Palliative Care in ALS

Deborah Gelinas, M.D.April, 2012

Amyotrophic Lateral Sclerosis

• Progressively lethal motor neuron disorder• Incidence 2–3 / 100K• Progressive weakness, atrophy, spasticity,

dysarthria, dysphagia, sialhorrhea, respiratory failure, pseudobulbar affect, frontal dysfunction (behavioral, semantic, executive)

Diagnosis El Escorial

ProgressiveWeakness atrophy

hyper-reflexia spasticity

PossibleLMN + UMN

1 region(*SOD-1)

ProbableLMN + UMN

2 regions(EMG 2 limbs)

DefiniteLMN + UMN

3 regions

Age Specific Incidence of ALS

Genetics : 10% of all ALS is Familial

– *SOD-1 (25%): anti-oxidant, toxic gain of function, protein aggregation

– *TDP-43 (2%): protein chaperone – *FUS (4%): protein chaperone– ALSIN childhood onset– VAPB LMN only– Senetaxin limb only, no bulbar– FIG4 – Atrogen – Chromosome 9 trinucleotide repeat sequence

* Genetic testing available through Athena

Vulnerability Genes in Sporadic ALS

– PON (metabolizes pesticides, etc.)– VEGF (promotes vascular supply)– ANG (metabolized statins)* 34 separate vulnerability genes now identified (present

in ALS but not control populations)

* Environmental risk factors: tobacco, injury, electrocution, heavy athleticism, chronic stress

Survival Curve of Patients with ALS

Chio et al .J Neurol Neurosurg Psychiatry 2006;77:948-950

Positive effects of tertiary centres for amyotrophic lateral sclerosis on outcome

and use of hospital facilities

Hospice and Palliative Care

• Hospice: Organized program for delivery of Palliative Care

• Medicare Criteria for Hospice:– Medicare Eligibility– Less than 6 months expected survival– Elect Medicare Hospice coverage, foregoing

other Medicare Insurance Options.

Palliative Care

• “In the absence of curative treatments, the focus is on enabling the patient to achieve maximal function and independence at each stage of illness b provident relief of the multiple symptoms that develop over time”

• Multi-disciplinary teams are the cornerstone.

Models of Palliative Care

First Step in Palliation: Delivering the Diagnosis

• Diagnostic Odyssey: Delay in Diagnosis 9 – 11+ months from symptom onset.

• McCluskey 2004: Mail Survey of – 94 patient-caregiver pairs– 50 patients– 19 caregiversOnly 44% of patients and 52% of caregivers

rated the physician’s manner of breaking the news as good or excellent

First Step in Palliation: Delivering the Diagnosis

• Failures to discuss• Symptom management• ALS patient assistance organizations• Clinical trials

• ALS is not contagious• Nearly all symptoms can be managed• Educational information is available.• Decisions will be jointly made, respecting autonomy

AAN Guidelines for Care of Patients with Amyotrophic Lateral Sclerosis• 1999 AAN Guidelines for the Care of ALS• 2004 AAN Guidelines Update

– Respiratory Management– Nutrition Management– Sialorrhea Management– Palliative Care / Delivering the Diagnosis/

Terminal Dyspnea/ Termination of Ventilator Support

Figure 1. Algorithm for sialorrhea management.

Miller R et al. Neurology 1999;52:1311-1311

©1999 by Lippincott Williams & Wilkins

Figure 2. Algorithm for nutrition management. 1Rule out contraindications. 2Prolonged mealtime, ending meal prematurely because of fatigue, accelerated weight loss due to poor

caloric intake, family concern about feeding difficulties. *Forced vital capacity...

Miller R et al. Neurology 1999;52:1311-1311

©1999 by Lippincott Williams & Wilkins

Figure 3. Algorithm for respiratory management. 1Forced vital capacity (FVC) or vital capacity (VC) can be used.

Miller R et al. Neurology 1999;52:1311-1311

©1999 by Lippincott Williams & Wilkins

Are Hospice Criteria Adequate for ALS?

• McCluskey 2004 J. Palliative Medicine:• Highlighted need for expansion of

Palliative Care Options in ALS– Retrospective Evaluation of 97 consecutive

patients with ALS who were accepted to Hospice Programs in Philadelphia Area.

– Only 5/97 met Hospice Criteria. – Mean number of Hospice Days = 85 (1 – 534)

Are Hospice Criteria Adequate for ALS?

