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Efns guidelines on the clinical management of amyotrophic lateral sclerosis (mals) revised report of an efns task force

European Journal of Neurology 2012, 19: 360–375 EFNS guidelines on the Clinical Management of AmyotrophicLateral Sclerosis (MALS) – revised report of an EFNS task force The EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis: Peter M.
Andersena, Sharon Abrahamsb, Gian D. Borasioc, Mamede de Carvalhod, Adriano Chioe, PhilipVan Dammef, Orla Hardimang, Katja Kolleweh, Karen E. Morrisoni, Susanne Petrih,Pierre-Francois Pradatj, Vincenzo Silanik, Barbara Tomikl, Maria Wasnerm and Markus WebernaUmea˚ University, Umea˚, Sweden; bUniversity of Edinburgh, Edinburgh, UK; cCentre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland; dHospital de Santa Maria, Lisbon, Portugal; eUniversity of Turin and San Giovanni Hospital, Turin, Italy;fUniversity of Leuven and VIB, Leuven, Belgium; gTrinity College and Beaumont Hospital, Dublin, Ireland; hMedizinische Hochschule Hannover, Germany; iSchool of Clinical and Experimental Medicine, University of Birmingham and Queen Elizabeth Hospital, Birmingham, UK;jHoˆpital de la Salpeˆtrie re, Paris, France; kUniversity of Milan Medical School, Milan, Italy; lJagiellonian University Medical College, Krakow, Poland; mMunich University Hospital, Munich, Germany; and nKantonsspital St Gallen and University Hospital Basel, Basel, Switzerland Background: The evidence base for the diagnosis and management of amyotrophic ALS, breaking the lateral sclerosis (ALS) is weak.
diagnosis, bronchial Objectives: To provide evidence-based or expert recommendations for the diagnosis secretions, caregiver, and management of ALS based on a literature search and the consensus of an expert cognitive dysfunction, drooling, Evidence-based Methods: All available medical reference systems were searched, and original papers, medicine, genetic meta-analyses, review papers, book chapters and guidelines recommendations were counselling, nutrition, reviewed. The final literature search was performed in February 2011. Recommen- palliative care, terminal dations were reached by consensus.
care, ventilation Recommendations: Patients with symptoms suggestive of ALS should be assessed assoon as possible by an experienced neurologist. Early diagnosis should be pursued, Received 16 November 2010 and investigations, including neurophysiology, performed with a high priority. The Accepted 12 July 2011 patient should be informed of the diagnosis by a consultant with a good knowledge ofthe patient and the disease. Following diagnosis, the patient and relatives/carersshould receive regular support from a multidisciplinary care team. Medication withriluzole should be initiated as early as possible. Control of symptoms such assialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should beattempted. Percutaneous endoscopic gastrostomy feeding improves nutrition andquality of life, and gastrostomy tubes should be placed before respiratory insufficiencydevelops. Non-invasive positive-pressure ventilation also improves survival andquality of life. Maintaining the patientÕs ability to communicate is essential. Duringthe entire course of the disease, every effort should be made to maintain patientautonomy. Advance directives for palliative end-of-life care should be discussed earlywith the patient and carers, respecting the patientÕs social and cultural background.
warrant an updating of the 2005 EFNS guidelines [1] with the primary aim of establishing evidence-based This systematic review is an objective appraisal of the and patient- and carer-centred guidelines for diagnosing evidence regarding the diagnosis and clinical manage- and managing patients with ALS for clinicians, with the ment of patients with amyotrophic lateral sclerosis secondary aim of identifying areas where further (ALS). Advances in the knowledge and care of ALS research is needed.
Correspondence: Peter Munch Andersen, Professor of Neurology, Institute of Clinical Neuroscience, Umea˚ University, SE-901 85 Umea˚, Amyotrophic lateral sclerosis is characterized by Sweden (tel.: +46 90 7852372; fax: +46 90 14 31 07; e-mail:[email protected]).
symptoms and signs of degeneration of the upper and Ó 2011 The Author(s) European Journal of Neurology Ó 2011 EFNS EFNS Task Force on Management of ALS lower motor neurons, leading to progressive weakness resulting in level A, B or C recommendations [6]. Where of the bulbar, limb, thoracic and abdominal muscles.
there was lack of evidence but consensus was clear, we Other brain functions, including oculomotor and have stated our opinion as Good Clinical Practice sphincter function, are relatively spared, but may be Points (GCPP).
involved in some patients. Cognitive dysfunction occursin 20–50% of cases, and 5–15% develop dementia usually of frontotemporal type. Death because ofrespiratory failure follows on average 2–4 years after Diagnosing ALS is usually straightforward if the patient symptom onset, but 5–10% of patients may survive for has progressive, generalized symptoms in the bulbar and a decade or more [2]. The mean age of onset is 43– limb regions (Table 1) [7]. Diagnosis early in the course 52 years in familial and 58–63 years in sporadic cases of of the disease when the patient has symptoms limited to ALS [3]. The life-time risk of developing ALS is 1 in one or two regions (bulbar, upper limb, trunk, lower 350–500, with male sex, increasing age and hereditary limb) may be difficult and depends on the presence of disposition being the main risk factors [3–5].
signs in other regions and supportive findings in ancill-iary investigations [7–9] (class IV). The mean time fromthe onset of symptoms to confirmation of the diagnosis of ALS is 10–18 months [10,11] (class IV). Delays may From 2008 through February 2011, we searched the arise if early or intermittent symptoms are unrecognized or denied by the patient, or because of inefficient referral (CENTRAL) (The Cochrane Library to date); MED- pathways to a neurologist. There are cogent reasons for LINE-OVID (January 1966 on); MEDLINE-ProQuest; making the diagnosis as early as possible [12]. Psycho- MEDLINE-EIFL; EMBASE-OVID (January 1990 logically, the absence of a definitive diagnosis, even of a on); the Science Citation Index (ISI); the National disorder carrying a poor prognosis, causes distress and Research Register; the Oxford Centre for Evidence- anxiety. Early diagnosis may obviate onerous and based Medicine; the American Speech Language potentially expensive tours of the healthcare system and Hearing Association (ASHA); the World Federation of facilitate future planning. Early diagnosis may also Neurology ALS page of reviews of published research; provide opportunities for treatment with neuroprotec- the Oxford Textbook of Palliative Medicine, the UK tive agents at a time when fewer cells are irreversibly Department of Health National Research Register compromised. Studies in experimental animal models and humans with SOD1 gene mutations indicate that AtoZ/DH_4002357) and national neurological data- the loss of motor neurons is preceded by a period of cellular dysfunction [13] which may be reversible.
ac.uk/). There were no constraints based on language or Our objective is to present guidelines for making the publication status. Conflicts of interest were disclosed.
correct diagnosis as early as possible. As no single Panellists were not compensated.
investigation is specific for ALS, and there is no Table 1 Diagnostic criteria for ALS Method for reaching consensus The diagnosis of ALS requires the presence of: (positive criteria) Initially, two investigators performed an independent Lower motor neuron signs (including EMG features in clinically literature search for each of 13 subjects addressed. Each unaffected muscles) pair of investigators prepared a written analysis that Upper motor neuron signs was communicated and discussed by email with the Progression of symptoms and signs The diagnosis of ALS requires the absence of (diagnosis by exclusion): other members of the task force. A combined draft was then written by the chairman and circulated to the task Sphincter disturbances force for further discussions. All recommendations had Visual disturbances to be agreed to by all members of the task force Autonomic features Basal ganglion dysfunctionAlzheimer-type dementiaALS ÔmimicÕ syndromes (Table 3) The diagnosis of ALS is supported by: Fasciculations in one or more regions The literature concerning 13 issues in the management Neurogenic changes in EMG results of ALS was evaluated by the task force. The findings Normal motor and sensory nerve conductionAbsence of conduction block were evaluated according to the recommendations ofthe European Federation of Neurological Societies ALS, amyotrophic lateral sclerosis; EMG, electromyography.
