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CNS Drugs 2O11.-25(1): 1-16 1172-7047/11/CX)01-OCI01/S49.96/0 THERAPY IN PRACTICE © 2011 Adb Dota Intormatlon BV. All rights reserved. Amyotrophic Lateral Sclerosis Pathophysiology, Diagnosis and Management Paul H. Gordon Fédération des Maladies du Système Nerveux, Assistance Publique - Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Paris, France Contents Abstract 1. Introduction 2. Manifestations and Diagnosis 3. tVlanagement 3.1 .Speoiflo Ttierapy: Riluzole 3.2 Multidisciplinary Care 3.3 Nutrition 3.4 Respiration 4. Symptomatic Treatment 4.1 Cognitive Decline and Depression 4.2 Emotional Labiiity/Pseudobuibar Affect 4.3 Sialorrhoea 4.4 Spasticity 4.5 Urinary Urgency 4.6 Impaired Sieep 4.7 Fatigue 4.8 Constipation 4.9 Pain 4.10 Palliative Care and Hospice 5. Novel Therapies 6. Conclusions Abstract 1 2 3 4 4 5 .5 6 6 6 8 8 8 9 9 9 10 10 10 11 12 Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease associated with a life expectancy of approximately 3 years after symptom onset, but the range of survival extends from a few months for some to decades for approximately 5% of patients. There is no clear cause in the majority of cases and just one medication, riluzole, has been shown to modestly prolong survival. Research has identified some of the cellular processes that occur after disease onset, including mitochondrial dysfunction, protein aggregation, generation of free radicals, excitotoxicity, inflammation and apoptosis, but for most patients the underlying cause is unknown. While ALS is considered to be a complex genetic disorder in which multiple genes in combination with environmental exposures combine to render a person susceptible, few genetic or environmental risks have been discovered to date. Gordon The diagnosis is based on the history and examination showing progressive upper and lower motor neuron findings. The electromyogram can help confirm the diagnosis, and additional tests are used to exclude other conditions. Published practice parameters guide the care of patients with ALS. Until the elucidation of aetiologies leads to the development of more robust neuroprotective agents, both pharmacological and nonpharmacological treatments are directed at maintaining quality of life and prolonging life to the greatest extent possible. Riluzole, ventilatory support for those with respiratory insufficiency, gastrostomy for those with dysphagia and multidisciplinary care may help extend life. The off-label use of many symptomatic agents can have a meaningful impact for those with the illness. Palliative care ensures dignity toward the end stages of the disease. Clinical trials currently aim to slow disease progression by testing drugs that impact one or more of the processes that are initiated after disease onset. Novel therapies currently in trials include potential neuroprotective agents with differing mechanisms of action, vaccine therapies, stem cell injections and diaphragmatic pacing. 1. introduction Amyotrophic lateral sclerosis (ALS) is considered a complex genetic disorder, in which multiple genetic and environmental factors combine to cause the disease, with the contribution of any single factor being small. There is currently very little evidence, however, to support the contribution of any major genetic or environmental risk factor in most cases of sporadic ALS (sALS). The causes of ALS have proved difficult to identify, in part because the disease is rare, with an incidence of approximately 2 per 100000/year in Western countries,!'1 but also because the nerve cells are hidden and ephemeral, and antecedents may act in sequence over decades, so that once the illness develops, the aetiology might be long since past. Many environmental factors have been examined in s ALS. Accepted risks include age, with most cases occurring between 55 and 65 years, male sex and likely cigarette smoking.'^'^^ Physical stress, exposure to pesticides and athleticism are possible contributors, but the associations are small and inconsistently reproducible.I^'^1 It could be that risks have not yet been examined in correct sequence, for example, if they interact over a lifetime, or that science has not yet developed an awareness of the important risks. © 2011 Adis Data Information BV. All rights reserved. Between 5% and 10% of cases are inherited (familial ALS; fALS) as a Mendelian trait, usually autosomal dominant, of which 15-20% are due to one of more than 100 mutations in the Cu-Zn Superoxide dismutase type 1 (SODl) gene,'^' which normally reduces oxidative stress by converting Superoxide anions to hydrogen peroxide. The mechanisms by which mutant SOD] is toxic to motor neurons are poorly understood. After discovery of the gene, an animal model was created that has contributed to improved understanding of cellular processes that occur, at least in this genetic form of ALS, after the disease process has begun.['°l Other rare genetic loci have been labelled ALSl through ALS 10, ALS with frontotemporal dementia (ALSFTD) and ALS-FTD with Parkinson's disease {ALS-FTDP)P^ Mutations infused in sarcoma {FUS) genes account for approximately 5% of Co-segregation of ALS with other neurodegenerative disorders in families suggests common genetic risks,f'^l but genome-wide association studies have demonstrated that there is no single gene that accounts for most sALS."^' TAR DNA binding protein (TDP-43), a ubiquitously expressed nuclear protein that regulates messenger RNA transcription and splicing, is found in inclusions of ALS and most forms of CNS Drugs 2011:25(1) Amyotrophic Lateral Sclerosis Mutations in the TDP gene have been identified in some patients with sALS or fALS,^'^' suggesting a possible pathogenic link, but the inclusions have also been identified in other conditions, so their true role is still unknown.''