PPT

3. Amyotrophic Lateral Sclerosis
Kim Rendell N. Villanueva, MD

4. Outline
• I. Motor Neuron Diseases
• II. Differences in UMN vs. LMN lesions
• III. Etiology of Motor Neuron Diseases
• IV. ALS
• Overview
• Pathophysiology
• Epidemiology
• Diagnosis
• Treatment
• V. ALS Variants

5. MOTOR NEURON DISEASE: An overview
• What is a motor neuron?
• A kind of neuron whose cell body is located in the central
nervous system (brain, spinal cord) and whose axon is
projects to the spinal cord or outside of the spinal cord to
directly or indirectly control effector organs, mainly the
muscles or glands.
• There are 2 kinds of motor neurons
• UPPER & LOWER MOTOR NEURONS

6. UPPER VS. LOWER MOTOR NEURON CLINICAL
MANIFESTATIONS
UPPER MOTOR NEURON
LESION
LOWER MOTOR NEURON
LESION
Weakness Atrophy
Spasticity Flaccidity
Hyperreflexia Hyporeflexia
Upgoing Plantar Response Fasciculations

7. ETIOLOGY
UPPER MOTOR
NEURON DISEASE
LOWER MOTOR
NEURON DISEASE
COMBINED UPPER &
LOWER MOTOR
NEURON DISEASE
Primary Lateral
Sclerosis
Spinal Muscle Atrophy Amyotrophic Lateral
Sclerosis
Hereditary Spastic
Paraplegia
Poliomyelitis

10. AMYOTROPHIC LATERAL SCLEROSIS
• A motor neuron disorder characterised by the combination of lower
and upper motor neuron signs, resulting in spasticity and diffuse
muscular atrophy and weakness.
• Also called “Lou Gehrig’s Disease”, named after the baseball player
who had the disease.
• Typically begins in the 6th and 7th decades of life.
• Men > Women (1.6:1)
• 10% are familial cases and usually inherited as an Autosomal
Dominant trait (AD)

11. AMYOTROPHIC LATERAL SCLEROSIS
• A distinctive feature of ALS is the selectivity of
degeneration of both UMNs and LMNs, with relative
sparing of other neurons in most cases.
• Undefined pathologic mechanisms.
• Numerous pathogenic gene mutations have been
described
• Identification of hexanucleotide repeat expansion in the
chromosome 9 open reading frame 72 (C9ORF72)
Physical Medicine & Rehabilitation, Randall Braddom, 5th Edition

12. Pathophysiology
• About 15% of cases result from a gene defect on
chromosome 21q12.1 which leads to a toxic gain
function in the antioxidant Cu/Zn Superoxide
Dismutase.
• Excess in the excitatory neurotransmitter Glutamate
plays an important role.
• Reduced clearance of glutamate from critical motor
control areas in ALS as well as decreased levels of
glutamate transport protein.
Delisa's Physical Medicine & Rehabilitation, 5th Edition

13. Epidemiology
• Most commonly strikes people between 40 and 60 years of
age with a mean onset of 58 years.
• Higher incidence in urban areas.
• Alcohol was not associated with an increased risk
• Smoking
• Dietary fat
• Poor prognosticating factors:
• Older age at the time of onset
• Bulbar / Pulmonary Dysfunction early
• Predominance of LMN findings at the time of the diagnosis
Delisa's Physical Medicine & Rehabilitation, 5th Edition

14. Diagnosis
• Diagnosis and other forms of adult motor neuron disease is primarily
a process of exclusion.
• Only in FALS with known SOD1 mutations, Kennedy’s disease and the
few adult-onset SMA cases in which SMN mutations are detected is a
definitive diagnostic test available.
• For most patients with ALS or its variants (PMA and PLS),
electrodiagnostic testing (EDX), laboratory testing, neuroimaging and
occasionally, a muscle biopsy are used to assess the certainty of ALS
once other diseases have been excluded.

15. Diagnosis
• A thorough H&PE is vital
• Focus on when the patient first noticed symptoms and the distribution and
characteristics of symptoms.
• Establishing the rate of progression is very helpful
• Family history
• Associated features such as sensory symptoms or complaints attributable
to sphincter or autonomic dysfunction are unusual and should prompt
consideration of an alternative process.
• Respiratory or bulbar involvement may be subtle and may take some time
probing to identify
• Orthopnea or morning headaches may suggest diaphragm paralysis or
nocturnal hypoventilation, respectively.

