Motor Neuron Disorders

Question 1

Anterior Horn Cell diseases affect primarily the motor neurons in the spinal cord. Such diseases include, for example:

Answer 1

Familial Spinal Muscular Atrophy and poliomyelitis.

Question 2

T or F. In Amyotrophic Lateral Sclerosis (ALS) the upper motor neurons and the lower motor neurons are affected.

Answer 2

T. These disorders cause weakness with muscle atrophy and are usually accompanied by muscles fasciculations and signs of denervation on the EMG.

The reflexes are usually depressed except in Amyotrophic Lateral Sclerosis in which they could be increased because of involvement of the upper motor neurons. There are no sensory deficits because the sensory axons are not affected. Anterior Horn Cell diseases may be hereditary or sporadic, and usually they have no cure.

Question 3

This diagram shows the different areas affected in neuromuscular diseases.

In motor neuron diseases the motor neurons, their motor axons, and secondarily the muscle fibers they innervated are affected (the motor unit).

Question 4

What are the major anterior horn cell diseases?

Answer 4

INFANTILE SPINAL MUSCULAR ATROPHY: Werdnig-Hoffman

JUVENILE PROXIMAL CHRONIC SPINAL MUSCULAR ATROPHY: Wolfart-Kugelberg-Welander

ADULT ONSET SPINAL MUSCULAR ATROPHY

Question 5

Describe INFANTILE SPINAL MUSCULAR ATROPHY: Werdnig-Hoffman

Answer 5

This is a fatal AR disease marked by:

• hypotonicity and hyporeflexia
• tongue fasciculations
• poor suck reflex
• abdominal respirations

Question 6

Describe JUVENILE PROXIMAL CHRONIC SPINAL MUSCULAR ATROPHY: Wolfart-Kugelberg-Welande

Answer 6

This is a AR disease marked by:

slowly progressive proximal weakness that resembles myopathy and fasciculations

Question 7

Descrive ADULT ONSET SPINAL MUSCULAR ATROPHY

Answer 7

This is a sporadic (some familial) syndrome marked by:

hypotonicity, hyporeflexia and

proximal and distal wekaness

Question 8

Here is a baby with the most severe motor neuron disease manifesting at birth with weakness , hypotonia, (floppy baby), areflexia, muscle atrophy, difficulty breathing and swallowing. They usually die early of respiratory failure.

Answer 8

Note the “frog leg posture” with the hips abducted do to weakness. The disease is called Werdnig-Hoffman Disease.

The EMG will show signs of denervation and fasciculations. The muscle biopsy will show group fiber atrophy.

Question 9

What causes infantile spinal muscular atrophy?

Answer 9

This is an autosomal recessive disease from mutations of the ‘survival motor neuron gene’ on chromosome 5q.

Question 10

this is a patient with juvenile spinal muscular atrophy. This disease manifests in childhood and clinically resembles a muscular dystrophy.

Note the atrophy of the pectoralis and thigh muscles. Unlike myopathies, the EMG and biopsy show denervation changes, and the serum CK is usually normal.

Question 11

What causes juvenile spinal muscular atrophy?

Answer 11

This disease is also caused by mutation of the ‘survival motor neuron gene’. The survival motor neuron gene has two copies, SMN1 and SMN2. SNM1 is absent in spinal muscular atrophy, and the size of SMN2 determines if the patients has the neonatal or the juvenile form (larger in the later). This disease is called Kugelberg Welander Disease.

Question 12

How does PROGRESIVE BULBAR PALSY present?

Answer 12

Sporadic, Fasciculations, Bulbar muscles weakness, Rapidly progressive, Tongue atrophy (adult onset)

Progressive bulbar palsy affects primarily the muscles innervated by the medulla (form bulb or medulla in French) neurons , causing tongue and palate weakness. Patients with Progressive Bulbar Palsy may later develop classical ALS.

Question 13

How does ALS present?

Answer 13

Mostly sporadic, Some familial cases, Hyperreflexia, Spasticity, Muscle atrophy, Fasciculations, Tongue atrophy, Rapidly progressive (adult onset)

ALS manifests with upper and lower motor neuron symptoms and findings as well as “bulbar” weakness.

Question 14

How does progressive lateral sclerosis present?

Answer 14

Sporadic, Involves only the upper motor neurons, Spasticity, Hyperreflexia, More benign course

Progressive lateral sclerosis affects primarily the upper motor neurons with little atrophy or signs of denervation. Although these patients could later develop signs of classical ALS, progression of symptoms is slower as this appears to be a more benign form of the disease.

