Amyotrophic Lateral Sclerosis (1 of 8)

1 Patient presents w/ signs & symptoms suggestive of amyotrophic lateral sclerosis (ALS)

2 DIAGNOSIS No ALTERNATIVE Is ALS likely, based on DIAGNOSIS history & physical exam?

Yes

Mainstay of management is symptomatic relief & palliative care A multidisciplinary team approach should be used A Non-pharmacological therapy • Patient & family education • Nutritional management • Respiratory management • Communication • Symptomatic management • Palliative care B Pharmacological therapy Disease-modifying agent • Riluzole • Edaravone Symptomatic managementMIMS FOLLOWUP • Schedule visits every 2-3 months to monitor © & manage progression of the disease

Not all products are available or approved for above use in all countries. Speciﬁ c prescribing information may be found in the latest MIMS.

B13 © MIMS 2019 ALS • • • • &Progression Course • • • • • • • &Symptoms Signs • • • • of Presentations Main • • ofALS Hallmarks Clinical Presentation Clinical • • • • • • • • • - Death is usually caused by respiratory failure respiratory by is usuallycaused Death - Weakness assistance forventilatory todisability &eventual need progresses delaydiagnostic younger age at presentation, disease, include &shorter limb-onset survival ofprolonged Independent predictors &bulbar-onset disease dysfunction respiratory early are olderFactors age ofonset, that reduce survival onset symptom after 5-10years 20%survive - 30months 50%diewithin onset ofsymptom - Amyotrophic lateral sclerosis isrelentlessly progressive ofmotorsymptoms the onset orafter may Symptoms before appear ofcognitive dysfunction - prognosis w/ apoorer occurs inuptohalfofpatientsA frontotemporal w/amyotrophic syndrome lateral sclerosis &isassociated disabling socially be laughingcan oryawning) Prominent features (eg pathological weeping, pseudobulbar - notcorrelate It does w/cognitive impairment - patients emotional halfof lability ofthe occurs inat presence least orabsence ofbulbarmotorsigns, Irrespective may remainintegrity unaffected &skin ganglia basal disturbances, visual function, control, bladder &bowel sensory muscles, Extraocular - - - are present symptoms initiallyin 19-25%ofpatientsBulbar joint complications inpainful results &spasticity weakness Immobilityfrom - Patients may experience muscle pain/cramps duetoclonus &hyperreflexia - muscle worsen, atrophy symptoms apparent As complicates becomes &spasticity &dexterity gait - - - limbinvolvements &lower upper Both are present 30-40%ofpatients inabout at diagnosis &weakness wasting tomuscle leads fasciculations, dysfunction motorneuron Lower tendon refl deep &brisk spasticity tomuscle leads weakness, Upper dysfunction motorneuron exes (DTR) muscular atrophyProgressive w/pure involvement motorneuron lower lateral involvement motorneuron sclerosis w/pure upper Primary in the course ofdisease diffi &swallowing Bulbar-onset amyotrophic Speech lateral sclerosis: later w/limbfeaturesculties developing inthe limbs signs (LMN) motorneuron &lower amyotrophic (UMN) motorneuron Combination ofupper lateralLimb-onset sclerosis: &dysphagia dysarthria insuffi respiratory limbweakness, Progressive ciency, spasticity, hyperrefl such as &bulbarsymptoms exia, spinal cord features involving the brainstem & (LMN) motorneuron &lower (UMN) Presence motorneuron ofupper &nutritional status) failure respiratory of onset early (eg progression, factors presentation, clinical rate isdependent onseveral ofdisease Survival tracheostomy &ventilator without is2-5years support ere isnocure &the duration mean ofsurvival dementia &5-15%develop usuallyoffrontotemporal type occurs in30-50%ofcases, dysfunction Cognitive the factors being mainrisk disposition ageA 1.5:1maletofemale ratio, &hereditary increasing cases oldinsporadic &58-63years oldinfamilial is43-52years ageMean ofonset ofamyotrophic foundfamilial lateral be butcan sclerosis cases are sporadic Some brainstem &spinalcord It neurodegenerative disorder that involves isaprogressive the inthe motorneurons primarily cerebral cortex, Gehrig’s or Lou disease disease motorneuron as known Also Amyotrophic ofthe lateral motorsystem sclerosis isthe common most neurodegenerative disease © & dysphagia fl fasciculations, weakness, wasting, totongue leads accid dysfunction motorneuron lower Bulbar dysarthria &jaw gag pathologically brisk refl quality; w/nasal speech distorted noted exes may be also slow, by characterized & dysarthria labored spastic as presents dysfunction motorneuron upper Bulbar patient’s &quality oflife lifeexpectancy are the common inamyotrophic &dysphagia most bulbarsymptoms lateral reduce sclerosis &can Dysarthria keys turning mayUpper fi limbweakness diffi noticed as rst be or picking upsmallobjects culty inbuttoning clothes, orrunning walking Weakness ofthe extremities lower may fi when orawkwardness stumbling, frequent tripping, as noted rst be ALS 1 AMYOTROPHIC LATERAL SCLEROSIS (ALS) : : Amyotrophic LateralSclerosis(2of8)