16. Diagnosis
• Past medical history and review of systems can identify a systemic process
that may be related to the motor neuron dysfunction
• Functional and social history is critical in prescribing orthotics, assistive
devices and therapy
• ALS and other MNDs usually have painless weakness
• Foot drop or hand weakness
• Focal painless weakness and atrophy without sensory loss should
immediately raise flags
• Initial weakness in ALS is divided into thirds: 1/3 bulbar, 1/3 upper, 1/3
lower limbs.
• Weakness is usually ASYMMETRICAL and DISTALLY predominant manner

17. Diagnosis
• Bulbar involvement at presentation is twice as common in women as
men and more common in older patients.
• Patients with bulbar symptoms most often have dysarthria
• Dysphagia is rare
• Cramping – present in 10% of patients
• Physical Examination would reveal signs of LMN injury, such as
fasciculations. Upper motor signs would show spasticity, clumsiness,
increased DTRs
• Hoffman sign and Babinski
• Exaggerated jawjerk, pseudobulbar affect, positive snout or palmomental
reflexes can help establish UMN in bulbar musculature

18. Diagnosis
• Laboratory testing may be utilized to confirm clinically suspected MND
• Genetic testing
• Homozygous deletion or mutation of SMN1
• CAG trinucleotide repeat
• Generally used to help exclude alternate diagnoses when the diagnosis is
uncertain
• In ALS, CK is often elevated; CSF fluid protein may be elevated, Anti-GM1
• Muscle biopsy – signs of denervation; reinnervation is seen in
approximately 50% of biopsies
• Can be used if EMG is not available

20. Diagnostic Categories
CLINICALLY DEFINITE Clinical or electrophysiologic evidence by the presence
of LMN as well as UMN signs in the bulbar region and
at least two spinal regions or the presence of LMN and
UMN signs in three spinal regions
CLINICALLY PROBABLE Clinical or Electrophysiological evidence by LMN and
UMN signs in at least two regions with some UMN
signs necessarily rostral to the LMN signs
CLINICALLY POSSIBLE Clinical or Electrophysiologic signs of UMN and LMN
dysfunction are found in only one region; or UMN
signs are found alone in two or more regions; or LMN
signs are found rostral to UMN signs. Neuroimaging
and clinical laboratory studies will have been
performed and other diagnoses must be excluded.

22. General Approach
• Assess if there is clinical bulbar or pseudobulbar
involvement
• MRI should be obtained, if cervical, thoracic, and
lumbar regions are involved, then Spinal MRI should
be considered.
• EMG is essential – helps in determining the pattern of
LMN involvement more accurately

23. Treatment
•No treatments that can dramatically counteract
effects or stop progression of most Motor
Neuron Diseases
•Treatment strategies are designed to reduce the
symptomatic impact

24. Exercise
• Some form of therapeutic exercises should be offered
• ROM, Stretching
• Gentle Aerobic Exercises for ambulatory patients
• Resistance exercise programmes of mild-to-moderate
resistance for 15 minutes
• Avoid:
• Exercising to fatigue
• Exercising to dyspnea
• Eccentric Exercise

25. Nutrition
• Monitor weight every 3 months
• PEG or RIG tube
• Discuss with patients with indications:
• Decreased caloric intake
• Dehydration
• Meals limited by dysphagia and choking
• Weight loss
• Not aspiration pneumonia

26. Medications
• Riluzole
•Only medication shown to slow the progression of
ALS
•50mg twice daily
•Inhibits presynaptic release of glutamate
•Reduces mortality 23% at 6 months and 15% at 12
months
•Liver function test elevation is common – monitor

27. Rehabilitation
• Designed to target depending on disease impact and natural history
• Stage 1 – patients who are ambulatory and fully independent, with mild
weakness or clumsiness
• Maintain ROM, carry on with ADLs and can benefit with strengthening of muscles
that are unaffected
• Stage 2 – remain ambulatory and independent but have moderate
weakness.
• May benefit with AFOs, Dorsiflexion assists, Wrist-hand orthoses
• Stage 3 – remain ambulatory but haves severe weakness in selected muscle
groups.
• Stage 4 – nonambulatory but remain independent
• Stage 5 – No longer independent
• Stage 6 – Completely bedriddent, dependent and requiring maximal
assistance.

