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Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials

Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management... Volume 4, Number 5; 295-310, October 2013 http://dx.doi.org/10.14336/AD.2013.0400295 Review Article Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials 1,2* Paul H. Gordon AP-HP, Hô pital de la Pitié -Salpê triè re, Dé partement des Maladies du Systè me Nerveux, Paris, France Northern Navajo Medical Center, Shiprock, NM 87420, USA [Received July 29, 2013; Revised August 26, 2013; Accepted August 27, 2013] ABSTRACT: Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot in the 1870s, is an age-related disorder that leads to degeneration of motor neurons. The disease begins focally in the central nervous system and then spreads relentlessly. The clinical diagnosis, defined by progressive signs and symptoms of upper and lower motor neuron dysfunction, is confirmed by electromyography. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of respiratory muscle weakness less than 3 years from symptom-onset. Like other age-related neurodegenerative diseases, ALS has genetic and environmental triggers. Of the five to 10% of cases that are inherited, mutations have been discovered for a high proportion. In addition to genetic factors, age, tobacco use, and athleticism may contribute to sporadic ALS, but important etiologies are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. The mechanisms leading to disease propagation in the brain are a current focus of research. To date, one medication, riluzole, licensed in 1996, has been proved to prolong survival in ALS. Numerous clinical trials have so far been unable to identify another neuroprotective agent. Researchers now aim to slow disease progression by targeting known pathophysiological pathways or genetic defects. Current approaches are directed at muscle proteins such as Nogo, energetic balance, cell replacement, and abnormal gene products resulting from mutations. Until better understanding of the causes and mechanisms underlying progression lead to more robust neuroprotective agents, symptomatic therapies can extend life and improve quality of life. Palliative care programs such as hospice give emotional and physical support to patients and families throughout much of the disease course. Key words: amyotrophic lateral sclerosis, neurodegeneration, epidemiology, pathophysiology, diagnosis, treatment Amyotrophic Lateral Sclerosis (ALS) is characterized by UMN features probably carries a better prognosis, even progressive degeneration of upper (UMN) and lower for patients with ALS [2]. Incidence rates for ALS range (LMN) motor neurons in the brain and spinal cord. It is from 1.2-4.0 per 100,000 person-years in Caucasians [3- the most common motor neuron disease (MND), which 6]. The rate may be lower in some ethnic populations includes primary lateral sclerosis, a disease restricted to including American Indians [7], and, historically, as much UMNs that makes up 1-3% of MND, and progressive as 50 times higher in Guam, Japan’s Kii Peninsula, and muscular atrophy, limited to LMNs, which is responsible western New Guinea [8]. Incidence rates increase with for approximately 10% of MND [1]. Predominance of *Correspondence should be addressed to: Paul H. Gordon, MD, PhD, Dé partement des Maladies du Systè me Nerveux, Centre ré fé rent maladie rare SLA, 75651 Paris, France. Email: paul.gordon@psl.aphp.fr ISSN: 2152-5250 295 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 age, peaking between 70 and 80 years, and are higher in The lethal prognosis and absence of treatments for ALS men than women [9,10]. mean that all care is palliative. One medication, riluzole, ALS begins in limb or bulbar muscles and then approved for use in 1996, slows deterioration by spreads to contiguous, and eventually respiratory, approximately two months, but 17 years and numerous myotomes. Survival ranges from months to decades, but trials later, no treatment can halt the course of the disease. is usually less than three years from when symptoms first Multi-disciplinary clinics [19] and non-invasive appear [11]. ventilation for those with respiratory failure also appear to Jean-Martin Charcot, employing the clinicoanatomic ameliorate the outcome modestly. Clinical trials currently method that he devised, described the clinical and test medications aimed to interfere with a known cellular pathological features of ALS during a series of lectures in event and slow the disease course; participation in the 1860s and 1870s [12]. The methodology available to research conveys hope to patients and may also improve Charcot was primitive by contemporary standards, but his survival time [20]. approach was so insightful that his original descriptions This review summarizes the clinical manifestations, are considered accurate today. Sir William Gowers and disease mechanisms, approaches to care and design of Lord Russell Brain made major contributions in the trials for ALS, giving an overview of the current United Kingdom, using the label MND instead of ALS understanding of the disease, and concludes with a section because they believed that all patients have pathology of on future directions. both UMNs and LMNs, either during life or at autopsy. th The paucity of American neurologists early in the 20 CLINICAL FEATURES AND DIAGNOSIS Century meant that the illness was largely overlooked in the New World until 1939 when Lou Gehrig, the notable ALS leads to progressive degeneration of the motor first baseman for the New York Yankees, contracted ALS. neurons that supply voluntary muscles, including LMNs Gehrig, nicknamed the “iron horse” for playing 2130 in the medulla and anterior horn of the spinal cord as well consecutive games over 14 years, first exhibited signs in as UMNs in the cerebral cortex. The effect clinically is 1938; he finished the season but with a batting average 45 progressive muscle weakness leading to death, usually points below his career average [13,14]. By April 1939, from respiratory failure. Median survival ranges from he was no longer able to play and removed himself from months to decades but is 19 months from diagnosis and the lineup. Gehrig died two years later, having 30 months from onset on average [11,21]. The variability participating in an early clinical trial [15]. Gehrig’s name and overall rapid progression make it difficult to predict is still used as an eponym for ALS in the United States; survival time or the timing of interventions. In general, MND is used in the U.K., whereas SLA (sclé rose laté rale limb-onset, younger age, better motor function, higher amyotrophique), the term Charcot gave the disease, is breathing capacity, stable weight, and longer interval preferred in France. between symptom onset and diagnosis are associated with While ALS is nearly as mysterious today as it was in longer survival [22]. th the first part of the 20 Century, recent breakthroughs in Loss of LMNs causes fasciculation, cramps, muscle understanding familial forms (fALS) have led to new atrophy and marked weakness, which is often more hypotheses for disease triggers and mechanisms of disabling for patients than the spasticity, hyperreflexia propagation. Known mutations now account for much of and modest weakness associated with UMN disease. the rare instances of inherited ALS. Sporadic ALS (sALS) Babinski and Hoffmann signs, along with emotional is thought to have both genetic and environmental lability are also characteristic findings of UMN influences, but the principal causes await discovery. degeneration. Once the disease begins, a number of processes transpire ALS is clinically heterogeneous even among family in both neurons and surrounding glial cells; how these members harboring the same gene mutation; a single mechanisms interact is an area of active research [16]. As etiology can lead to numerous clinical syndromes. In in other neurodegenerative diseases, a prominent event in addition to variable progression rate, UMN and LMNs are damaged neurons is aggregation of misfolded protein, differentially affected, onset occurs in different body which might influence nearby wild type protein to change regions, and cognitive as well as behavioral disturbances conformation, and in this way, explain how a disease that vary. begins in one area is transmitted widely in the brain [17]. ALS begins in the limbs, usually the arms, in about Defects in RNA processing might also contribute to two-thirds of patients. The first symptoms are most often disease propagation, which could occur by local spread, unilateral and focal. Early findings include foot drop, through neuronal networks or by affecting populations of difficulty walking, loss of hand dexterity or weakness cells rendered vulnerable by developmental errors [18]. when lifting the arms. As limb function deteriorates, patients become dependent on caregivers. They may fall Aging and Disease • Volume 4, Number 5, October 2013 296 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 and lose the ability to walk. Bulbar-onset ALS, which is cervical, thoracic or lumbosacral. Recent modifications more frequent in older women, carries a worse prognosis created on Awaji Island near Japan may improve [23]. The first symptom is often dysarthria followed by diagnostic sensitivity, particularly for those with bulbar- dysphagia, which may progress to sialorrhea, malnutrition onset in whom limb findings can be subtle [32]. and anarthria. An atrophied fasciculating tongue is practically diagnostic of bulbar ALS. Axial weakness can Table 1. Summary of Revised El Escorial Diagnostic cause dropped head and kyphosis, which are associated Criteria for ALS [31] with pain and poor balance. Sphincter and sensory functions are usually, but not always, spared. Eye Clinically possible UMN and LMN sings in one ALS region, or movements are preserved until advanced stages. UMN signs in at least two Cognitive impairment in ALS was described by th regions, or Pierre Marie in the 19 century [24], but was considered UMN and LMN signs in two uncommon until recently. Overt frontotemporal dementia regions with no UMN signs (FTD) occurs in approximately 15% of people with ALS, rostral to LMN signs but up to 50% are classified as impaired if measured by Laboratory- UMN signs in one or more neuropsychological tests [25,26]. Primary progressive supported probable regions and LMN signs aphasia, semantic dementia and the behavioral variant are ALS defined by EMG in a least two subtypes of FTD that affect executive function, language, regions judgment, personality, and behavior. Patients with ALS Clinically probable UMN and LMN signs in two and dementia have shorter survival, possibly as a result of ALS regions with some UMN signs indecisiveness about care [27]. rostral to the LMN signs Depression and anxiety can occur during any stage of Clinically definite UMN and LMN signs in three the disease, from time of diagnosis to respiratory failure, ALS regions but patients with ALS often approach the disease EMG – electromyogram; LMN- lower motor neuron; UMN – philosophically and rates of depression seem to be lower upper motor neuron than expected [28]. When present, emotional symptoms impair quality of life through poor sleep and appetite, as well as feelings of hopelessness [29]. PATHOGENESIS Pain can occasionally result from involvement of sensory neurons, and frequently from contractures, More than a century after Charcot described ALS, the immobility, inability to turn in bed, or bedsores. The etiologies are undiscovered for most patients, but genetic suffering that arises from being unable to move can be discoveries have recently improved understanding of intense (www.nybooks.com/articles/archives/2010/jan/ fALS. Approximately 5-10% of ALS is inherited, with 14/night). responsible mutations identified in nearly 60%. Morning headache, weak cough, orthopnea, and Among the genes reported in ALS pedigrees, there is exertional dyspnea are early respiratory symptoms. As the strong evidence supporting a pathogenic role for the Cu / disease advances, shortness of breath occurs during Zn superoxide dismutase 1 (SOD1), transactive response simple tasks such as dressing and eating, and eventually DNA-binding protein of 43 kD (TARDBP), fused in at rest. sarcoma (FUS) and c9ORF72 genes [33]. Other genes The diagnosis, which depends on progressive UNM possibly implicated in fALS include the angiogenin, and LMN findings by history and examination, is accurate ataxin-2, optineurin, profiling 1, ubiquilin-2, valosin 95% of the time when made by an experienced clinician containing protein (VCP) and VAMP-associated protein [30]. Electromyography confirms widespread LMN type B (VAPB) genes [34]. disease and excludes other diseases such as multifocal A single mutation can lead to different clinical motor neuropathy with conduction block. Brain and spinal presentations, suggesting that varying mechanisms MRI rule out conditions that affect the UMN, including influence outcome, and similar ALS phenotypes result cervical spondylosis. Occasionally the brain MRI shows from different mutations, implying that ALS is a bilateral signal changes within the corticospinal tracts, a syndrome of different causes that share like finding that is pathognomonic of ALS. pathophysiological pathways [18]. The El Escorial criteria help standardize diagnosis for Gene mutations cause motor neuron death through clinical research studies [31] (Table 1). Progressive LMN different pathways: SOD1 mutations lead to oxidative disease by clinical and electromyographic examination, stress; TARDBP, FUS and c9ORF72 induce disturbances and clinical UMN signs are the core. Patients are in RNA machinery; VAPB affects endosomal vesicle classified by the number of involved body regions: bulbar, trafficking; and UBQLN2 contributes to ubiquitination. Aging and Disease • Volume 4, Number 5, October 2013 297 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 The first mutation discovered was in the SOD1 gene Abnormal SMN1 copy number is one such risk gene [50]. on chromosome 21 [35]. The SOD1 mutation was used to Other associations, including the DPP6 and VEGF genes, create a transgenic animal model that has been used to could not be identified by independent researchers or were screen new drugs and study disease physiology. found only in certain geographic regions [51-55]. GWAS Currently, 15–20% of fALS cases, inherited mostly in an are a difficult undertaking in ALS because sample sizes autosomal dominant pattern, are due to one of more than must be very large to detect small genetic effects [41]. 