B14 MIMS © MIMS 2019 ALS • • Studies Electrophysiological • Sclerosis Possible Amyotrophic Lateral • Sclerosis Amyotrophic Lateral Probable • Defi nite 2008: criteria, Shima theAwaji- 1998(incorporating criteria House Airlie Revised Upon Based Requirements Diagnostic • Sclerosis Possible Amyotrophic Lateral Clinically • Laboratory-Supported Sclerosis: Amyotrophic Lateral Probable Clinically • Sclerosis Amyotrophic Lateral Probable Clinically • DefiClinically Sclerosis nite Amyotrophic Lateral • • absent: be must efollowing • • • present: be must efollowing criteria) Escorial El 1998(Revised Diseases Neuron World Upon onMotor Committee Based Research Federation ofNeurology Requirements Diagnostic • • • • Exclude other pathophysiological processes - uninvolved inclinically regions dysfunction motorneuron oflower evidence electrophysiological Detect - Confi aff inclinically dysfunction motorneuron lower rm - regions ected to: performed should be ofamyotrophic studies electrophysiological If diagnosis lateral sclerosis isconsidered grounds, onclinical conduction &absence nerve ofconduction block motor&sensory normal results, changes inEMG neurogenic in1ormore regions, fasciculations ofamyotrophic by ediagnosis lateral sclerosis issupported signs motor neuron toupper rostral signs motorneuron orlower alonein2ormore regions, signs motorneuron orupper region, inonly1 dysfunction motorneuron &lower motorneuron ofupper evidence orelectrophysiological Clinical signs tothe rostral motorneuron lower necessarily signs motorneuron upper w/some 2spinalregions, in at least signs motorneuron &lower motorneuron upper demonstrated by evidence, orelectrophysiological Clinical in3spinalregions signs motor neuron orthe &lower presence motorneuron ofupper 2spinalregions, &at inthe least bulbarregion signs neuron the demonstrated by motor &lower presence motorneuron evidence, ofupper orelectrophysiological Clinical signs motor neuron are toupper foundrostral signs motorneuron alone;orlower are foundin≥2regions signs motor neuron onlyorupper are foundin1region dysfunction motorneuron &lower motorneuron ofupper signs Clinical are 2limbs present criteria inat least (EMG) defi signs motorneuron aloneare&lower present signs motor neuron inoneregion electromyography by ned only, are in1region dysfunction motorneuron &lower motorneuron ofupper signs orwhen upper Clinical the signs motorneuron lower to(above) rostral necessarily signs motorneuron upper some w/ in2regions signs motorneuron &lower presence motorneuron ofupper alonereveals evidence Clinical spinalcord) lumbosacral thoracic, cervical, (brainstem, regions in3ofthe 4 signs motorneuron &lower presence motorneuron ofupper alonereveals evidence Clinical signs &electrophysiological clinical that might explainthe ofother observed evidence diseases Neuroimaging degeneration motorneuron upper which may &/or motorneuron lower cause ofother &pathological evidence diseases Electrophysiological orhistory exam physical by ortoother which isdetermined aregion regions within orsymptoms ere of signs isprogression Evidence degeneration motorneuron ofupper Evidence degeneration motorneuron oflower fimisinterpretation orneuroradiological ofneurophysiological ndings uncertainty ofdiagnostic indexofsuspicion& include low causes unusualCommon presentations, clinical timeof14months w/amedian reached alongdelay adefi before &nature isexperienced tothe insidious onset Due ofdisease, is nitive diagnosis certainty ofdiagnostic levels acombination toestablish signs motorneuron &lower uses motorneuron ofupper criteria eElEscorial ofspecifi Lack marker presentation inclinical &variability makedefic biological - diffinitive diagnosis cult fordefiPatient neurologist toexperienced referred shouldbe nitive diagnosis © Sclerosis Amyotrophic Lateral Amyotrophic LateralSclerosis(3of8) 2 DIAGNOSIS