Ó 2011 The Author(s)European Journal of Neurology Ó 2011 EFNS European Journal of Neurology P. M. Andersen et al.
Table 2 Diagnosing amyotrophic lateral sclerosis/motor neuron disease: recommended investigations in selected cases Clinical chemistryBlood Erythrocyte sedimentation rate C-reactive protein Haematological screen ASAT, ALAT, lactate dehydrogenase Thyroid-stimulating hormone, free T4, free T3 hormone assays Vitamin B12 and folate Serum protein electrophoresis Electrolytes (Na+, K+, Cl), Ca2+, HPO2 ) Hexoaminidase A and B assay Ganglioside GM-1 antibodies Anti-Hu, anti-MAG RA, antinuclear antibodies, anti-DNA Anti-acetylcholine receptor and anti-muscle-specific receptor tyrosine kinase antibodies Serology (Borrelia, virus including HIV) DNA analysis (for SOD1, SMN, SBMA, TDP43, FUS) Total protein concentration Protein electrophoresis including IgG index Serology (Borrelia, virus) Ganglioside antibodies Lead (24-h secretion) Nerve conduction velocity Magnetic resonance imaging/computed tomography (cranial/cervical, thoracic, lumbar) sensitive and specific disease biomarker, diagnosis is Great care should be taken to rule out diseases that based on symptoms, clinical examination findings and can masquerade as ALS (Table 3) [15,16]. In specialist the results of electrodiagnostic, neuroimaging and lab- practice, 5–8% of apparent patients with ALS have an oratory studies (Tables 1 and 2) [14].
alternative diagnosis, which may be treatable in up to Ó 2011 The Author(s) European Journal of Neurology Ó 2011 EFNS European Journal of Neurology EFNS Task Force on Management of ALS Table 3 Diseases that can masquerade as ALS.
Table 3 (Continued) Anatomical abnormalities/compression syndromes ÔStiff person plusÕ syndromes Arnold–Chiari type 1 and other hindbrain malformations Cervical, foraman magnum or posterior fossa region tumours Electric shock neuronopathy Cervical disc herniation with osteochondrosis Cervical meningeoma Vascular disorders Retropharyngeal tumour Spinal epidural cyst DejerineÕs anterior bulbar artery syndrome Spondylotic myelopathy and/or motor radiculopathy Acquired enzyme defects Other neurological conditions Adult GM2 gangliosidosis (hexosaminidase A or B deficiency) Western Pacific atypical forms of MND/ALS (Guam, New Guinea, Polyglucosan body disease Kii Peninsula of Japan) PompeÕs Disease (Glycogen Storage Disease type II) Carribean atypical forms of MND–dementia–PSP (Guadeloupe) Autoimmune syndromes Madras-form of juvenile onset MND/ALS (South India) Monoclonal gammopathy with motor neuropathy Frontotemporal dementia with MND/ALS (including PickÕs Multifocal motor neuropathy with/without conduction block disease with amyotrophy) Dysimmune lower motor neuron syndromes (with GM1, GD1b Multiple system atrophy and asialo-GM1 antibodies) Olivo-ponto cerebellar atrophy syndromes Other dysimmune lower motor neuron syndromes, including CIDP Primary lateral sclerosis (some subtypes not related to ALS) Multiple sclerosis Progressive encephalomyelitis with rigidity Myasthenia gravis (in particular the anti-muscle-specific receptor tyrosine kinase positive variant) Hereditary spastic paraplegia (many variants, some subtypes with Endocrine abnormalities distal amyotrophy) Allgrove syndrome Progressive spinal muscular atrophy (some subtypes not related Diabetic ÔamyotrophyÕ Insulinoma causing neuropathy Spinobulbar muscular atrophy with/without dynactin or Hyperthyroidism with myopathy Hypothyroidism with myopathy Spinal muscular atrophy I–IV Brown–Vialetto–van Laere syndrome (early-onset bulbar and Hyperparathyroidism (secondary due to vitamin D deficiency) spinal ALS with sensorineural deafness) Hypokalemia (ConnÕs syndrome) Fazio–Londe syndrome (infantile progressive bulbar palsy) Harper–Young syndrome (laryngeal and distal spinal muscular Lead (?), mercury (?), cadmium, aluminium, arsenic, thallium, manganese, organic pesticides; neurolathyrism, konzo Monomelic sporadic spinal muscular atrophy (benign focal amyotrophy, including Hirayama syndrome) Acute poliomyelitis Polyneuropathies with dominating motor symptoms (like hereditary Post-poliomyelitis progressive muscular atrophy syndrome motor and sensory neuropathy type 2, hereditary motor HIV-1 (with vacuolar myelopathy) neuropathy type 5) HTLV-1-associated myelopathy (tropical spastic paraplegia) Familial amyloid polyneuropathy Benign fasciculations Syphilitic hypertrophic pachymeningitis Spinal encephalitis lethargica, varicella-zosterTrichinosis ALS, amyotrophic lateral sclerosis; MND, motor neuron disease; PSP, Brucellosis, cat-scratch disease Progressive supranuclear palsy.
Cachectic myopathy 50% of the cases [16–19] (class IV). An evolution of Carcinoid myopathy atypical symptoms and a lack of progression of typical symptoms are the most important Ôred flagsÕ suggesting Inclusion body myositisInflammatory myopathies an alternative diagnosis [16]. The diagnosis should be Nemaline myopathy regularly reviewed [18,19]. The revised El Escorial cri- teria [20, summarized in Table 4] are excessively restrictive and are not designed for use in routine clin- Neoplastic syndromes ical practice [21]. The new Awaji electrodiagnostic Chronic lymphocytic leukaemiaIntramedullary glioma algorithm [22] added to the El Escorial criteria Lymphoproliferative disorders with paraproteinemia and/or improves diagnostic sensitivity with no loss in specific- oligoclonal bands in the cerebrospinal fluid ity [23] and improves early diagnosis as shown in sev- Pancoast tumour syndrome eral class IV studies [24–27]. The clinician must decide, Paraneoplastic encephalomyelitis with anterior horn cell on the balance of probability, whether or not the patient has ALS, even in the absence of unequivocal Ó 2011 The Author(s)European Journal of Neurology Ó 2011 EFNS European Journal of Neurology P. M. Andersen et al.
Table 4 The Revised El Escorial research diagnostic criteria for ALS Table 5 How should a physician tell patients that they have ALS? with the Awaji electrodiagnostic algorithm included – a summary(Modified from [20] and [22]) Clinically definite ALS Quiet, comfortable and private UMN and LMN clinical signs or electrophysiological evidence In person, face-to-face Convenient time (at least 45–60 min) Clinically definite ALS – laboratory supported Enough time to ensure there is no rushing or UMN and/or LMN clinical signs in one region and the patient is a carrier of a pathogenic SOD1-gene mutation Make eye contact and sit close to the patient Clinically probable ALS Know the patient before the meeting, including the UMN and LMN clinical or electrophysiological evidence by LMN family, emotional and social situation, case history, and UMN signs in two regions with some UMN signs rostral to the and all relevant test results. Have all the facts at Clinically possible ALS Have the patientÕs support network present UMN and LMN clinical or electrophysiological signs in one region (relatives), it is often an advantage that the patients network ÔoutnumberÕ the hospital staff present at UMN signs in at least two regions, or the meeting. Have a clinical nurse specialist or UMN and LMN signs in two regions with no UMN signs rostral to social counsellor available.
LMN signs. Neuroimaging and laboratory studies (Table 2) have Find out what the patient already knows about the excluded other diagnoses.
