Motor Neuron Diseases

Question 1

Acquired motor neuron diseases

Answer 1

Question 2

Spectrum of motor neuron disease

Answer 2

• ALS

Υπομορφές νόσου κινητικού νευρώνα:

• Progressive muscular atrophy (progressive lower motor neuron disorder)
• Primary lateral sclerosis (progressive isolated upper motor neuron neurodegenerative disorder)
• Progressive bulbar palsy (progressive upper and lower motor neuron disorder of cranial muscles)
• Flail arm syndrome (progressive lower motor neuron weakness and wasting that predominantly affects the proximal arm)
• Flail leg syndrome (progressive lower motor neuron weakness and wasting with onset in the distal leg - Patrikios)
• ALS-plus syndromes

Question 3

What is ALS-plus and which is the most common

Answer 3

Classically defined, ALS is considered a degenerative disorder of the upper and lower motor neurons and does not include symptoms or signs outside of the voluntary motor system.

However, some patients have the clinical features of ALS along with features of other disorders such as
* frontotemporal dementia (FTD)
* autonomic insufficiency
* parkinsonism
* supranuclear gaze paresis and/or
* sensory loss

Such patients are considered to have ALS-plus syndrome

Of these, ALS-FTD is the most common.

Question 4

Inherited motor neuron disorders classification

Answer 4

Inherited motor neuron diseases are grouped according to the motor neuron involvement:
1) when only UMNs are affected: hereditary spastic paraparesis
2) when only LMNs are involved:
Spinal muscular atrophy
Spinobulbar muscular atrophy (Kennedy sisease)
3) when both UMNs and LMNs degenerate: familial ALS

Question 5

Which are the only established risk factors for ALS

Answer 5

The only established risk factors for ALS are age and family history

Question 6

Percent of inherited forms of ALS

Answer 6

5-10%

Question 7

Which is the most common mutation of familial ALS (+percentage)

Answer 7

C9ORF72
25-40% of familial ALS

Question 8

Most common gene mutations in ALS

Answer 8

C9orf72, SOD1, TARDBP and FUS
account for the disease in up to 70% of people with familial ALS

Question 9

Which patients with ALS should have genetic test?

Answer 9

Genetic testing for at least SOD1 and C9ORF72 is encouraged in all patients, as
* genotype-specific therapies are in clinical trials and
* pathogenic genetic variants are occasionally identified in patients without a family history

Question 10

Mean age of onset of sporadic ALS

Answer 10

58-63

Question 11

Symptoms and signs of upper and lower motor neuron dysfunction

Answer 11

Question 12

Pattern of spasticity in upper motor neuron dysfunction

Answer 12

In arms, usually affects flexor muscles to a greater extent than extensor muscles

Conversely, in the legs, extensor muscles of the legs are affected to a greater degree than flexors

Spasticity is more prominent at the initiation of passive movement and then diminishes, and it is velocity dependent

Question 13

Symptoms of upper motor neuron dysfunction

Answer 13

Upper motor neuron findings result from degeneration of frontal lobe motor neurons and the corticospinal tract

• weakness
• spasticity
• slowed rapid alternating movements
• hyperactive tendon reflexes (clonus or spread)
• pathologic reflexes (including Babinski and Hoffman sign)
• Dysfunction of corticobulbar tracts causes dysphagia, dysarthria, and pseudobulbar affect (a tendency to laugh or cry spontaneously or with mild provocation)
• Frontal release signs indicate corticobulbar degeneration and include hyperactive jaw jerk and snout and suck reflexes.

Question 14

Symptoms of lower motor neuron dysfunction

Answer 14

• weakness
• wasting of muscles
• Fasciculations (spontaneous discharges of individual LMNs)
• Hyporeflexia and areflexia

Question 15

Limb signs and symptoms associated with ALS

Answer 15

Question 16

Bulbar signs and symptoms associated with ALS

Answer 16

https://www.uptodate.com/contents/image?imageKey=NEURO%2F75146&topicKey=NEURO%2F5136&search=motor%20neuron%20disease&source=outline_link&selectedTitle=1~150

Question 17

Axial signs and symptoms associated with ALS

Answer 17

Question 18

Respiratory signs and symptoms associated with ALS

Answer 18

Question 19

Is there cognitive dysfunction in ALS?