^' Once the disease is initiated, a cascade of cellular events occurs, including oxidative stress, glutamate-induced excitotoxicity, intracellular protein aggregation, mitochondrial dysfunction, growth factor deficiency, abnormal axonal transport and caspase enzyme activation.t'^ Nerve cells appear to eventually die through caspase enzyme-mediated apoptotic or inflammatory pathways. Current clinical trials test drugs that may interfere with these downstream pathways, but only one drug has been shown to modestly prolong survival, and most trials have been negative or shown the agent under study to be harmfulJ'^i Clinical trials are difficult to conduct in ALS because there are, as yet, no biomarkers of disease progression; trials use clinical outcome measures and must be large and of long duration in order to reliably detect changes. Dosage selection is especially important so that correct dosages of medications are tested for efficacy, but it is challenging to determine the most effective dosage for neuroprotection outside of a large efficacy trial. Additionally, there is great pressure within the field to identify new therapies as quickly as possible, which, in the past at least, has prompted investigators and pharmaceutical companies to sometimes minimize the role of early-phase dosage-selection trials and move quickly to large phase III trials. It is likely that better treatments and preventative measures will be ascertained after the causes of ALS are found. In the meantime, treatment is aimed at maintaining quality of life and prolonging life to the greatest extent possible, through multi-disciplinary clinics, management of nutrition and respiratory insufficiency, off-label use of medications to control symptoms and palliative care. Ongoing basic and clinical research aims to gain a better understanding of the disease. The purpose of the current article is to give an overview of the manifestations and diagnosis of ALS, and to describe the current approach to treatment. © 2011 Adis Data Information BV. All rigtits reserved. 2. Manifestations and Diagnosis ALS begins with limb weakness in about 65% of patients.t"! Foot drop, difficulty walking, loss of hand dexterity or shoulder weakness are typical early symptoms. Approximately one-third of the time, weakness begins in bulbar muscles, usually with dysarthria followed by dysphagia. Symptoms due to lower motor neuron (LMN) degeneration, including weakness, atrophy, cramps and fasciculation, often eclipse those associated with upper motor neuron (UMN) disease. Eventually, limb function is lost, leading to dependence on caregivers; walking and standing, as well as bearing weight for transfers, become impossible. Falls are common. With time, some patients become anarthric. Swallowing problems can lead to drooling, dehydration, malnutrition with weight loss and aspiration. Weakness of the axial musculature leads to head drop and kyphosis, which can cause pain, imbalance due to change in the centre of gravity and problems with activities such as eating and driving. Sphincter and sensory function are often spared. Cognition is impaired in 25-50% of patients who receive neuropsychological tests, and approximately 15% develop overt dementia, most often FTD.[^°1 The cognitive abnormalities lead to changes in personality, language, judgement, decision making or affect. The associated abulia and reduced judgement can render patients less able to participate in decisions about their medical treatments and to shorter survival.'^'' Emotional lability, or pseudobulbar affect, due to loss of normal inhibition of laughter and crying, which depend on neural pathways mediating emotion, respiration, vocalization and facial movements, may be associated with UMN Depression and anxiety can be prominent features at all stages of the disease. Anxiety can accompany symptoms of respiratory insufficiency, and depression may lead to reduced appetite, poor sleep, hopelessness and impaired ability to make decisions. ALS is usually described as causing painless weakness, but pain can occur, resulting from loss of mobility, the inability to turn in bed, joint CNS Drugs 2011:25(1) Gordon contractures or bedsores. The psychological and physical discomfort that arises from the inability to move can be profound.'^^' Occasionally, pain seems to be a feature of the disease itself, possibly related to degeneration of sensory tracts or nuclei. Cramps can also be painful and may interfere with sleep or physical activity. Shortness of breath or other respiratory symptoms usually occur later in the disease course. Symptoms include orthopnoea, morning headaches and weakened cough. Patients develop dyspnoea on exertion and eventually during inactivity. Respiratory failure and pulmonary complications of bulbar weakness, such as aspiration pneumonia, are the most common causes of death. The diagnosis is based on the history and examination that shows progressive UMN and LMN findings. An electromyogram, done in three limbs, and bulbar as well as paraspinal muscles, confirms the presence of widespread LMN disease, and helps to exclude potential mimicking disorders such as multi-focal motor neuropathy with conduction block. A sensory neuropathy detected by nerve conduction studies suggests the possibility of Kennedy's disease (X-linked bulbo-spinal atrophy), but sensory loss can rarely be a feature of typical ALS. Brain and cervical spine MRI are done to exclude other conditions that affect the UMN, such as cervical spondylosis. The El Escorial criteria, developed in 1990 and revised in 1998 to standardize the diagnosis for clinical research, can be applied.'