Cape Breton ALS Update

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McMaster ALS Conference June 6, 2008
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ObjectivesWe should be able to

• 1. Define ALS
• 2. Understand the incidence and prevalence
• 3. Understand main goals of treatment
• 4. Understand possible causes of ALS
• 5. Understand new possibilities in treatment
• 6. Prepare the ground for subsequent talks

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Flow

• What is ALS
• How do we apply it to patients
• What effects does ALS have
• What is the prognosis of ALS
• What can we do about it

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ALS is not getting simpler

• Those who are not shocked when they first come
  across quantum theory cannot possibly have
  understood it. Niels Bohr.
• If you are not completely confused by quantum
  mechanics, you do not understand it. John
  Wheeler.
• It is safe to say that nobody understands quantum
  mechanics. Richard Feynman.

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UMN
LMN
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PMA
Cruveilhier J Sur la paralysie musculaire,
progressive, atrophique. Bull Acad Med (Paris)
185218667
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Primary Lateral Sclerosis
WH Erb 1875 Spasmodic Spinal Paresis- A
primary degeneration of the pyramidal tract
Wilhelm Erb 1840 - 1921
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ALS
Charcot J. De la sclérose laterale
amyotrophique. Prog Med 18742325-327
André Brouillet, 1887
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Clinical Pathological Correlation

• However, neither Charcot, nor Erb, nor
  Creuveilhier had a real notion of the
  neuropathology involved
• Microscopic study did not begin until 1840
• 1850 before fixed cells could be stained
• 1851 before pyramidal tract recognized
• 1890 H E, then Weigert, Golgi, Nissl
• 1898 before Raymond made the link of clinical
  presentation with UMN and LMN
• With minor modifications, this scheme reflects
  our present classification of ALS

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PMA / ALS / PLS
ALS
PLS
PMA
The motor neuron diseases at the turn of the 20th
century
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Diagnosis used to be simple Unfortunately, the
situation has become much less simpler in recent
years, even over the last 3 years!
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PMA / ALS / PLS
ALS
PMA
PLS, with a prevalence of about 2 per million
However, what about PMA ?
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PMA / ALS / PLS
ALS
PLS, with a prevalence of about 2 per million
PMA
The size of the circles is not clear. The
relative prevalence of PMA, compared to ALS, is
said to be 1, 2.4, 9, or 19
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Brain WR. Motor Neuron disease Diseases of the
Nervous System. Oxford UP 1962
Disease spectrum UMN / UMNLMN / LMN
The following may or may not be
synonyms Maladie de Charcot MND ALS Lou
Gehrig's disease
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What is the present view of ALS ?

• Traditionally defined on clinical grounds
• Fatal neuromuscular disorder
• Progressive paralysis of voluntary muscles
• Little sensory involvement
• Usually asymmetrical at onset
• Limb (75) or bulbar (25) onset
• Sporadic (90) or familial (10)
• 9,999/10,000 fatal

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Does Steven Hawking have ALS ?
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Essentialist vs Nominalist
ALS is better viewed as a disease phenotype,
reflecting predominantly (but not exclusively)
dysfunction and death of motor neurons. To
facilitate discourse, and to facilitate clinical
trials, it is better considered in nominalist
terms, not essentialist terms.
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El Escorial Criteria for the diagnosis of ALS
1990, 1998

• Presence of
• LMN degeneration (clinical, EMG, neuropath)
• UMN degeneration (by clinical exam)
• Progressive spread (by history or observation)
• Absence of
• EMG or path evidence of other disease processes
  to explain the UMN and LMN signs
• Neuro-imaging evidence of other disease processes
  to explain clinical and EMG findings

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El Escorial
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El Escorial

