionally, a
letter or audiotape summarizing what the physician
has discussed can be very helpful for the patients and
family.
7 Assure the patient that he or her and their family will
not be on their own (abandoned) but will be
Table 2 Diagnosing ALS/MND: recommended investigations
Clinical chemistry Test Evidence class
Recommended
C-reactive protein (CRP) IV x
Hematological screen IV x
TSH, FT4, FT3 hormone assays IV x
Vitamins B12 and folate IV x
Serum protein electrophoresis IV x
Serum immunoelectrophoresis IV x
Creatinine IV x
Glucose IV x
Lactate IV x
Ganglioside GM-1 antibodies IV x
Anti-Hu, anti-MAG IV x
Serology (Borrelia, virus including HIV) IV x
DNA analysis (for details see Fig. 1) IV x
CSF Cell count IV x
Cytology IV x
Glucose, lactate IV x
Serology (Borrelia, virus) IV x
Ganglioside antibodies IV x
Urine Cadmium IV x
Mercury IV x
Manganese IV x
MEP IV x
Chest X-ray IV x
2005 EFNS European Journal of Neurology 12, 921–938
supported by a professional ALS-care team (where
available) and with regular follow-up visits to a
neurologist. Make arrangements for a close follow-
up visit before the end of the consultation, ideally
within 2–4 weeks (or sooner if appropriate).
8 Avoid the following: withholding the diagnosis,
providing insufficient information, delivering infor-
mation callously, or taking away or not providing
hope. Remember to switch off mobile phones and
pagers, and put up Do not disturb signs.
3 Multidisciplinary care in management of ALS
Specialist multidisciplinary (MD) clinics provide sec-
ondary or tertiary services to patients with ALS.
These clinics comprise a wide range of health care
professionals with expertise in ALS. Ideally, such
clinics provide both diagnostic and management ser-
vices, and facilitate continuity of care by close liaising
with the primary care physician and community-
based services (Chio et al., 2001; Howard and Orrell,
2002; Leigh et al., 2003; Traynor et al., 2003). The
Table 3 Revised El Escorial research diagnostic criteria for ALS
(summary)
Clinically definite ALS – Laboratory supported
UMN and/or LMN signs in one region and the patient is a carrier of
a pathogenic gene mutation
Clinically probable ALS
UMN and LMN signs in two regions with some UMN signs rostral
to the LMN signs
Clinically probable ALS – laboratory supported
UMN signs in one or more regions and LMN signs defined by EMG
in at least two regions
Clinically possible ALS
UMN and LMN signs in one region, or
UMN signs in at least two regions, or
UMN and LMN signs in two regions with no UMN signs rostral
to LMN signs
Table 4 How should a physician tell the patient that they have ALS modified from Miller et al. (1999)
Task Recommendations
Structure In person, face-to-face
Enough time to ensure no rushing or interruptions
Make eye contact and sit close to patient
Participants Know the patient before the meeting including family, emotional and social situation, case history,
and all relevant test results. Have all the facts at hand
Have patient’s support network present (relatives). Have a clinical nurse specialist or equivalent present or available
What is said Find out what the patient already knows about the condition
Ascertain how much the patient wants to know about ALS and tailor your information accordingly
Give a warning comment that bad news is coming. The whole truth may need to come by installments
Use the correct ALS-term, not wear and tear of the motor nerves Explain the anatomy of the disease (make a simple drawing)
If the patient indicates that they want to know the course of the disease, be honest about the probable progression
and prognosis but give a broad time frame, and recognize the limitations of any predictions
There is no cure, symptoms tend to steadily worsen, and prognosis is highly variable.
Some patients survives 5 or 10 or more years
Acknowledge and explore patient’s reaction and allow for emotional expression
Summarize the discussion verbally, in writing, and/or audiotape
Allow plenty of time for questions
Reassurance Acknowledge that this is devastating news but discuss reasons for hope such as research,
drug trials and the variability of the disease
Explain that the complications of ALS are treatable
Reassure that every attempt will be made to maintain the patient’s function and that
the patient’s treatment decisions will be respected
Reassure that the patient will continue to be cared for and will not be abandoned
Inform about patient support groups (offer contact details and leaflets)
Inform about neuroprotective treatment (i.e. riluzole) and ongoing research
Discuss opportunities to participate in research treatment protocols (if available)
Acknowledge willingness to get a second opinion if the patient wishes
How it is said Emotional manner: warmth, caring, empathy, respect
Be honest, sympathetic but not sentimental
Give news at person’s pace; allow the patient to dictate what he or she is told
Language Simple and careful word choice, yet direct; no euphemisms or medical jargon
EFNS guidelines on management of amyotrophic lateral sclerosis 925
2005 EFNS European Journal of Neurology 12, 921–938
emphasis of care should be on patient autonomy and
choice. Patients who attend specialist MD clinics tend
to be younger and to have had symptoms for longer
than those who do not (Lee et al., 1995; Traynor
et al., 2003). Comparisons between clinic-based
cohorts and population-based cohorts of patients
have confirmed a referral bias (Lee et al., 1995;
Traynor et al., 2003). However, an independent sur-
vival benefit has been identified in two studies, which
is independent of other prognostic factors including
age, disease duration, bulbar onset disease and rate of
progression (Traynor et al., 2003; Chio et al., 2004a).
Importantly, patients attending a multidisciplinary
clinic have fewer hospital admissions and shorter
durations of stay than those who attend general
clinics (Chio et al., 2004a). Increased use of non-
invasive ventilation, attention to nutrition and
earlier referral to palliative referral services prob-
ably contribute to the increased survival of those
attending MD clinics (Leigh et al., 2003; Traynor
et al., 2003a).
Good practice points
affected by ALS as attendance at a MD clinic
improves care, and may extend survival.
2 The following specialists should be part of or be
readily available to the MD team: a consultant in
neurology, pulmonologist, gastroenterologist, reha-
physical therapist, dietitian, psychologist, dentist.
3 Schedule clinical visits every 2–3 months and more
frequently if needed. This is particularly often the
case in the first half year following diagnosis, and in
late stages of the disease. Patients with very slowly
progressing disease can be seen once or twice a year.
4 It is important that between visits the patient support
team maintain regular contact with the patient and
relatives (e.g. by phone, letter or email).
5 Ideally, from the outset the patient should be fol-
lowed by a single named neurologist working in close
liason with the patients primary care physician
(family general practitioner).
MD-team, the primary care team, the palliative care
team and community services.
At present, only riluzole, a presumed glutamate-release
antagonist, has been shown to slow the course of ALS in
two class…