Ascertain how much the patient wants to know ALS, amyotrophic lateral sclerosis; EMG, electromyography; LMN, about ALS and tailor your information accordingly lower motor neuron; UMN, upper motor neuron.
Give a warning comment that bad news is coming.
The whole truth may need to come by instalmentsUse the correct ALS-term, not Ôwear and tear of upper and lower motor neuron signs [28]. Experience the motor nervesÕ suggests that pursuing an early diagnosis of ALS out- Explain the anatomy of the disease (make a simple weighs the potential increase in risk of misdiagnosis If the patient indicates that they want to know the course of the disease, be honest about the likelyprogression and prognosis, but give a broad time frame and recognise the limitations of any 1. The diagnosis should be pursued as early as possible.
Patients in whom ALS is suspected should be referred Say that there is currently no cure and symptoms with high priority to an experienced neurologist tend to steadily worsen Mention that prognosis is highly variable and that some patients survive for 5, 10 or more years 2. All suspected new cases should undergo prompt de- Acknowledge and explore the patientÕs reaction and tailed clinical and paraclinical examinations (see allow for emotional expression Tables 1 and 2) (GCPP).
Summarise the discussion verbally, in writing, and/ 3. In some cases, additional investigations may be or on an audiotape needed (see Table 2).
Allow time for questions Acknowledge that this is devastating news, but 4. Repetition of the investigations may be required if discuss reasons for hope such as research, drug initial tests are equivocal (GCPP).
trials and the variability of the disease 5. Review of the diagnosis is advisable if there is no Explain that the complications of ALS are treatable evidence of typical progression or the patient develops Reassure that every attempt will be made to atypical features (see Table 1) (GCPP).
maintain the patientÕs function and that thepatientÕs treatment decisions will be respected Reassure that the patient will continue to be cared for and will not be abandoned Breaking the news: communicating the diagnosis Inform about patient support groups (offer contact Imparting a diagnosis of ALS requires skill. If not details and leaflets) performed appropriately, the effect can be devastating, Inform about neuroprotective treatment (i.e.
riluzole) and ongoing research leaving the patient with a sense of abandonment and Discuss opportunities to participate in research destroying the patient–physician relationship [29] (class treatment protocols (if available) III). More than half of surveyed patients and caregivers Acknowledge a willingness to get a second opinion if state that they are dissatisfied by the manner in which the patient wishes the diagnosis has been communicated [29,30] (class IV).
Emotional manner: warmth, caring, empathy, Studies of other fatal illnesses [31] demonstrate advan- Be honest and sympathetic, but not sentimental tages in using specific techniques such as those outlined Give news at the personÕs pace; allow the patient to in Table 5 [32]. Patients/caregivers are more satisfied if dictate what he or she is told Ó 2011 The Author(s) European Journal of Neurology Ó 2011 EFNS European Journal of Neurology EFNS Task Force on Management of ALS Table 5 (Continued) are likely to contribute to the increased survival of thoseattending multidisciplinary clinics [36,38,40,41]. Ter- tiary centres can also increase quality of life of patients Simple and careful word choice, yet direct; no with ALS (class III), perhaps related to a greater pro- euphemisms or medical jargon vision of appropriate aids and appliances [40,42,43].
Modified from [1].
Recommendations1. Multidisciplinary care should be available for people effective communication strategies are used, and more affected by ALS. Attendance at multidisciplinary clinics time is spent discussing the diagnosis [30,33] (class IV).
may extend survival, decrease medical complications Callous delivery of the diagnosis may affect the fami- (level B) and improve quality of life (level C).
liesÕ/carersÕ psychological adjustment to bereavement 2. The following specialists should be part of or readily later [34] (class IV).
available to the multidisciplinary clinic team: neurolo-gist, respiratory physician, gastroenterologist, rehabili- 1. The diagnosis should be communicated by a con- occupational therapist, speech therapist, respiratory sultant with a good knowledge of the patient (GCPP).
therapist, specialized nurse, physical therapist, dietitian, 2. The physician should start the consultation by asking psychologist, dentist and palliative care physician what the patient already knows or suspects (GCPP).
3. The diagnosis should be given in person, ensuring enough time for discussion (suggest at least 45–60 min).
2–3 months, although they may require more frequent Provide printed materials about the disease, about review in the months following diagnosis or in the later support and advocacy organizations and informative stages of disease, and less frequent review if their dis- websites. A copy letter summarising the discussion can ease is progressing slowly. The patient support team be helpful for patients and carers (GCPP).
should maintain regular contact with the patient and 4. Assure patients that they will not be ÔabandonedÕ by relatives between visits (GCPP).
healthcare services and will be supported by a profes- 4. Ideally, the patient should be followed by the same sional ALS care team (where available), with regular neurologist liaising closely with the patientÕs primary follow-up visits to a neurologist. Make arrangements care physician (family general practitioner) (GCPP).
for a first follow-up visit, ideally within 2–4 weeks 5. Effective channels of communication and co-ordi- nation are essential between the hospital-based multi- 5. Avoid the following: withholding the diagnosis, disciplinary clinic team, the primary healthcare sector, providing insufficient information, imposing unwanted the palliative care team and community services information, delivering information callously, taking away or not providing hope (GCPP).
ALS caregivers and burden of care Multidisciplinary care ALS causes progressive loss of independence and an Specialist multidisciplinary clinics (tertiary centres) can increased need for help with activities of everyday life.
provide optimized diagnostic and management services Carers progressively increase the time they devote to for patients with ALS [28,32,35,36]. Comparisons caring [44]. The caregiversÕ burden relates to personal between clinic-based cohorts and population-based and social restrictions and to psychological and emo- cohorts of patients have confirmed a referral bias: patients attending multidisciplinary clinics tend to be frequently search for information about ALS, and younger and to have had symptoms for longer than many actively participate in interactions between the those who do not [35–39] (Class II). An independent patient and physician, from the time of diagnosis survival benefit has been identified in two studies (Class through to decision-making regarding advance direc- II) [36,38], more relevant in bulbar patients, whilst an- tives and end-of-life care. Certain ALS symptoms cause other study has shown no effect [39]. Patients attending particular strain in carers. If the patient loses effective multidisciplinary clinics have fewer hospital admissions communication, carers can become intellectually and and shorter inpatient stays than those who attend emotionally isolated. The use of augmentative alterna- general clinics [36] (Class II). The increased use of tive communication devices can help to restore com- riluzole and non-invasive ventilation, attention to munication. Several studies have shown that the nutrition and earlier referral to palliative care services provision of mechanical ventilation for patients causes Ó 2011 The Author(s)European Journal of Neurology Ó 2011 EFNS European Journal of Neurology P. M. Andersen et al.
particular strain on caregivers, reducing their quality of studies did not include patients with early disease. La- life and raising their responsibilities related to manag- ter, retrospective Phase IV studies from five clinical ing the ventilator and providing for the increasing databases indicate that the overall gain in survival (i.e.
caring costs (Class IV) [47–49]. Sexuality may be a over the whole extent of the disease course) may extend problematic issue for many ALS patient–caregiver from 6 (Class III) [60], 10 (Class IV) [61], 12 (Class IV) couples. Reported problems include decreased libido, [62], 14 (Class IV) [63] or 21 (Class IV) [64] months, passivity of the partner and the carerÕs own passivity.
although these estimates are almost certainly subject to The most frequent reasons cited were the physical statistical biases. The drug is safe, with few serious side weakness and the body image changes because of ALS effects. Fatigue was a side effect in 26% of patients (Class IV) [50].
taking riluzole compared with 13% receiving placebo Half of patients with ALS in a cohort from the UK (number needed to harm = 8) [55]. Although patients and Germany died at home [51]. The anticipation of with progressive muscular atrophy or primary lateral patientsÕ imminent deaths may increase caregiver dis- sclerosis were not included in the riluzole trials, path- tress and anxiety. However, Neudert et al. report that ological and genetic studies show that some patients most patients with ALS die peacefully and no patient with progressive muscular atrophy and primary lateral Ôchokes to deathÕ if good palliative care measures are in sclerosis fall within the ALS syndrome, so may benefit place (Class IV) [51].
from the drug [16,65] (Class IV). Riluzole may have Some caregivers go through a grieving process starting little effect in late-stage ALS, and it is not clear whether from the time that diagnosis is given [52,53]. Anticipa- and when treatment should be terminated. A large tion of future loss is as important as the loss itself in number of other drugs have been tested in ALS, leading to psychological difficulties. Caregivers risk unfortunately with negative results (Table 6).
feelings of burn out, repercussions from forced changesin living arrangements and financial hardships [53,54].
