Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes progressive weakness due to the loss of motor neurons in the brain and spinal cord. The cause of ALS is largely unknown, though some genetic and environmental factors have been associated with increased risk. While currently there is no cure for ALS, treatments aim to slow progression and manage symptoms such as spasticity, pain, and respiratory failure through medications, nutrition support, and respiratory assistance.

1. Amyotrophic Lateral Sclerosis
Gwen C. Claussen, MD
University of Alabama - Birmingham
Birmingham, Alabama

2. Amyotrophic Lateral Sclerosis
 Neurodegenerative disorder of motor
neurons
 Progressive weakness
 Variability in region of onset, time
course, relative degree of upper and
lower motor neuron signs (many
subtypes)

3. Anatomy of ALS
yassermetwally.files.wordpress.com

4. ALS Epidemiology and Etiology
 More prevalent; 3-5/100,000, mid-late life
onset, slight male predominance, 3-5 y LE
 Unknown etiology
 Only known association- smoking
 Enviromental-Gulf War/ military; Toxic waste site
study; Soccer and football players
 Infection- viruses (polio, HIV) increased levels of
reverse transcriptase (retroviral enzyme) in ALS
pts.
 Familial 5-10% (SOD1 20%of these)/ genetic
predisposition

5. Variability of Disease Progression
 ALS
compared to
PLS (primary
lateral
sclerosis)
patientslikeme.com/
wp

6. Common Clinical Features
 Lower motor neuron- weakness, atrophy,
fasciculations, cramps
 Fasciculations rarely present as an
isolated sign of ALS
 Benign fasciculations
 Other LMN disorders- radiculopathy,
neuropathy, occasionally myopathy

7. ALS- Anterior Horn Cell

8. Hand Muscle Atrophy

9. Bulbar Involvement in ALS
 20% ALS patients present with bulbar palsy
 Brainstem motor nuclei and corticobulbar
tracts
 Slurred speech, tongue atrophy, fasciculations
 Hyperactive gag response, brisk jaw jerk
 Pseudobulbar palsy (bilateral corticobulbar
tracks)- emotional lability
 Swallowing problems, increased saliva, and
laryngospasm

10. Tongue Atrophy and Fasciculations
neuromuscular.wustl.edu/.../alstonguerest.jpg

11. Uncommon Clinical Features
 Dementia- 5-10%, memory loss,
personality change, loss of normal
inhibitions, loss of judgment
 Sensory involvement, 25% minor
sensory complaints
 Autonomic dysfunction, only occasional
bladder involvement

12. Other Motor Neuron Diseases
 Spinal muscular atrophy- LMN disorder
 Primary lateral sclerosis- UMN disorder
 Progressive bulbar palsy- brainstem
motor nuclei and corticobulbar tracks
 Monomelic amyotrophy
 X- linked spinobulbar muscular atrophy
(Kennedy’s disease)

13. ALS Differential Diagnosis
 Unique to each presentation
 Neuropathy (MMN, CIDP), myasthenia gravis,
myopathy (IBM, acid maltase deficiency),
polyradiculopathy
 myelopathy, multisystem atrophy,
adrenomyeloneuropathy, brainstem lesion
 Metabolic - hyperparathyroid , hyperthyroid,
vit. B12 deficiency

14. Diagnostic Studies
 NCS/EMG is critical to document loss of
motor neuron and to evaluate for another
etiology
 Denervation findings are not specific to
ALS
 Electrodiagnostic criteria

15. EMG-Denervation and
Reinnervation in ALS
www.ncbi.nlm.nih.gov/
bookshelf/picrender.fcgi

16. Other Diagnostic Studies
 Imaging of brain and spinal cord
 Laboratory studies- decide on individual basis
CBC, Chem profile (Ca, phos), CPK, ESR,
RPR, Vit B12, TFT’s, serum immunofixation
electropheresis, GM1 antibody,
hexosaminidase A, urine heavy metals
 Lumbar puncture
 Familial ALS- SOD1 mutation
 Muscle biopsy

18. Symptomatic Treatment of ALS
 Spasticity - lioresal, tizanidine
 Increased saliva- Amitriptyline, Sal-
tropine (atropine), scopalamine patch,
suction machine, Botulinum toxin
 Pseudobulbar Affect- antidepressants,
dextromethorphan 30mg/ quinidine 30
mg bid

19. Symptomatic Treatment of ALS
 Pain- Cramps, muscle fatigue
 Thick mucous/ saliva- hydration,
guaifenesin, Cough Assist
 Depression- SSRI’s-serotonin reuptake
inhibitors
 Insomnia- watch hypoventilation

20. Swallowing Problems
 Malnutrition and aspiration pneumonia
 Treatment decreases mortality
(Desport et, al., Neurology, 1999)
 Signs- Drooling, wet voice, coughing,
excessive time to eat
 Modified barium swallow, swallowing tx,
electrical stimulation

21. PEG Tube in ALS
 PEG tube needed before significant breathing
problems (percutaneous endoscopically-
placed gastric tube)
 Needed when wt loss >10%, aspiratrion,
impaired quality of life
 PEG morbidity 2-19%, mortality 0-10% (Chio
et. al., Neurology, 1999; Strong et.al., J Neurol
Sci, 1999); no randomized trials
 Mortality- respiratory failure
 Reversible

22. PEG Tube

23. Respiratory Weakness
 Symptoms- insomnia, headache, orthopnea,
dyspnea on exertion
 Signs- frequent sighing, shallow breathing,
short phrase speech, weak cough, use of
accessory muscles
 Treatment- BiPAP, trachiostomy, mechanical
ventilation- or oxygen for palliative care