160 mutations that affect five exons and some introns of Advancing age and exposure to tobacco smoke are the gene. Five percent of patients with sALS carry similar associated with sALS [56], but there is currently little mutations. SOD1 mutations are associated with evidence to support the contribution of other deposition of ubiquitinated TDP-43 negative SOD1 environmental risk factors [1,56-60]. A pooled analysis of protein in neurons [36]. SOD1 appears to trigger disease five large cohorts found modest but significant in motor neurons, but astrocytes and microglia promote associations with active smoking, former smoking, disease progression, perhaps through mishandling of duration of smoking, and quantity of cigarettes [61]. Other glutamate [37]. Clinical characteristics of families possible associations include athleticism [62], particularly harboring SOD1 mutations include young age-of-onset, professional sports, pesticide exposure [63], and service onset in the leg with predominance of LMN features, and in the first Gulf war [64]. A study in Italy from 1970-2001 low frequency of cognitive disturbances. Disease duration found a 6.5 times higher risk in soccer players than non- spans an average of 9 months (A4V mutation) to decades players [65]. Trauma is a possible contributor to all (D90A mutation) [38]. neurodegenerative diseases [66]. Associations with TARDBP mutations account for about 5% of FALS electrical fields, viral infection and various toxins are [39]. Nearly 50 mutations have been identified, mostly uncorroborated [67,68]. involving the C-terminal glycine-rich region of the Pathophysiological mechanisms that contribute to protein. Similar to sALS, mutations in the TARDBP gene cell death after disease-onset include mitochondrial cause TDP-43 positive inclusions in the brain, which, dysfunction, protein aggregation, generation of free along with FUS+ aggregates, may lead to defects in RNA radicals, excitotoxicity, disrupted axonal transport, processing. Caucasians with ALS linked to TARDBP inflammation, and apoptosis [69]. Levels of Nogo-A, a mutations typically have onset in the arm while people of protein that inhibits regrowth of axons, are increased in Asian descent have bulbar onset [40], longer disease the muscle of patients and transgenic mice, suggesting duration and infrequent cognitive disturbances [33]. that muscle function could influence the health of motor Mutations in the FUS gene account for about 5% of neurons [70,71]. Cell death may occur, at least in SOD1 FALS and less than 1% SALS. More than 50 mutations ALS, by non-cell autonomous mechanisms in which have been identified, most affecting the last 17 amino surrounding support cells are required [72]. acids of the protein, the commonest being Arg521Cys There is now evidence that pathological protein [41]. All except one mutation is dominant [42]. FUS aggregates in the brain are actively disseminated. MRI positive TDP negative inclusions are found studies suggest that ALS could spread through vulnerable pathologically. FUS mutations cause ALS with age-of- neuronal networks [73], and SOD1 and TDP-43 proteins onset younger than 40 years in one-third of cases, usual possess prion-like domains, which might induce normal onset in the arm, and survival of less than two years [33]. protein to change confirmation, leading to cell-to-cell The c9ORF72 gene is now thought to be the most transmission [74]. frequent cause of genetic ALS. A hexanucleotide repeat in the gene accounts for up to 40% of fALS and 7% of MANAGEMENT sALS [43]. Mutations in the c9ORF72 gene cause FTD or ALS that are marked by TDP-43 protein accumulation in There is no cure yet for ALS, so, while research continues, the brain along with deposits of p62 [44]. C9ORF72 the objective of clinical care is to maintain quality of life mutations are also linked to other neurological diseases and prolonging life as much as possible. Management is [45]. centered on a combination of a neuroprotective There are a few leads for the causes of sALS. An medication, multidisciplinary clinics and respiratory elevated estimate of heritability in twin studies [46]; support. Controlled trials are needed to define the best gender predominance depending on phenotype [47]; and timing and role for gastrostomy. Many therapies can help familial aggregation of neurodegenerative disorders relieve symptoms, including anxiolytics and analgesics, [48,49] suggest genetic factors at play. Genome-wide which bring comfort in the advanced stages. association studies (GWAS) have been used to search for susceptibility factors that promote motor neuron death in Riluzole patients with sALS, yielding few successes so far. Aging and Disease • Volume 4, Number 5, October 2013 298 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 Riluzole was developed because it possesses anti- ensure that problems are identified and treated glutamatergic properties that might reduce exitotoxicity in expeditiously. Patients and families see professionals ALS. Riluzole slowed disease progression in two from different disciplines in one sitting, preserving energy randomized controlled trials [21,75], reducing mortality and time. The level of experience is high because the albeit modestly [76]. The most common side effects are teams see many patients with ALS, a rare disease. Patients diarrhea, dizziness, fatigue, nausea, and somnolence. receive information about advanced directives, treatments Elevation of liver enzymes can occur, but rarely to levels for nutritional and respiratory insufficiency, and research that are clinically meaningful. Most patients in Europe, [20]. The education and support help patients decide where the health systems pay the cost, and more than half ahead of time whether to choose life support and help of patients in the U.S. take riluzole [77]. guide the multidisciplinary team in setting goals for care. A standard team is highlighted in Table 2. Multidisciplinary care Additional staff available to clinics may include a respiratory therapist, a pulmonologist, a Specialty clinics for ALS emerged in the 1980s and most gastroenterologist, a psychiatrist, a neuropsychologist, large centers in developed countries currently offer and an orthotist. The neurologist formulates a treatment multidisciplinary care [20]. Patients treated by ALS care plan with the information gathered by the various teams may have higher quality of life [78] and longer professionals. The recommendations are conveyed to the survival [19]. patient’s primary physician so that care continues in Consensus guidelines help standardize diagnosis and tandem. treatment [79,80]. A neurologist oversees clinical evaluations, which are usually done every 3 months to Table 2. Standard evaluation in multidisciplinary consultation [31] Multidisciplinary team members Standard evaluation ALS Nurse Organizes and supervises the practice Welcomes and orients the patient Helps in various tests (weighing, measuring lung capacity). Oversees collection of clinical data Dietician Evaluates nutritional status and dietary needs. Advises means maintain caloric balance. Evaluates dexterity and independence Occupational therapist Physical therapist Evaluates motor function and safety; Assesses need for adaptive equipment. Psychologist Assesses the presence of anxiety-depressive disorders Provides a supportive environment Assesses cognitive disorders (memory, attention, concentration) Provides coping strategies Helps with disability plans, insurance, home care, advance directives Social worker Provides emotional support Speech therapist Evaluates the voice, speech and swallowing. Advises regarding alternative communication devices (communication boards, speech synthesis) Nutrition and gastrostomy less physical activity accentuate muscle turnover. The end result is weight loss, which can be rapid and lead to Inadequate nutrition and dehydration, which become accelerated clinical deterioration [83]. The rate of weight common as ALS advances [81,82], have multifactorial loss may be a more important predictor of disease causes. Bulbar muscle weakness and dysphagia, arm progression than being under or overweight at diagnosis weakness that limits the ability to lift the arm to carry food [82]. to the mouth, and hypermetabolism all contribute to Monitoring weight in the clinic is the simplest way to negative calorie balance. Reduced lean body mass and assess caloric balance. Calculation of body mass index Aging and Disease • Volume 4, Number 5, October 2013 299 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 (BMI) using height and weight is also used. Guidelines for prescription of NIV [86,93] are Recommendations vary according to symptom severity: summarized in Table 3. Adaptations in food texture and postural changes such as the chin tuck are sufficient for mild dysphagia. Nutritional supplements can be tried once oral intake of adequate Table 3. Criteria for initiation of respiratory support in ALS patients calories becomes difficult. When positive caloric balance is no longer possible by mouth, a gastrostomy is indicated. While gastrostomy ensures ample nutrition, PaCO2 greater than 45 mm Hg and / or beneficial effects on quality of life and life expectancy Vital capacity less than 50% have not yet been demonstrated [83,84] and there are no Presence of of normal and / or randomized controlled trials that examine the effect of symptoms related to Nasal inspiratory pressure gastrostomy in ALS. Some patients may agree to the respiratory failure and maximum pressure sniff procedure too late in the disease to receive meaningful associated with one below 60% of normal and / benefit [85]. The ideal timing for gastrostomy awaits of the following or definition, but practice guidelines suggest that placement objective criteria: Nocturnal desaturation is safer while the vital capacity is above 50% of predicted below 90% PaO2 more than [82,86]. Parenteral supplementation can be tried for those 5% of the time too ill to withstand a procedure [87]. Ventilatory support Invasive ventilation may extend survival but requires 24-hour supervision, is expensive, and is ultimately When respiratory muscles become weak, symptoms of chosen by fewer than 5% of patients [89,94]. Some long- dyspnea, orthopnea, sleep fragmentation, daytime fatigue, term survivors progress to a total locked in syndrome in and morning headaches develop. A forceless cough due to which all ability to communicate, even with eye diaphragm and bulbar muscle weakness can lead to movement, is lost. Some patients choose to have excessive secretions, poor airway clearance, and respiratory support withdrawn, a decision that is ethical as aspiration. Serial assessment of respiratory function long as analgesics and anxiolytics are prescribed to avoid includes history, physical examination, overnight pulse suffering when the ventilator is disconnected. Brain- oximetry and vital capacity (VC). The maximal computer interface technology is being tested in ALS (see inspiratory and expiratory pressures (MIP and MEP) below) because some patients retain the cognitive correlate with respiratory muscle weakness [86]. A MIP function needed to operate a computer using brain waves of <60 cm H2O is a predictor of reduced survival. Sniff and biofeedback. nasal inspiratory pressure (SNIP), a noninvasive measure Diaphragm pacing is an approach to treating of inspiratory force, estimates intrathoracic pressure, is respiratory failure that is undergoing evaluation in ALS sensitive to respiratory muscle weakness, declines [95]. A system was approved by the U.S. Food and Drug predictably over time, and predicts survival. A Administration in 2011 for ALS, not because it was transcutaneous carbon dioxide sensor can detect elevated proven effective, but under a Humanitarian Device carbon dioxide levels due to muscle weakness [88]. Exemption, which allows patients with a terminal illness The cause of death in ALS is normally respiratory. to use an unproved but apparently safe device while Approximately 60 % of patients have a predictable awaiting the results of a clinical trial. Phrenic nerve decline in function and the remainder die suddenly, pacing is available to patients with other disorders that sometimes from other causes [89]. cause hypoventilation but leave the phrenic nerve Non-invasive ventilation (NIV) is an established unaffected, such as spinal cord injury [96]. Phrenic nerve treatment for patients with respiratory insufficiency [20]. systems help maintain diaphragm strength by giving low- The bi-level intermittent positive-pressure ventilator, frequency stimulation via electrodes that are surgically which is triggered by a patient’s inspiratory effort and attached to the nerve. Diaphragm pacing evolved from the shuts off during exhalation, facilitates physiological nerve systems because the phrenic nerve degenerates in breathing. When used at least four hours per day, NIV ALS [97]. A randomized controlled trial is currently reduces the work of breathing, improves gas exchange, recruiting patients in France. enhances sleep quality [90], extends survival [91], and An assisted cough device, suction machine, may improve cognition [92], as well as help stabilize theophylline, antibiotics, mucolytics, and expectorants weight. Oxygen is usually prescribed only in conjunction can help ease respiratory symptoms [98]. Pneumonia and with NIV to prevent inhibiting respiratory drive in the influenza vaccines reduce pulmonary infections [86]. setting of elevated serum carbon dioxide levels. Aging and Disease • Volume 4, Number 5, October 2013 300 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 Table 4. Treatments used for ALS Treatment Administration Indication *Riluzole 50 mg bid ALS *Multidisciplinary care Every three monthly All symptoms of ALS visits *Non-invasive ventilation Nighttime and Respiratory insufficiency during symptoms at least 4 hours/day Gastrostomy Daily calorie Dysphagia and malnutrition supplements *Dextromethorphan/quinidine 20mg/10mg bid Pseudobulbar affect Diaphragm Pacing Up to 24 hours/day Respiratory insufficiency Brain-computer interface Experimental Communication Amitriptyline 12.5-125 mg qhs SSRI antidepressants 20-100 mg qd Mirtazapine 15-30 mg qhs Buspirone 10 mg tid Anxiety Diazepam 2-10 mg tid Lorazepam 0.5-2 mg tid Mirtazapine 15-30 mg qhs SSRI antidepressants 10-100 mg qd Diazepam 2-10 mg tid Phenytoin 100-300 mg qhs Cramps Vitamin E 400 IU tid Mirtazapine 15-30 