Answer 19

Cognitive impairment, typically related to frontotemporal executive dysfunction, may precede or follow the onset of upper motor neuron and/or lower motor neuron dysfunction in patients with ALS.

Question 20

In which percent is frontotemporal dementia associated to ALS?

Answer 20

Frontotemporal dementia may be associated with ALS in 15 to 50 percent of cases.

Question 21

Pattern of disease spread in ALS

Answer 21

Symptoms initially spread within the segment of onset and then to other regions in a relatively predictable pattern.

In patients with unilateral arm onset, the most common (approximately 60 to 70 percent of patients) pattern of spread is to the contralateral arm, then to the ipsilateral leg, then to the contralateral remaining leg, and then to the bulbar muscles.

In patients with unilateral leg onset, the most common (approximately 60 to 70 percent of patients) pattern of spread is to the contralateral leg, then to the ipsilateral arm, then to the contralateral arm, and then to bulbar muscles.

In patients with bulbar onset, the most common pattern of spread is to one arm and then to the contralateral arm.

Question 22

What distinguishes motor neuron diseases from peripheral neuropathies

Answer 22

Absence of sensory changes

(pure or predominantly motor neuropathies may manifest as weakness without sensory symptoms)

Question 23

Revised El Escorial and Awaji diagnostic criteria for amyotrophic lateral sclerosis

Answer 23

Question 24

Gold coast criteria for ALS

Answer 24

Question 25

Which condition (rare) can cause a motor neuropathy with characteristic wrist drop?

Answer 25

Lead toxicity

Question 26

Laboratory testing in ALS workup

Answer 26

Routine laboratory work usually includes:
* complete blood count with differential
* electrolytes including calcium and phosphate
In patients with an elevated serum calcium level, the serum parathyroid hormone level should be checked
* liver function tests
* thyroid studies
* creatine phosphokinase
* erythrocyte sedimentation rate
* antinuclear antibody
* rheumatoid factor
* vitamin B12
* anti-GM1 antibody
* serum protein electrophoresis with immunofixation
Identification of a serum paraprotein –> look for myeloma and lymphoma
* urine protein electrophoresis with immunofixation
* anti-glutamic acid decarboxylase (GAD) antibody testing may be indicated in the setting of significant upper motor neuron disease

Question 27

Role of neuroimaging in ALS

Answer 27

MRI evaluation should include all segments rostral (closer to the head) to the clinical findings

this includes the brain, cervical spine, and thoracic spine when upper motor neuron findings are in the legs.
Conventional MRI is usually normal in ALS

Question 28

Role of LP in ALS workup

Answer 28

Lumbar puncture for cerebrospinal fluid analysis is performed if there is clinical suspicion for the diagnosis of:
* chronic inflammatory demyelinating polyneuropathy
* Lyme disease
* HIV infection
* lymphoma (elevated protein)
* polyradiculopathy (elevated protein)

or if there is a rapidly progressive isolated lower motor neuron syndrome (symptoms that have progressed over a period of less than two years) because multiple types of cancer can produce a subacutely progressive lower motor disorder by direct infiltration of the meninges, motor roots, and cranial nerves.

Question 29

When is it most likely for a genetic cause to be found in ALS?

Answer 29

The presence of atypical features such as
* young age of onset
* sensory loss
* a positive family history of ALS
* other neurodegenerative disorders and
* dementia
should alert the clinician to the possibility of familial ALS

Question 30

Differential diagnosis of ALS

Answer 30

https://www.uptodate.com/contents/image?imageKey=NEURO%2F64932&topicKey=NEURO%2F5138&search=als&rank=2~150&source=see_link

Question 31

ALS disease modifying treatments

Answer 31

• Initial treatment with riluzole
  For all patients with ALS, initial treatment with riluzole is recommended.
• Treatment with edaravone and PB-TURSO for patients with ALS who are established on riluzole and to those who are unwilling or unable to take riluzole is also recommended.
  We typically begin each additional treatment option within weeks after starting the prior agent.
• Additional treatment with tofersen for patients with SOD1-associated ALS is recommended

Question 32

Riluzole: mechanism of action and dosage

Answer 32

Mechanism of action is not known.