• Clinically Definite ALS
• UMN and LMN signs in 3 regions
• Clinically Probable ALS
• UMN and LMN signs in 2 regions, with some UMN
  signs rostral to LMN
• Clinically Probable ALS, lab supported
• UMN and LMN signs in 1 region, OR
• UMN signs alone in 1 region
• AND
• LMN signs by EMG in 2 limbs
• Clinically Possible ALS
• UMN and LMN signs in 1 region OR
• UMN signs alone in 2 regions, OR
• LMN signs rostral to UMN signs, above
• Clinically Suspect ALS
• Pure LMN signs removed in Airlie House revision

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Utility of EEC

• The EEC have been used to study treatments in
  ALS.
• To increase the specificity, and
• To reduce the heterogeneity
• Trials have usually enrolled
• Clinically Definite
• Clinically Probable (including lab supported)

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Specificity of EECTraynor BJ et al. Arch Neurol
2000571171-76
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• However, other processes can converge to produce
  the same clinical picture.
• Thus, ALS is really a disease phenotype

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FALS and ALS

• FALS and sporadic ALS look the same
• Same disease onset, extent, progression
• Generally the same neuropathology
• Hence, considerable optimism that understanding
  FALS will unlock the secret of sporadic ALS

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Lessons from the genetics of ALS

• Familial in 5-10
• SOD-1 mutation in about 20 of FALS
• ALS-1 mutation
• AD in nearly all cases
• Penetrance variable approx 90-95
• Multiple other genes have been found (ALS-2,
  ALS-3, ALS-4, etc) of uncertain relevance
• It is estimated that 43 genes may influence MN
  survival.

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SOD-1

• Rosen DR, Siddique T, Patterson D et al.
  Mutations in the superoxide dismutase gene are
  associated with familial amyotrophic lateral
  sclerosis. Nature 199336259-62
• Deng HX, Hentati A, Tainer JA, Iqbal Z, Cayabuab
  A, et al. Amyotrophic lateral sclerosis and
  structural defects in Cu, Zn superoxide
  dismutase. Science 19932611047-1051

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SOD-1 (Cu /Zn SOD)

• 153 aa
• 5 exons
• Presently about 150 mutations described
• 105 substitutions 1 compound substitution
• 3 insertions
• 4 deletions
• Ergo- a gain of function mutation

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Overlap cases

• eg Anderson PM et al. Phenotypic heterogeneity in
  motor neuron disease patients with CuZn
  superoxide dismutase mutations in Scandinavia.
  Brain 19971201723-7
• 12 of 51 families had SOD-1 mutations
• Within these 12 families
• -some patients with PMA
• -some patients with PLS
• -some patients with ALS

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5 SOD1 mutations (Anderson)
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Additional atypical features in FALS

• Some forms with prominent sensory changes can be
  seen.
• About 5 show features of Parkinsonism
• Some forms with frontal dementia can be seen.

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Curious features in FALS

• A4V onsets at 52 years, with survival of 1.4
  0.9 years after onset. Usually LMN.
• G37R, G93V onset at same age, yet have survival
  of 15-20 years !

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PMA / ALS / PLS/ FALS
ALS
PLS, with a prevalence of about 2 per million
PMA
FALS
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Overlap of ALS with FTD

• All patients with fronto-temporal dementia and
  with ALS have ubiquitinated inclusions.
• Some patients with FTD show tau staining.
• Of particular interest, others do not.
• Some patients with ALS manifest a fronto-temporal
  dementia. (There is no tau deposition in ALS).
• Recently, this has become clarified
• Neumann et al. Science Oct 2006314130

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• In patients with FTD without tau staining
• Neurons in the frontal cortex, as well as some
  neurons in the anterior horn, stain for
  ubiquitinated TDP-43 (a TAR binding protein)
• In some patients with ALS
• Neurons in the anterior horn, as well as in the
  frontal cortex, stain with TDP-43

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Spinal cord in ALS, stained for ubiquitin,
TDP-43, or both.
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FTD / PMA / ALS / PLS / FALS
ALS
FALS
PLS
PMA
FTD
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Recently seen
Dementia, Parkinsons Disease
Dementia
ALS
PLS ALS
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FTD / PMA / ALS / PLS / FALS
Lyme
HTLV 1,2
ALS
HIV
FALS
PLS
PMA
FTD
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Could this be a disease continuum blending with
normal?
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• Typical ALS is easy to diagnose
• Around the edges, there are problems
• Cures may arise around the edges first
• In spite of this, we rarely make mistakes,
  especially if we remember ALS is a phenotype