• Euthanasia Practice in the Netherlands

• 4.1% of all deaths due to ALS happen through physician-assisted suicide (twice the frequency of that reported for malignant tumors).

• Are patients receiving adequate palliative care?

» Van der Wal BMJ:1996

How Do Patients With ALS Die?

• Structured Telephone Interview with relatives of 121 patients (Germany) and 50 patients (England) who died with ALS to answer the question:

• Do Patients with ALS Choke to Death?

Neudert et al, J Neurol (2001)

Terminal Suffering

How they died Germany United Kingdom

Peacefully 88% 98%

Moderate Suffering

5% 0%

Severe Suffering 1% 2%

After Resuscitation Attempt

5% 0%

Suicide 1% 0%

Symptoms during the last 24 hours

Symptom Germany United Kingdom

Dyspnea 20% 30%

Restlessness/ Anxiety

8% 6%

Choking on Saliva

7% 0%

Coughing 4% 20%

Diffuse Pain 2% 2%

Palliative Effect of Nutrition, Ventilation and Medication in the Terminal Phase

PEG Ventilation

Morphine BDZ

# Patients(121 Ger,50 UK)

27% Ger14% UK

21% Ger 0% UK

27% Ger82% UK

32% Ger64% UK

Beneficial

91% 95% 91% 85%

“The final month of life in patients with ALS”

Ganzini. Neurology: 2002

• Survey of 50 Caregivers (66% in Hospice)• Difficulty Communicating 62%• Dyspnea 56%• Insomnia 42%• Discomfort 48%• Pain Frequent and Severe* Hospice patients were more likely to die in

preferred location and receive morphine

Spinocerebellar Ataxias

• Prevalence 10.2/100K• Most are early onset Friedreich’s AR• Mitochondrial Ataxias• Fragile X

Autosomal Dominant Ataxias

• SCA Harding type Clinical/other features• SCA1 I Pyramidal involvement, ophthalmoplegia• SCA2 I Slow saccades, peripheral neuropathy• SCA3 I Also known as Machado-Joseph. Pyramidal involvement,• ophthalmoplegia, peripheral neuropathy, in a subgroup Parkinsonian• phenotype• SCA6 III Allelic with EA2 / Familial Hemiplegic Migraine, mild ataxic syndrome• SCA7 II Macular degeneration• SCA8 III Not specific test*• SCA10 III Seizures, Mexican origin• SCA11 III• 13• SCA12 I Tremors, common in India• SCA13 I Mental retardation• SCA15 III• SCA17 I Psychiatric features, dementia, chorea• SCA28 I Slow saccades, ophthalmoplegia

Associated Professionals

• Geneticist: Diagnostic Odyssey• Cardiologist: CMP, Arrhymias• Urologist: Neurogenic Bladder• Gastroenterologist: Dysphagia• Rehabilitation Specialists: Speech/PT/OT• Behavioral Medicine/Educational Specialist:

Learning Disabilities, Behavioral Disturbances• Orthopedists: Scoliosis, Foot Deformities

Medical Management

• Tremor: Deep Brain Stimulation• Dystonia: Botox• Depression: SSRI’s, counseling• Decreased Visual Acuity: Lenses

Symptoms

• • Gait ataxia and in extreme cases impaired sitting balance

• • Horizontal gaze-evoked nystagmus, hypermetropic / hypometropic saccades

• and saccadic interposition (jerky pursuit), which may be revealed by extra-ocular

• movement testing• • Speech may be slurred (dysarthric) and have a

staccato quality• • Intention tremor• • Dysmetria or ‘past-pointing’• • Dysdiadochokinesis

Is It Weakness?

• Asthenia: a sense of weariness or exhaustion (depression, sleep d/o, chronic heart/lung/kidney diseases)

• Fatigue: inability to continue performing a task after multiple repetitions (myasthenic syndromes, multiple sclerosis)

• Primary weakness: unable to perform a task

Neuromuscular Pathway

Differential Diagnosis of Weakness

• UMN Stroke, PLS• Anterior Horn Cell Polio, SMA• Peripheral Nerve

acquired/gene• Neuro-muscular Junction MG, LEMS• Muscle acquired/

gene

Pattern of Weakness Localization

• Extensors in UE’s, flexors in LE’s

• Hemiparesis• Proximal Symmetric • Distal Symmetric S>M• Distal Symmetric M>S• Multiple nerves in one

limb (S & M)• Single Root• Single Nerve

• UMN

• UMN• Myopathy• Length-dep. Neuropathy• dSMA, CMT• Plexopathy

• Radiculopathy• Mononeuropathy

Testing in Neuromuscular Disease: Where to Begin?