Pharmacologic properties include inhibitory effect on glutamate release, inactivation of voltage-dependent sodium channels; and ability to interfere with intracellular events that follow transmitter binding at excitatory amino acid receptors

Oral: 50 mg twice daily.

Question 33

Riluzole: 1) adverse effects and 2) contraindications

Answer 33

1)
Gastrointestinal: Nausea, oral hypoesthesia
Hepatic: Increased serum alanine aminotransferase
Nervous system: Dizziness
Neuromuscular & skeletal: Asthenia

2) Hepatic disease or baseline serum transaminases >3 times ULN; pregnancy; breast-feeding

Question 34

Edaravone (Radicava): mechanism of action and dosage

Answer 34

The mechanism by which edaravone slows the decline of physical function in patients with ALS is unknown.
Edaravone is a free radical and peroxynitrite scavenger that prevents oxidative damage to cell membranes and may contribute to inhibiting the progression of ALS

IV:

Initial cycle: 60 mg once daily for 14 days, followed by a 14-day drug-free period.

Subsequent cycles: 60 mg once daily for 10 days within a 14-day period, followed by a 14-day drug-free period.

Oral:

Initial cycle: 105 mg (5 mL) once daily for 14 days, followed by a 14-day drug-free period.

Subsequent cycles: 105 mg (5 mL) once daily for 10 days within a 14-day period, followed by a 14-day drug-free period.

Question 35

Edaravone: 1) adverse effects and 2) contraindications

Answer 35

1)
Hematologic & oncologic: Bruise

Nervous system: Abnormal gait

2) None

Question 36

SODIUM PHENYLBUTYRATE-TAURURSODIOL (RELYVRIO): mechanism of action, dosage

Answer 36

The mechanism by which RELYVRIO exerts its therapeutic effects in patients with ALS is unknown

The recommended initial dosage of RELYVRIO for oral suspension is 1 packet (3 g sodium phenylbutyrate and 1 g taurursodiol) daily for the first 3 weeks.
After 3 weeks, increase to the maintenance dosage of 1 packet twice daily.

Question 37

SODIUM PHENYLBUTYRATE-TAURURSODIOL: 1) adverse effects and 2) contraindications

Answer 37

1) diarrhea, abdominal pain, nausea, and upper respiratory tract infection

2) none

Question 38

Tofersen: mechanism of action, dosage, adverse effects, contraindications

Answer 38

1) Anti-sense oligonucleotide that induces ribonuclease H-mediated degradation of superoxide dismutase 1 (SOD1) mRNA, resulting in SOD1 protein synthesis reduction

2) Loading dose: Intrathecal: 100 mg every 14 days for 3 doses; follow with maintenance dosing

Maintenance dose: Intrathecal: 100 mg every 28 days, starting 28 days following third loading dose

3)
Hematologic & oncologic: Leukocytosis (cerebrospinal fluid)

Nervous system: Fatigue, pain

Neuromuscular & skeletal: Arthralgia, myalgia

4) none

Question 39

Pharmacologic palliation for ALS

Answer 39

Question 40

Spinal muscular atrophy: etiology, clinical findings

Answer 40

1)
- autosomal recessive motor neuron disease
- deletions or mutations in the SMN1 gene on chromosome 5q13
- is characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem, which results in progressive muscle weakness and atrophy

2)
- extraocular muscles are spared
- Facial weakness is mild or absent
- tongue fasciculations are seen in nearly all patients
- diffuse symmetric proximal muscle weakness that is greater in the lower than upper limbs
- absent or markedly decreased deep tendon reflexes
- Postural tremor is common
- Respiratory muscles are affected
- Weakness of axial muscles can lead to scoliosis, which may further impair respiration.

Pulmonary insufficiency and pneumonia are common complications

Question 41

Spinal muscular atrophy: subclassification, diagnosis

Answer 41

1)
SMA I (Werdnig Hoffmann disease) begins within the first 6 months of life and is a frequent cause of floppy infant syndrome. Affected infants never sit independently and usually die before 2 years of age.