Recommendations1. Patients with ALS should be offered treatment with riluzole 50 mg twice daily (level A).
1. Caregivers should be acknowledged in their double 2. Treatment should be initiated as early as possible role in the disease process: they are the most important after diagnosis (GCPP). Realistic expectations for resource for the patient, yet they are affected them- treatment effects and potential side effects should be selves, and their own needs as carers need to be discussed with the patient and caregivers (GCPP).
addressed (GCPP).
3. Patients with progressive muscular atrophy, primary 2. Ideally, caregivers should be involved from the time lateral sclerosis or hereditary spastic paraplegia should of diagnosis, whilst preserving patientsÕ autonomy as a rule not be treated with riluzole (GCPP).
4. Irrespective of familial disposition, all patients with a 3. CarersÕ own health needs should be considered.
symptomatic progressive MND and carrying a SOD1 Physical, psychological and spiritual support should be gene mutation should be offered treatment with riluzole provided when needed (GCPP).
4. Maintaining communication between patients and 5. Currently, there is insufficient evidence to recom- caregivers is important (GCPP).
mend treatment with vitamins, testosterone, antioxi- 5. The likelihood of a peaceful death process should be dants such as co-enzyme Q-10 and gingko biloba, communicated to patients and their caregivers/relatives interferons, Copaxone, KDI tripeptide, neurotrophic 6. Bereavement counselling and support should be factors (including BDNF, IGF-1 and mecasermin offered to all caregivers (GCPP).
rinfabate), ceftriaxone, creatine, gabapentin, minocy-cline, stem cells or lithium (GCPP).
Symptomatic treatment To date, riluzole is the only drug that has been shown toslow the course of ALS in four Class I studies [55–58]; a Symptomatic treatment aims to improve the quality of Cochrane review has also been published [59]. Oral life of patients and caregivers. Symptoms should be administration of 100 mg riluzole daily improved the treated as they become prominent and incapacitating.
1-year survival by 15% and prolonged survival by3 months after 18 monthsÕ treatment. There was a clear dose effect. Eleven people needed to be treated Sialorrhoea (drooling or excessive salivation) is com- with riluzole to delay one death for 12 months. These mon and may be socially disabling. Amitriptyline is Ó 2011 The Author(s) European Journal of Neurology Ó 2011 EFNS European Journal of Neurology EFNS Task Force on Management of ALS Table 6 (Continued) Table 6 Summary of the most important controlled therapeuticstudies in amyotrophic lateral sclerosis Intracerebroventricular delivery of VEGF IGF-1, Insulin-like growth factor.
Branched-chain amino acids* *No therapeutic benefit was observed.
often used, but there are no formal studies proving its Ciliary neurotrophic factor* efficacy [66]. Oral doses of 10 mg three times a day are often sufficient. Atropine drops, 0.5% or 1%, administered three or four times a day sublingually have the advantage of a short duration of action – valuable in patients who suffer from sialorrhoea Glial-derived neurotrophic factor* alternating with an uncomfortably dry mouth. Gly- copyrrolate (in nebulized or i.v. form) has been shown to be effective in patients with ParkinsonÕs disease [67] (Class I), but there are no studies in ALS. Transder- mal hyoscine (scopolamine), 1.5 mg every third day, Lymphoid irradiation* reduces salivary flow (Class IV) [68,69]. Care is needed in elderly patients, because of the frequent side effects of confusion or loss of bladder control. Studies with botulinum toxin (type A) (Class IV) [70–72] and a single randomized trial with botulinum toxin type B (Class I) [73] injected into the salivary glands reduced saliva in patients with refractory sialorrhoea. The injections were well tolerated. Caution is needed in patients with significant bulbar palsy as increased dysphagia may occur, with serious consequences [74].
Another option is external irradiation of the salivary glands, with four studies showing satisfactory results Verapamil*Vitamin E* (Class IV) [75–78]. Surgical interventions may lead to problematic effects such as increased secretion of thick Ongoing Phase II/III trials (2009–2011) Cistanche total glycosidesCombination therapy (celecoxib, creatine, minocycline) Treat sialorrhoea in ALS with amitriptyline, oral or transdermal hyoscine, or sublingual atropine drops Granulocyte colony-stimulating factor 1. In patients with refractory sialorrhoea, botulinum R(+) pramipexole (KNS-760704) toxin injections into the parotid and/or submandibular gland are effective and generally well tolerated (level B for botulinum toxin type B, level C for type A toxin).
2. Irradiation of the salivary glands may be tried when pharmacological treatment fails (GCPP).
3. Surgical interventions are not recommended (GCPP).
SOD1 DNA antisense oligonucleotidesTauroursodeoxycholic acid Phase III trials being planned or considered Bronchial secretions Patients with bulbar or respiratory insufficiency com- monly report difficulties in effectively clearing tenacious IGF-1 – viral delivery sputum, and mucus accumulation is a negative prognostic factor in patients with ALS treated with Ritonavir and hydroxyurea non-invasive ventilation [80]. The mucosa of the nasalcavity, larynx, trachea, bronchial airways and lungs Ó 2011 The Author(s)European Journal of Neurology Ó 2011 EFNS European Journal of Neurology P. M. Andersen et al.
contribute a constant flow of serous and mucoid fluids.
3. A combination of dextrometorphan and quinidine Medication with mucolytics like guaifenesin or N-ace- has been shown to be effective (level A).
tylcysteine, a beta-receptor antagonist (such as meto-prolol or propranolol) [81] (Class IV), and/or an anticholinergic bronchodilator like ipratropium and/or Cramps may be a troublesome symptom, particularly at theophylline, or even furosemide, may be of value, but night. A single randomized controlled trial with tetra- no controlled studies in ALS exist. Mechanical cough- hydrocannnabinol failed to show efficacy in patients assisting devices (insufflator–exsufflator) via a face with ALS with moderate to severe cramps [90] (Class I).
mask have been effective in patients with ALS in Levetiracetam was beneficial in an open-label small uncontrolled trials [82,83] (Class IV).
pilot study [91] (Class IV). Quinine sulphate has beenbanned by the FDA because of safety concerns [92].
However, a recent Cochrane Review in non-ALS 1. A mucolytic including N-acetylcysteine, 200–400 mg cramps found quinine sulphate to be effective with no three times daily, may be beneficial (GCPP).
difference serious adverse events between the placebo 2. Beta-receptor antagonists and a nebulizer with saline and active drug [93]. Treatments such as massage, and/or an anticholinergic bronchodilator and/or a physical exercise, hydrotherapy in heated pools, car- mucolytic and/or furosemide may be used in combi- bamazepine, diazepam, phenytoin and verapamil have nation. Mucolytics should only be used if sufficient been tried, but there are no controlled studies in ALS.
cough flow is present (GCPP).
3. The patient and carer should be taught the technique of assisting expiratory movements using a manual-assisted 1. Levetiracetam may be tried. If unsuccessful or side cough (can also be performed by a physical therapist) effects, quinine sulphate (200 mg twice daily) may be of benefit (GCPP).