^'*' Transcranial magnetic stimulation and magnetic resonance spectroscopy examine the UMN,'^^' but are often limited to large centres or research protocols. Spinal fluid is analysed only when the disorder is atypical, or if a secondary cause, such as carcinomatous meningitis or infection, is suspected. In the hands of an experienced ALS specialist and electromyographer, the diagnosis is correct more than 95% of the time. Patients with both UMN and LMN disease are labelled as having ALS, those with only LMN signs are diagnosed as having progressive muscular atrophy and those with only UMN signs for 4 years or longer as having primary lateral sclerosis. Genetic testing is not a routine part of the evaluation unless there is a family history of the disorder. The progression is insidious and time to diagnosis is often more than 1 © 2011 Adis Data information BV. Aii rigtits reserved. Practice guidelines'^^'^^' suggest that the diagnosis should be given in person, not by telephone, with family or friends present to give support, and that a follow-up appointment be scheduled soon afterward. The process of breaking the news may require 45 minutes or longer.'^^' The neurologist usually summarizes the main points of the discussion verbally or in writing and proposes a plan of care before the patient leaves the office. Patients are also informed about ALS resources, including patient advocacy groups, and a discussion of ongoing research into better treatments conveys hope.'^^' While ALS is an incurable disease, many symptoms are amenable to supportive therapies, some of which may even improve the disease course. Unfortunately, there are few controlled trials of symptom management. As a result, the selection of therapies is still based largely upon physician experience. Practice parameters outline common strategies, but there is a wide variety of management practices,'^"' and more controlled trials are needed. 3. Management 3.1 Specific Therapy: Riiuzoie Excess glutamate, an excitatory neurotransmitter, may be associated with neurodegeneration. Riluzole, first developed as an antiepileptic drug (AED), inhibits the presynaptic release of glutamate, but its exact mechanism in ALS is unknown. Riluzole is currently the only drug approved to slow the course of ALS. In two randomized, controlled trials, riluzole prolonged survival by approximately 4 months.'^''^^' The first trial showed mild slowing in deterioration of strength, but neither study showed improvements in quality of life. The small beneficial effect was not apparent to patients, family members or physicians.'^^' The Cochrane Library conducted a meta-analysis of three published trials, which included a total of 876 riluzole-treated and 406 placebo-treated patients.'^'*' The meta-analysis indicated that riluzole lOOmg/day prolongs survival by approximately 11%, or about 2 months. CNS Drugs 2011; 25(1) Amyotrophic Lateral Sclerosis The long-term safety of riluzole therapy has been established,'-'^' including in the elderly and those with advanced disease.'^^' The most common adverse effects are fatigue, somnolence, nausea, diarrhoea and dizziness. Liver enzyme level elevation can occur, but rarely to levels that are clinically meaningful. Serum concentrations of riluzole vary between individuals, probably resulting from different rates of metabolism.'^^' Adverse effects tend to be more frequent in those with high serum concentrations. Dose adjustment based on serum concentrations is one approach to optimizing treatment, but is rarely used in practice. More than half of US patients'^^' and nearly all patients in Europe, where the health systems cover the cost,'^'' take riluzole. The Canadian health system does not pay for riluzole, but many patients there are provided with the drug based on compassionate use. 3.2 Multidisciplinary Care The care of patients is challenging because ALS is progressive and terminal, and there are, as yet, no truly effective treatments.''*^' Most large centres currently use a multidisciplinary approach to care,''*'' and some data suggest that patients cared for at multidisciplinary clinics may survive longerP^' Patients are evaluated frequently so that impending problems are detected and treated early. The care plan is centred on the patient's decisions, focusing on support and education. The neurologist and allied health team provide information to help in treatment decisions; discussions include advanced directives, and means to aid in nutritional and respiratory care.''"' The neurologist also explains clinical and scientific advances in thefield.While all specialty care can be obtained through regular consultation, patients and families benefit from having questions addressed by professionals from different disciplines in one visit to a multidisciplinary clinic, which conserves energy and time. The neurologist is responsible for patient care, an ALS nurse provides nursing care, physical therapists evaluate limb strength, occupational therapists address the skilled motor functions © 2011 AdIs Data Information BV. Ali rights reserved. that enable patients to engage in activities of daily living, a dietitian assesses nutritional status, a speech pathologist evaluates bulbar function and a respiratory therapist aids in treating respiratory symptoms. Either in or outside of the multidisciplinary clinic, a social worker assists with health insurance coverage and disability payments, a pulmonologist treats respiratory problems, a gastroenterologist is consulted for enterai feeding and gastrostomy placement and an orthotist fits braces for those with focal weakness. A psychiatrist or psychologist treats symptoms related to depression and anxiety. The ALS team also directs patients to services outside the clinic,''*'' ensuring that home care, palliative care and hospice are used effectively. Important nonpharmacological therapies include: communication devices and voice amplifiers; gaze communication technology; assistive devices such as canes, orthoses, walkers and wheelchairs; home adaptations; and exercise. Until stronger neuroprotective agents are identified, the goal of multidisciplinary care is to help patients achieve the highest quality of life possible throughout the course of the disease. 