SMA II (intermediate or chronic infantile disease) starts between ages 6 and 18 months, and affected children develop the ability to sit unsupported. Survival is variable; most patients live into their twenties or thirties.

SMA III (Kugelberg-Welander or chronic juvenile disease), patients develop symptoms after age 18 months, usually manifesting as difficulty climbing stairs or impaired walking, and have normal life expectancies

SMA type 4 is notable for adult onset and is the mildest form

2)
- mildly elevated serum creatine kinase, typically one to two times the upper limit of normal.
- Electromyography reveals spontaneous activity (fibrillations and positive sharp waves). Fasciculations are more common in SMA II and III than in SMA I. Reduced recruitment and long-duration, high-amplitude motor unit action potentials are prominent.
- The diagnosis is definitively confirmed by the identification of SMN1 gene mutation

Question 42

Spinal muscular atrophy: treatment

Answer 42

1) Supportive (Nutrition and gastrointestinal, pulmonary, orthopedic and musculoskeletal)

2) Disease-modifying therapy (DMT) –
i) Nusinersen
ii) onasemnogene abeparvovec
iii) risdiplam

For infants and very young children with SMA who are not ventilator-dependent, treatment with DMT using either nusinersen, onasemnogene abeparvovec, or risdiplam is recommended.

For older children (age ≥2 years) and adults with moderate symptoms of SMA, treatment with nusinersen or risdiplam is suggested.
The efficacy of onasemnogene abeparvovec for children age ≥2 years is unknown.

Question 43

Nusinersen: indication, dosage, mechanism of action

Answer 43

Spinal muscular atrophy

Nusinersen is an antisense oligonucleotide (ASO) which increases the proportion of exon 7 inclusion in survival motor neuron 2 (SMN2) messenger ribonucleic acid (mRNA) transcripts by binding to an intronic splice silencing site (ISS-N1) found in intron 7 of the SMN2 pre-messenger ribonucleic acid (pre-mRNA).

αύξηση έκφρασης υπολειτουργούντος SMN2 γονιδίου και παραγωγής full-length SMN πρωτείνης

Intrathecal:
Loading dose: 12 mg once every 14 days for 3 doses; then 12 mg as a single dose 30 days after the third dose, followed by maintenance dosing.

Maintenance: 12 mg once every 4 months

Question 44

Nusinersen: adverse effects, contraindications

Answer 44

1)
Central nervous system: Headache
Gastrointestinal: Constipation , vomiting
Genitourinary: Proteinuria
Hematologic & oncologic: Thrombocytopenia
Neuromuscular & skeletal: Back pain
Respiratory: Lower respiratory tract infection, atelectasis
Miscellaneous: Fever

2) none

Question 45

onasemnogene: indication, dosage, mechanism of action

Answer 45

Spinal muscular atrophy (treatment of children <2 years of age)

gene replacement of mutated SMN1 with normal SMN1

a one-time intravenous infusion

Question 46

onasemnogene: adverse effects, contraindications

Answer 46

1)
Hepatic: Increased serum alanine aminotransferase , increased serum aspartate aminotransferase

Immunologic: Antibody development

2) none

Question 47

Risdiplam: indication, dosage, mechanism of action

Answer 47

Το Evrysdi ενδείκνυται για τη θεραπεία της 5q νωτιαίας μυϊκής ατροφίας (SMA) σε ασθενείς ηλικίας 2 μηνών και άνω, με κλινική διάγνωση SMA Τύπου 1, Τύπου 2 ή Τύπου 3 ή με ένα έως τέσσερα αντίγραφα του SMN2.

Oral: 5 mg once daily

Treats spinal muscular atrophy caused by mutations in chromosome 5q that lead to survival motor neuron (SMN) protein deficiency; exerts effect by increasing exon 7 inclusion in SMN2 messenger ribonucleic acid transcripts and production of full-length SMN protein.