Question 15

How does PROGRESSIVE SPINAL MUSCULAR ATROPHY present?

Answer 15

Mostly sporadic, Progressive weakness, Muscle atrophy, Fasciculations, Areflexia (adult onset)

Question 16

What are some signs/symptoms of motor neuron diseases?

Answer 16

• Symmetrical or asymmetrical weakness
• Atrophy

Increased or decreased reflexes- dependent upon corticospinal tract involvement (ALS)

• Fasciculations
• Normal sensation

Question 17

Lab findings of motor neuron diseases

Answer 17

• Normal nerve conduction velocities
• Denervation on EMG
• Decreased # of motor units
• Muscle biopsy shows atrophic fibers & fiber grouping

Question 18

ALS is caused by degeneration of the upper and lower motor neurons. It is progressive and lethal. Patients present how?

Answer 18

They are weak, have atrophic muscles fasciculations, hyperreflexia and spasticity, but normal sensation. Characteristically patients develop difficulty swallowing and breathing.

Most cases are sporadic but about 10% of cases are hereditary.

Question 19

Answer 19

This woman with ALS shows early atrophy and weakness of the distal muscles.

Question 20

This woman has a more advanced case of ALS with difficulty closing her mouth. She is wheelchair bound and has hyperreflexia, bilateral Babinski signs, fasciculations, atrophy, and normal sensation.

Question 21

The differential diagnosis of ALS is large. One should always search for a more benign disorder or a treatable one. What should be included?

Answer 21

• Multisystem atrophy, spinocerebellar degeneration (Hereditary cerebellar degenerations could present with difficult swallowing but they have ataxia.)
• Craniocervical junction disorders
• Cervical spondylosis
• Post polio syndrome
• Polyglucosan body disease
• Hexoaminidase A deficiency

Question 22

What is Multisystem atrophy?

Answer 22

A late onset degenerative disease that could affect the lower motor neurons, autonomic neurons and also cerebellar neurons. This is also a progressive disorders, but slower than ALS.

Question 23

Note about craniocervical jucntion disorders being on the Ddx for ALS:

Tumors of the craniocervical junction could present with arm weakness and difficulty swallowing , thus patients with these symptoms should always have a MRI before diagnosing ALS

Answer 23

Cervical canal disease such as spondylosis, with degenerative disc disease, could present with arm , hand atrophy, weakness, and spasticity from compression of the pyramidal tracts. Sensory deficits could be absent or minimal. MRI of the spine is thus very important.

Question 24

More on the Ddx of ALS

Answer 24

Patients with a history of poliomyelitis in childhood, later may develop a progressive lower motor neuron disease. The cause is unclear and it is not from infection , but likely do to age-related degeneration of the surviving motor neurons. The previous history of polio is paramount in making this diagnosis.

Milder phenotypes of Tay Sachs disease present like ALS in younger individuals. They also usually have intellectual deterioration and ataxia

Question 25

What is polyglucosan body disease?

Answer 25

A glycogen storage disorder that presents in younger individuals with a lower motor neuron type of weakness. The muscle or nerve biopsy show the characteristic polyglucosan inclusions.

Question 26

MRI of a patient with cervical spondylosis. Note several protruding discs pressing the spinal cord. Patients with cervical spondylosis may present with lower motor neuron signs in the upper extremities secondary to nerve root compression and upper motor neuron signs in the lower extremities secondary to compression of the spinal cord and corticospinal tracts.

Question 27

What else should be on the Ddx for ALS?

Answer 27

• Hyperparathyroidism (Patients with hyperparathyroidism may present with progressive muscle weakness resembling ALS. An elevated serum calcium and parathyroid hormone level are diagnostic)
• Heavy metal (lead) intoxication- Lead poisoning rarely causes lower motor neuron degeneration resembling the lower motor neuron type of ALS.
• Bulbo-spinal muscular atrophy (Kennedy’s disease) and other motor neuron disorders

Other benign variants of motor neuron disorders such as benign focal amyotrophy and benign cramp fasciculation syndrome

Question 28

What is Kennedy disease?

Answer 28

Kennedy disease is a more benign disorder than ALS that may present without a family history. The disease is caused by mutations of the androgen receptor gene on the X chromosome.

Question 29

The classical phenotype of Kennedy disease includes:

Answer 29

gynecomastia and testicular atrophy, lower motor neuron syndrome, i.e., atrophy , fasciculations , signs of denervation in limbs and tongue, and they may have a mild neuropathy.

The serum CPK may be elevated. DNA testing is diagnostic.