3.3 Nutrition Poor nutrition, a predictor of survival, can result from dysphagia, arm weakness limiting the ability to eat, and hypermetabolism.''*^' Monitoring weight is the simplest way to assess caloric balance. A speech therapist's examination provides information about risk of aspiration, ability to maintain adequate nutrition and compensatory strategies. Management includes modification of diet consistency, postural changes such as the chin tuck, and enterai feeding via a percutaneous endoscopie gastrostomy for those with symptomatic dysphagia or weight loss.'"*^' There may be lower morbidity if the procedure is done when the vital capacity (VC) is >50% of predicted and before sniff nasal inspiratory pressure (SNIP) falls below 40 cm H2O. Radiologically inserted gastrostomy can be done when respiratory compromise is present, and patients can use non-invasive ventilation during the procedure. CNS Drugs 2011.-25(1) Gordon 3.4 Respiration Symptoms of respiratory muscle weakness include dyspnoea, orthopnoea, sleep fragmentation, moming headaches and daytime fatigue. Bulbar weakness and weakened cough can lead to excess secretions and poor airway clearance, which can cause aspiration and pneumonia. The history, physical examination, overnight pulse oximetry and VC are standard assessments and are done serially, typically every 3 months. The maximal inspiratory and expiratory pressures (MIP and MEP) are also often reduced in ALS patients and correlate with respiratory muscle weakness;^''^' a reduction of MIP to <60 cm H2O is a predictor of reduced survival. SNIP, a noninvasive measure of inspiratory pressure, estimates intrathoracic pressure and may provide an early marker of respiratory muscle weakness. It decreases predictably over time in ALS patients, predicts survival and may better refiect hypercapnoea than VC or MIP. A transcutaneous carbon dioxide sensor can also be Nocturnal noninvasive positive-pressure ventilation (NTPPV) has become the standard treatment for ALS patients with respiratory insufficiency.t'*'^ The bi-level intermittent positive-pressure ventilator imitates physiological function; it is triggered by the patient's inspiratory efforts, reduces the work of breathing and improves gas exchange and sleep quality.t"*^ Patients are counselled on the use of NIPPV with the onset of respiratory symptoms, when the VC drops to 50% of predicted, or when the MIP falls to <60cm HjO.f'^^i NIPPV extends survival, particularly in those compliant at least 4 hours per day, enhances quality of life!''*] and may improve cognition.!'*^ In general, oxygen is not prescribed without NIPPV so as not to risk inhibition of respiratory drive in the setting of elevated serum carbon dioxide levels. Theoretically, using NIPPV can reduce energy loss from overworked respiratory muscles, and so may have dual benefits of supporting respiration and reducing calorie expenditure. Invasive ventilation is instituted when longterm survival is the goal. Tracheostomy, ultimately chosen by fewer than 5% of patients,^'**! is expensivef'*^^ and requires 24-hour supervision. Great emotional and physical burden is placed on © 2011 Adis Data Intormation BV. All rights reserved. caregivers; a reason that some patients refuse tracheostomy. Some patients, who are unable to decide for or against tracheostomy, receive mechanical ventilation on an emergency basis due to respiratory failure. Inadvertent performance of tracheostomy is usually permanent,''*^' and may lead to nursing home placement if home recourses are inadequate. Patients may choose to withdrawal respiratory support, a decision that is considered ethical when the treating physician prescribes adequate dosages of opiates and anxiolytics to avoid suffering when the ventilator is turned off. Interventions that facilitate the clearance of secretions consist of air stacking, assisted cough, either manually or mechanically through an insuffiator-exsufflator, and use of a suction machine to remove oropharyngeal secretions.t'"' Mucolytics, expectorants, theophylline, antibacterials and oxygen may help to relieve symptoms. Pneumovax® immunization and yearly influenza immunizations help reduce pulmonary infection.t'*^' High-frequency chest wall oscillation may help clear airways.'^^l 4. Symptomatic Treatment The following sections outline the use of standard therapies that are used to combat symptoms of ALS (table I). Few of the therapies have been tested in clinical trials in ALS. Some are approved for treating the symptoms in other disorders, some are used off-label for ALS, and most are used based on clinical experience rather than solid clinical trial data. Future trials of symptomatic agents may help refine which therapies are most helpful in ALS. 4.1 Cognitive Decline and Depression Cognitive symptoms in ALS are usually due to frontotemporal impairment and include personality change, irritability, obsessions, poor insight and impairments in language.t^'' Patients with dementia are less compliant with interventions, and probably have shorter survival.f^'l No therapy has been shown to slow the progression of dementia in ALS. Symptoms of disinhibition can CNS Drugs 2011; 25(1) Amyotrophic Lateral Sclerosis Table I. Symptomatic treatments used in patients with amyotrophic iateral sclerosis Table I. Contd Medication Cramps Dosage Slalorrhoea Amitriptyiine 12.5-125 mgqhs Atropine suiphate 0.4 mg q4-6h 1-2 ophthaimic drops SL q4-6h Glycopyrrolate Hyoscyamine suiphate Medication Dosage Vitamin E 400 iU tid Phenytoin 300 mg qhs Diazepam 2-10mgtid Urinary urgency 1-2 mg tid 0.125-0.25 mgq4h Oxybutynin 2.5-5 mg bid 12.5-75 mgqhs Diphenhydramine 25-50 mg tid Amitriptyiine Scopoiamine transdermal patch 0.5 mg behind ear q72h Toiterodine 1-2 mg