mg qhs SSRI antidepressants 20-100 mg qd Depression Tricyclic antidepressants 12.5-150 mg qhs Venlafaxine 37.5-75 mg qd Amantadine 100 mg qAM, qnoon Bupropion SR 150-450 mg qd Fluoxetine 20-80 mg qd Fatigue Pemoline 18.75-93.75 mg qd Pyridostigmine 60 mg tid Venlafaxine 75-225 mg qd Amitriptyline 12.5-125 mg qhs Atropine sulphate 0.4 mg q4-6h 1-2 ophthalmic drops SL q4-6h Sialorrhea Diphenhydramine 25-50 mg tid Hyoscyamine sulfate 0.125-0.25 mg q4h Scopolamine transdermal patch 0.5 mg q72h Baclofen 10-60 mg tid Benzodiazepines 2-10 mg tid Spasticity Dantrolene 25-100 mg tid Tizanidine 2-8 mg tid Amitriptyline 12.5-75 mg qhs Oxybutynin 2.5-5 mg bid Urinary urgency 3.9 mg patch qd Tolterodine 1-2 mg bid Bid = twice daily; IU = international units; qAM = every morning qd = daily; qhs = every day qt bedtime; qid = four times daily; qnoon = every day at noon; qxh = every x hours; SL = sublingual; SR = slow release; SSRI = serotonin-specific reuptake inhibitor; tid = there times daily. *shown to have a beneficial effect in ALS Aging and Disease • Volume 4, Number 5, October 2013 301 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 Symptomatic agents muscular atrophy occurs [106]. One ongoing trial aims to determine the place for exercise in ALS. Many medications, most used off-label, can reduce Energy depletion also appears to influence the symptoms due to ALS (Table 4). Some treatments development of the disease, and is associated with worse improve quality of life and a few appear to extend life. prognosis [82]. Two clinical trials evaluating nutritional interventions are underway. The first trial is assessing a high fat diet given by tube feedings and the second is Palliative care examining the safety and efficacy olanzapine, a drug that All of ALS care is palliative because of the relentlessly promotes weight gain. progressive course. Open communication is the key to Stem cell therapies are also being tested [107]. There preparing patients for end-of-life decisions, and, even is considerable scientific evidence that stem cells exercise though discussions have become more matter-of-fact, the a variety of beneficial effects in neurodegeneration, topic is still sensitive. Hospice can be especially helpful including in the ALS mouse model, and now phase I in providing a framework for conversations about life clinical trials are being conducted in patients to determine support. the safety and feasibility of transplantation using different The goal of ALS care in the terminal phases is to types of stem cells. Cell therapy strategies utilize various avoid suffering. Hospice teams provide symptom types of stem cells to replace degenerating cells, support management through the use of medications, as well as neurons and surrounding cells through release of emotional support for patients and families. Medications neurotrophic factors, and study disease physiology. to relieve suffering such as anxiolytics and opioids, can be Possible sources of stem cells for ALS include bone prescribed under the direction of a physician with marrow, neural stem cells, mesenchymal stem cells, knowledge of treating terminal diseases or a hospice team. astrocyte precursor cells, and induced pluripotent stem Narcotic medications are effective for treating pain, cells [108]. dyspnea and nocturnal discomfort long before the final Stem cell models of neurodegeneration can be used to phase of the illness [99]. End-of-life palliation is usually study the disease and to rapidly screen potential done at home, but inpatient hospice wards can be used for therapeutic compounds. Transplanted stem cells in patients who do not wish to die at home. animals and people appear to have an effect by supporting degenerating neurons and enhancing production of CLINICAL TRIALS growth factors [109]. The cells might also be used as vectors for gene or drug therapy. Open questions include Since two randomized controlled trials showed the which stem cell type will be safest and most effective for effectiveness of riluzole, more than 30 trials have ended use in ALS, as well as how to target both motor neurons in negative results [100]. This lamentable history over 18 and their surrounding astrocytes and microglial cells. years despite advances in other areas of ALS research has Numerous exploratory trials are underway across the prompted researchers to create standard methodologies to world, but the clinical administration of cell replacement improve animal studies [101] and human trials is still in its infancy, and patients must guard against [16,102,103]. ALS is a complicated disease to study; the ‘medical tourism’ clinics that make unsubstantiated disorder is rare and heterogeneous, correct doses for promises for expensive treatments [110,111]. neuroprotection are difficult to identify, outcomes are Current trials are also aimed at genetic defects. The clinical and have high variance, and progressive weakness identification of mutations responsible for ALS has led to can lead to missing data [16]. An active search for the advent of antisense therapy, which utilizes injections biomarkers is underway so that diagnosis and measures of of short synthetically modified nucleic acid that binds to progression are more sensitive [104]. an mRNA target, silencing its function [112]. The Current trails are targeting muscle proteins, seeking molecules are too large to cross the blood-brain barrier ways to stabilize energy expenditure, utilizing cell and so must be administered by intrathecal injection. Anti- replacement therapies, and ascertaining whether abnormal sense therapy reduces the expression of wild-type and genes can be silenced. Patients can find trials enrolling mutated SOD1 protein in human cell cultures and participants at www.clinicaltrials.gov. transgenic animals [112]. In a recent phase I study, anti- Antagonsim of Nogo, a muscle protein that inhibits sense therapy was given to 22 ALS patients harboring neurite outgrowth, might enhance reinervation in ALS SOD1 mutations without toxic effects [113]. [105]. Some studies suggest that exercise programs might have positive physiological and psychological effects for Testing New Agents and Trial Design people with ALS, especially when implemented before Aging and Disease • Volume 4, Number 5, October 2013 302 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 Riluzole extends survival by about 11% [76]. The only Once adequate scientific justification for an agent is other clearly positive trial that tested efficacy of a established at the bench, only robust clinical trials can medication was of the combination of dextromethorphan ensure that the true effect of the agent is measured. The and quinidine (AVP-923; Nuedexta), which alleviated the clinical trials process includes several phases. Phase-I symptoms of pseudobulbar affect in a multicenter, studies, test pharmacokinetic characteristics and clinical randomized, controlled trial [114]. Dextromethorphan safety as well as toxicity of the drug at a range of doses, modulates the presynaptic release of glutamate and usually in less than 100 human subjects. dopamine by blocking the NMDA receptor and acting as Phase-II studies explore dose regimen, safety and an σ-1 receptor agonist. Quinidine was included because toxicity, feasibility, and early evidence of efficacy or non- it inhibits the metabolism and, therefore, prolonging the futility, and generally include up to several 100 patients. half-life, of dextromethorphan. The combination is now Dose-ranging is considered crucial in ALS [117-119]. commercially available. Definition of the correct dose and regimen prior to A worldwide resource-intensive search is underway embarking on an efficacy trial is difficult but without it, at the bench to improve understanding of ALS phase III trials can be fatally handicapped before they pathogenesis and physiology and in translational research begin. The phase-II study seeking early evidence of to identify more effective neuroprotective therapies. New efficacy, however, risks masquerading as an therapy development for ALS currently involves the underpowered phase-III trial. Innovative pilot designs that twofold process of identifying potential neuroprotective act as efficient screens before proceeding to efficacy agents in the laboratory and then testing them in human trials, can test multiple medications or doses at once and clinical trials. Summary articles on basic science do so more efficiently than standard parallel group techniques and clinical trial design are listed below. designs [120]. Generating the scientific justification for a new agent The phase-III trial is the final test of efficacy and entails evaluating the compound in in vitro models, which safety and is usually undertaken in several hundred to can include cell culture preparations and models of several thousand patients. The ALS Functional Rating glutamate toxicity or mitochondrial dysfunction among Scale (ALSFRS-R) and survival are clinical endpoints others [104], followed by placebo-controlled trials in widely used to establish efficacy until biomarkers become transgenic animal models to determine how an agent available. Phase-IV studies are occasionally conducted might affect the disease physiology. There is no model once a drug has received marketing approval, with the that perfectly recapitulates the human condition; many goal of detecting rare, serious side effects that may have positive studies in animals could not be replicated in escaped detection in earlier phase studies. people, partly because of deficiencies in the design of the The randomized double-blind placebo-controlled animal and human trials and partly because of the parallel study is the gold standard for testing efficacy, is complex nature of ALS [16]. While other transgenic simplest to interpret, and is needed for approval of a new animal models are under development, the SOD1 rodent medication in most countries. Typically, in this study is still considered the gold standard for screening potential design, patients are randomly assigned to one of two new drugs [115]. Standard approaches to testing agents in groups. One group of patients receives the drug to be the model, including assessment of dose and tested, while the other group receives placebo (or the pharmacokinetic profiles as well as the importance of standard treatment). Both the patients and investigators publishing negative trials to avoid bias are now published are blinded to the assignments. The effects of different [101]. Animal studies test mechanism, pharmacokinetics, dose levels can be investigated in multiple parallel arms. and efficacy, ideally helping to refine the dose, route and The strengths of this design include the ability to regimen for human studies. A negative animal study randomize patients at the same stage of the disease for suggests that more scientific work is needed to determine direct prospective comparison, and negation of the the best approach in the laboratory before dedicating the placebo effect because both blinded groups presumably financial and human resources needed to test a new drug experience the placebo effect to the same degree. in humans. In sum, since no in vitro or in vivo system can The randomized controlled trial is not fool-proof, guarantee success in humans ALS, consistency of however. Potential pitfalls include finding no difference preclinical data, identification of a credible mechanism, in a study with low power and concluding that the two evidence of CNS penetration and efficacy in a well- groups are equivalent, when in fact they are not. Such designed animal trial are the foundation of suficient studies are not negative but inconclusive; not enough data scientific rationale to study a new drug in people were collected to detect a clinically important difference [116,117]. Adequate toxicology studies in animals also if one existed. Statistical planning prior to study roll out are needed before the US Food and Drug Administration is necessary to decide on adequate power and effect size. will allow human trials. Without known causes, neuroprotective drugs cannot Aging and Disease • Volume 4, Number 5, October 2013 303 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 target the root triggers, and anticipated effects of any large efficacy trials. Another approach is the non- agent are small. Given the 11% impact riluzole, choosing superiority or futility design in which the hypothesis an effect size of more than 15-20% in present trials may statement is reversed and superiority is assumed. If the be unrealistic [118,121]. Trials powered to detect larger decline in an outcome such as ALSFRS-R is less than a effects risk being too insensitive to detect small effects, predetermined percentage, then the null hypothesis of positive or negative [121]. superiority is not rejected, inadequate evidence of futility An important component of the trial is the day-to-day is concluded, and the drug is deemed eligible for a Phase logistics of reducing missing data, minimizing subject III trial. The futility design permits investigators to protect dropout, accurate data collection and management, as well against falsely rejecting a drug as ineffective due to as clear analysis. Biomarkers of disease progression are inadequate power, while at the same time providing not yet available for ALS, but including reassurance of a reasonable likelihood of success in a pharmacodynamic measures as part of a trial can improve well-powered efficacy trial. These phase II designs have understanding of the disease and provide insights into the not, so far, led to false positive results the way standard effect of the drug [122]. parallel group phase II trials have, and guard against the Many past trials may not have been negative so much fatal flaw in phase II design of mimicking a phase III trial as inconclusive due missteps in the process, but each trial but with lower power. has improved our understanding of methodology and the scrutiny of their designs, strengths and weaknesses has FUTURE DIRECTIONS helped direct present endeavors. Because ALS is a rare disorder, there are few patients who can participate in Disease propagation trials: a sound trial design is essential for the judicious use of resources. The riluzole trials used survival as the The future lies in finding causes for sALS and, until then, primary outcome measure, but survival trials need the elucidating how the disease spreads in the brain once greatest number of patients and study duration to discern initiated; stopping either