4. The use of a mechanical insufflator–exsufflator may 2. Physiotherapy, physical exercise and/or hydrother- be helpful, particularly in the setting of an acute apy may be helpful (GCPP).
respiratory infection (GCPP).
5. A portable home suction device and a room humidifier may be of use (GCPP).
Physical therapy is the mainstay of treatment of spas-ticity in ALS and has been found effective (Class III) Pseudobulbar emotional lability [94]. Other interventions such as hydrotherapy, heat, Emotional lability occurs in at least 50% of patients cold, ultrasound, electrical stimulation, chemodener- with ALS irrespective of the presence or absence of vation and in rare cases surgery have been used, bulbar motor signs [84]. Emotional lability does not although no controlled studies in ALS exist. In patients correlate with cognitive impairment [85]. Prominent with ALS, intractable spasticity, and associated pain, pseudobulbar features such as pathological weeping, intrathecal baclofen was more effective than oral med- laughing or yawning can be socially disabling and affect ication and greatly improved patientsÕ quality of life patientsÕquality of life. The most commonly used agents (Class IV) [95,96]. Although not formally tested in are tricyclic antidepressants and selective serotonin ALS, in clinical practice, gabapentin (900–2400 mg reuptake inhibitors (SSRIs), which were effective in daily), tizanidine (6–24 mg daily), memantine (10– small placebo-controlled studies or case series [86,87] 60 mg daily), dantrolene (25–100 mg daily), tetrazepam (Class IV). Two randomized controlled trials of a fixed (100–200 mg daily) and diazepam (10–30 mg daily) dose combination of dextrometorphan and quinidine have been used. Botulinum toxin A has successfully have shown efficacy in improving emotional lability and been used to treat trismus and stridor in single cases quality of life [88,89] (Class I). This medication has been approved by the US FDA.
1. Regular physical therapy can help relieve significant 1. Inform the patient and relatives that emotional spasticity (GCPP).
lability is not a sign of an additional mood disorder but 2. Antispastic drugs such as baclofen and tizanidine is because of the effects of ALS on the brain (GCPP).
may be tried (GCPP).
2. Troublesome emotional lability should be treated 3. If spasticity is severe despite oral medications, (GCPP). Antidepressants such as amitriptyline (in intrathecal baclofen may be helpful (GCPP).
particular in patients with drooling), fluvoxamine and 4. Hydrotherapy with exercises in warm pools (32– citalopram are usually sufficient (level C).
34°C) and cryotherapy may be considered (GCPP).
Ó 2011 The Author(s) European Journal of Neurology Ó 2011 EFNS European Journal of Neurology EFNS Task Force on Management of ALS Depression and anxiety There are no studies regarding the management of DVT Depression and anxiety occur frequently in patients in patients with ALS.
with ALS and their caregivers [98]. Anxiety is particu-larly prevalent during the diagnostic and terminal phases [99]. No formal studies with antidepressants 1. DVT should be treated with anticoagulants (GCPP).
have been conducted in patients with ALS, but empir- 2. The optimum management of risk factors for venous ically tricyclic antidepressants (e.g. amitriptyline) and thrombosis should be pursued. Physiotherapy, limb SSRIs such as escitalopram may be effective. Mirtaza- elevation and compression stockings are recommended pine may be better tolerated in the later stages than SSRIs or amitriptyline. The choice may be guided by 3. There is currently insufficient evidence to recommend additional symptoms (e.g. sialorrhoea, insomnia, apa- prophylactic medical treatment with anticoagulants.
thy, appetite loss), which are differently affected by thevarious antidepressants. There are no systematic studies Unproven therapies on anxiolytics in ALS. Some antidepressants, such asescitalopram, exert anxiolytic effects, but additional Patients with ALS frequently use complementary and oral diazepam or sublingual lorazepam, may be neces- alternative medicines (CAM) suchs as vitamins, herbal supplements, homoeopathy and acupuncture [105].
Series of Class IV trials have tested interferon-alfa [106], human recombinant SOD1 [107], ciliary neurotrophic 1. Treat depression in ALS with an appropriate anti- factor [108], brain-derived neurotrophic factor [109] depressant, for example amitriptyline, an SSRI, or and similar drugs, all without evidence of clinical ben- mirtazapine. SSRI may be preferably in elderly or efit. Insulin-like growth factor-1 has been injected cognitively impaired patients (GCPP).
intrathecally safely, with a modest clinical effect 2. Treat anxiety with bupropion or benzodiazepines reported [110] (Class IV). In randomized, controlled such as diazepam tablets or suppositories, Temesta and open studies, liquorpheresis (filtration of cerebro- tablets 0.5 mg two or three times daily, or sublingual spinal fluid) has been performed in 11 patients with lorazepam (GCPP).
ALS, without clinical effect [111,112] (Class IV). APhase 1 safety study of hyperbaric oxygen therapy Insomnia and fatigue reported some efficacy on fatigue in four of five patients Insomnia is common in the final months of life in with ALS [113], whilst a phase II study was reported as patients with ALS [100]. There are likely to be several negative [114] (Class IV). Repetitive transcranial mag- causes, including depression, cramps, pain and respi- netic stimulation of the motor cortex had a beneficial ratory distress, which if identified should be treated.
effect in a pilot trial (Class IV) [115] but did not delay For insomnia in ALS, amitriptyline and zolpidem are functional deterioration in a double-blind placebo- the most commonly used medications [66]. Fatigue is a controlled study in 20 patients [116] (Class III).
frequent and potentially debilitating symptom. It may Stem cell therapy is still in experimental development be of central and/or peripheral origin [100]. One open- in ALS. The intravenous, intrathecal or intraparen- label study and one small Class I study with modafinil chymal administration of haematopoietic stem cells revealed a significant reduction of fatigue with a num- derived from peripheral blood or bone marrow has ber-needed-to-treat of 1.6 [101,102]. However, the long- been tested in small series of patients [117–122] (Class term effects in ALS have not yet been studied.
IV). Even if these procedures are safe in the short term,the studies to date have not yielded sufficiently robust data to allow translation to clinical practice [123].
1. Treat insomnia with amitriptyline, mirtazapine or Clinical efficacy is unproven, and long-term safety still appropriate hypnotics (e.g. zolpidem) (GCPP).
needs to be demonstrated.
2. For debilitating fatigue, modafinil may be considered A number of patients with ALS have, in a non-scientific setting, received intracerebral transplantation of olfac-tory ensheathing cells [124,125], resulting in serious side Venous thrombosis effects in some [126] (Class IV).
Patients with ALS have an increased risk of deepvenous thrombosis (DVT), with an annual incidence rate of at least 2.7% [103,104]. The increased risk cor- 1. Before cellular therapies become a reality, a more relates with greater immobility and impaired respira- thorough preclinical evaluation and elucidation of tory function, but is independent of the patientÕs age.
several open questions is mandatory (GCPP).
Ó 2011 The Author(s)European Journal of Neurology Ó 2011 EFNS European Journal of Neurology P. M. Andersen et al.
2. No well-designed clinical trials testing cellular ther- 127] (Class IV). There is no specific therapy for patients apies have as yet been completed demonstrating safety with SOD1 gene mutations, but three clinical trials and clinical efficacy supported by pathological evidence targeting SOD1 specifically are currently underway.
in a sufficient number of patients.
Presymptomatic (predictive) genetic testing is possible 3. Patients with ALS should be carefully informed but is a sensitive issue with emotional, ethical and legal about existing reliable data related to cell therapies. All implications that must be addressed before analysis current treatments with cell transplantation are purely should take place [131]. Special consideration should be experimental, and there is no proven effect on disease taken before presymptomatic testing is performed in outcome. If they decide to undergo transplantation, familial ALS families where the mutation is associated thorough examination before and after the stem cell with reduced disease penetrance or variable prognosis treatment should be performed and documented to (Class IV) [65,127,130].
improve the knowledge of benefits and/or side effects(GCPP).