• EMG/NCS• Quantitative Sensory Testing• Autonomic Nervous System Testing• Routine laboratory Testing (electrolytes, CK)• Serological Testing (ANA, ESR, SSA/SSB)• Biochemical Testing Inborn Errors Metabolism• DNA Mutational analysis• Cerebrospinal fluid analysis• Nerve and Muscle Biopsy• Nerve and Muscle Imaging

Myopathic or Neuropathic?

Myopathic• Proximal>Distal• Hyopotonic• Normal or slightly

reduced DTR’s• CK in thousands

Neuropathic• Distal>Proximal• Hypotonic-Hypertonic • Absent – Brisk DTR’s• CK in hundreds

Muscle Biopsy Myopathic Neuropathic fiber size variation fiber type grouping central nuclei angular atrophic fibers split fibers inflammatory cells

EMG/NCSMyopathic: Neuropathic:Fibs, PSW’s Fibs, PSW’sSmall Amplitude Large AmplitudeEarly Recruitment Decreased

Recruitment

Myopathic Weakness

• Genetic (AD, AR, X, Mitochondrial)• Endocrine (thyroid & parathyroid

disease)• Inflammatory (PM, DM)• Infiltrative (amyloid, sarcoid)• Electrolyte (inc CA,inc/dec K, inc/dec

Mg)• Drug-Induced (Steroids,Statins)

Statin Myopathy

• Rare complication of widely-used class of drugs

• Incidence 0.1%• Myalgias comprise 25% of myopathies• Classification:

– Statin Myopathy: any muscle complaint on statins– Myalgia: muscle complaints without elevation CK– Myositis: muscle complaints with elevation CK– Rhabdomyolysis: CK > 10 elevated• Doesn’t address asymptomatic CK elevation

Statin Myopathy

• Cerivastatin (baycol) 3.16/million• Simvastatin (zocor) 0.12/million• Atorvastatin (lipitor) 0.04/million• Pravastatin (pravachol) 0.04/million

• Increased risk with Cyt P450 drugs:– Mibefradil, fibrates, cyclosporine, macrolide antibiotics,

warfarin, digoxin, antifungals

Mechanism of Injury: membrane instability, mitochondrial dysfuntion

Muscular Dystrophies:Pathogenic Variability• Extracellular matrix

• Sarcolemma

• Sarcolemmal repair / maintenance / trafficking / signal transduction

• Sarcoplasm

• Sarcomere

• Intermediate filaments

• Nucleus

Genetic: Muscular Dystrophies

X-linked • Duchenne/Becker • EDMD Autosomal Dominant• FSH • DM1• DM2Autosomal Recessive • Myoshi• Fukutin• Dystrophin-associated glycoproteins• Sarcoglycanopathies

X - linked: Duchenne

• Delayed motor milestones (central vs. muscle)

• Slightly lower IQ (mean = 85)• Ambulate: 18 months• Weakness obvious by age 5

(playground)• Pseudohypertrophy (calf, tongue,

cardiac)• Deformities: Achilles and Iliopsoas

tightness, scoliosis• Progession: proximal to distal, LE to

UE• Wheelchair Bound by 7 – 13y/o• Treatment: Steroids to prolong

ambulation• Non-Invasive Ventilation by

teenage years• Death (cardiac) by 30 years

Dystrophin Staining: Rim of Myofiber

• Control • Duchenne/Becker

X - linked:Becker Muscular Dystrophy

• Less severe (some functioning dystrophin)

• Ambulation beyond 13 y/o• Attention Deficit Disorder• Cardiomyopathy • Nocturnal Respiratory

Problems• Survival past 4th or 5th

decade• Treatment: Steroids to prolong

ambulation, ACEI, ARB, NIV

• Death usually Cardiac

DM1 and DM2 The most common cause of Adult

MD

Myotonic Dystrophies (DM1 & DM2)

• The most common cause of adult MD• DM1: Steinert’s Disease Chromosome 19 Tri-

nucleotide repeat sequence – length of repeat correlates with age of onset & severity