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Epidemiology of ALS

• 1-2 per 100,000 per year incidence
• 6-10 per 100,000 prevalence
• Slight male predominance
• Very rare under 20
• Rare over 80
• Roughly uniform around the world
• ALS / Parkinsonism /dementia

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Epidemiology of ALS
Onset
Survival
Limb vs Bulbar
Age 45
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The variability of ALS makes clinical trials
difficult
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Survival from onset among Irish patients with
amyotrophic lateral sclerosis classified
according to El Escorial category at diagnosis
Traynor, B. J. et al. Arch Neurol
2000571171-1176.

• There is no difference in survival in any group
• All shown considerable heterogeneity in survival

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One Possibility Regression Analysis
Paillise et al looked at 100 variables measured
at enrollment in a French Riluzole study,
involving 2069 patients with ALS, and then did a
regression Analysis at study end.

• Age
• Disease duration
• Creatinine
• Atrophy
• Pyramidal signs
• Spasticity

• 7. Fasciculations
• 8. Muscle Strength
• 9. Cough
• Swallowing
• Slow Vital Capacity

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Survival based on RL401 scorePaillisse et al.
ALS 2005637-44
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The ALS History 1

• Family History
• Education, work, social history
• Hobbies
• Financial situation, insurance
• Availability of friends or acquaintances
• House
• Driving
• What have you been told ?
• How much do you know ?

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ALS History - 2

• Evidence of respiratory compromise
• -nocturnal compromise
• sweats, headaches, sleep flat?
• - Any history of sleep apnea?
• Exercise tolerance / fatigue
• Evidence of hyper-metabolic state
• Evidence of weight loss / choking

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The ALS Physical Exam

• Usual tests of mentation, speech, strength,
  sensation, coordination, gait, etc
• Neck and truncal strength
• Subtle wasting
• Fasciculations
• Spasticity and up-going toes
• Spasticity and down-going toes
• Baseline- grip dynamometry

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ALS Investigations

• MRI Head and neck, /- whole cord
• EMG and NCS motor unit counting
• Baseline spirometry
• Blood (may r/o heavy metals, anti GM1)
• May do LP
• Proteomics as diagnostic tool

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Treatment

• Supportive treatments
• Attempts at curative treatments

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Our ALS Team

• Physicians
• Neurologist, Respirologist, Gastroenterologist,
  Physiatrist
• Clinic Coordinator
• RT
• OT SLP (TAC)
• Social Worker
• Chaplain
• Regional ALS Office
• Laboratory and research staff

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Supportive Treatment

• Shortness of breath, secretion control,
  pneumonia, vaccinations (JC)
• Difficulty chewing, swallowing, choking, weight
  loss (BS)
• Palliatve Care (SW)

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Supportive TherapyDepression

• Worse in the winter
• Counseling
• Antidepressants
• SSRIs
• SSRI TCA
• SSRI Bz
• Try Modafanil for lethargy
• Try amitriptylline for pseudobulbar affect

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Supportive treatments

• Saliva topical /- oral anticholinergics,
  transdermal scopolomine, Botox
• Thick secretions lime juice, papaya juice,
  Robitussin
• Constipation stool softeners, Sennakot,
  lactulose, hydration, (enemas)
• Fasciculation usually not treated, try
  anticonvulsants if necessary (eg dilantin)

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Supportive Treatments

• Spasticity Bz, Baclofen or Zanaflex, pump
• stretching at night can be helpful
• Cramping Quinine or Tums, baclofen
• Urinary spasticity Detrol
• Insomia Usually Bz, try Imovane,
  dextromethorphan, (melatonin)
• sedating antidepressants
• Extreme restlessness quetiapine, olanzepine,
  risperidone

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Supportive TherapyCaregivers

• Counseling
• Respite care
• Support groups
• Mentoring

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Supportive TherapySleeping

• Rails
• Hospital bed
• Wedge cushion
• Baffle mattress
• (BiPAP)
• Be attentive to spousal stress

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Supportive TherapyBereavement

• 32 Families surveyed 6 months -7 years
• Often long lasting effects
• Family dynamics may be altered
• No clear relation of coping with elapsed time

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Supportive Treatments

• There are very important roles played by OT and
  PT, SLP, nursing, seating, social work, that we
  will touch on later.