bid Oxybutynin patches 3.9 mgod Emotional lability/ pseudobulbar affect impaired sleep Dextromethorphan/quinidine 20mg/10mgbid Amitriptyiine 12.5-125 mgqhs SSRI antidepressants 20-100mgod MIrtazapine 15-30 mgqhs Venlafaxine 37.5-75 mgbid-tid Fatigue Zoipidem 5-10 mgqhs Zaieplon 5-10 mgqhs Amitriptyiine 12.5-125 mgqhs Mirtazapine 10-30 mgqhs Temazepam 7.5-30 mg qhs Amantadine lOOmgqAM, qnoon Diphenhydramine 25-50 mg qhs Modafinii 100-200 mgqAM Chioral hydrate 500-1000 mgqhs Pemoline 18.75-93.75 mgod Constipation Bupropion SR 150-450 mgod Docusate 240 mg od Fiuoxetine 20-60 mg od Magnesium hydroxide 30-60 mL prn Venlafaxine 75-225 mg od Bisacodyi 10-15mLprn Methylphenidate 10 mgbid-tid Pyridostigmine 60 mg tid Depression Mirtazapine 15-30 mgqhs SSRi antidepressants 20-100 mgod TCAs 20-150 mgod Veniafaxine 37.5-75 mg od Lactuiose 15-30 mgod Magnesium citrate 75-150 mL bid bld=twice daiiy; iU = internationai units; od==once daiiy; prn^^as needed; qAM = every morning; qhs = every day at bedtime; qid = four times daiiy; qnoon-every day at noon; q>iti=every x hours; SL-subiinguai; SR= siow release; SSRI = seiective serotonin reuptake inhibitor; TCAs=tricyciic antidepressants; tid = three times daiiy. Anxiety Diazepam 2-10mgtid Lorazepam 0.5-2 mg bid-tid Buspirone lOmgtid SSRi antidepressants 10-100 mgod Mirtazapine 15-30 mgqhs Spasticity Bacioten 10-60 mg tid Dantroiene 25-100mgtid-qid Tizanidine 2-9 mg qid Benzodiazepines 2-10mgtid Continued © 2011 Adis Data information BV. Aii rights reserved. be relieved with behaviour modification, and atypical antipsychotics such as olanzapine or quetiapine, AEDs such as carbamazepine or valproic acid and selective serotonin reuptake inhibitors (SSRIs) in standard doses. Depression and anxiety can occur in ALS and may impair quality of life for patients and caregivers.'^^' Depression occurs in at least 10% of patients, but does not appear to increase with advancing disease.'^-'! Psychotherapy, tricyciic antidepressants (TCAs) such as amitriptyiine (which may also help with insomnia, drooling and CNS Dajgs 2011; 25(1) Gordon emotional lability), SSRIs or other antidepressant medications in standard doses may be helpful. Benzodiazepines, SSRIs, buspirone and mirtazapine are used to treat anxiety, after ensuring that symptoms of respiratory insufficiency are adequately controlled. 4.2 Emotional Lability/Pseudobulbar Affect Features of emotional lability are uncontrolled laughter or crying, often with minimal provocation, and often inappropriate to the context of the situation. The symptoms can limit social interactions and quality of life. A combination of dextromethorphan hydrobromide (30 mg) and quinidine sulphate (30 mg), which acts to prolong the halflife of dextromethorphan by inhibiting its metabolism, is effective,'^'*' reducing emotional lability and improving quality of life, and a formulation combining dextromethorphan 20 mg and quinidine 10 mg has been approved by the US FDA for this indication. SSRIs, TCAs, mirtazapine and venlafaxine might also be beneficial.'^^1 4.3 Sialorrhoea Sialorrhoea in ALS is caused by dysphagia, rather than increased saliva production, and affects 50% of patients.'^'' Sialorrhoea is socially embarrassing and excess saliva can lead to aspiration pneumonia. Pharmacological and nonpharmacological interventions can help. Suction machines and in-exsuffiator or cough-assist devices are nonpharmacological approaches. Anticholinergic medications are initial pharmacological therapy, but the response can be inadequate and adverse effects are common, including constipation, fatigue, urinary retention, blurred vision, tachycardia, orthostatic hypotension, confusion and dizziness. Anticholinergic medications are relatively contraindicated in patients with glaucoma, prostatic hypertrophy and cardiac conduction disorders. Concomitant use of a stool softener may be helpful for those with constipation. Adverse effects may be less common with sublingual forms, such as hyoscyamine sulphate, than with the oral medications. Sialorrhoea associated with mealtimes or a particular time of day can be treated with hyoscyamine because of its transient effect. Transdermal © 2011 Adis Data Intormation BV. All rights resen/ed. scopolamine, oral glycopyrrolate or TCA medications provide a more continuous effect.'^^' Patients who have difficulty swallowing medications can use sublingual, transdermal or liquid forms that can be administered through a gastrostomy. Injections of botulinum toxin into the salivary glands can also reduce sialorrhoea by blocking neural stimulation of the salivary glands.'^^' While there were few adverse events in clinical trials, worsening of dysphagia and chewing difficulties have been reported. Radiotherapy of the salivary glands has also been tried in ALS,'^^' but controlled trials are needed. Thick mucous secretions can result from treatment of sialorrhoea or inadequate water intake. Patients report a sensation of something caught in the back of the throat. Pharmacological treatments include high-dose guaifenesin, nebulized acetylcysteine, nebulized saline or ß-adrenoceptor antagonists (ß-blockers) such as propranolol. A survey of alternative measures reported that dark grape juice, papaya tablets, sugar-free citrus lozenges and grape-seed oil can also be helpful.'^^1 Reduction of alcohol, caffeine and dairy products along with increased fluid intake may also help. Some find a cool mist humidifier to be helpful. Mechanical insufflation-exsufïlation'^^' and chest wall oscillation therapy might also improve clearance of upper airway secretions.'^''' 4.4 Spasticity Spasticity is caused by loss of the normal inhibition from descending UMNs. Baclofen, a GABA analogue that facilitates motor neuron inhibition, may be beneficial to some patients. Dosing begins at 10 mg one to three times per day and increases by 10 mg every 3-5 days. Maximum tolerated doses range from 30 to 180mg/day and responses vary. Adverse effects include fatigue, sedation and a sense of looseness or weakness.'