process could halt the disease. a difference between groups. Survival is a robust outcome Similar to other neurodegenerative disorders, affected measure for Phase III trials, but survival trials are neurons in ALS contain aggregated protein inclusions. becoming increasingly difficult to perform as more agents The focal onset and contiguous spread of the disease are tested; surrogate outcomes are better suited for early clinically is mirrored by migration of misfolded protein in phase trials especially. Other outcome measures can also degenerating neurons in the brain [18]. In ALS, the reliably measure change over time. inclusions occur first in motor neurons in the cortex and The ALS Functional Rating Scale (ALSFRS-R) is an brainstem. In patients with ALS and dementia, the often-used endpoint because it predicts survival, is easily inclusions are found throughout the frontal and temporal administered over the phone, thereby reducing dropout, is lobes. Some of these proteins may have prion-like inexpensive and provides information on function, which domains. They are not infectious like true prions, but have may be more meaningful to patients than survival alone a propensity to self-aggregate, and act as templates for [123]. normal protein, inducing conformational changes in Since the early 2000s, trials have also explored previously unaffected protein. The change in different statistical methods to enhance efficiency in drug conformation in normal protein appears to result in testing in ALS. A Phase III trial of creatine using survival migration from diseased to healthy cells. Protein as the primary outcome measure called attention to aggregates are themselves associated with other sequential data monitoring by an independent unblinded pathophysiological processes such as mitochondrial statistician who was able to stop the trial 18 months earlier dysfunction and energy depletion, glutamate excitoxicity, than expected when a positive outcome was no longer and induction of inflammatory mediators. Misfolded statistically possible [124]. This method saved human and protein could be a target for therapeutic intervention [74] financial resources compared to a standard fixed duration and a breakthrough in one neurodegenerative disorder design. Other designs are being tried in early phase trials would likely translate rapidly to other disorders. [125,126]. A Phase II selection trial is conducted between two or more experimental arms, with the aim of choosing Brain Computer Interface the empirically superior treatment at the end of study. This design differs from a conventional trial, which requires As ALS advances, patients can lose the ability to proof of a statistically significant difference between communicate. Bulbar symptoms can progress to anarthria arms. The selection design allows investigators to screen making meaningful voice communication impossible; multiple agents or doses in small sample size trials to motor function can deteriorate so that the ability to operate identify the most likely to succeed before proceeding to a computer with the limbs is lost; and eventually Aging and Disease • Volume 4, Number 5, October 2013 304 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 communication using eye movement is no longer causes and much about the disease physiology. Important possible. Ultimately, some patients become completely ways to intervene in the pathophysiology, including locked in, unable to move any voluntary muscle. supporting or replacing degenerating cells, slowing the Considerable research is being done to enable patients spread of aggregated protein, and silencing mutated genes with ALS to continue to communicate and even operate could have clinical impact soon. Clinical trials are aids to assist in daily functions using brain-computer becoming increasingly sophisticated so that the effect of interfaces (BCI)[127]. BCIs measure brain activity and new therapies is determined accurately. translate it into directions that control a computer. Most As new theories shed increasing light on the clinical applications use biofeedback to teach patients to physiology, we await the next great breakthrough; control brain wave output; computers interpret brain wave discovery of the causes of sALS and the medicines that activity and patients can learn to regulate the activity to follow. Meanwhile, patients are offered modern care that achieve goals through the computer. The technology can can help ensure comfort and dignity during this most be used to provide patients with a device that does not rely difficult disease. on muscle activity. Learning BCI appears to involve the same brain systems and information processing as other References skills. Patients can learn to spell using a virtual keyboard [1] Rowland LP, Shneider NA (2001). Amyotrophic lateral and to move virtual limbs. sclerosis. N Engl J Med, 344:1688-1700. Despite widespread degeneration in ALS, skill [2] Gordon PH, Cheng B, Katz IB, Pinto M, Hays AP, learning seems to remain intact up to the very final stages Mitsumoto H, Rowland LP (2006). The natural history [128]. A downside to the technology is that the systems of primary lateral sclerosis. Neurology, 66:647-653. with high accuracy and speed also place great demand on [3] Logroscino G, Traynor BJ, Hardiman O, Chio A, attention and memory. In some patients, cognitive Mitchell D, Swingler RJ, Millul A, Benn E, Beghi E deterioration may make operating a BCI impossible. (2010). Incidence of amyotrophic lateral sclerosis in Several clinical studies examining various BCI Europe. J Neurol Neurosurg Psychiatry, 81:385-390. technologies in ALS are currently enrolling patients. A [4] Marin B, Gil J, Preux PM, Funalot B, Couratier P (2009). feasibility study of an intracortical neural interface being Incidence of amyotrophic lateral sclerosis in the Limousin region of France, 1997-2007. Amyotroph done in the U.S. aims to determine the safety of the system Lateral Scler, 10:216-220. and to describe the algorithms and outcomes needed for a [5] Ragonese P, Filippini G, Salemi G, Beghi E, Citterio A, larger trial. The device is implanted onto the motor cortex D'Alessandro R, Marini C, Monsurro MR, Aiello I, of patients and neuronal recordings are made over time. Morgante L, et al. (2004). Accuracy of death certificates An EEG-based BCI using scalp recordings that assist for amyotrophic lateral sclerosis varies significantly patients with severely advanced ALS is being studied in from north to south of Italy: implications for mortality Philadelphia. This trial is expected to conclude in 2014. A studies. Neuroepidemiology, 23:73-77. study in France is testing severely progressed patients’ [6] Sorenson EJ, Stalker AP, Kurland LT, Windebank AJ ability to communicate via spelling using summed brain (2002). Amyotrophic lateral sclerosis in Olmsted County, Minnesota, 1925 to 1998. Neurology, 59:280- potentials and is expected to finish in 2015. [7] Gordon PH, Mehal JM, Holman RC, Rowland LP, SUMMARY Rowland AS, Cheek JE (2013). Incidence of Amyotrophic Lateral Sclerosis Among American In 2013, ALS is still so rapidly progressing that it is Indians and Alaska Natives. JAMA Neurol, 1-5. physically and emotionally overwhelming for patients, [8] Kurland LT, Hirano A, Malamud N, LESSELL S (1961). families and care givers. Health care teams spend their Parkinsonism-dementia complex, en endemic disease on time helping patients cope and trying to keep pace with a the island of Guam. Clinical, pathological, genetic and disease that produces new degrees of impairment and epidemiological features. Trans Am Neurol Assoc, disability almost without pause. Current care is 86:115-120. [9] Alonso A, Logroscino G, Jick SS, Hernan MA (2009). multidisciplinary and includes respiratory support, Incidence and lifetime risk of motor neuron disease in the supplemental feeding, and riluzole, which appear to United Kingdom: a population-based study. Eur J extend survival modestly. Symptomatic medications can Neurol, 16:745-751. improve quality of life, but more need to be tested in trials [10] Fang F, Valdimarsdottir U, Bellocco R, Ronnevi LO, for ALS. Numerous potential neuroprotective agents Sparen P, Fall K, Ye W (2009). Amyotrophic lateral targeting pathophysiological processes have been studied, sclerosis in Sweden, 1991-2005. Arch Neurol, 66:515- but there have been no recent successes. Yet, hope seems almost around the corner. Scientific [11] Logroscino G, Traynor BJ, Hardiman O, Chio' A, advances have uncovered several important genetic Couratier P, Mitchell JD, Swingler RJ, Beghi E (2008). Aging and Disease • Volume 4, Number 5, October 2013 305 P. H. 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Abitbol JL, Cudkowicz M, Leigh PN, Meininger V [78] Lee JR, Annegers JF, Appel SH (1995). Prognosis of (2009). Defining survival as an outcome measure in amyotrophic lateral sclerosis and the effect of referral amyotrophic lateral sclerosis. Arch Neurol, 66:758-761. selection. J Neurol Sci, 132:207-215. [90] Heckmatt JZ, Loh L, Dubowitz V (1990). Night-time [79] Haute Autorité de Santé . Prise en charge de personnes nasal ventilation in neuromuscular disease. Lancet, atteintes de sclé rose laté ral amyotrophique; confé rence 335:579-582. de consensus. 2006. [91] Bourke SC, Tomlinson M, Williams TL, Bullock RE, [80] Miller RG, Jackson CE, Kasarskis EJ, England JD, Shaw PJ, Gibson GJ (2006). Effects of non-invasive Forshew D, Johnston W, Kalra S, Katz JS, Mitsumoto H, ventilation on survival and quality of life in patients with Rosenfeld J, et al. (2009). Practice parameter update: The amyotrophic lateral sclerosis: a randomised controlled care of the patient with amyotrophic lateral sclerosis: trial. Lancet Neurol, 5:140-147. multidisciplinary care, symptom management, and [92] Newsom-Davis IC, Lyall RA, Leigh PN, Moxham J, cognitive/behavioral impairment (an evidence-based Goldstein LH (2001). The effect of non-invasive positive review): report of the Quality Standards Subcommittee pressure ventilation (NIPPV) on cognitive function in of the American Academy of Neurology. Neurology, amyotrophic lateral sclerosis (ALS): a prospective study. 73:1227-1233. J Neurol Neurosurg Psychiatry, 71:482-487. Aging and Disease • Volume 4, Number 5, October 2013 308 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 [93] Heiman-Patterson TD, Miller RG (2006). NIPPV: a integration into the segmental motor circuitry. J Comp treatment for ALS whose time has come. Neurology, Neurol, 514:297-309. 67:736-737. [110] Chew S, Khandji AG, Montes J, Mitsumoto H, Gordon [94] Lechtzin N, Wiener CM, Clawson L, Davidson MC, PH (2007). Olfactory ensheathing glia injections in Anderson F, Gowda N, Diette GB (2004). Use of Beijing: misleading patients with ALS. Amyotroph noninvasive ventilation in patients with amyotrophic Lateral Scler, 8:314-316. lateral sclerosis. Amyotroph Lateral Scler Other Motor [111] Abukhalil F, Lam BL, Guy J (2012). Visual observations Neuron Disord, 5:9-15. of an American patient with Leber hereditary optic [95] Amirjani N, Kiernan MC, McKenzie DK, Butler JE, neuropathy after purported injections of stem cells in Gandevia SC (2012). Is there a case for diaphragm China. Arch Ophthalmol, 130:532-534. pacing for amyotrophic lateral sclerosis patients? [112] Winer L, Srinivasan D, Chun S, Lacomis D, Jaffa M, Amyotroph Lateral Scler, 13:521-527. Fagan A, Holtzman DM, Wancewicz E, Bennett CF, [96] Gater DR, Jr., Dolbow D, Tsui B, Gorgey AS (2011). Bowser R, et al. (2013). SOD1 in cerebral spinal fluid as Functional electrical stimulation therapies after spinal a pharmacodynamic marker for antisense cord injury. NeuroRehabilitation, 28:231-248. oligonucleotide therapy. JAMA Neurol, 70:201-207. [97] Scherer K, Bedlack RS (2012). Diaphragm pacing in [113] Miller TM, Pestronk A, David W, Rothstein J, Simpson amyotrophic lateral sclerosis: a literature review. Muscle E, Appel SH, Andres PL, Mahoney K, Allred P, Nerve, 46:1-8. Alexander K, et al. (2013). An antisense oligonucleotide [98] Gordon PH (2011). Amyotrophic lateral sclerosis: against SOD1 delivered intrathecally for patients with pathophysiology, diagnosis and management. CNS SOD1 familial amyotrophic lateral sclerosis: a phase 1, Drugs, 25:1-15. randomised, first-in-man study. Lancet Neurol, 12:435- [99] Oliver D (1998). Opioid medication in the palliative care 442. of motor neurone disease. Palliat Med, 12:113-115. [114] Brooks BR, Thisted RA, Appel SH, Bradley WG, Olney [100] Aggarwal S, Cudkowicz M (2008). ALS drug RK, Berg JE, Pope LE, Smith RA (2004). Treatment of development: reflections from the past and a way pseudobulbar affect in ALS with forward. Neurotherapeutics, 5:516-527. dextromethorphan/quinidine: a randomized trial. [101] Ludolph AC, Bendotti C, Blaugrund E, Chio A, Neurology, 63:1364-1370. Greensmith L, Loeffler JP, Mead R, Niessen HG, Petri [115] Ludolph AC, Bendotti C, Blaugrund E, Hengerer B, S, Pradat PF, et al. (2010). Guidelines for preclinical Loffler JP, Martin J, Meininger V, Meyer T, Moussaoui animal research in ALS/MND: A consensus meeting. S, Robberecht W, et al. (2007). Guidelines for the Amyotroph Lateral Scler, 11:38-45. preclinical in vivo evaluation of pharmacological active [102] Mitsumoto H, Gordon P, Kaufmann P, Gooch CL, drugs for ALS/MND: report on the 142nd ENMC Przedborski S, Rowland LP (2004). Randomized control international workshop. Amyotroph Lateral Scler, 8:217- trials in ALS: lessons learned. Amyotroph Lateral Scler 223. Other Motor Neuron Disord, 5 Suppl 1:8-13. [116] Ravina BM, Fagan SC, Hart RG, Hovinga CA, Murphy [103] Cudkowicz ME, Katz J, Moore DH, O'Neill G, Glass JD, DD, Dawson TM, Marler JR (2003). Neuroprotective Mitsumoto H, Appel S, Ravina B, Kieburtz K, Shoulson agents for clinical trials in Parkinson's disease: a I, et al. (2010). Toward more efficient clinical trials for systematic assessment. Neurology, 60:1234-1240. amyotrophic lateral sclerosis. Amyotroph Lateral Scler, [117] raynor BJ, Bruijn L, Conwit R, Beal F, O'Neill G, Fagan 11:259-265. SC, Cudkowicz ME (2006). Neuroprotective agents for [104] Otto M, Bowser R, Turner M, Berry J, Brettschneider J, clinical trials in ALS: a systematic assessment. Connor J, Costa J, Cudkowicz M, Glass J, Jahn O, et al. Neurology, 67:20-27. (2012). Roadmap and standard operating procedures for [118] Leigh PN, Swash M, Iwasaki Y, Ludolph A, Meininger biobanking and discovery of neurochemical markers in V, Miller RG, Mitsumoto H, Shaw P, Tashiro K, van den ALS. Amyotroph Lateral Scler, 13:1-10. BL (2004). Amyotrophic lateral sclerosis: a consensus [105] Walmsley AR, Mir AK (2007). Targeting the Nogo-A viewpoint on designing and implementing a clinical trial. signalling pathway to promote recovery following acute Amyotroph Lateral Scler Other Motor Neuron Disord, CNS injury. Curr Pharm Des, 13:2470-2484. 