4. Accurate and unbiased information related to cell 1. In all patients with suspected ALS, progressive therapies and other unproven/alternative therapies muscular atrophy, primary lateral sclerosis or fronto- needs to be delivered to the patient community (GCPP).
temporal dementia, a detailed medical history of the 5. All procedures involving the injection and trans- patient, siblings, parents and grandparents and their plantation of stem cells to a patient with ALS should be siblings should be obtained to potentially disclose a considered experimental and should be approved by a medical research ethical review board and performed in full accordance with the Declaration of Helsinki 2. Clinical DNA analysis for gene mutations should (WMA, 1964) (GCPP).
only be performed in cases with a known family historyof ALS, and in sporadic ALS cases with the charac-teristic phenotype of the recessive D90A mutation Genetic testing and counselling In different populations, the frequency of familial ALS 3. Clinical DNA analysis for gene mutations should not is between 5 and 23% of all ALS cases [2,3,127]. Since be performed in cases with sporadic ALS with a typical 1993, mutations in ten genes – SOD1, VAPB, SETX, classical ALS phenotype (GCPP).
ALSIN, ANG, FUS, TARDBP, ATXN2, OPTN and 4. In familial or sporadic cases where the diagnosis is VCP – have been associated with ALS (http://alsod.
uncertain, SMN, androgen receptor or TARDBP, FUS, iop.kcl.ac.uk/als/). Mutations in the latter nine genes ANG or SOD1 DNA analysis may accelerate the appear to be rare, it is unclear whether all reported diagnostic process (GCPP).
mutations are pathogenic, and analysis of these genes is 5. Before blood is drawn for DNA analysis, the patient at present usually only performed in research settings. A should receive genetic counselling. Give the patient time few patients (often diagnosed as sporadic ALS) with for consideration. DNA analysis should be performed mutations in other genes have also been reported, but only with the patientÕs informed consent (GCPP).
causation remains to be proved. Since 1993, 164 muta- 6. Presymptomatic genetic testing should only be per- tions have been reported in the SOD1 gene (http:// formed in first-degree adult blood relatives of patients alsod.iop.kcl.ac.uk/als/). The most frequent mutation is with a known gene mutation. Testing should only be the D90A, which in many European countries is inher- performed on a strictly voluntary basis as outlined ited as a recessive trait with a characteristic slowly (Table 7) and should follow accepted ethical principles progressing phenotype, although pedigrees with domi- nantly (heterozygous) inherited D90A-SOD1 and an 7. Results of DNA analysis performed on patients and aggressive phenotype have also been reported [65,128].
their relatives as part of a research project should not be Around 12–23% of patients diagnosed with familial used in clinical practice or disclosed to unaffected rela- ALS carry a SOD1 mutation [127]. SOD1, FUS and tives. The research results should be kept in a separate file TARDBP mutations have been described in a small and not in the patientÕs standard medical chart (GCPP).
proportion of apparently sporadic patients with ALS,suggesting that some mutations have reduced disease Respiratory management in patients with ALS penetrance [http://alsod.iop.kcl.ac.uk/als/, 65,127–130].
A DNA SOD1 diagnostic test speeds up the diagnostic Respiratory complications are the main cause of death process and can be of help in diagnosing patients with in ALS (Fig. 1), primarily as a consequence of atypical features [65,127,130], as well as providing some diaphragmatic weakness combined with aspiration and infection [132]. Erect forced vital capacity and vital Ó 2011 The Author(s) European Journal of Neurology Ó 2011 EFNS European Journal of Neurology EFNS Task Force on Management of ALS Table 7 Guidelines for presymptomatic genetic testing amyotrophic lateral sclerosis The test subject should belong to a family with a known SOD1, FUS or TARDBP gene mutation The test subject should be a first-degree relative of an affected blood relative, or a second-degree relative of an affected case if the first-degree relative is deceased The test subject should be 18 years or older The test subject should be mentally and physically healthy The test subject should not be under emotional stress (e.g. recently married or divorced, has become unemployed, pregnant, etc.) The test subject should participate as a volunteer without influence from a third party The test subject should receive a minimum of two genetic counselling sessions before the blood is drawn The test subject can request more than two genetic counselling sessions Genetic counselling should be given by professionals with a specific knowledge about amyotrophic lateral sclerosis and genetics After the blood sample has been drawn, the mutation analysis should be performed as quickly as possible to minimise the emotional discomfort of the procedure The test subject should be informed of the test result at a personal meeting with a genetic counsellor. The test result should never be given by letter or electronic communication It is advisable that the test subject be accompanied by a close friend at the genetic counselling sessions and when the test result is announced The test subject can at any time demand that the blood sample and test records be destroyed The test subject can at any time and without explanation withdraw from the test procedure and choose not to be informed of the test result Professional and community resources should be available to deal with the impact of the test result on the test subject and relatives The test result is private and should be kept in a separate file in the medical chart The test result is private, and no third party can request taking part in the result (unless regulated otherwise by national legislation) Respiratory symptoms Table 8 Symptoms and signs of respiratory insufficiency in amyo- and signs (table 8) trophic lateral sclerosis Discuss respiratory Dyspnoea on minor exertion treatment options with patient and family Use of auxilliary respiratory If severe bulbar Frequent nocturnal awakenings Paradoxical movement of the Excessive daytime sleepiness Decreased chest wall movement Difficulty clearing secretions Morning confusion, hallucinations Propose invasive Poor concentration and/or mechanical ventilation Modified from Leigh et al. [28].
nerve responses may predict hypoventilation in ALS Figure 1 Flowchart for the management of respiratory dysfunc- [135]. Blood gas abnormalities are generally a late tion in amyotrophic lateral sclerosis (ALS)/motor neuron disease finding. Cough effectiveness can be assessed by mea- (MND). NIPPV, non-invasive positive pressure.
suring peak cough flow [136].
Non-invasive positive-pressure ventilation and, less capacity are the most widely used tests to evaluate frequently, invasive mechanical ventilation (IMV) are respiratory function and should be performed regularly, used to alleviate symptoms of respiratory insufficiency along with an assessment of symptoms suggestive of and prolong survival. There is no clear evidence respiratory insufficiency (Table 8). Sniff nasal pressure regarding the timing and criteria for use of NIPPV and (SNP) may be more accurate in patients with weak lips, IMV in patients with ALS (Table 9). The use of but neither forced vital capacity nor SNP is a sensitive predictor of respiratory insufficiency in patients with reflecting economic and cultural differences [28,142].
severe bulbar involvement [133]. Percutaneous noctur- Ideally, the patientÕs advance directives and a plan for nal oximetry is an easy tool to screen patients with and management of respiratory insufficiency should be can be useful to determine the need for non-invasive established before respiratory complications occur positive-pressure ventilation (NIPPV) [134]. Phrenic Ó 2011 The Author(s)European Journal of Neurology Ó 2011 EFNS European Journal of Neurology P. M. Andersen et al.