^^' Dantrolene sodium, which acts by blocking calcium release from the sarcoplasmic reticulum, reduces both rigidity and spasticity. There may be a synergistic effect when used with baclofen.'^^' Dosing is initiated at 25 mg three times per day, with a maximum dose of 100 mg four times daily. Liver function is checked regularly. CNS Drugs 201I;25(l) Amyotrophic Lateral Sclerosis Tizanidine, an a2-adrenergic agonist, reduces rigidity and spasticity by inhibiting excitatory interneurons in the spinal cord, and can be used as monotherapy or in conjunction with other antispasticity medications. Initial doses of 2-4 mg/day are increased to 36 mg/day in divided doses. Adverse effects are similar to those with baclofen and are minimized by slow dose titration. Benzodiazepines can reduce spasms and cramps that accompany spasticity. The use of these drugs is weighed against the potential for sedation and respiratory suppression. Stretching exercises can also reduce spasms and cramping.'^"' If the maximum tolerated dose of oral medications is not effective, intrathecal baclofen can be tried. Botulinum toxin injections reduce spasticity in other conditions, but have not yet been formally studied in ALS. The risk of muscle paralysis may limit their use in large muscle groups in ALS. Laryngospasm, related to spasticity, is due to hyper-adduction of the vocal cords, and usually follows aspiration of liquids or saliva, or acid reflux. It typically resolves spontaneously within several seconds, and is lessened by repeated swallowing while breathing through the nose. If the episodes occur frequently, treatment with a few drops of sublingual liquid lorazepam can abort the attacks.'^^' Antacids and proton pump inhibitors can help reduce symptoms due to reflux. Some patients develop jaw quivering or clenching due to UMN degeneration. Treatment with benzodiazepines such as clonazepam, diazepam or lorazepam can be helpful. Botulinum toxin injected at two sites within the masseter muscles may also be effective. 4.5 Urinary Urgency Urinary urgency or incontinence can occur in ALS, especially in those with leg spasticity, and are compounded by impaired mobility and the fear of not being able to reach the toilet in time. The likely aetiology is spasm of the urinary sphincter or detrussor muscle. Urinary tract infection or prostatism should be excluded before initiating pharmacotherapy. If no other cause can be identified, a trial of a spasmolytic agent is in© 2011 Adis Data Information BV. All rights reserved. dicated. Oxybutynin is inexpensive and can be crushed and put through a gastrostomy tube. An extended-release form that is administered once daily is also available, but cannot be crushed. Tolterodine tartrate is prescribed twice daily. Oxybutynin patches can be used along with oral tablets for those with refractory symptoms. The anticholinergic properties of amitriptyiine make it an alternative for some patients. A voiding schedule in which patients attempt to urinate every 2-3 hours regardless of whether they have an urge or not can help reduce accidents. 4.6 Impaired Sleep Poor sleep in patients with ALS has numerous causes, including respiratory insufficiency, difficulty repositioning in bed, pain, anxiety and depression.'^'' Sleeplessness leads to daytime fatigue, weakness, worsening respiratory compromise and depression. Physical measures such as a power hospital bed and alternating pressure mattress can enhance mobility and comfort. NIPPV can improve respiration and sleep quality. Antidepressant medications may relieve depression and promote sleep. Mirtazapine and the TCAs are especially helpful. Anxiolytic medications such as benzodiazepines can be helpful when used selectively. Zolpidem tartrate, or other similar non-benzodiazepine sleep aids, carries a low risk of respiratory depression. Antihistamine medications or chloral hydrate are also sedating. Alternative agents, such as melatonin, passionfiower, lavender and hops, have been effective for some patients, but their benefits are untested.'^^' 4.7 Fatigue Fatigue, which is common in ALS, can be caused by over-expenditure of physical energy, stress or depression, poor sleep and medication side effects.'""' Energy conservation is a simple treatment. Riluzole, which has fatigue as an adverse effect, can be stopped.'^'' Nocturnal respiratory insufficiency is treated with NIPPV. Offlabel use of pyridostigmine can reduce symptoms of weakness by enhancing neuromuscular junction transmission. Methylphenidate can also provide benefit in selected patients. Adverse efTects include CNS Drugs 2011;25(l) 10 Cordon anorexia, restlessness, anxiety or palpitations. Modafinil can also be tried,'^^' and amantadine, pemoline, bupropion, SSRIs and venlafaxine have been helpful for some patients. 4.8 Constipation Constipation results from immobility, medication adverse effects (especially with anticholinergic and narcotic agents) and inadequate fluid intake. In the later stages of ALS, abdominal wall muscle weakness contributes. Management includes the use of stool softeners such as docusate or senna leaf extract. Increasing fluid intake and substituting medications with fewer anticholinergic effects is helpful. Increasing dietary fibre in the form of prunes, fruit juices, apple sauce and bran is important. Milk of magnesia or bisacodyl tablets can be added to the regimen. Lactulose can be administered through a gastrostomy tube, and enemas or magnesium citrate are used in urgent situations. 