5:84-98. [106] bello-Haas V, Florence JM, Krivickas LS (2008). [119] Shefner JM (2008). Designing clinical trials in Therapeutic exercise for people with amyotrophic lateral amyotrophic lateral sclerosis. Phys Med Rehabil Clin N sclerosis or motor neuron disease. Cochrane Database Am, 19:495-508, ix. Syst Rev, CD005229. [120] Gordon PH, Cheung YK, Levin B, Andrews H, Doorish [107] Maragakis NJ (2010). Stem cells and the ALS C, MacArthur RB, Montes J, Bednarz K, Florence J, neurologist. Amyotroph Lateral Scler, 11:417-423. Rowin J, et al. (2008). A novel, efficient, randomized [108] Traub R, Mitsumoto H, Rowland LP (2011). Research selection trial comparing combinations of drug therapy advances in amyotrophic lateral sclerosis, 2009 to 2010. for ALS. Amyotroph Lateral Scler, 9:212-222. Curr Neurol Neurosci Rep, 11:67-77. [121] Dibernardo AB, Cudkowicz ME (2006). Translating [109] Xu L, Ryugo DK, Pongstaporn T, Johe K, Koliatsos VE preclinical insights into effective human trials in ALS. (2009). Human neural stem cell grafts in the spinal cord Biochim Biophys Acta, 1762:1139-1149. of SOD1 transgenic rats: differentiation and structural Aging and Disease • Volume 4, Number 5, October 2013 309 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 [122] Cudkowicz M, Qureshi M, Shefner J (2004). Measures et al. (2006). A two-stage design for a phase II clinical and markers in amyotrophic lateral sclerosis. NeuroRx, trial of coenzyme Q10 in ALS. Neurology, 66:660-663. 1:273-283. [127] Riccio A, Mattia D, Simione L, Olivetti M, Cincotti F [123] Gordon PH, Miller RG, Moore DH (2004). ALSFRS-R. (2012). Eye-gaze independent EEG-based brain- Amyotroph Lateral Scler Other Motor Neuron Disord, 5 computer interfaces for communication. J Neural Eng, Suppl 1:90-93. 9:045001. [124] Groeneveld GJ, Veldink JH, van dT, I, Kalmijn S, Beijer [128] Silvoni S, Cavinato M, Volpato C, Ruf CA, Birbaumer C, de VM, Wokke JH, Franssen H, van den Berg LH N, Piccione F (2013). Amyotrophic lateral sclerosis (2003). A randomized sequential trial of creatine in progression and stability of brain-computer interface amyotrophic lateral sclerosis. Ann Neurol, 53:437-445. communication. Amyotroph Lateral Scler [125] Cheung YK, Gordon PH, Levin B (2006). Selecting Frontotemporal Degener, in press. promising ALS therapies in clinical trials. Neurology, 67:1748-1751. [126] Levy G, Kaufmann P, Buchsbaum R, Montes J, Barsdorf A, Arbing R, Battista V, Zhou X, Mitsumoto H, Levin B, Aging and Disease • Volume 4, Number 5, October 2013 310 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Aging and Disease Unpaywall

Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials

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Volume 4, Number 5; 295-310, October 2013 http://dx.doi.org/10.14336/AD.2013.0400295 Review Article Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials 1,2* Paul H. Gordon AP-HP, Hô pital de la Pitié -Salpê triè re, Dé partement des Maladies du Systè me Nerveux, Paris, France Northern Navajo Medical Center, Shiprock, NM 87420, USA [Received July 29, 2013; Revised August 26, 2013; Accepted August 27, 2013] ABSTRACT: Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot in the 1870s, is an age-related disorder that leads to degeneration of motor neurons. The disease begins focally in the central nervous system and then spreads relentlessly. The clinical diagnosis, defined by progressive signs and symptoms of upper and lower motor neuron dysfunction, is confirmed by electromyography. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of respiratory muscle weakness less than 3 years from symptom-onset. Like other age-related neurodegenerative diseases, ALS has genetic and environmental triggers. Of the five to 10% of cases that are inherited, mutations have been discovered for a high proportion. In addition to genetic factors, age, tobacco use, and athleticism may contribute to sporadic ALS, but important etiologies are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. The mechanisms leading to disease propagation in the brain are a current focus of research. To date, one medication, riluzole, licensed in 1996, has been proved to prolong survival in ALS. Numerous clinical trials have so far been unable to identify another neuroprotective agent. Researchers now aim to slow disease progression by targeting known pathophysiological pathways or genetic defects. Current approaches are directed at muscle proteins such as Nogo, energetic balance, cell replacement, and abnormal gene products resulting from mutations. Until better understanding of the causes and mechanisms underlying progression lead to more robust neuroprotective agents, symptomatic therapies can extend life and improve quality of life. Palliative care programs such as hospice give emotional and physical support to patients and families throughout much of the disease course. Key words: amyotrophic lateral sclerosis, neurodegeneration, epidemiology, pathophysiology, diagnosis, treatment Amyotrophic Lateral Sclerosis (ALS) is characterized by UMN features probably carries a better prognosis, even progressive degeneration of upper (UMN) and lower for patients with ALS [2]. Incidence rates for ALS range (LMN) motor neurons in the brain and spinal cord. It is from 1.2-4.0 per 100,000 person-years in Caucasians [3- the most common motor neuron disease (MND), which 6]. The rate may be lower in some ethnic populations includes primary lateral sclerosis, a disease restricted to including American Indians [7], and, historically, as much UMNs that makes up 1-3% of MND, and progressive as 50 times higher in Guam, Japan’s Kii Peninsula, and muscular atrophy, limited to LMNs, which is responsible western New Guinea [8]. Incidence rates increase with for approximately 10% of MND [1]. Predominance of *Correspondence should be addressed to: Paul H. Gordon, MD, PhD, Dé partement des Maladies du Systè me Nerveux, Centre ré fé rent maladie rare SLA, 75651 Paris, France. Email: paul.gordon@psl.aphp.fr ISSN: 2152-5250 295 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 age, peaking between 70 and 80 years, and are higher in The lethal prognosis and absence of treatments for ALS men than women [9,10]. mean that all care is palliative. One medication, riluzole, ALS begins in limb or bulbar muscles and then approved for use in 1996, slows deterioration by spreads to contiguous, and eventually respiratory, approximately two months, but 17 years and numerous myotomes. Survival ranges from months to decades, but trials later, no treatment can halt the course of the disease. is usually less than three years from when symptoms first Multi-disciplinary clinics [19] and non-invasive appear [11]. ventilation for those with respiratory failure also appear to Jean-Martin Charcot, employing the clinicoanatomic ameliorate the outcome modestly. Clinical trials currently method that he devised, described the clinical and test medications aimed to interfere with a known cellular pathological features of ALS during a series of lectures in event and slow the disease course; participation in the 1860s and 1870s [12]. The methodology available to research conveys hope to patients and may also improve Charcot was primitive by contemporary standards, but his survival time [20]. approach was so insightful that his original descriptions This review summarizes the clinical manifestations, are considered accurate today. Sir William Gowers and disease mechanisms, approaches to care and design of Lord Russell Brain made major contributions in the trials for ALS, giving an overview of the current United Kingdom, using the label MND instead of ALS understanding of the disease, and concludes with a section because they believed that all patients have pathology of on future directions. both UMNs and LMNs, either during life or at autopsy. th The paucity of American neurologists early in the 20 CLINICAL FEATURES AND DIAGNOSIS Century meant that the illness was largely overlooked in the New World until 1939 when Lou Gehrig, the notable ALS leads to progressive degeneration of the motor first baseman for the New York Yankees, contracted ALS. neurons that supply voluntary muscles, including LMNs Gehrig, nicknamed the “iron horse” for playing 2130 in the medulla and anterior horn of the spinal cord as well consecutive games over 14 years, first exhibited signs in as UMNs in the cerebral cortex. The effect clinically is 1938; he finished the season but with a batting average 45 progressive muscle weakness leading to death, usually points below his career average [13,14]. By April 1939, from respiratory failure. Median survival ranges from he was no longer able to play and removed himself from months to decades but is 19 months from diagnosis and the lineup. Gehrig died two years later, having 30 months from onset on average [11,21]. The variability participating in an early clinical trial [15]. Gehrig’s name and overall rapid progression make it difficult to predict is still used as an eponym for ALS in the United States; survival time or the timing of interventions. In general, MND is used in the U.K., whereas SLA (sclé rose laté rale limb-onset, younger age, better motor function, higher amyotrophique), the term Charcot gave the disease, is breathing capacity, stable weight, and longer interval preferred in France. between symptom onset and diagnosis are associated with While ALS is nearly as mysterious today as it was in longer survival [22]. th the first part of the 20 Century, recent breakthroughs in Loss of LMNs causes fasciculation, cramps, muscle understanding familial forms (fALS) have led to new atrophy and marked weakness, which is often more hypotheses for disease triggers and mechanisms of disabling for patients than the spasticity, hyperreflexia propagation. Known mutations now account for much of and modest weakness associated with UMN disease. the rare instances of inherited ALS. Sporadic ALS (sALS) Babinski and Hoffmann signs, along with emotional is thought to have both genetic and environmental lability are also characteristic findings of UMN influences, but the principal causes await discovery. degeneration. Once the disease begins, a number of processes transpire ALS is clinically heterogeneous even among family in both neurons and surrounding glial cells; how these members harboring the same gene mutation; a single mechanisms interact is an area of active research [16]. As etiology can lead to numerous clinical syndromes. In in other neurodegenerative diseases, a prominent event in addition to variable progression rate, UMN and LMNs are damaged neurons is aggregation of misfolded protein, differentially affected, onset occurs in different body which might influence nearby wild type protein to change regions, and cognitive as well as behavioral disturbances conformation, and in this way, explain how a disease that vary. begins in one area is transmitted widely in the brain [17]. ALS begins in the limbs, usually the arms, in about Defects in RNA processing might also contribute to two-thirds of patients. The first symptoms are most often disease propagation, which could occur by local spread, unilateral and focal. Early findings include foot drop, through neuronal networks or by affecting populations of difficulty walking, loss of hand dexterity or weakness cells rendered vulnerable by developmental errors [18]. when lifting the arms. As limb function deteriorates, patients become dependent on caregivers. They may fall Aging and Disease • Volume 4, Number 5, October 2013 296 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 and lose the ability to walk. Bulbar-onset ALS, which is cervical, thoracic or lumbosacral. Recent modifications more frequent in older women, carries a worse prognosis created on Awaji Island near Japan may improve [23]. The first symptom is often dysarthria followed by diagnostic sensitivity, particularly for those with bulbar- dysphagia, which may progress to sialorrhea, malnutrition onset in whom limb findings can be subtle [32]. and anarthria. An atrophied fasciculating tongue is practically diagnostic of bulbar ALS. Axial weakness can Table 1. Summary of Revised El Escorial Diagnostic cause dropped head and kyphosis, which are associated Criteria for ALS [31] with pain and poor balance. Sphincter and sensory functions are usually, but not always, spared. Eye Clinically possible UMN and LMN sings in one ALS region, or movements are preserved until advanced stages. UMN signs in at least two Cognitive impairment in ALS was described by th regions, or Pierre Marie in the 19 century [24], but was considered UMN and LMN signs in two uncommon until recently. Overt frontotemporal dementia regions with no UMN signs (FTD) occurs in approximately 15% of people with ALS, rostral to LMN signs but up to 50% are classified as impaired if measured by Laboratory- UMN signs in one or more neuropsychological tests [25,26]. Primary progressive supported probable regions and LMN signs aphasia, semantic dementia and the behavioral variant are ALS defined by EMG in a least two subtypes of FTD that affect executive function, language, regions judgment, personality, and behavior. Patients with ALS Clinically probable UMN and LMN signs in two and dementia have shorter survival, possibly as a result of ALS regions with some UMN signs indecisiveness about care [27]. rostral to the LMN signs Depression and anxiety can occur during any stage of Clinically definite UMN and LMN signs in three the disease, from time of diagnosis to respiratory failure, ALS regions but patients with ALS often approach the disease EMG – electromyogram; LMN- lower motor neuron; UMN – philosophically and rates of depression seem to be lower upper motor neuron than expected [28]. When present, emotional symptoms impair quality of life through poor sleep and appetite, as well as feelings of hopelessness [29]. PATHOGENESIS Pain can occasionally result from involvement of sensory neurons, and frequently from contractures, More than a century after Charcot described ALS, the immobility, inability to turn in bed, or bedsores. The etiologies are undiscovered for most patients, but genetic suffering that arises from being unable to move can be discoveries have recently improved understanding of intense (www.nybooks.com/articles/archives/2010/jan/ fALS. Approximately 5-10% of ALS is inherited, with 14/night). responsible mutations identified in nearly 60%. Morning headache, weak cough, orthopnea, and Among the genes reported in ALS pedigrees, there is exertional dyspnea are early respiratory symptoms. As the strong evidence supporting a pathogenic role for the Cu / disease advances, shortness of breath occurs during Zn superoxide dismutase 1 (SOD1), transactive response simple tasks such as dressing and eating, and eventually DNA-binding protein of 43 kD (TARDBP), fused in at rest. sarcoma (FUS) and c9ORF72 genes [33]. Other genes The diagnosis, which depends on progressive UNM possibly implicated in fALS include the angiogenin, and LMN findings by history and examination, is accurate ataxin-2, optineurin, profiling 1, ubiquilin-2, valosin 95% of the time when made by an experienced clinician containing protein (VCP) and VAMP-associated protein [30]. Electromyography confirms widespread LMN type B (VAPB) genes [34]. disease and excludes other diseases such as multifocal A single mutation can lead to different clinical motor neuropathy with conduction block. Brain and spinal presentations, suggesting that varying mechanisms MRI rule out conditions that affect the UMN, including influence outcome, and similar ALS phenotypes result cervical spondylosis. Occasionally the brain MRI shows from different mutations, implying that ALS is a bilateral signal changes within the corticospinal tracts, a syndrome of different causes that share like finding that is pathognomonic of ALS. pathophysiological pathways [18]. The El Escorial criteria help standardize diagnosis for Gene mutations cause motor neuron death through clinical research studies [31] (Table 1). Progressive LMN different pathways: SOD1 mutations lead to oxidative disease by clinical and electromyographic examination, stress; TARDBP, FUS and c9ORF72 induce disturbances and clinical UMN signs are the core. Patients are in RNA machinery; VAPB affects endosomal vesicle classified by the number of involved body regions: bulbar, trafficking; and UBQLN2 contributes to ubiquitination. Aging and Disease • Volume 4, Number 5, October 2013 297 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 The first mutation discovered was in the SOD1 gene Abnormal SMN1 copy number is one such risk gene [50]. on chromosome 21 [35]. The SOD1 mutation was used to Other associations, including the DPP6 and VEGF genes, create a transgenic animal model that has been used to could not be identified by independent researchers or were screen new drugs and study disease physiology. found only in certain geographic regions [51-55]. GWAS Currently, 15–20% of fALS cases, inherited mostly in an are a difficult undertaking in ALS because sample sizes autosomal dominant pattern, are due to one of more than must be very large to detect small genetic effects [41]. 160 mutations that affect five exons and some introns of Advancing age and exposure to tobacco smoke are the gene. Five percent of patients with sALS carry similar associated with sALS [56], but there is currently little mutations. SOD1 mutations are associated with evidence to support the contribution of other deposition of ubiquitinated TDP-43 negative SOD1 environmental risk factors [1,56-60]. A pooled analysis of protein in neurons [36]. SOD1 appears to trigger disease five large cohorts found modest but significant in motor neurons, but astrocytes and microglia promote associations with active smoking, former smoking, disease progression, perhaps through mishandling of duration of smoking, and quantity of cigarettes [61]. Other glutamate [37]. Clinical characteristics of families possible associations include athleticism [62], particularly harboring SOD1 mutations include young age-of-onset, professional sports, pesticide exposure [63], and service onset in the leg with predominance of LMN features, and in the first Gulf war [64]. A study in Italy from 1970-2001 low frequency of cognitive disturbances. Disease duration found a 6.5 times higher risk in soccer players than non- spans an average of 9 months (A4V mutation) to decades players [65]. Trauma is a possible contributor to all (D90A mutation) [38]. neurodegenerative diseases [66]. Associations with TARDBP mutations account for about 5% of FALS electrical fields, viral infection and various toxins are [39]. Nearly 50 mutations have been identified, mostly uncorroborated [67,68]. involving the C-terminal glycine-rich region of the Pathophysiological mechanisms that contribute to protein. Similar to sALS, mutations in the TARDBP gene cell death after disease-onset include mitochondrial cause TDP-43 positive inclusions in the brain, which, dysfunction, protein aggregation, generation of free along with FUS+ aggregates, may lead to defects in RNA radicals, excitotoxicity, disrupted axonal transport, processing. Caucasians with ALS linked to TARDBP inflammation, and apoptosis [69]. Levels of Nogo-A, a mutations typically have onset in the arm while people of protein that inhibits regrowth of axons, are increased in Asian descent have bulbar onset [40], longer disease the muscle of patients and transgenic mice, suggesting duration and infrequent cognitive disturbances [33]. that muscle function could influence the health of motor Mutations in the FUS gene account for about 5% of neurons [70,71]. Cell death may occur, at least in SOD1 FALS and less than 1% SALS. More than 50 mutations ALS, by non-cell autonomous mechanisms in which have been identified, most affecting the last 17 amino surrounding support cells are required [72]. acids of the protein, the commonest being Arg521Cys There is now evidence that pathological protein [41]. All except one mutation is dominant [42]. FUS aggregates in the brain are actively disseminated. MRI positive TDP negative inclusions are found studies suggest that ALS could spread through vulnerable pathologically. FUS mutations cause ALS with age-of- neuronal networks [73], and SOD1 and TDP-43 proteins onset younger than 40 years in one-third of cases, usual possess prion-like domains, which might induce normal onset in the arm, and survival of less than two years [33]. protein to change confirmation, leading to cell-to-cell The c9ORF72 gene is now thought to be the most transmission [74]. frequent cause of genetic ALS. A hexanucleotide repeat in the gene accounts for up to 40% of fALS and 7% of MANAGEMENT sALS [43]. Mutations in the c9ORF72 gene cause FTD or ALS that are marked by TDP-43 protein accumulation in There is no cure yet for ALS, so, while research continues, the brain along with deposits of p62 [44]. C9ORF72 the objective of clinical care is to maintain quality of life mutations are also linked to other neurological diseases and prolonging life as much as possible. Management is [45]. centered on a combination of a neuroprotective There are a few leads for the causes of sALS. An medication, multidisciplinary clinics and respiratory elevated estimate of heritability in twin studies [46]; support. Controlled trials are needed to define the best gender predominance depending on phenotype [47]; and timing and role for gastrostomy. Many therapies can help familial aggregation of neurodegenerative disorders relieve symptoms, including anxiolytics and analgesics, [48,49] suggest genetic factors at play. Genome-wide which bring comfort in the advanced stages. association studies (GWAS) have been used to search for susceptibility factors that promote motor neuron death in Riluzole patients with sALS, yielding few successes so far. Aging and Disease • Volume 4, Number 5, October 2013 298 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 Riluzole was developed because it possesses anti- ensure that problems are identified and treated glutamatergic properties that might reduce exitotoxicity in expeditiously. Patients and families see professionals ALS. Riluzole slowed disease progression in two from different disciplines in one sitting, preserving energy randomized controlled trials [21,75], reducing mortality and time. The level of experience is high because the albeit modestly [76]. The most common side effects are teams see many patients with ALS, a rare disease. Patients diarrhea, dizziness, fatigue, nausea, and somnolence. receive information about advanced directives, treatments Elevation of liver enzymes can occur, but rarely to levels for nutritional and respiratory insufficiency, and research that are clinically meaningful. Most patients in Europe, [20]. The education and support help patients decide where the health systems pay the cost, and more than half ahead of time whether to choose life support and help of patients in the U.S. take riluzole [77]. guide the multidisciplinary team in setting goals for care. A standard team is highlighted in Table 2. Multidisciplinary care Additional staff available to clinics may include a respiratory therapist, a pulmonologist, a Specialty clinics for ALS emerged in the 1980s and most gastroenterologist, a psychiatrist, a neuropsychologist, large centers in developed countries currently offer and an orthotist. The neurologist formulates a treatment multidisciplinary care [20]. Patients treated by ALS care plan with the information gathered by the various teams may have higher quality of life [78] and longer professionals. The recommendations are conveyed to the survival [19]. patient’s primary physician so that care continues in Consensus guidelines help standardize diagnosis and tandem. treatment [79,80]. A neurologist oversees clinical evaluations, which are usually done every 3 months to Table 2. Standard evaluation in multidisciplinary consultation [31] Multidisciplinary team members Standard evaluation ALS Nurse Organizes and supervises the practice Welcomes and orients the patient Helps in various tests (weighing, measuring lung capacity). Oversees collection of clinical data Dietician Evaluates nutritional status and dietary needs. Advises means maintain caloric balance. Evaluates dexterity and independence Occupational therapist Physical therapist Evaluates motor function and safety; Assesses need for adaptive equipment. Psychologist Assesses the presence of anxiety-depressive disorders Provides a supportive environment Assesses cognitive disorders (memory, attention, concentration) Provides coping strategies Helps with disability plans, insurance, home care, advance directives Social worker Provides emotional support Speech therapist Evaluates the voice, speech and swallowing. Advises regarding alternative communication devices (communication boards, speech synthesis) Nutrition and gastrostomy less physical activity accentuate muscle turnover. The end result is weight loss, which can be rapid and lead to Inadequate nutrition and dehydration, which become accelerated clinical deterioration [83]. The rate of weight common as ALS advances [81,82], have multifactorial loss may be a more important predictor of disease causes. Bulbar muscle weakness and dysphagia, arm progression than being under or overweight at diagnosis weakness that limits the ability to lift the arm to carry food [82]. to the mouth, and hypermetabolism all contribute to Monitoring weight in the clinic is the simplest way to negative calorie balance. Reduced lean body mass and assess caloric balance. Calculation of body mass index Aging and Disease • Volume 4, Number 5, October 2013 299 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 (BMI) using height and weight is also used. Guidelines for prescription of NIV [86,93] are Recommendations vary according to symptom severity: summarized in Table 3. Adaptations in food texture and postural changes such as the chin tuck are sufficient for mild dysphagia. Nutritional supplements can be tried once oral intake of adequate Table 3. Criteria for initiation of respiratory support in ALS patients calories becomes difficult. When positive caloric balance is no longer possible by mouth, a gastrostomy is indicated. While gastrostomy ensures ample nutrition, PaCO2 greater than 45 mm Hg and / or beneficial effects on quality of life and life expectancy Vital capacity less than 50% have not yet been demonstrated [83,84] and there are no Presence of of normal and / or randomized controlled trials that examine the effect of symptoms related to Nasal inspiratory pressure gastrostomy in ALS. Some patients may agree to the respiratory failure and maximum pressure sniff procedure too late in the disease to receive meaningful associated with one below 60% of normal and / benefit [85]. The ideal timing for gastrostomy awaits of the following or definition, but practice guidelines suggest that placement objective criteria: Nocturnal desaturation is safer while the vital capacity is above 50% of predicted below 90% PaO2 more than [82,86]. Parenteral supplementation can be tried for those 5% of the time too ill to withstand a procedure [87]. Ventilatory support Invasive ventilation may extend survival but requires 24-hour supervision, is expensive, and is ultimately When respiratory muscles become weak, symptoms of chosen by fewer than 5% of patients [89,94]. Some long- dyspnea, orthopnea, sleep fragmentation, daytime fatigue, term survivors progress to a total locked in syndrome in and morning headaches develop. A forceless cough due to which all ability to communicate, even with eye diaphragm and bulbar muscle weakness can lead to movement, is lost. Some patients choose to have excessive secretions, poor airway clearance, and respiratory support withdrawn, a decision that is ethical as aspiration. Serial assessment of respiratory function long as analgesics and anxiolytics are prescribed to avoid includes history, physical examination, overnight pulse suffering when the ventilator is disconnected. Brain- oximetry and vital capacity (VC). The maximal computer interface technology is being tested in ALS (see inspiratory and expiratory pressures (MIP and MEP) below) because some patients retain the cognitive correlate with respiratory muscle weakness [86]. A MIP function needed to operate a computer using brain waves of <60 cm H2O is a predictor of reduced survival. Sniff and biofeedback. nasal inspiratory pressure (SNIP), a noninvasive measure Diaphragm pacing is an approach to treating of inspiratory force, estimates intrathoracic pressure, is respiratory failure that is undergoing evaluation in ALS sensitive to respiratory muscle weakness, declines [95]. A system was approved by the U.S. Food and Drug predictably over time, and predicts