24. Caregiver/ Social Burden
 Financial crisis- expedited disability, drug
assistance programs, MDA clinic, ALS
Association, family medical leave
 Over-extended caregiver-extended family and
care teams, home health services, long term
care policies, Hospice services
 Other resources- ALS Foundation, MDA, ALS
Ironhorse Foundation, NORD

25. Neurobiology of ALS
 Unidentified trigger, superimposed upon a
genetic predisposition of aging motor neurons,
leads to a final molecular cascade of motor
neuron death
 Multifactorial process
 Cellular cytoskeleton derangements,
mitochondrial dysfunction, microglial
activation, changes in metabolism of reactive
oxygenating species and glutamate

26. Biomarkers- Proteinopathy?
 RNA Protein Processing Disorder
 TAR DNA binding protein located in the
nucleus acts as a RNA protein processor
 Abnormal inclusions of this protein found in
the cytoplasm of 90% sporadic ALS
 Familial ALS-
 5% have TDP 43 gene mutation
 4% have FUS/TLS gene mutation (another RNA
processing protein)

27. Neurobiology of ALS
Mutations of Cu/Zn superoxide dismutase
 3% ALS, gene promotes apoptosis
 Toxic gain of function
 Mutant enzyme accumulates at mitochondria,
interacts with antiapoptotic protein Bcl-2
 Oxidative stress
 Mitochondrial dysfunction (treatment- co-
enzyme Q10, creatine)
 Neurofilaments accumulation(secondary to
oxidative stress)

28. Oxidative Stress Hypothesis
www.als.ca/.../images/damaged-cells

29. Neurobiology of ALS
 Excitotoxicity
 ALS decreased excess glutamate transport
Rothstein 1992
 Numerous studies demonstrating glutamate
transport/receptor abnormalities
 SMN selectively vulnarable to AMPA
receptor mediated excitotoxicity (massive
calcium influx) Kawahara 2005

30. Neurobiology of ALS
 Inflammation
 Increase in activated microglia and astrocytes
 Upregulation of proinfammatory cytokines (tumor
necrosis factor)
 Marked elevation of serum activated moncytes/
macrophages in sALS, degree of activation
correlated with rate of progression (systemic
immunological role?) Zhang 2005

31. Neurobiology
 Inflammation-
activation of
microglia
 Upregulation of
proinflammatory
cytokines
www.als-mda.org/

32. Therapy of ALS
 Riluzole-antiglutamate agent
 Prolonged survival in SOD1 mouse model
 Prolonged survival in ALS patients
compared to placebo (1100 pts)
 Expensive ($10,000 a year)
 Monitor LFT and CBC
 Only drug FDA approved for ALS

33. Therapy of ALS
 Difficulty in development has been lack
of clear understanding of cause
 Once disease begins, we haven’t been
able to stop or reverse progression
 All current and future trials of proposed
therapy has only shown slowing of
progression in animal models
 Importance of basic science research

34. Recent Trials
 Lithium-Fornai et al. PNAS, 2/08
 Neuroprotective in mice (suppression of reactive
astrogliosis, increased mitochondria in motor
neurons, decreased MN necrosis)
 Study Design- 44 pts. , riluzole alone vs. riluzole
plus lithium, followed for 15 months
 Results- Slower progression in lithium group
measuring functional rating scale (14.3 % loss vs
39.8%) and FVC; reduced deaths in lithium group
 Small trial- needs follow up

35. Recent Trials
 Thalidomide- anti-inflammatory properties- modulates cytokines
TNF, extends life in ALS mice
 Dose 400 mg
 Pilot, phase II
 Co Q10- mitochondrial co-factor, antioxidant, prolonged survival
mice
 Vit C, Vit E- Antioxidant trials in ALS patients have had mixed
(predominantly negative) results
 Minocycline- inhibitor of nitric oxide synthase and caspase
enzymes
 5/1/07- ineffective in large US trial
 Detrimental

36. Current and Planned Trials
 Arimoclomol- up-regulator of molecular
chaperones involved in cellular response to
stress/ protein misfolding
 Ceftriaxone- stimulates glutamate transporter
GLT1 through increased GLT1 gene
transcription, inactivates glutamate.
 Initial study- CNS penetration of IV ceftriaxone
 Follow-up- efficacy trial

37. Current and Future Trials
 Talampanel – antiglutamate activity,
completed safety study and
demonstrated preliminary efficacy
 Tamoxifen-completed safety study and
demonstrated preliminary efficacy
 Sodium phenylbutyrate- early phase II-
tolerable/safe in 40 pts. , now needs
efficacy trial

38. Current and Planned Trials
 Fetal cell implants- Beijing, China
 Dr. H Huang, >150 ALS pts., human fetal
olfactory ensheathing glial cells injected in
subcortical white matter, some reports of
“improvement”
 Stem cells- embryonic stem cells and
animal studies of SOD1 mutation

39. Recent and Current Trials
 Diaphragm pacing- implanted pacing
device of the phrenic nerves and
diaphragm
 Attempt to maintain muscle bulk/ decrease
atrophy
 Promote axonal sprouting of the phrenic
nerve- must have intact motor neurons
 May delay need for the ventilator

40. Recent and Planned Trials
 Mild to moderate resistance exercise
and stretching increased function and
quality of life (V Dal Bello-Has,
Neurology 2007)
 Early BiPAP prolongs survival (Lechtzin
et al., ALS, 2007)

41. Available Treatment of ALS
 Riluzole 50 mg bid
 Co-enzyme Q10 300mg- 1200mg /day
 Antioxidant vitamins-
 Vit C
 Vit E
 Beta carotene
 Excellent nutrition, hopeful attitude, large
support group
 Early BiPAP and PEG