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
Progressive
Weakness
atrophy
hyper-reflexia
spasticity
Possible
LMN + UMN
1 region
(*SOD-1)
Probable
LMN + UMN
2 regions
(EMG 2 limbs)
Definite
LMN + UMN
3 regions
Age Specific Incidence of ALS
Genetics : 10% of all ALS is Familial
– *SOD-1 (25%):
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aggregation
*TDP-43 (2%):
*FUS (4%):
ALSIN
VAPB
Senetaxin
FIG4
Atrogen
anti-oxidant, toxic gain of function, protein
protein chaperone
protein chaperone
childhood onset
LMN only
limb only, no bulbar
– 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 caregivers
Only 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
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Failures to discuss
Symptom management
ALS patient assistance organizations
Clinical trials
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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
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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
Severe Suffering
5%
0%
1%
2%
After Resuscitation 5%
Attempt
0%
Suicide
0%
1%
Symptoms during the last 24 hours
Symptom
Germany
United Kingdom
Dyspnea
20%
30%
Restlessness/
8%
Anxiety
Choking on Saliva 7%
6%
Coughing
4%
20%
Diffuse Pain
2%
2%
0%
Palliative Effect of Nutrition, Ventilation
and Medication in the Terminal Phase
PEG
Ventilation Morphine
BDZ
# Patients 27% Ger
(121 Ger, 14% UK
50 UK)
21% Ger
0% UK
27% Ger
82% UK
32% Ger
64% UK
Beneficial
95%
91%
85%
91%
“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
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Prevalence 10.2/100K
Most are early onset Friedreich’s AR
Mitochondrial Ataxias
Fragile X
Autosomal Dominant Ataxias
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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
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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
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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
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UMN
Anterior Horn Cell
Peripheral Nerve
Neuro-muscular Junction
Muscle
Stroke, PLS
Polio, SMA
acquired/gene
MG, LEMS
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
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UMN
Myopathy
Length-dep. Neuropathy
dSMA, CMT
Plexopathy
• Radiculopathy
• Mononeuropathy
Testing in Neuromuscular Disease:
Where to Begin?
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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
Myopathic
fiber size variation
central nuclei
split fibers
inflammatory cells
Neuropathic
fiber type grouping
angular atrophic fibers
EMG/NCS
Myopathic:
Fibs, PSW’s
Small Amplitude
Early Recruitment
Neuropathic:
Fibs, PSW’s
Large Amplitude
Decreased
Recruitment
Myopathic Weakness
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Genetic
Endocrine
Inflammatory
Infiltrative
Electrolyte
Drug-Induced
(AD, AR, X, Mitochondrial)
(thyroid & parathyroid disease)
(PM, DM)
(amyloid, sarcoid)
(inc CA,inc/dec K, inc/dec Mg)
(Steroids,Statins)
Statin Myopathy
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Rare complication of widely-used class of drugs
Incidence 0.1%
Myalgias comprise 25% of myopathies
Classification:
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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
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Cerivastatin (baycol)
Simvastatin (zocor)
Atorvastatin (lipitor)
Pravastatin (pravachol)
3.16/million
0.12/million
0.04/million
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
• DM2
Autosomal Recessive
• Myoshi
• Fukutin
• Dystrophin-associated glycoproteins
• Sarcoglycanopathies
X - linked: Duchenne
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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
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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 Dystrophy
Mutations in nuclear envelope
proteins
• X-linked Emerin
• AD Lamin A/C
• SYNE1
• SYNE2
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Phenotype
Mild Weakness
Early Contractures
Sudden Death (40%)
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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
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Distal weakness?
Bulbar weakness?
Cramps?
Cardiomyopathy?
Respiratory?
Family History?
Classification of the LGMD’s
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Autosomal Dominant
LGMD1A myotilin
LGMD1B lamin A/C
LGMD1C caveolin
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Autosomal Recessive
LGMD2A
calpain
LGMD2B
dysferlin
LGMD2C-F sarcoglycan
LGMD2I
fukutin
LGMD1
Generalities
• Less common
• Passed generation to
generation
• NL or mildly elevated CK
levels
• Toxic Gain of Function
• Amenable to Anti-sense
Oligonucleotide Therapy
LGMD2
• Greater prevalence
• Multiple Siblings Affected
in one family
• Higher CK levels
• Loss of Function
• Gene Replacement
• Exon Skipping
AR: Miyoshi Myopathy: Dysferlinopathy
Prominent deltoids
& biceps atrophy
Rosales, X
Muscle Nerve 2010;42:14
Calf hypertrophy
early in course
Rosales, X
Muscle 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
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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 3,4diaminopyridine, 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 Neuropathies
Pathophysiology
• Axonal
• Demyelinating*
• Mixed
Type of Involvement
• Sensory
• Motor*
• Autonomic
Distribution
• Focal
• Multi-focal*
• Distal Symmetric
Time Course
• Acute*
• Subacute*
• Chronic
* Obtain Neurology Consultation
Diabetic Neuropathy
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Most Common Cause in Developed Countries
5-66% of DM patients develop neuropathy
Related: poor control, retinopathy, nephropathy
Multiple types:
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Generalized Polyneuropathy
Carpal Tunnel Syndrome
Autonomic
Various Mononeuropathies
54%
33%
7%
3%
Charcot Marie Tooth Neuropathies
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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 Sclerosis
Motor 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
Risk factors
Genes Implicated
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
• TARDPB
Permissive Genes
• MHCII
• VEGF
• SMN
• Angiogenin
• Atrogen
Prognosis
• Median survival from symptom onset
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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 years
LMN 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
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Riluzole
1995
Myotrophin (IGF-1)
CNTF
BDNF
GDNF
Gabapentin
Myotrophin
Xaliproden
Topiramate
Lithium
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Present Research in ALS
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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.”