B15 MIMS © MIMS 2019 ALS • studies Laboratory • Radiology • • Studies Neuroimaging • (EMG) Electromyography • • Studies Conduction Nerve • • • (PEG) Gastrostomy Endoscopic Percutaneous • Management Nutritional • • &Testing Counseling Genetic • ofInformation Sharing • • Reassurance • • • • • • News ofDiagnostic Delivery Patient &Family Education • (weight loss >10%), respiratory function &the patient’s function (weight >10%),respiratory loss general condition approach onanindividual takinginto malnutrition account etimingofPEG/PRG isbased bulbarsymptoms, dehydrogenase lactase glucose, thyroid Cl, Ca), tests, function K, (Na, electrolytes creatinine kinase, tests, function sedimentation rate, C-reactive protein, count, complete liver blood are erythrocyte tests Essential blood x-rayChest done shouldbe motorcortex N-acetylaspartate tocreatine resonance ratio spectroscopy inmagnetic primary Reduced - tracthyperintensity &cerebral Corticospinal inMRI atrophy detected - sclerosis: fi to the following led Advances inneuroimaging suggestive but not specifindings c to amyotrophic lateral toexcludeUsed other conditions - reinnervation Findings inamyotrophic lateral sclerosis patients & include features ofacute&chronic denervation &this the reduces muscle actionpotential amplitude isobserved denervation conduction inthe stages, stages is normal early ofamyotrophic butinadvanced Motor nerve lateral sclerosis, toexclude demyelinating used May which be mimicamyotrophic motorneuropathies, lateral sclerosis Adequate nutrition intake, weightAdvantages: stabilization &route formedication off Should be in the absence even topatientsered ofdysphagia w/substantial weight loss, - <50%ofpredicted falling It capacity (FVC) to forced that isrecommended vital placed prior PEGbe suffi Ensures - cient &fl caloric uid intake supplemental considered as progresses PEG shouldbe oralternative dysphagia nutritional route as - &modifi techniques Safeswallowing are highlyrecommended diet ed - problems patients inassisting whohave helpful may pathologists swallowing be Speech - choking onfl Drooling, Symptoms ofdysphagia: eating slow jaw weakness, uid/food, - Patients are at fordehydration w/dysphagia risk &nutritional deficiencies Testing consent voluntarily &w/informed availed shouldbe offShould be ofamyotrophic lateral history sclerosis familial w/known onlyincases ered delivered well tobe inadvance ofmajor management Needs ventilation) (eg decisions mechanical - to patient in a timely provided & family manner which to be is appropriate making for decision Information needs Involve patient patient &reassure decisions incare that their respected treatment be will decisions complicationsExplain are manageable Off opinion,iftheer asecond patient it wants ifavailable groups, &support disease information about written Provide background ofpatient cultural &social Respect reassurance &give forquestions Allow - patient’sDetermine ofamyotrophic knowledge lateral sclerosis Patient’s present shouldbe orcaregiver family comfortable location &private inaquiet, Ensure that inperson isgiven diagnosis compression signifi thecant tocause abnormality ofamyotrophic suggest adiagnosis & distallimbs lateral root sclerosis when there nerve isnocorresponding muscles ofproximal inseveral Not pathognomonic butsimilarabnormalities foramyotrophic lateral sclerosis, Early insertion of a feeding tube isrecommended tube ofafeeding insertion Early © A NON-PHARMACOLOGICAL THERAPY Amyotrophic LateralSclerosis(4of8) 2 DIAGNOSIS (CONT’D)