4.9 Pain Immobility, emotional distress, muscle spasms, cramps, oedema or the illness itself may all cause pain. Identification of the précipitants leading to pain is the first priority. Medication can often be avoided through physical therapy, stretching and range of motion exercises, massage and limb elevation, as well as a support hose to reduce oedema. Medical management includes NSAIDs, benzodiazepines and opioids, which are generally safe but can cause constipation, respiratory depression in high doses and tolerance. Liberal use of narcotics and anxiolytics to prevent suffering is often necessary at the end stages of the illness. Cramps can be reduced by vitamins E and C,'^^' and anti-spasticity agents such as baclofen.'-'^' For those who are bothered by fasciculation, gabapentin or anti-spasticity agents can be tried.'^*'' 4.10 Palliative Care and Hospice All of ALS care is currently palliative. Palliation at the end of life is a time when particular care is needed to avoid physical suffering.'^' The © 2011 Adis Data Information BV. Aii rigtits reserved. transition to this phase is less abrupt if continuous palliative care has been provided from the outset. Around 60% of ALS patients die within 24 hours of deterioration in their clinical condition and some die suddenly. Advance directives can help prevent invasive ventilation being instituted in a crisis, but the key to good care is ongoing and open communication between the patient and the healthcare team. Anticipating symptoms before they occur is crucial. Medications, including opioids, sedatives and anticholinergic agents, can be prescribed in the home under the direction of the neurologist and hospice team. Morphine is effective for treating pain, breathlessness and nocturnal discomfort long before the terminal phase of the illness.'^^ Fentanyl transdermal patches, 12.5-100 ng/hour, worn for 72 hours can be used alone or in conjunction with morphine. It is best to start with low doses of morphine, typically 5 mg every 4-6 hours and to titrate slowly. Doses can be increased to control new symptoms, but dose escalation is often unnecessary. Constipation is a common adverse effect and needs to be treated concurrently. There is no evidence that opioids shorten life, but relief of distress is the goal, and some sedation may be necessary. In patients with gastrostomy, the route of administration of medications can remain unchanged toward the end of life. In those who require non-oral administration, subcutaneous, intravenous, rectal or transdermal dosing is possible, but requires recalculation ofthe equivalent dose.'^' NSAIDs, if previously effective, can be administered by suppository. Anxiolytics are helpful for symptoms of anxiety and restlessness, and a benzodiazepine is often used in combination with morphine.'^^' Benzodiazepines and morphine are also used to prevent any distress that might occur during ventilator withdrawal when a patient, family and professionals agree that life is being prolonged by assisted ventilation to a degree that is intolerable.'^'^' It may not be possible to stop noisy breathing; thefirststep in management is to explain to the patient's family the causes of noisy breathing, and to reassure them that the patient is not aware of the sounds. Atropine tends to be arousing, but other antiCNS Drugs 2011:25(1) Amyotrophic Lateral Sclerosis cholinergic medications are used to control rattly breathing in those with reduced ability to cough or unsuccessful treatment of a lung infection.'^! The quality of a patient's dying is a powerful memory for those left behind and good care at this time shapes public attitudes towards disability and serious illness. Hospice teams provide adequate symptom management and also counselling and emotional support for patients, families and caregivers. Palliation at the end of life is usually done at home, but inpatient palliative care teams and suites can be used for those patients uncomfortable dying at home. 5. Novel Iherapies An important element of ALS care is participation in research. According to the website for the National Institutes of Health (NIH) [www. clinicaltrials.gov], at the time of this article, there were more than 100 clinical research studies in ALS. Clinical trials offer patients the chance to share in the search for better treatments and to have successive evaluations by the ALS team. These assessments, which may occur on a monthly basis depending on the study, provide a level of attention that could not be had otherwise. The patients usually meet with the neurologist, nurse and physical therapist during the research visit, and new problems are treated. The psychological benefit of participating in research can be great, but patients must also understand the goal of obtaining accurate data so that a trial's conclusions will be valid. For this reason, investigators must explain the importance of compliance and the purpose of research to patients before they enrol.'^^1 Patients are prone to drop out if benefits do not occur or adverse effects develop. They may lose interest in the trial as their disease advances, they may drop out to participate in another study or they may use other available investigational agents. During clinical trials, it is important to monitor adherence and to implement effective adherence-improving strategies.'™! A number of potentially neuroprotective agents and new treatment modalities are being tried. One © 2011 Adis Data information BV. Ailrightsreserved. 11 preliminary study showed a positive effect of lithium carbonate in an ALS mouse model, and possible improvement in 16 patients given the drug.'^'l The mechanism of lithium in ALS is unknown, but it might act through ameliorating excitotoxicity. Another phase II trial is ongoing, but a small efficacy trial was terminated following enrolment of 84 patients after the data and safety monitoring board deemed it statistically futile to Ceftriaxone, a semi-synthetic, third-generation, cephalosporin antibacterial, was selected for study after an NIH-driven high-throughput screen initiative of 1040 available medications, and a positive mouse study.'