• Sx: Myotonia, forearm and calf muscle atrophy and weakness, cataracts, cardiac conduction deficits, decreased VC, sleep apnes, frontal executive dysfunction, dysarthria GERD. Death secondary to Cardiac Arrythmias

• Congenital Onset: hypotonia, mental retardation, ventilatory insufficiency

Myotonic Muscular Dystrophy 1

Myotonic Dystrophies (DM1 & DM2)

• DM2: Chromosome 4 nucleotide repeat sequence

• Less myotonia but more cramping and pain

• Mild proximal weakness, Cataracts, dysarthria, Sleep apnea, Frontal executive dysfunction,

• More cardiomyopathy (with sudden death)

AD: Facioscapular Muscular Dystrophy

• Scapular Winging and “Trapezius Hump”

• AD variable penetrance• Chromosome 9 nucleotide

repeat sequence• Inverse relationship

between size of repeat unit mutation and severity of disease

• Onset 3-75 years• May be assymetric• Treatment: no benefit

with steroids, albuterol, creatine, NIV, AON

Emery Dreifuss Muscular DystrophyMutations in nuclear

envelope proteins• X-linked Emerin • AD Lamin A/C • SYNE1• SYNE2

• Phenotype• Mild Weakness• Early Contractures• Sudden Death (40%)

– Atrial arrythmias– Bradycardias– AV conduction block– Atrial paralysis– Cardiomyopathy

EDMD Phenotype: Early Contractures Mild Weakness

Muscular Dystrophy:Differential Diagnosis of the Limb Girdle Muscular

Dystrophies

• Exclude Dystrophinopathy

• Look for other clinical features– Distal weakness?– Bulbar weakness?– Cramps?– Cardiomyopathy?– Respiratory?– Family History?

Classification of the LGMD’s

• Autosomal Dominant• LGMD1A myotilin• LGMD1B lamin A/C• LGMD1C caveolin

• Autosomal Recessive• LGMD2A calpain• LGMD2B dysferlin• LGMD2C-F

sarcoglycan• LGMD2I fukutin

LGMD1 LGMD2Generalities

• Less common• Passed generation to

generation• NL or mildly elevated

CK levels• Toxic Gain of Function• Amenable to Anti-

sense Oligonucleotide Therapy

• Greater prevalence• Multiple Siblings

Affected in one family• Higher CK levels• Loss of Function• Gene Replacement • Exon Skipping

Prominent deltoids& biceps atrophy

Calf hypertrophyearly in course

AR: Miyoshi Myopathy: Dysferlinopathy

Rosales, XMuscle Nerve 2010;42:14

Rosales, XMuscle Nerve 2010;42:14

Neuromuscular Junction:Myasthenia Gravis

Immune Mediated Myasthenic Syndromes

• Ach R Ab’s*– Fatigue, ptosis, diplopia, ventilatory insufficiency– muscle weakness increases with repetition

• Anti-MUSK Ab’s*– Females over 40– More bulbar involvement– Poor response to Mestinon

• LEMS– Paraneoplastic Syndrome (40% often SC Ca Lung)– Muscle weakness improves with repetition– Prognosis related to underlying cause

* R/O Thymoma

Ocular Symptoms in Myasthenia

Immune-Mediated MG Treatment

• First line– Thymectomy

• 25% remission 1 year• 40% 2 years• 50% and up 5 years

– Prednisone *– Mestinon

• Second line– IGIV– Imuran– Cyclosporine– (Cellcept)

• Third line– Cellcept– Plasmapheresis

• Fourth line– Rituxin– Methotrexate

• Fifth line– Cyclophosphamide– Tacrolinus

Congenital Myasthenic Syndromes

• Onset birth or early childhood• Fatigue weakness of ocular, bulbar and limb Mm• Sudden exacerbations precipitated by fatigue,

infection, excitement• Delayed milestones• Negative Ach R and MUSK antibodies• Gene defects coding proteins of Ach Receptor• Tx: AChE inhibitors +/- Potassium Channel blockers

3,4-diaminopyridine, Quinidine, Fluoxetine, Ephedrine

Congenital MG

Myasthenic Syndromes

Myasthenic Syndromes

• Presynaptic Deficits• Synaptic Basal lamina defects• Postsynaptic defects

Neuropathic Weakness

Common: leprosy, diabetes, EtOH, HIV **88% no identifiable cause!• Hereditary (up to 44%) (AD, AR, X-linked)• Toxic (vincristine, taxol, colchicine, retrovirals, DPH)• Metabolic (DM, thyroid, Vit E, Vit B12, thiamine,