Table 9 Proposed criteria for NIPPV [from references 28,135,138] Table 10 The advantages and drawbacks of invasive mechanicalventilation Symptoms/signs related to respiratory muscle weakness. At least oneof the following Increases survival time Prevents aspiration Ability to provide more effective ventilator pressures and better gas Disturbed sleep due to nocturnal desaturation/arousals Use of auxiliary respiratory muscles at rest Generates more bronchial secretions Paradoxical respiration Increases risk of infection Introduces risk of tracheo-oesophageal fistula, tracheal stenosis or Excessive daytime sleepiness (ESS > 9) Abnormal respiratory function tests. At least one of the following Greatly increased costs Forced vital capacity <80% of predicted value Increased family and carer burden, including 24-h nursing Sniff nasal pressure <40 cmH2O PI max <60 mmH2O Ethical issues regarding discontinuation Significant nocturnal desaturation on overnight oximetryMorning blood gas pCO2 > 45 mmHg ESS, Epworth Sleepiness Score; NIPPV, non-invasive positive- 1. Symptoms or signs of respiratory insufficiency(including symptoms of nocturnal hypoventilation) Non-invasive positive-pressure ventilation increases should be checked at each visit (GCPP).
survival and improves patientsÕ quality of life and is the 2. Forced vital capacity and vital capacity are the most preferred therapy to alleviate symptoms of respiratory available and practical tests for the regular monitoring insufficiency [47,49,137–142] (of which [140] is Class I).
of respiratory function (GCPP).
Treatment is usually initiated at night to alleviate 3. SNP may be used for monitoring, particularly in symptoms of nocturnal hypoventilation (Table 9).
bulbar patients with weak lips (GCPP).
NIPPV improves quality of life and prolongs survival in 4. Percutaneous nocturnal oximetry is recommended as a screening test and for monitoring respiratory function although this has not been confirmed in patients with bulbar onset disease [140,142]. Patients with bulbar palsy 5. Symptoms or signs of respiratory insufficiency should are less compliant with NIPPV, due in part to increased prompt discussions with the patient and caregivers secretions [81]. The use of diaphragmatic pacing or about treatment options and the terminal phase. Early respiratory exercises in ALS is not established [143,144].
discussions are needed to allow advance planning and Invasive mechanical ventilation can prolong survival directives (GCPP).
in ALS, in some cases for many years. However, no 6. NIPPV should be considered in preference to IMV in documented improvement in quality of life has been patients with symptoms or signs of respiratory insuffi- reported, and there is a risk that some patients will ciency (GCPP).
develop a Ôlocked-inÕ state. The availability and cultural 7. NIPPV can prolong survival for many months (level acceptability of IMV in patients with ALS varies A) and may improve the patientÕs quality of life greatly between different countries and cultures. It is costly and has significant emotional and social impacts 8. Active management of secretions and provision of on patients and caregivers (Table 10) [33,48,145,146].
cough-assist devices can increase the effectiveness of Parenteral morphine, a benzodiazepine and an assisted ventilation in ALS (GCPP).
antiemetic are used when the patient decides that ven- 9. IMV has a major impact upon caregivers and tilatory support should be withdrawn [146]. There is should be initiated only after informed discussion Class I evidence for the use of opioids and/or oxygen to treat dyspnoea in patients with terminal cancer or 10. Unplanned (emergency) IMV should be avoided chronic obstructive pulmonary disease [reviewed in through an early discussion of end-of-life issues, co- 147,148], but no controlled studies in ALS exist.
ordination with palliative care teams and appropriate Improving the clearance of bronchial secretions is advance directives (GCPP).
important in patients with ALS to promote quality of 11. Oxygen therapy alone should be avoided as it may life, improve NIV tolerance and decrease the risk of exacerbate carbon dioxide retention and oral dryness.
infection [81]. Cough-assisting devices and chest wall Use oxygen only if symptomatic hypoxia is present oscillation may be of value [149,150].
Ó 2011 The Author(s) European Journal of Neurology Ó 2011 EFNS European Journal of Neurology EFNS Task Force on Management of ALS 12. The medical treatment of intermittent dyspnoea factory and better tolerated than PEG [158–161], but PRG is not widely available. NGT insertion is a minor a for short dyspnoeic bouts: relieve anxiety and give procedure that can be performed on all patients, but it lorazepam 0.5–2.5 mg sublingually; can have drawbacks such as increasing oropharyngeal b for longer phases of dyspnoea (>30 min): give mor- secretions or causing nasopharyngeal discomfort or phine 2.5 mg orally or s.c. (GCPP) even ulceration [162,163].
Recent studies suggest that home parenteral nutrition 13. For the medical treatment of chronic dyspnoea, is possible as an alternative to enteral feeding in patients start with morphine 2.5 mg orally four to six times with advanced ALS and poor respiratory function daily. For severe dyspnoea, give morphine s.c. or as [163,164] (Class IV).
an i.v. infusion. Start with 0.5 mg/h and titrate. Ifneeded, add midazolam (2.5–5 mg) or diazepam for nocturnal symptom control and to relieve anxiety 1. Bulbar dysfunction and nutritional status, including body weight, should be checked at each visit. Difficultydrinking tap water is frequently the first sign of signif-icant dysphagia (GCPP).
Enteral nutrition in patients with ALS 2. Patients should be referred to a dietitian as soon as Weight loss at time of diagnosis is an independent dysphagia appears. A speech and language therapist prognostic factor of survival in ALS [151]. Data indi- can give valuable advice on swallowing techniques cate that patients with ALS have an increased resting energy expenditure [152]. The initial management of 3. The timing of PEG/PRG is based on an individual dysphagia is based on the following: dietary counsel- approach taking into account bulbar symptoms, mal- ling, modification of food and fluid consistency nutrition (weight loss of over 10%), respiratory func- (blending food, adding thickeners to liquids), prescrip- tion and the patientÕs general condition. Early insertion tion of high-protein and high-caloric supplements, of a feeding tube is recommended (GCPP).
education of the patient and carers in feeding and 4. When PEG is indicated, patient and carers should be swallowing techniques such as supraglottic swallowing informed: (i) of the benefits and risks of the procedure; and postural changes [153,154] and flexing the neck (ii) that it is possible to continue to take food orally as forward on swallowing to protect the airway (Ôchin-tuck long as it is possible; and (iii) that deferring PEG to a manoeuvreÕ). Some patients with difficulty swallowing late disease stage may increase the risk of the procedure tap water can more easily drink carbonated fluids and/ or ice-cold liquids. When tube feeding is needed, three 5. PRG is a suitable alternative to PEG. This procedure procedures obviate the need for major surgery and can be used as the procedure of choice or when PEG is general anaesthesia: percutaneous endoscopic gastros- deemed hazardous (GCPP).
tomy (PEG), percutaneous radiologic gastrostomy 6. Tubes with relatively large diameter (e.g. 18–22 (PRG, or radiologically inserted gastrostomy) and Charrie re) are recommended for both PEG and PRG to nasogastric tube (NGT) feeding.
prevent tube obstruction (GCPP).
Percutaneous endoscopic gastrostomy is the standard 7. Prophylactic medication with antibiotics on the day procedure for enteral nutrition in ALS and is widely of the operation may reduce the risk of infection available [153,154]. PEG improves nutrition, but there is no convincing evidence that it prevents aspiration or 8. NGT feeding may be used in the short-term and improves quality of life or survival [154] (Class III). The when PEG or PRG is not suitable (GCPP).
procedure requires mild sedation and is therefore more 9. Home parenteral nutrition may be used in patients hazardous in patients with respiratory impairment and/ with advanced ALS (GCPP).
or at an advanced stage of the disease [153,154]. Non-invasive ventilation during the PEG procedure may befeasible in patients with respiratory impairment (Class IV) [155]. The timing of PEG is mainly based on Amyotrophic lateral sclerosis is associated with a symptoms, nutritional status and respiratory function frontotemporal syndrome in a significant proportion of [156]. To minimize risks, PEG should be performed cases, and these patients have a shorter survival [165– before vital capacity falls below 50% of predicted [154– 167] (Class IV). Approximately 5–15% of patients with 156] (Class IV). PRG is a newer alternative to PEG and ALS meet the diagnostic criteria for frontotemporal has the major advantage that it does not require patient dementia, typically frontal variant with executive dys- sedation for insertion [155–158]. PRG may be as satis- function and behaviour change [168,169] (Class III) Ó 2011 The Author(s)European Journal of Neurology Ó 2011 EFNS European Journal of Neurology P. M. Andersen et al.