survival. A Administration in 2011 for ALS, not because it was transcutaneous carbon dioxide sensor can detect elevated proven effective, but under a Humanitarian Device carbon dioxide levels due to muscle weakness [88]. Exemption, which allows patients with a terminal illness The cause of death in ALS is normally respiratory. to use an unproved but apparently safe device while Approximately 60 % of patients have a predictable awaiting the results of a clinical trial. Phrenic nerve decline in function and the remainder die suddenly, pacing is available to patients with other disorders that sometimes from other causes [89]. cause hypoventilation but leave the phrenic nerve Non-invasive ventilation (NIV) is an established unaffected, such as spinal cord injury [96]. Phrenic nerve treatment for patients with respiratory insufficiency [20]. systems help maintain diaphragm strength by giving low- The bi-level intermittent positive-pressure ventilator, frequency stimulation via electrodes that are surgically which is triggered by a patient’s inspiratory effort and attached to the nerve. Diaphragm pacing evolved from the shuts off during exhalation, facilitates physiological nerve systems because the phrenic nerve degenerates in breathing. When used at least four hours per day, NIV ALS [97]. A randomized controlled trial is currently reduces the work of breathing, improves gas exchange, recruiting patients in France. enhances sleep quality [90], extends survival [91], and An assisted cough device, suction machine, may improve cognition [92], as well as help stabilize theophylline, antibiotics, mucolytics, and expectorants weight. Oxygen is usually prescribed only in conjunction can help ease respiratory symptoms [98]. Pneumonia and with NIV to prevent inhibiting respiratory drive in the influenza vaccines reduce pulmonary infections [86]. setting of elevated serum carbon dioxide levels. Aging and Disease • Volume 4, Number 5, October 2013 300 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 Table 4. Treatments used for ALS Treatment Administration Indication *Riluzole 50 mg bid ALS *Multidisciplinary care Every three monthly All symptoms of ALS visits *Non-invasive ventilation Nighttime and Respiratory insufficiency during symptoms at least 4 hours/day Gastrostomy Daily calorie Dysphagia and malnutrition supplements *Dextromethorphan/quinidine 20mg/10mg bid Pseudobulbar affect Diaphragm Pacing Up to 24 hours/day Respiratory insufficiency Brain-computer interface Experimental Communication Amitriptyline 12.5-125 mg qhs SSRI antidepressants 20-100 mg qd Mirtazapine 15-30 mg qhs Buspirone 10 mg tid Anxiety Diazepam 2-10 mg tid Lorazepam 0.5-2 mg tid Mirtazapine 15-30 mg qhs SSRI antidepressants 10-100 mg qd Diazepam 2-10 mg tid Phenytoin 100-300 mg qhs Cramps Vitamin E 400 IU tid Mirtazapine 15-30 mg qhs SSRI antidepressants 20-100 mg qd Depression Tricyclic antidepressants 12.5-150 mg qhs Venlafaxine 37.5-75 mg qd Amantadine 100 mg qAM, qnoon Bupropion SR 150-450 mg qd Fluoxetine 20-80 mg qd Fatigue Pemoline 18.75-93.75 mg qd Pyridostigmine 60 mg tid Venlafaxine 75-225 mg qd Amitriptyline 12.5-125 mg qhs Atropine sulphate 0.4 mg q4-6h 1-2 ophthalmic drops SL q4-6h Sialorrhea Diphenhydramine 25-50 mg tid Hyoscyamine sulfate 0.125-0.25 mg q4h Scopolamine transdermal patch 0.5 mg q72h Baclofen 10-60 mg tid Benzodiazepines 2-10 mg tid Spasticity Dantrolene 25-100 mg tid Tizanidine 2-8 mg tid Amitriptyline 12.5-75 mg qhs Oxybutynin 2.5-5 mg bid Urinary urgency 3.9 mg patch qd Tolterodine 1-2 mg bid Bid = twice daily; IU = international units; qAM = every morning qd = daily; qhs = every day qt bedtime; qid = four times daily; qnoon = every day at noon; qxh = every x hours; SL = sublingual; SR = slow release; SSRI = serotonin-specific reuptake inhibitor; tid = there times daily. *shown to have a beneficial effect in ALS Aging and Disease • Volume 4, Number 5, October 2013 301 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 Symptomatic agents muscular atrophy occurs [106]. One ongoing trial aims to determine the place for exercise in ALS. Many medications, most used off-label, can reduce Energy depletion also appears to influence the symptoms due to ALS (Table 4). Some treatments development of the disease, and is associated with worse improve quality of life and a few appear to extend life. prognosis [82]. Two clinical trials evaluating nutritional interventions are underway. The first trial is assessing a high fat diet given by tube feedings and the second is Palliative care examining the safety and efficacy olanzapine, a drug that All of ALS care is palliative because of the relentlessly promotes weight gain. progressive course. Open communication is the key to Stem cell therapies are also being tested [107]. There preparing patients for end-of-life decisions, and, even is considerable scientific evidence that stem cells exercise though discussions have become more matter-of-fact, the a variety of beneficial effects in neurodegeneration, topic is still sensitive. Hospice can be especially helpful including in the ALS mouse model, and now phase I in providing a framework for conversations about life clinical trials are being conducted in patients to determine support. the safety and feasibility of transplantation using different The goal of ALS care in the terminal phases is to types of stem cells. Cell therapy strategies utilize various avoid suffering. Hospice teams provide symptom types of stem cells to replace degenerating cells, support management through the use of medications, as well as neurons and surrounding cells through release of emotional support for patients and families. Medications neurotrophic factors, and study disease physiology. to relieve suffering such as anxiolytics and opioids, can be Possible sources of stem cells for ALS include bone prescribed under the direction of a physician with marrow, neural stem cells, mesenchymal stem cells, knowledge of treating terminal diseases or a hospice team. astrocyte precursor cells, and induced pluripotent stem Narcotic medications are effective for treating pain, cells [108]. dyspnea and nocturnal discomfort long before the final Stem cell models of neurodegeneration can be used to phase of the illness [99]. End-of-life palliation is usually study the disease and to rapidly screen potential done at home, but inpatient hospice wards can be used for therapeutic compounds. Transplanted stem cells in patients who do not wish to die at home. animals and people appear to have an effect by supporting degenerating neurons and enhancing production of CLINICAL TRIALS growth factors [109]. The cells might also be used as vectors for gene or drug therapy. Open questions include Since two randomized controlled trials showed the which stem cell type will be safest and most effective for effectiveness of riluzole, more than 30 trials have ended use in ALS, as well as how to target both motor neurons in negative results [100]. This lamentable history over 18 and their surrounding astrocytes and microglial cells. years despite advances in other areas of ALS research has Numerous exploratory trials are underway across the prompted researchers to create standard methodologies to world, but the clinical administration of cell replacement improve animal studies [101] and human trials is still in its infancy, and patients must guard against [16,102,103]. ALS is a complicated disease to study; the ‘medical tourism’ clinics that make unsubstantiated disorder is rare and heterogeneous, correct doses for promises for expensive treatments [110,111]. neuroprotection are difficult to identify, outcomes are Current trials are also aimed at genetic defects. The clinical and have high variance, and progressive weakness identification of mutations responsible for ALS has led to can lead to missing data [16]. An active search for the advent of antisense therapy, which utilizes injections biomarkers is underway so that diagnosis and measures of of short synthetically modified nucleic acid that binds to progression are more sensitive [104]. an mRNA target, silencing its function [112]. The Current trails are targeting muscle proteins, seeking molecules are too large to cross the blood-brain barrier ways to stabilize energy expenditure, utilizing cell and so must be administered by intrathecal injection. Anti- replacement therapies, and ascertaining whether abnormal sense therapy reduces the expression of wild-type and genes can be silenced. Patients can find trials enrolling mutated SOD1 protein in human cell cultures and participants at www.clinicaltrials.gov. transgenic animals [112]. In a recent phase I study, anti- Antagonsim of Nogo, a muscle protein that inhibits sense therapy was given to 22 ALS patients harboring neurite outgrowth, might enhance reinervation in ALS SOD1 mutations without toxic effects [113]. [105]. Some studies suggest that exercise programs might have positive physiological and psychological effects for Testing New Agents and Trial Design people with ALS, especially when implemented before Aging and Disease • Volume 4, Number 5, October 2013 302 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 Riluzole extends survival by about 11% [76]. The only Once adequate scientific justification for an agent is other clearly positive trial that tested efficacy of a established at the bench, only robust clinical trials can medication was of the combination of dextromethorphan ensure that the true effect of the agent is measured. The and quinidine (AVP-923; Nuedexta), which alleviated the clinical trials process includes several phases. Phase-I symptoms of pseudobulbar affect in a multicenter, studies, test pharmacokinetic characteristics and clinical randomized, controlled trial [114]. Dextromethorphan safety as well as toxicity of the drug at a range of doses, modulates the presynaptic release of glutamate and usually in less than 100 human subjects. dopamine by blocking the NMDA receptor and acting as Phase-II studies explore dose regimen, safety and an σ-1 receptor agonist. Quinidine was included because toxicity, feasibility, and early evidence of efficacy or non- it inhibits the metabolism and, therefore, prolonging the futility, and generally include up to several 100 patients. half-life, of dextromethorphan. The combination is now Dose-ranging is considered crucial in ALS [117-119]. commercially available. Definition of the correct dose and regimen prior to A worldwide resource-intensive search is underway embarking on an efficacy trial is difficult but without it, at the bench to improve understanding of ALS phase III trials can be fatally handicapped before they pathogenesis and physiology and in translational research begin. The phase-II study seeking early evidence of to identify more effective neuroprotective therapies. New efficacy, however, risks masquerading as an therapy development for ALS currently involves the underpowered phase-III trial. Innovative pilot designs that twofold process of identifying potential neuroprotective act as efficient screens before proceeding to efficacy agents in the laboratory and then testing them in human trials, can test multiple medications or doses at once and clinical trials. Summary articles on basic science do so more efficiently than standard parallel group techniques and clinical trial design are listed below. designs [120]. Generating the scientific justification for a new agent The phase-III trial is the final test of efficacy and entails evaluating the compound in in vitro models, which safety and is usually undertaken in several hundred to can include cell culture preparations and models of several thousand patients. The ALS Functional Rating glutamate toxicity or mitochondrial dysfunction among Scale (ALSFRS-R) and survival are clinical endpoints others [104], followed by placebo-controlled trials in widely used to establish efficacy until biomarkers become transgenic animal models to determine how an agent available. Phase-IV studies are occasionally conducted might affect the disease physiology. There is no model once a drug has received marketing approval, with the that perfectly recapitulates the human condition; many goal of detecting rare, serious side effects that may have positive studies in animals could not be replicated in escaped detection in earlier phase studies. people, partly because of deficiencies in the design of the The randomized double-blind placebo-controlled animal and human trials and partly because of the parallel study is the gold standard for testing efficacy, is complex nature of ALS [16]. While other transgenic simplest to interpret, and is needed for approval of a new animal models are under development, the SOD1 rodent medication in most countries. Typically, in this study is still considered the gold standard for screening potential design, patients are randomly assigned to one of two new drugs [115]. Standard approaches to testing agents in groups. One group of patients receives the drug to be the model, including assessment of dose and tested, while the other group receives placebo (or the pharmacokinetic profiles as well as the importance of standard treatment). Both the patients and investigators publishing negative trials to avoid bias are now published are blinded to the assignments. The effects of different [101]. Animal studies test mechanism, pharmacokinetics, dose levels can be investigated in multiple parallel arms. and efficacy, ideally helping to refine the dose, route and The strengths of this design include the ability to regimen for human studies. A negative animal study randomize patients at the same stage of the disease for suggests that more scientific work is needed to determine direct prospective comparison, and negation of the the best approach in the laboratory before dedicating the placebo effect because both blinded groups presumably financial and human resources needed to test a new drug experience the placebo effect to the same degree. in humans. In sum, since no in vitro or in vivo system can The randomized controlled trial is not fool-proof, guarantee success in humans ALS, consistency of however. Potential pitfalls include finding no difference preclinical data, identification of a credible mechanism, in a study with low power and concluding that the two evidence of CNS penetration and efficacy in a well- groups are equivalent, when in fact they are not. Such designed animal trial are the foundation of suficient studies are not negative but inconclusive; not enough data scientific rationale to study