EtOH)• Infectious (HIV, Lyme)• Inflammatory (AIDP, CIDP)• Ischemic (SLE, PAN, Sjogrens, Scleroderma)• Paraneoplastic (monoclonal gammopathies)• Infiltrative (Sarcoid, Neoplastic)

Ways of Classifying NeuropathiesPathophysiology • Axonal• Demyelinating*• Mixed

Distribution• Focal• Multi-focal*• Distal Symmetric

* Obtain Neurology Consultation

Type of Involvement• Sensory • Motor*• Autonomic

Time Course• Acute*• Subacute*• Chronic

Diabetic Neuropathy

• Most Common Cause in Developed Countries• 5-66% of DM patients develop neuropathy• Related: poor control, retinopathy,

nephropathy• Multiple types:

– Generalized Polyneuropathy 54%– Carpal Tunnel Syndrome 33%– Autonomic 7%– Various Mononeuropathies 3%

Charcot Marie Tooth Neuropathies

• Hereditary Neuropathies• Motor > Sensory +/- Autonomic• Demyelinating (HSMN1), Axonal (HSMN2)• Slowly Progressive• May have associated tremor, cerebellar

signs• Usually very good level of function despite

prominent atrophy

Charcot Marie Tooth Disease: AD, AR, X-linked

Amyotrophic Lateral SclerosisMotor Neuron Disease

LMN• Muscle Atrophy• Flaccid Tone• Fasciculations• Absent DTR’s

UMN• Disuse Atrophy• Spastic Tone• Slow Movements• Brisk DTR’s

Amyotrophic Lateral Sclerosis

• Progressive neurodegenerative disease of the upper and lower motor neurons

• Incidence 3/100K• Prevalence 7/100K• Survival approx. 3 years from the time of diagnosis• Limb weakness• Dysarthria• Dysphagia• Dyspnea• +/- Pseudobulbar Affect• +/- Frontal Executive Dysfunction

Clinical Features of ALS

AUTOSOMAL DOMINANT fALS

ALS Database Genes Implicated Risk factors in ALS

Relative risk III,IV,V

• Pesticides: 2.5• Selenium: 5.7• Head Trauma 2.6-3.1,

repetitive• Physical Activity

1.5-3.1• Statin Drugs 1.6-8.5

(Atrogen I gene)• Tobacco

1.89• Coffee

***Protective! 0.7***(Beghi, 21st International symposium on

ALS/MND 2010)

More than 60 gene defects in MND syndromes

• Chromosome 9 nucleotide repeat sequence

• SOD-1• FUS• TARDPBPermissive Genes• MHCII• VEGF• SMN• Angiogenin• Atrogen

Prognosis

• Median survival from symptom onset– 27.5 mos (6.6 – 97.8)– 95% survive 1 year– 73% survive 2 years– 41% survive 4 years

• Median survival from diagnosis– 15.7 mos (0.3-46.9)– 71% survive 1 year– 44% survive 2 years– 27% survive 4 yearsLMN involvement trends toward shorter survival– Zoccolella,S. J Neurol Neurosurg Psychiatry. 2008;79:33-37

Riluzole: Only FDA-approved Drug for the treatment of ALS. Presynaptic Blockage of Glutamate Release

ALS STANDARD OF CARE

• Multi-disciplinary Clinic visits q 3 months• Optimization of nutrition (extends life 6-9

mos.)• Use of Non-Invasive Ventilatory Support

for treatment of fatigue, dyspnea, orthopnea (extends life up to 48 mos.)

• Rilutek (extends life 3 mos.)• Hope: Research, Advocacy, Relationships

Negative Clinical Trials in ALS

• Riluzole 1995• Myotrophin (IGF-1)• CNTF• BDNF• GDNF• Gabapentin• Myotrophin• Xaliproden• Topiramate• Lithium

•

Present Research in ALS

• Stem Cells: Embryonic & Autologous• Mitochondrial Agents: Dexpramipexole• Anti-glutamatergics: Rilutek, Arimoclomol• Anti-inflammatories: Gilenya• Anti-Sense Oligonucleotides

“And now I cling tight to little hopes, aware that they may quickly be destroyed, but also that they may grow, and perhaps even evolve into other avenues of my life. I cannot guess, nor do I want to create illusions of unrealistic hope, but I will nourish the seeds which begin to come into my life.”