B16 MIMS © MIMS 2019 ALS • • Decline Cognitive • • • Weakness & Disability • Venous rombosis • • • Immobility) by Pain caused Pressure Pain, Skin Pain (Musculoskeletal • &Spasticity Cramps • • • • Secretions Bronchial • • • Sialorrhea Symptomatic Management • • • Communication • • • • • • Management Respiratory their management in &trained syndrome ofdysexecutive ofthe symptoms informed shouldbe professionals Carers/healthcare considered tobe may capacity issues need decision-making; consent taken toensure tobe informed during needs care In allpatients syndromes, w/frontal dysexecutive Adaptive wheelchair) aids(eg frame, walking collars) neck (eg orthosis, Orthotics anklefoot muscle Exercise strength, may endurance increase &range ofmotion - Physiotherapy allthroughout &physical therapy the used course may ofdisease be physiotherapy, by prevented May be &compression limbelevation stockings cushions&mattress used Pressure-relieving shouldbe &pressure care area Repositioning Physiotherapy Physical therapy, exercise &hydrotherapy may help reduce cramps &spasticity bronchial secretions &severe spasms myotomy doneforfrequent may cricopharyngeal Cricopharyngeal be (insuffl cough-assisting device A mechanical ator-exsuffl infection foracuterespiratory ator) used may be also cough movements usingamanual-assisted taughtPatient shouldbe expiratory the &caregiver ofassisting technique &humidifi suctiondevice aportable Provide er side eff throat, sore nausea) (eg erythema, ects butmay production, cause salivary reduces sialorrhea radiation refractory therapy for medically Low-dose thick mucus &sialorrhea production between Distinguish isrecommended homesuctiondevice usingaportable Suctioning ofsecretions - Tends handlingofsaliva duetopoor tobe - pneumonia w/aspiration &isassociated stress may social ordrooling Sialorrhea cause educated Family shouldbe &caregivers - therapist aspeech by &managed assessed regularly Should be - tocommunication leads diffiDysarthria culties rate ofamyotrophicSpeaking lateral indicator bulbardeterioration ofoverall sclerosis patients isa good - - ventilationNoninvasive ventilation invasive over isusuallypreferred w/tracheostomy Patient’s discussed termination regarding ofventilation tobe wish needs - w/patient/family discussed ventilation tobe ornoninvasive planningforinvasive needs inabsence ofsymptoms, <50%even falls If FVC mouth dryness loss, weight nations, halluci- confusion, morning tachycardia, cough, weak movement, sweating, wall chest the abdomen, decreased insuffi ofrespiratory Signs movement paradoxical of muscles, respiratory ofauxillary use are tachypnea, ciency apathy, concentration poor secretions, appetite, &/ormemory poor diffi headache, morning fatigue, daytime excessive sleepiness, daytime awakenings, nocturnal culty clearing insuffiSymptoms ofrespiratory frequent orthopnea, onminorexertion ortalking, dyspnea includes ciency recommended insuffiRespiratory are measurements function continuously must be pulmonary ciency &serial monitored to the phrenic nerve combined degeneration indicates failure ofcentral centersRespiratory respiratory contributing &motor neurons speech synthesizers speech fiUse w/ appropriate boards pointing from communication systems support or words tocomputerized gures patient care ventilationInvasive more may eff be more &requires butismore expensive survival, inincreasing ective quality oflife ventilationNoninvasive offers benefi clinical t topatient ofhypoventilation &therefore improving symptoms by