a new drug in people were collected to detect a clinically important difference [116,117]. Adequate toxicology studies in animals also if one existed. Statistical planning prior to study roll out are needed before the US Food and Drug Administration is necessary to decide on adequate power and effect size. will allow human trials. Without known causes, neuroprotective drugs cannot Aging and Disease • Volume 4, Number 5, October 2013 303 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 target the root triggers, and anticipated effects of any large efficacy trials. Another approach is the non- agent are small. Given the 11% impact riluzole, choosing superiority or futility design in which the hypothesis an effect size of more than 15-20% in present trials may statement is reversed and superiority is assumed. If the be unrealistic [118,121]. Trials powered to detect larger decline in an outcome such as ALSFRS-R is less than a effects risk being too insensitive to detect small effects, predetermined percentage, then the null hypothesis of positive or negative [121]. superiority is not rejected, inadequate evidence of futility An important component of the trial is the day-to-day is concluded, and the drug is deemed eligible for a Phase logistics of reducing missing data, minimizing subject III trial. The futility design permits investigators to protect dropout, accurate data collection and management, as well against falsely rejecting a drug as ineffective due to as clear analysis. Biomarkers of disease progression are inadequate power, while at the same time providing not yet available for ALS, but including reassurance of a reasonable likelihood of success in a pharmacodynamic measures as part of a trial can improve well-powered efficacy trial. These phase II designs have understanding of the disease and provide insights into the not, so far, led to false positive results the way standard effect of the drug [122]. parallel group phase II trials have, and guard against the Many past trials may not have been negative so much fatal flaw in phase II design of mimicking a phase III trial as inconclusive due missteps in the process, but each trial but with lower power. has improved our understanding of methodology and the scrutiny of their designs, strengths and weaknesses has FUTURE DIRECTIONS helped direct present endeavors. Because ALS is a rare disorder, there are few patients who can participate in Disease propagation trials: a sound trial design is essential for the judicious use of resources. The riluzole trials used survival as the The future lies in finding causes for sALS and, until then, primary outcome measure, but survival trials need the elucidating how the disease spreads in the brain once greatest number of patients and study duration to discern initiated; stopping either process could halt the disease. a difference between groups. Survival is a robust outcome Similar to other neurodegenerative disorders, affected measure for Phase III trials, but survival trials are neurons in ALS contain aggregated protein inclusions. becoming increasingly difficult to perform as more agents The focal onset and contiguous spread of the disease are tested; surrogate outcomes are better suited for early clinically is mirrored by migration of misfolded protein in phase trials especially. Other outcome measures can also degenerating neurons in the brain [18]. In ALS, the reliably measure change over time. inclusions occur first in motor neurons in the cortex and The ALS Functional Rating Scale (ALSFRS-R) is an brainstem. In patients with ALS and dementia, the often-used endpoint because it predicts survival, is easily inclusions are found throughout the frontal and temporal administered over the phone, thereby reducing dropout, is lobes. Some of these proteins may have prion-like inexpensive and provides information on function, which domains. They are not infectious like true prions, but have may be more meaningful to patients than survival alone a propensity to self-aggregate, and act as templates for [123]. normal protein, inducing conformational changes in Since the early 2000s, trials have also explored previously unaffected protein. The change in different statistical methods to enhance efficiency in drug conformation in normal protein appears to result in testing in ALS. A Phase III trial of creatine using survival migration from diseased to healthy cells. Protein as the primary outcome measure called attention to aggregates are themselves associated with other sequential data monitoring by an independent unblinded pathophysiological processes such as mitochondrial statistician who was able to stop the trial 18 months earlier dysfunction and energy depletion, glutamate excitoxicity, than expected when a positive outcome was no longer and induction of inflammatory mediators. Misfolded statistically possible [124]. This method saved human and protein could be a target for therapeutic intervention [74] financial resources compared to a standard fixed duration and a breakthrough in one neurodegenerative disorder design. Other designs are being tried in early phase trials would likely translate rapidly to other disorders. [125,126]. A Phase II selection trial is conducted between two or more experimental arms, with the aim of choosing Brain Computer Interface the empirically superior treatment at the end of study. This design differs from a conventional trial, which requires As ALS advances, patients can lose the ability to proof of a statistically significant difference between communicate. Bulbar symptoms can progress to anarthria arms. The selection design allows investigators to screen making meaningful voice communication impossible; multiple agents or doses in small sample size trials to motor function can deteriorate so that the ability to operate identify the most likely to succeed before proceeding to a computer with the limbs is lost; and eventually Aging and Disease • Volume 4, Number 5, October 2013 304 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 communication using eye movement is no longer causes and much about the disease physiology. Important possible. Ultimately, some patients become completely ways to intervene in the pathophysiology, including locked in, unable to move any voluntary muscle. supporting or replacing degenerating cells, slowing the Considerable research is being done to enable patients spread of aggregated protein, and silencing mutated genes with ALS to continue to communicate and even operate could have clinical impact soon. Clinical trials are aids to assist in daily functions using brain-computer becoming increasingly sophisticated so that the effect of interfaces (BCI)[127]. BCIs measure brain activity and new therapies is determined accurately. translate it into directions that control a computer. Most As new theories shed increasing light on the clinical applications use biofeedback to teach patients to physiology, we await the next great breakthrough; control brain wave output; computers interpret brain wave discovery of the causes of sALS and the medicines that activity and patients can learn to regulate the activity to follow. Meanwhile, patients are offered modern care that achieve goals through the computer. The technology can can help ensure comfort and dignity during this most be used to provide patients with a device that does not rely difficult disease. on muscle activity. Learning BCI appears to involve the same brain systems and information processing as other References skills. Patients can learn to spell using a virtual keyboard [1] Rowland LP, Shneider NA (2001). Amyotrophic lateral and to move virtual limbs. sclerosis. N Engl J Med, 344:1688-1700. Despite widespread degeneration in ALS, skill [2] Gordon PH, Cheng B, Katz IB, Pinto M, Hays AP, learning seems to remain intact up to the very final stages Mitsumoto H, Rowland LP (2006). The natural history [128]. A downside to the technology is that the systems of primary lateral sclerosis. Neurology, 66:647-653. with high accuracy and speed also place great demand on [3] Logroscino G, Traynor BJ, Hardiman O, Chio A, attention and memory. In some patients, cognitive Mitchell D, Swingler RJ, Millul A, Benn E, Beghi E deterioration may make operating a BCI impossible. (2010). Incidence of amyotrophic lateral sclerosis in Several clinical studies examining various BCI Europe. J Neurol Neurosurg Psychiatry, 81:385-390. technologies in ALS are currently enrolling patients. A [4] Marin B, Gil J, Preux PM, Funalot B, Couratier P (2009). feasibility study of an intracortical neural interface being Incidence of amyotrophic lateral sclerosis in the Limousin region of France, 1997-2007. Amyotroph done in the U.S. aims to determine the safety of the system Lateral Scler, 10:216-220. and to describe the algorithms and outcomes needed for a [5] Ragonese P, Filippini G, Salemi G, Beghi E, Citterio A, larger trial. The device is implanted onto the motor cortex D'Alessandro R, Marini C, Monsurro MR, Aiello I, of patients and neuronal recordings are made over time. Morgante L, et al. (2004). Accuracy of death certificates An EEG-based BCI using scalp recordings that assist for amyotrophic lateral sclerosis varies significantly patients with severely advanced ALS is being studied in from north to south of Italy: implications for mortality Philadelphia. This trial is expected to conclude in 2014. A studies. Neuroepidemiology, 23:73-77. study in France is testing severely progressed patients’ [6] Sorenson EJ, Stalker AP, Kurland LT, Windebank AJ ability to communicate via spelling using summed brain (2002). Amyotrophic lateral sclerosis in Olmsted County, Minnesota, 1925 to 1998. Neurology, 59:280- potentials and is expected to finish in 2015. [7] Gordon PH, Mehal JM, Holman RC, Rowland LP, SUMMARY Rowland AS, Cheek JE (2013). Incidence of Amyotrophic Lateral Sclerosis Among American In 2013, ALS is still so rapidly progressing that it is Indians and Alaska Natives. JAMA Neurol, 1-5. physically and emotionally overwhelming for patients, [8] Kurland LT, Hirano A, Malamud N, LESSELL S (1961). families and care givers. Health care teams spend their Parkinsonism-dementia complex, en endemic disease on time helping patients cope and trying to keep pace with a the island of Guam. Clinical, pathological, genetic and disease that produces new degrees of impairment and epidemiological features. Trans Am Neurol Assoc, disability almost without pause. Current care is 86:115-120. [9] Alonso A, Logroscino G, Jick SS, Hernan MA (2009). multidisciplinary and includes respiratory support, Incidence and lifetime risk of motor neuron disease in the supplemental feeding, and riluzole, which appear to United Kingdom: a population-based study. Eur J extend survival modestly. Symptomatic medications can Neurol, 16:745-751. improve quality of life, but more need to be tested in trials [10] Fang F, Valdimarsdottir U, Bellocco R, Ronnevi LO, for ALS. Numerous potential neuroprotective agents Sparen P, Fall K, Ye W (2009). Amyotrophic lateral targeting pathophysiological processes have been studied, sclerosis in Sweden, 1991-2005. Arch Neurol, 66:515- but there have been no recent successes. Yet, hope seems almost around the corner. Scientific [11] Logroscino G, Traynor BJ, Hardiman O, Chio' A, advances have uncovered several important genetic Couratier P, Mitchell JD, Swingler RJ, Beghi E (2008). Aging and Disease • Volume 4, Number 5, October 2013 305 P. H. Gordon Amyotrophic Lateral Sclerosis 2013 Descriptive epidemiology of amyotrophic lateral cross-sectional study of neuropsychological test sclerosis: new evidence and unsolved issues. J Neurol performance. Amyotroph Lateral Scler. Neurosurg Psychiatry, 79:6-11. [27] Olney RK, Murphy J, Forshew D, Garwood E, Miller [12] Gordon P. History of ALS. In: Mitsumoto H, BL, Langmore S, Kohn MA, Lomen-Hoerth C (2005). Przedborski S, Gordon P, editors. Amyotrophic Lateral The effects of executive and behavioral dysfunction on Sclerosis. New York: Taylor & Francis Group; 2006. p. the course of ALS. Neurology, 65:1774-1777. 1-16. [28] Rabkin JG, Albert SM, Rowland LP, Mitsumoto H [13] Kasarskis EJ, Winslow M (1989). When did Lou (2009). How common is depression among ALS Gehrig's personal illness begin? Neurology, 39:1243- caregivers? A longitudinal study. Amyotroph Lateral 1245. Scler, 10:448-455. [14] Lewis M, Gordon PH (2007). Lou Gehrig, rawhide, and [29] Lou JS, Reeves A, Benice T, Sexton G (2003). Fatigue 1938. Neurology, 68:615-618. and depression are associated with poor quality of life in [15] Wechsler I (1940). The treatment of amyotrophic lateral ALS. Neurology, 60:122-123. sclerosis with vitamin E (tocopherol). American Journal [30] Rowland LP, Mitsumoto H, Przedborski S. Amyotrophic of the Medical Sciences, 200:765-778. lateral sclerosis, progressive muscular atrophy, and [16] Gordon PH, Meininger V (2011). How can we improve primary lateral sclerosis. In: Rowland LP, Pedley TA, clinical trials in amyotrophic lateral sclerosis? Nat Rev editors. Merritt's Neurology. 12 ed. Philadelphia: Neurol, 7:650-654. Lippincott, Williams & Wilkins; 2010. p. 802-808. [17] Kanouchi T, Ohkubo T, Yokota T (2012). Can regional [31] Brooks BR, Miller RG, Swash M, Munsat TL (2000). El spreading of amyotrophic lateral sclerosis motor Escorial revisited: revised criteria for the diagnosis of symptoms be explained by prion-like propagation? J amyotrophic lateral sclerosis. Amyotroph Lateral Scler Neurol Neurosurg Psychiatry, 83:739-745. Other Motor Neuron Disord, 1:293-299. [18] Ravits J, Appel S, Baloh RH, Barohn R, Brooks BR, [32] Carvalho MD, Swash M (2009). Awaji diagnostic Elman L, Floeter MK, Henderson C, Lomen-Hoerth C, algorithm increases sensitivity of El Escorial criteria for Macklis JD, et al. (2013). Deciphering amyotrophic ALS diagnosis. Amyotroph Lateral Scler, 10:53-57. lateral sclerosis: what phenotype, neuropathology and [33] Millecamps S, Salachas F, Cazeneuve C, Gordon P, genetics are telling us about pathogenesis. Amyotroph Bricka B, Camuzat A, Guillot-Noel L, Russaouen O, Lateral Scler Frontotemporal Degener, 14 Suppl 1:5-18. Bruneteau G, Pradat PF, et al. (2010). 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Selecting Frontotemporal Degener, in press. promising ALS therapies in clinical trials. Neurology, 67:1748-1751. [126] Levy G, Kaufmann P, Buchsbaum R, Montes J, Barsdorf A, Arbing R, Battista V, Zhou X, Mitsumoto H, Levin B, Aging and Disease • Volume 4, Number 5, October 2013 310

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