Question 30

There are patients that have more benign motor neuron syndromes such as a non progressive unilateral limb weakness and atrophy. The etiology of this syndrome is unclear, but could be caused by chronic dural compression of the cord. There are some families that present with a benign syndrome of fasciculations and cramps.

Question 31

Rarely patients with Myasthenia Gravis or Eaton-Lambert Syndrome may resemble ALS, especially when they do not have eye muscle weakness. Their diagnosis is established by EMG testing.

Answer 31

Myopathies should also be considered in the differential diagnosis of ALS. The serum CPK, EMG and muscle biopsy help in the diagnosis.

Question 32

This patient has Kennedy’s disease. Despite the gene defect in the androgen receptor he had children, no testicular atrophy and did not show gynecomastia. He did have mild, generalized weakness

Question 33

This is a spinal cord section from a patient that died from ALS. Note the lack of myelin stain (pale) in the corticospinal tracts. There was also a loss of the anterior horn neurons.

Answer 33

Bunina eosinophilic inclusions may be seen in anterior horn cell neurons. These are ubiquitin accumulations. (ALS)

Question 34

Although most cases of ALS are sporadic, some are familial. What are some possible causes?

Answer 34

• SOD (superoxide dismutase-cause an toxic gain of function of this enzyme) gene mutations in chromosome 21 in AD familial ALS
• Juvenile ALS: in chromosome 2q33 (also in gene 9q34, 15q15, 8q21), and also ALS associated with mutation of 9q21, XP, others
• ALS associated with other diseases such as chromosome 17-linked fronto-temporal dementia (FTD)

Question 35

What is the most common cause of familial ALS with or without FTD?

Answer 35

An expanded section of DNA on chromosome 9 in the gene C90RF72

Question 36

Question 37

How is ALS tx?

Answer 37

• Glutamate antagonists, such as riluzole is helpful.
• Experimental: Creatine and antioxidants such as carotene, coenzyme Q10, vitamins C and E could be of benefit, COX 2 inhibitors?, Nerve growth factors?.
• Physical therapy

Question 38

These are some of the treatments that help relief symptoms of ALS. Local Botox injections in the salivary glands are used to decrease excessive salivation do to poor swallowing. Botox injections in muscles are also used to relief spasticity.

Physical bracing is used for foot drop. Feeding gastrostomy is used for feedings in those with difficulty swallowing and risk of aspiration. Finally non-invasive, continuous pressure, external mask ventilation, or invasive thru tracheostomy, ventilation prolong survival.

Question 39

Proximal myopathy- proximal weakness, Gower sign, difficult ascending stairs, etc.

Answer 39

Neuropathies are often marked by distal weakness and cause sensory loss (while in motor neuron disease there is only weakness)

Question 40

In ALS there are increased reflexes and wasting but no sensory loss

Answer 40

With contraction, motor units are recruited 1 by 1

Question 41

Normally, muscles are mixed with type 1 and 2 fibers

Answer 41

Denervation causes muscle fiber atrophy

Question 42

After denervation, other motor neurons take over and cover more fibers leading to a larger action potential

Answer 42

In myopathies you dont have decreased motor units (but the fibers are damaged leading to small APs) but you do in neuropathies

Question 43

Myopathies have decreased numbers of muscle fibers, not motor units

Answer 43

Question 44

Question 45

Question 46

hypereflexia= UMN disease

Answer 46

Sensory is normal in ALS

Question 47

1 (and possibly 3) and probably an EMG

Answer 47

5.

Question 48

4.

Answer 48

4.

Question 49

1 and 2

Question 50

Probably Kennedy Disease

Question 51

Answer 51

2. Peripheral nerves

Question 52

4.

Answer 52

Question 53

Note the inheritance

Answer 53

D. Spinal muscular atrophy

Could be cerebral palsy but usually reflexes are present

Question 54

A and C

Answer 54

Question 55

Probably a primary myopathy (proximal weakness) or juvenile spinal muscular atrophy

Cerebral palsy= usually have reflexes

Answer 55

A (CPK is not high with spinal atrophy, only myopathy) and C

Question 56

suggests spinal muscular atrophy (anterior horn disease)

Answer 56

Muscle biopsy may show angular or grouping (dont need)

Answer: D. DNA testing

Question 57

Answer 57

Inflammatory myopathy doesnt usually cause facial weakness

Progressive bulbar palsy usually shows tongue fasciculations (could be though)

Answer: C Myasthenia gravis

Question 58

D. All of the above

Answer 58

Question 59

C.

Answer 59