^^' Ceftriaxone appears to possess antiexcitotoxic properties. A phase III trial is being conducted in 600 participants for at least 12 months, with survival as the primary outcome measure. The study consists of three stages, of which two have been completed. The first stage examined CSF concentrations of ceftriaxone. The second stage assessed the safety of the drug given over 20 weeks. The third stage, which began in early 2009, will determine whether intravenous ceftriaxone is effective in slowing the disease course. Pramipexole, which may possess antioxidant properties, has been tested in an early-phase safety trial, and a futility design phase II study.'^"*! In the futility study, slopes of decline in functional scores showed non-significant reductions during treatment. High doses of pramipexole were well tolerated and larger studies are planned. Memantine, a glutamate antagonist, is being studied in a phase II randomized, controlled, dose-ranging trial, using functional endpoints. Several different trials are under way to assess safety and efficacy. Arimoclomol, a coinducer of heat shock proteins, which serves as an intracellular chaperone and appears to have antiapoptotic properties, is also under study. Molecular chaperone proteins are critical in the cellular response to stress and protein misfolding. The drug increased the lifespan in ALS mice,'^^' but after completion of early-phase safety trials, a large trial in sALS was terminated, apparently because of the need for additional preclinical toxicology studies. Because SODl mutations might reduce the availability of molecular chaperones, and weaken their response to cellular stress, a separate CNS Drugs 2011:25(1) 12 Gordon Study in patients with SODl mutation-positive 6. Conclusions fALS is planned at two centres. ALS is still an incurable disease, but progress Talampanel delays mitochondrial vacuolization in motor neurons of mice. After an initial has been made, both in terms of understanding safety and tolerability study in humans, a ran- the underlying pathophysiology and in helping domized, controlled, phase III trial is planned.'^^' patients manage the numerous symptoms that The primary outcome measure will be change in arise. European researchers and the American functional scores over 52 weeks. Subjects will re- Academy of Neurology have published and receive talampanel 50 mg three times per day, ta- vised''*-''^'' practice guidelines on the symptomatic care of ALS patients. Many therapies can imlampanel 25 mg three times per day or placebo. AEOL 10150, a manganese porphyrin that prove quality of life, aiid some appear to extend scavenges peroxynitrite and other deleterious oxi- survival. Gastrostomy and NIPPV likely improve dized species, is in early-phase clinical trials. outcome for those with poor nutrition and resEdaravone (MCI-186), another free radical sca- piratory insufficiency. Depression and anxiety are venger with potential effects on mitochondrial common, but are highly treatable. The multifunction, is also being studied. A double-blind, disciplinary clinic, where patients have access to placebo-controlled trial of edaravone is ongoing specialists trained to provide assistive devices, in Japan, after an initial phase II trial.'^^' The pri- speech aids and home modifications, has become mary outcome measure of the larger study is func- the standard of care at most large centres. By tional decline over 36 weeks. Trials are planned in participating in clinical research, patients not only receive increased attention from the ALS team, the US. Sodium phenylbutyrate and valproic acid are but also contribute to the ongoing effort to find histone deacetylase inhibitors that may promote better treatments and refine current therapy. Paltranscriptional activation of antiapoptotic genes. liative care, particularly at the end of life, is one A safety and dose ranging trial of sodium phenyl- important means to relieving suffering. Once clear butyrate has been completed, and an efficacy trial aetiologies are determined for ALS, therapies that truly impact disease progression will surely folis planned.'^^' Olesoxime (cholest-4-en-3-one, oxime; TRO low, but until then, symptomatic therapies and 19622), identified via high-throughput screening, palliative care help patients meet the challenges of binds to the mitochondrial permeability transi- ALS with dignity and comfort. tion pore.t'''' A phase Will trial is under way. Vaccines strategies are being tried to remove aggregated SODl protein in fALS, but further Acknowledgements research is needed in animals before human trials.'^"' Methods to reduce the production of No sources of funding were used to prepare this article. abnormal SODl using RNA interference'*'' and The author has no conflicts of interest that are directly relantisense oligonucleotides'^^' are also under study. evant to the content of this article. Trials are planned, but research continues in animal models. Stem cell therapies are also being tested. At the References time of this writing, multiple centres are testing 1. Logroscino G, Traynor BJ, Hardiman O, et ai. Incidence of the safety of different approaches to stem cell inamyotrophic lateral sclerosis in Europe. J Neuroi Neurojections in ALS. Most of the trials are testing the surg Psychiatry 2010; 81: 385-90 safety of intraspinal infusions in small numbers 2. Rowland LP, Shneider NA. Amyotrophic lateral scierosis. 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Gordon, MD, Fédération des Maladies du Système Nerveux, Centre réfèrent maladie rare SLA, Hôpital de la Pitié-Salpêtrière, 47-83, Boulevard de l'Hôpital, 75651 Paris, France. E-mail: [email protected] CNS Drugs 2011:25(1) Copyright of CNS Drugs is the property of ADIS International Limited and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.