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Specific Treatments
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Specific Therapy

• There is good evidence to support each of several
  pathological mechanisms in ALS.
• It is likely that several processes each
  contribute to the cell death in ALS.
• However, it is also likely that we are still
  missing a key or central piece in the puzzle.
• Until such time, we will not have a successful
  treatment.

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The ALS Mouse
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The SOD-1 mouse

• Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow
  CY, et al.
• Motor neuron degeneration in mice that express
  a human Cu,Zn superoxide dismutase mutation.
• Science 19942641772-76

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What causes ALS ?

• Excitotoxicity
• Oxidative Stress
• Neurofilament disorder
• Neurotrophic factor deficiency
• Immunologic disturbance
• Other
• Terminal death may be apoptotic or other

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Anti-excitotoxicityhuman trials

• /- riluzole (Bensimon 1994 Lacomblez 1996)
• - BCAA (Plaitakis 1988 Italian Group 1993
  Tandan 1996)
• - L-threonine (Testa 1992 Blin 1992)
• - dextromethorphan (Appelbaum Ashmark Blin
  Gredal)
• - gabapentin (Miller 1996)
• - lamotrigine (Eisen 1993)
• - verapamil (Miller 1996)
• - nimodipine (Miller 1996 Ziv 1994)

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Anti-oxidantshuman studies

• - Acetylcysteine (Louwerse 1995)
• - vitamin E (Desnuelle 2001)
• - Creatine (preliminary)

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Neurotrophic factorshuman studies

• - CNTF (CNTF group 1996 Miller 1996)
• - Growth hormone (Smith 1993)
• - TSH (Brooke 1986 Caroscio 1986
  Mitsumoto 1986)
• /- IGF (Lai 1997)
• - BDNF (BDNF study group 1999)
• Retrograde AAV IGF (Kaspar 2003), VEGF

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Immuno-modulatory Factorshuman studies

• - cyclophosphamide (Brown 1986 Tan 1994)
• - cyclophosphamide and IvIg (Meucci 1996)
• - cyclophosphamide and prednisone (Tan 94)
• - plasmaphoresis (Olarte 1980)
• - cyclosporine (Appel 1988)
• - alpha-interferon (Beghi 2000)
• - azothiaprine (Werdelin 1990 Kelemen 1983)

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Miscellaneous

• - Deprenyl (Jossan 1994)
• - 3,4 DAP (Aisen 1996)
• - tetrahydroaminoacridine (Ashmark 90)
• - tolorone (Olson 1978)
• Celebrex (COX2)
• -/ HAART (preliminary)
• - minocycline (preliminary)

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OTC or Prescribed Approaches

• Commonly, we combine a cocktail of anti-oxidants,
  and excito-toxics, anti-apoptotics
• Creatine 5g
• CoEQ10 1200 mg
• Ginseng unknown
• Vit E,C 2000iu 1000mg
• Riluzole 50 bid
• Resveratrol unknown

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• mSOD-1 expression in glial cells does not cause
  disease
• mSOD1 expression in neurons does not cause
  disease
• Wild type non-neuronal cells extend survival of
  SOD1 mutant motor neurons in ALS mice. Clement
  Science 2003302113

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The ALS Mouse
How good a model is the ALS mouse anyway ?
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Future Directions
Update on stem cells Lithium
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Fornai et al. PNAS 2008 105 2052-7
Gephyrin is concentrated in inhibitory synapses
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