B17 MIMS © MIMS 2019 ALS • • Dyspnea • • Secretions Bronchial • • • Sialorrhea • Symptomatic Management • • • • Edaravone • • • • • Riluzole Agent Disease-Modifying • • • • Care Palliative Benzodiazepines (eg Midazolam, Diazepam, Lorazepam) may also be used may be also Lorazepam) (eg Diazepam, Midazolam, Benzodiazepines rest subcutaneously, given Morphine, may relief provide inamyotrophic lateral sclerosis patients at w/ dyspnea ifthere issuffi used Should onlybe - cient cough fl ow mucolytic &/orFurosemide incombination used may be are ineff measures If above &/oranticholinergics nebulization bronchodilator w/beta-agonists &/ora ective, benefi may be &Acetylcysteine Mucolytics likeGuaifenesin cial forthick mucus secretions sialorrhea patients w/refractory considered inamyotrophic glandsshouldbe lateral into sclerosis Binjection salivary toxinBotulinum type Side eff may limitusefulness ects - - inamyotrophic widely lateral used sclerosis patients been tocontrol Has sialorrhea - Amitriptyline - Trihexyphenidyl, Hyoscine, Glycopyrrolate, Benztropine, Atropine management ofsymptom Goal istoimprove quality the oflifeforboth patient &family stage inearly anadjunct ofamyotrophic toRiluzole be lateralCan sclerosis lateral sclerosis patients abilities insome itmay w/amyotrophicNot foracurethe offunctional butstudiesshows slow decline Approved inJapan, &recently Korea inthe States United fortreatment ofamyotrophic lateral sclerosis Potent scavenger radical &antioxidant free oxidative against that neuroprotection stress give can Notracheostomy - >60%predicted FVC - Symptoms present than forless 5years - Definite orprobable amyotrophic lateral World sclerosis by Federation criteria ofNeurology - features: inpatients administration clinical ofRiluzole w/the after following shown rates have been survival Increased Effi- ofdisease demonstrated inlate phase notbeen has cacy 3-6months by survival May increase - lengthening ofsurvival Not acure foramyotrophic modest butproduces lateral sclerosis, eff &interferes postsynaptic glutamate w/its release presynaptic Inhibits ects - Glutamate antagonist approximately 3months 18months after treatment by survival 15%&prolonged by to have survival have the improved seen mg Riluzole 1-year of100 Daily dose forpatients drug w/amyotrophicNeuroprotective lateral sclerosis Consider hospice ifavailable care, Treat required &painas anxiety dyspnea, - adequate relief at istoprovide symptoms the from stage terminal Goal their care throughoutContinued patient’s tounderstand discussion &follow illness change throughout ifthey choices even considered tobe needs &cultural Religious values - physician &patient between isneeded decision-making Shared sedation & possible weight gain) &possible sedation aff pseudobulbar to treat combination used (egMay sialorrhea, of symptoms be depression, nocturnal ect, palsy, developmentally disabled) tocontrol where isaproblem sialorrhea (eg used inpatientsHave cerebral sialorrhea w/other been diseases

© A NON-PHARMACOLOGICAL THERAPY (CONT’D) Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Speciﬁ c prescribing information may be found in the latest MIMS. latest the in found be may information Speciﬁc prescribing B Amyotrophic LateralSclerosis(6of8) PHARMACOLOGICAL THERAPY

B18 MIMS © MIMS 2019 ALS • Venous rombosis • • &Fatigue Insomnia • • • Depression • • Pain • • • &Spasticity Cramps • • • • AffPseudobulbar ect Symptomatic Management (Cont’d) Should be treated w/anticoagulants treated Should be Modafi considerednil may fordebilitating be fatigue totreat given may orappropriate insomnia (eg be Mirtazapine hypnotics Zolpidem) Amitryptiline, Lorazepam Diazepam, eg orbenzodiazepines w/Bupropion treated be can Anxiety serotonin inhibitorsare reuptake inelderly preferred Selective orcognitively impaired patients Mirtazapine Treat w/appropriate or serotonin inhibitor(SSRI), reuptake antidepressant aselective Amitriptyline, eg &nonsteroidalIf non-opioidanalgesics anti-infl toopioidanalgesics may fail, switch drugs ammatory &nonsteroidalNon-opioid analgesics anti-infl initialtreatment may be options (NSAIDs) drugs ammatory intrathecal helpful may Baclofen be oralmedications, despite issevere Ifspasticity - &Tizanidine Baclofen such as drugs Antispastic tried may be Ifunsuccessful orsideeff occur,ects (200mg twice sulfate ofbenefi daily)may Quinine be - t forcramps tried may be Levetiracetam &dizziness sedation Mayweakness, cause - Tizanidine,Baclofen, Memantine, Dantrolene, Diazepam, orTolperisone Eperisone given may be - w/Quinidine Dextrometorphan eff w/good tested been Has inother diseases neurologic ects - Citalopram inasinglestudy that amyotrophic included were lateral reported results sclerosis patients Satisfactory - Fluvoxamine benefi May be cial inpatients w/drooling - use its controlled inmultiple patients trial sclerosis (MS) Randomized supported - Amitriptyline © lacking eff to be shown Have been side eff on long-term study but tests IA in a Class ective & tolerability are still ects Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not B Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing PHARMACOLOGICAL THERAPY (CONT’D) Amyotrophic LateralSclerosis(7of8)