28. Exercise
• No controlled outcome study has shown worsening after exercise in
patients with ALS
• ROM and stretching are considered safe and should be prescribed for
all patients
• Cardiovascular response of patients with ALS to aerobic conditioning
is similar to healthy patients
• Resistance training has been shown to improve function and
spasticity

29. Specific Disease-Related Impact
• Spasticity
• Treatment is similar to other disease states
• Intrathecal baclofen
• Botolinum toxin – can lead to generalized weakness
• Tizanidine, Dantroline, Gabapentin and Benzodiazepines – not been studied
in ALS
• Communication
• Dysarthria is common
• Should be monitored by SLPs to optimize communication and monitor
changing needs during the course of the disease
• Palatal lift or palatal augmentation prosthesis
• AACs

30. Specific Disease-Related Impact
• Dysphagia
• Rarely noted at presentation
• Contributes to malnutrition
• Should begin with thin liquids and use thickeners eventually
• Moistening and softening solids can make swallowing easier
• Sialorrhoea
• Can be disabling and encourages oral infections
• Home suction machine
• Amitryptiline can be effective in treating concomitant mood disorder or
pseudobulbar affect

31. Specific Disease-Related Impact
• Respiratory Insufficiency
• Leads to respiratory failure
• Tracheostomy and long-term ventilation will help the patient to survive longer
• Rare presenting symptom
• 85% of patients with ALS will have an abnormal FVC at presentation
• Routine assessment of Respiratory physiologic measurements every 2-4 months is
recommended
• Mood and Cognitive Disorders
• Common in ALS
• Treated with Tricyclic Antidepressants and SSRIs
• Insomnia is treated with zolpidem and nonpharmacologic sleep hygiene.
• Anxiety
• Counseling
• Support Groups

32. Specific Disease-Related Impact
• Pseudobulbar Affect
• Pathologic weeping, laughing and yawning that is inappropriate or excessive
to the emotional state of the patient.
• Can be a result of loss of frontal lobe inhibition of spontaneous brain-stem
generated emotional responses.
• Seen in 50% of patients
• Levodopa and lithium
• Dextrometorphan (N-methyl-D-aspartate antagonist) and Quinidine – FDA
approved

33. Specific Disease-Related Impact
• Pain and Cramps
• Common in patients with various forms of MNDs.
• Empirical treatment such as massage, PT, magnesium,
carbamazepine, phenytoin, verapamil and gabapentin
have been show to cause improvement.
• Opioids are helpful towards the end of life of patients with
ALS

34. Prognosis

35. Other variants of ALS
• Primary Lateral Sclerosis
• Progressive Muscular Atrophy
• Progressive Bulbar Palsy

36. PRIMARY LATERAL SCLEROSIS
• Disorder associated with progressive spasticity and weakness of limb
and bulbar muscles related to degeneration of UMNs
• Rare and typically seen in the 5th decade of life
• Etiology is unknown
• Little or no LMN involvement clinically or by EMG
• Most patients with PLS eventually have fasciculations and cramps
with some evidence of LMN involvement on EMG
• Progresses much more slowly (8-15 lifespan at the time of diagnosis)

37. PRIMARY LATERAL SCLEROSIS
• May have unilateral leg spasticity, later involving the other leg then
progressing to upper limbs
• Mills Syndrome – hemiplegic variant of PLS. Unilateral presentation of
UMN signs in the Upper and Lower limbs.
• SPASTICITY and CLUMSINESS rather than weakness
• Bladder symptoms are common in the later stages
• Diagnosis: Cortical atrophy and increased T2 signal intensity of the
pyramidal tracts.

38. PROGRESSIVE MUSCULAR ATROPHY
• A motor neuron disease causing progressive weakness and
muscular atrophy attributatble to LMN degeneration
• No clinical evidence of UMN dysfunction at onset but
eventually will demonstrate signs of UMN degeneration.
• Show atrophy and weakness beginning in the lower limbs,
shoulder girdle and rarely bulbar musculature.
• EMG – fibrillation potentials, positive sharp waves,
fasciulation potentials and large motor unit action potentials
and normal to decreased motor unit action potential
recruitment.

39. REGIONAL ALS VARIANTS
• Familial ALS
• Mutation of SOD1
• ALS PLUS Syndromes
• ALS with involvement outside the motor system
• Meets clinical and EMG criteria for ALS but have associated nonmotor neuron
features that may include parkinsonism, frontotemporal dementia, ocular
motility abnormalities, extrapyramidal signs, autonomic dysfunction or
sensory loss
• TARDBP gene mutation – associated with features of parkinsonism
• C9ORF72 gene mutation – frontotemporal dementia