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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.”