B19 MIMS © MIMS 2019 ALS Baclofen Eperisone 150 mg PO 8hrly 150mgPO Eperisone Edaravone Riluzole 50 mg PO 12hrly 50mgPO Riluzole rgDosage Drug rgDosage Drug met are requirements individual until intervals 8 hrly atPO 3-day 5,10,15,20 mg by gradually Increase doses individed PO 15 mg dose: Initial drug-free period drug-free 14-day by followed 14-day period 10 days a within 24hrly x 60 mgIV cycle: Subsequent period 14-day drug-free by 14 days followed 24hrly x 60 mgIV cycle: Initial Products listed above may not be mentioned in the disease management chart but have been been have but chart management disease the in mentioned be not may above listed Products placed here based on indications listed in regional manufacturers’ product information. product manufacturers’ regional in listed indications on based here placed All dosage recommendations are for non-pregnant & non-breastfeeding women, women, &non-breastfeeding non-pregnant for are recommendations dosage All non-elderly adults w/ normal renal & hepatic function unless otherwise stated. otherwise unless function &hepatic renal w/ normal adults non-elderly © Not all products are available or approved for above use in all countries. all in use above for approved or available are products all Not Specifi c prescribing information may be found in the latest MIMS. latest the in found be may information Specific prescribing NEURODEGENERATIVE DISEASEDRUGS Please see the end of this section for the reference list. reference the for section this of end the see Please Amyotrophic LateralSclerosis(8of8) • • • Instructions Special • Reactions Adverse • • • • • • Instructions Special • Reactions Adverse • • • • Instructions Special • Reactions Adverse • • • Instructions Special • • Reactions Adverse Avoid bag Edaravone inthe infusion &other mixing medications Use w/caution inpatients orsulfi w/asthma te allergy Administer onlyintravenously reactions) effCNS Other headache); eff (abnormal gait, ects inj site (bruising, ects immediately (eg throat, sore fever) tophysician ofinfection signs Patient shouldreport &caregiver that require alertness tasks somnolence; caution inperforming use or that may dizziness cause Riluzole Patients warned shouldbe Use w/caution inpatients ofliver w/renal disorders impairment orhistory treatment to&during prior Monitor liver function values liverAvoid enzyme orraised inpatients w/hepatic disease Take ameal onanempty toor2hrafter 1hrprior stomach, at least lungfunction) decreased tachycardia, asthenia, neutropenia, constipation, vomiting);Other eff (anaphylactoid reactions, ects eff pain,diarrhea, abdominal nausea, (elevations inliver enzymes, ects effCNS vertigo, somnolence, anorexia); GI dizziness, (headache, ects Avoid abrupt withdrawal hepatic insuffi &lactationciency, renal pregnancy impairment, during statesconfusional orParkinson’s epilepsy, CVA disease, insuffi orresp ciency, schizophrenia, Use w/ caution inpatients disorders, w/psychotic Avoid ulcer inpatients disease w/peptic taken w/food Should be rash) output, cardiac decreased tremor, nystagmus, disturbances, visual weakness, nightmares, myalgia, Other eff dysuria); enuresis, exhaustion, (lassitude, muscular ects eff GIdisturbance, retching); (nausea, Renal effects (polyuria, ects effCNS GI ataxia); hallucinations, mood, euphoric (dizziness, ects Monitor for any signs of severe allergic reactions or shock allergic orshock reactions Monitor forany ofsevere signs Use w/caution inpatients w/hepatic disorders taken w/food Should be May muscle worsen weakness Other eff disorders) urinary changes, (hematological ects angioedema); urticaria, disturbances); Allergic (skinrashes, reactions GI trembling inthe extremities); GIeff (hepatic &renal dysfunction, ects effCNS numbness or drowsiness, insomnia, weakness, (dizziness, ects Dosage Guidelines MUSCLE RELAXANTS