Lecture 9: Amyotrophic Lateral Sclerosis Clinical and Genetic Features

Question 1

Amyotrophic Lateral Sclerosis

Clinical and Genetic Features

Answer 1

Stephen J. Kolb, M.D., Ph.D.

September 30, 2014

Question 2

“Final Common Pathway”

Answer 2

“…to move things is all that mankind can do, for such the
sole executant in muscle, whether in whispering a syllable
or felling a forest.”

-Charles Sherrington, 1924

Question 3

Neurons consume a lot of energy.

Answer 3

Motor neurons project very far.

Question 4

Clinical Features of ALS

Answer 4

Asymmetric Atrophy of the Hand =Split Hand Syndrome

Shoulders, Chest, & Back are atrophied

Ruffling of the tongue, looks like it has worms just underneath the surface of the tongue.

Trouble protruding the tongue, pooling of saliva

Question 5

Charcot’s Disease:

Amyotropic Lateral

Answer 5

1869 - Suggested grouping together diseases that affect the lateral horn of the spinal cord

Degeneration of corticospinal tracts and extensive loss of lower motor neurons

Question 6

Amyotrophic lateral sclerosis

Answer 6

Amyotrophic lateral sclerosis, or ALS, is a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement. ALS is also known as Lou Gehrig’s disease.

Disease of both the lower and upper motor neurons

Question 7

Ubiquitin-positive inclusions

Answer 7

Dense anti-ubiquitin positive deposit

“Skein-like” filamentous arrays

Question 8

Epidemiology of Amyotrophic Lateral Sclerosis

Answer 8

Incidence of ALS in Europe = 2.2 per 100,000

Men = 3 per 100,000; 
Women = 2.4 per 100,000

Overall lifetime risk:
Men = 1:350 / Women = 1:400

Peak age at onset:
Sporadic = 58 – 63 yrs; Familial = 47 – 52

Rates of ALS in Cuba are 60% lower than in US or Europe

Question 9

Pathophysiology of ALS

Answer 9

Denervation of the muscle

ALS, therefore, is not a primary disease of the muscle, but of the nerves.

If you lose a motor neuron, the naked muscle fibers call out to be innervated, they spontaneously move. Other neurons will send projections to the connect and innervate them. The only thing that

You can listen to the electrophysiological activity to help diagnose what’s going on in the motor neurons.

Question 10

A single motor neuron innervates a single muscle fiber

Answer 10

Manyyy genes can be involved in the development of this disease.

Question 11

Diagnostic Criteria

Answer 11

The diagnosis of amyotrophic lateral sclerosis [ALS] requires:

(A) the presence of
(1) evidence of lower motor neuron (LMN) degeneration by clinical,
electrophysiological or
neuropathological
examination
(2) evidence of upper motor neuron (UMN) degeneration by clinical examination; and
(3) progressive spread of symptoms or signs within a region or to other
regions, as determined by history, physical examination, or
electrophysiological tests

(B) the absence of
(1) electrophysiological or pathological evidence of other disease
processes that might explain the signs of LMN and/or UMN
degeneration, and
(2)
neuroimaging
evidence of other disease processes that might
explain the observed clinical and electrophysiological signs

Question 12

Diagnostic Criteria

Shorter version

Answer 12

(A) the presence of
(1) lower motor neuron (LMN) degeneration
(2) upper motor neuron (UMN) degeneration
(3) progressive spread of symptoms or signs within a region or to other
regions

(B) the absence of
(1) other disease processes that might explain the signs of LMN and/or UMN degeneration
(2) neuroimaging
evidence of other disease processes that might
explain the observed clinical and electrophysiological signs

Question 13

Diagnostic Criteria

Answer 13

Clinically definite ALS is defined by clinical or electrophysiological evidence by the presence of LMN and UMN signs in the bulbar region and at least 2 spinal regions or the presence of LMN and UMN signs in 3 spinal regions

Clinically probable ALS is defined on clinical or electrophysiological evidence by LMN and UMN signs in at least 2 regions with some UMN signs necessarily rostral to the LMN signs

Clinically possible ALS is defined when clinical or electrophysiological signs of UMN and LMN dysfunction are found in only one region; or UMN signs are found alone in 2 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 have been excluded

Question 14

“There’s no pregnany test for ALS…”

Answer 14

No easy “yes or no” test

So it’s hard to diagnose.

Question 15

Differential Diagnosis

Answer 15

ALS mimics…

Multifocal motor neuropathy => EDX, ganglioside GM1 antibodies

X-linked spinobulbar muscular atrophy => CAG repeats in AR
gene

Poliomyelitis => History, EDX

Hexosaminidase A deficiency => white cell enzyme testing

Spinal muscular atrophy =>
SMN deletion

Heavy metal poisoning => urine and blood screens

Cramp-fasciculation syndrome => EDX

Question 16

Differential Diagnosis:

Error Rate

Answer 16

False Positive = 8%

False Negative = up to 44%

Question 17

Management Goal

Answer 17

Optimize health care delivery, prolong survival, and enhance quality of life

Question 18

Management

Answer 18

Referral to multidisciplinary ALS clinic:
Prolongs survival and increased
utilization of therapies in multiple studies.

Riluzole should be offered:
4 clinical trials have confirmed
prolonged survival 2-3 months. Large retrospective studies indicate that benefit may be more substantial ( ~6-21 months)

Percutaneous endoscopic
gastrostomy (PEG) tube should be considered:
Probably improves survival although current studies unable to quantity survival advantage

Non-invasive ventilatory (NIV) support should be considered:
Prospective studies indicate a survival benefit of 5–11 months (excluding bulbar predominant patients)

Question 19

Sialorrhea

Answer 19

Sialorrhea = drooling

Should be treated aggressively:
An important cause of aspiration pneumonia and embarrassing, prevalence of 50%.
Anticholinergic medication tried first.
Botulinum toxin type B injections into parotid and
submandibular glands has been effective in clinical trials

Question 20

Pseudobulbar affect should be treated:

Answer 20

Dis-inhibition of emotional response, like giggling at a funeral.

Occurs in 20-50% and should not be confused with a mood disorder.
Dextromethorphan and quinidine combination is effective (Nuedexta).

Question 21

Screening for cognitive impairment should be considered:

Answer 21

Estimates of cognitive impairment range from 10–75%.

Dementia in 15 – 41%.

Insufficient data to support treatment of cognitive impairment.

Question 22

Evidence for Genetic Contribution to ALS

Answer 22

Familial ALS by family history: 5–20%

Mutations in Mendelian
genes account for:
• 75% of inherited forms
• 14% of those with no obvious family history

Twin studies indicate heritability of apparently sporadic ALS is ~0.61

There is clustering of neurodegenerative diseases in relatives of PALS

Question 23

C9orf72 hexanucleotide

repeat expansion

Answer 23

-­‐ Identified in large families with FTD/ALS

-­‐ Length of expansion ranges from 700­‐1600 repeats.
Majority of controls have 2 repeats

• ­‐ Accounts for ~12% of familial FTD and 3% sporadic FTD
• ­‐ Accounts for ~24% of familial ALS and 4% sporadic ALS
• ­‐ More severe course on average for familial ALS

Question 24

Rate of progression in ALS depends on mutation

Answer 24

…

Question 25

“Final Common Pathway?”

Answer 25

Protein degradation pathway
Axonal transport disruption
Oxidative Stress
RNA metabolism defect
Prion-like progression