although progressive aphasias have been described. A evidenced by reduced verbal output, reduced spelling further third of patients show mild cognitive (ALSci) ability, increased word-finding difficulties and impaired and/or behavioural (ALSbi) impairment [168,169].
auditory comprehension of specific classes of language ALSci is associated with early deficits in verbal (letter) (e.g. verbs more than nouns) and more complex lan- fluency and a mild dysexecutive syndrome [170], (Class guage constructs [179–181]. Deficits may be subtle and III). Language changes are sometimes reported as are only identifiable with formal neuropsychological testing symptoms of memory impairment, but these are more [170,182]. Language impairment can reduce the quality likely due to an encoding rather than a retention deficit of life of both patients and carers and can make clinical [170]. ALSbi shows behaviour change that partially management difficult (Class IV) [182]. Formal neuro- meets criteria for frontotemporal dementia, with apathy psychological evaluation and support may be required most commonly reported [171,172] (Class IV). Impair- in patients with concomitant evolving language deficits ment in emotional and social cognition has also been (see previous section). The overall goal should be to described [173,174] (Class III). Cerebral atrophy on optimize the effectiveness of communication, concen- magnetic resonance imaging or ocular fixation insta- trating on meaningful interpersonal communication bilities may be biomarkers of behavioural and cognitive with the primary carer and family. This should include abnormalities [175,176] (Class III).
strategies for effective conversation and the introduc- A number of cognitive screening batteries have been tion of alternative communication devices where developed [177,178] (Class III), [179] (Class IV). Verbal (letter) fluency deficits are a sensitive measure of cog- Augmentative and alternative communication sys- nitive dysfunction if testing is appropriately modified tems can substantially improve the quality of life for for physical deficits and results standardized to educa- both patients and carers. Prosthetic treatments (palatal tional attainment and premorbid IQ [170] (Class III).
lift and/or a palatal augmentation prosthesis) can be Carers may be unaware of mild impairment as useful in the reduction of hypernasality and improve- increasing physical disability results in a loss of ment of articulation, but no formal comparative studies autonomy and a greater reliance on others for daily in ALS exist. For those requiring full mechanical ven- tasks. Executive dysfunction may manifest as difficulties tilation, eye-pointing, eye-gaze or head-tracking aug- in managing affairs/finances, planning for the future, mentative high-tech communication devices may be making decisions and learning new tasks, including the use of equipment associated with symptomatic treat-ment for ALS (e.g. gastrostomy, NIV).
Recommendations1. Regular assessment (i.e. every 3–6 months) of speech and language function by a trained speech and language 1. A frontotemporal syndrome occurs in up to half of therapist is recommended (GCPP).
patients with ALS (level B) and is associated with a 2. Those with evidence of early language deficits should poorer prognosis. Symptoms of cognitive dysfunction undergo full neuropsychological testing (GCPP).
may appear before or after the onset of motor symptoms.
3. The use of appropriate communication support sys- 2. The Mini-Mental State Examination is an insensitive tems (ranging from pointing boards with figures or test for ALSci and ALSbi.
words, to computerized speech synthesizers) should be 3. Rapid screening tools that include tests of verbal individualized and appropriate training and support fluency can identify patients in whom more detailed provided as required (GCPP).
neuropsychological evaluation is mandated (level C).
4. In all patients with frontal dysexecutive syndromes, Palliative and end-of-life care care needs to be taken to ensure informed consentduring decision-making; capacity issues may need to be A palliative care approach should be incorporated into considered (GCPP).
the care plan for patients and carers from the time of 5. Carers/healthcare professionals should be informed diagnosis [183]. The aim of palliative care is to maxi- of the symptoms of dysexecutive syndrome and trained mize the quality of life of patients and families by in their management (GCPP).
relieving symptoms, providing emotional, psychologicaland spiritual support as needed, removing obstacles to apeaceful death and supporting the family in bereave- Communication in patients with ALS ment [184]. Early referral to a specialist palliative care The majority of clinically apparent communication team is appropriate. Palliative care based in the com- difficulties in ALS result from dysarthria. However, munity or through hospice contacts (e.g. home care subtle changes in language function may also occur, as teams) can proceed in partnership with clinic-based Ó 2011 The Author(s) European Journal of Neurology Ó 2011 EFNS European Journal of Neurology EFNS Task Force on Management of ALS neurological multidisciplinary care. A small proportion Research recommendations of patients with ALS express interest in assisted suicide 1. Further studies of biomarkers (imaging, blood and [185] and may choose euthanasia where it is legalized cerebrospinal fluid proteomics and metabolomics, neu- [186]. Other aspects of terminal care have been covered rophysiological markers) to aid earlier specific ALS in previous sections.
diagnosis and to monitor possible effects in clinical trials.
2. Further studies of the impact of specialist MND clinics on clinical outcomes, quality of life and carer 1. Whenever possible, offer input from a palliative care team early in the course of the disease.
3. Further studies to optimize the symptomatic treat- 2. Initiate discussions on end-of-life decisions when the ment of muscle cramps, drooling and bronchial secre- patient asks or provides an opportunity for discussion tions in patients with ALS.
on the provision of end-of-life information and/or 4. Better criteria for defining the use of PEG, PRG, NIV and IMV.
3. Discuss the options for respiratory support and end- 5. Further studies to evaluate the effects of PEG/PRG, of-life issues if the patient has dyspnoea, other symp- cough-assisting devices and ventilation support on toms of hypoventilation (see Table 8) or a forced vital quality of life and survival.
capacity below 50%.
6. Further studies to evaluate language dysfunction and 4. Inform the patient of the legal situation regarding its treatment in ALS.
advance directives and the naming of a healthcare 7. Systematic studies to assess cognitive impairment and proxy. Offer assistance in formulating an advance the frequency of frontal lobe dysfunction in ALS and to directive (GCPP).
standardize clinical, neuropsychological and neurora- 5. Re-discuss the patientÕs preferences for life-sustaining diological methods in this field. Future ALS diagnostic treatments every 6 months (GCPP).
criteria should include parameters regarding cognitive 6. Initiate early referral to hospice or homecare teams dysfunction and dementia.
well in advance of the terminal phase of ALS (GCPP).
8. Studies of the medico-economical impact of more 7. Be aware of the importance of spiritual issues for the expensive procedures (NIV, IMV, cough-assisting quality of life and treatment choices. Establish a liaison devices, advanced communication equipment).
with local pastoral care workers to be able to address 9. Further studies to harmonize the patient databases of the needs of the patient and relatives (GCPP).
ALS centres.
8. For the symptomatic treatment of dyspnoea and/or 10. Further studies on the psychosocial and spiritual intractable pain, use opioids alone or in combination determinants of quality of life in patients and their with benzodiazepines if anxiety is present. Titrating the family caregivers are needed, as well as studies on the dosages against the clinical symptoms will rarely if ever prevalence of, and determinants for, wishes for a has- result in life-threatening respiratory depression (GCPP).
tened death.
9. Terminal restlessness and confusion because ofhypercapnia can be treated with neuroleptics (e.g.
Conflicts of interest chlorpromazine 12.5 mg every 4–12 h p.o., i.v., or p.r.)(GCPP).
Dr. Andersen has served as a consultant for Avanir 10. Use oxygen only if symptomatic hypoxia is present Pharmaceuticals. The other authors report no conflicts of interest.
Future developments Being a syndrome with low incidence and short sur-vival, most recommendations are GCPPs based on the The present guidelines were prepared without external consensus of experts in the field of ALS. Further ran- financial support.
domized and double-blind clinical trials are urgentlyneeded to improve the management of ALS.
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