αύξηση έκφρασης υπολειτουργούντος SMN2 γονιδίου και παραγωγής full-length SMN πρωτείνης

Question 48

Risdiplam: adverse effects, contraindications

Answer 48

1)
Dermatologic: Skin rash
Gastrointestinal: Constipation, diarrhea, vomiting
Respiratory: Pneumonia, upper respiratory tract infection
Miscellaneous: Fever

2) none

Question 49

Monomelic ALS (Hirayama): epidemiology, clinical findings

Answer 49

weakness of one arm distal more prominent than proximal (although there are a few cases of single leg involvement)

The disease affects men more often than women (5:1 ratio), with onset typically in the late teens or twenties.
Weakness progresses slowly over 1–3 years before stabilizing.
Sensory examination is usually normal, but mild sensory abnormalities may be present in the dorsum of the hand.
Tendon reflexes are typically normal, and UMN signs are absent.

Question 50

Monomelic ALS: diagnosis, treatment

Answer 50

Nerve conduction studies and electromyography reveal normal sensory nerve functions, but neurogenic changes consistent with LMN disease are observed in the affected limb and, to a lesser extent, in the unaffected limbs.
MRI of the spine or CT-myelogram may reveal spinal cord atrophy in the lower cervical or upper thoracic cord.

No specific treatment has proven to be effective for the disorder.

Question 51

Kennedy disease: etiology, epidemiology, clinical findings

Answer 51

X-linked recessive disease
The disease is caused by expansions of a CAG trinucleotide repeat in the androgen receptor gene

There is degeneration of lower motor neurons in brainstem nuclei and spinal cord.

usually presents as progressive weakness in men in their twenties to forties.
Limb muscle weakness is more prominent proximally than distally.
Bulbar muscles are affected. Facial, tongue, and mastication muscles are often weak; dysarthria and dysphagia are late manifestations.
Fasciculations around the mouth and particularly in the chin are prominent.
Gynecomastia and impotence are caused by androgen receptor defects.

Question 52

Kennedy disease: diagnosis, treatment

Answer 52

Nerve conduction studies reveal absent or low-amplitude sensory nerve action potentials, and electromyography shows neurogenic abnormalities.
Although Kennedy disease is primarily a motor neuron disorder, serum creatine kinase is usually elevated to 900–8000 U/L.

the diagnosis can be confirmed by genetic testing.

Treatment is limited to supportive therapy

Question 53

Hereditary spastic paraparesis: etiology, epidemiology, clinical findings

Answer 53

HSP has been classified into 44 genetically distinct forms, including autosomal-dominant, autosomal recessive, and X-linked recessive types

Age at onset is variable.
Uncomplicated or pure HSP refers to spastic leg weakness with hyperreflexia and Babinski signs, and, in some patients, urinary urgency, frequency, or hesitancy as well as mild loss of vibratory sensation in the feet.
Rectal and sexual dysfunction is rarely associated with uncomplicated HSP.

Complicated HSP describes conditions in which spastic paraparesis is accompanied by such neurologic abnormalities as optic atrophy, retinopathy, seizures, mental retardation, dementia, extrapyramidal abnormalities, and peripheral neuropathy.

Question 54

Hereditary spastic paraparesis: diagnosis, treatment

Answer 54

MRI of the thoracic or lumbar spinal cord may reveal atrophy.
Somatosensory evoked potentials sometimes show delayed conductions with stimulation of the legs.
Magnetostimulation of the corticospinal tract typically demonstrates reduced conduction velocities and amplitude of evoked potentials in the legs.
Although genetic testing for HSP is available commercially, causative genes have been identified in less than half of the genetic subtypes.

Treatment for HSP is symptomatic.
Antispasticity medications include oral or intrathecal baclofen, and oral tizanidine hydrochloride.
Oxybutynin, 5 mg two to three times a day, or extended-release oxybutynin, 5–30 mg once a day, can reduce urinary urgency.
Physical therapy can reduce deconditioning.

Question 55

Primary lateral sclerosis: clinical findings, diagnosis

Answer 55

This is a progressive disorder that is clinically limited to the upper motor neurons.
Consensus diagnostic criteria for primary lateral sclerosis require
* presence of exclusively upper motor neuron signs in at least two of three body regions (bulbar, upper extremity, lower extremity)
* the absence of both sensory symptoms and lower motor neuron dysfunction.

Duration of progressive symptoms should be for at least four years since symptom onset.

If lower motor neuron signs appear before this time, then the diagnosis converts to upper motor neuron–onset ALS.
In addition, electromyographic findings are usually abnormal in ALS (even in the absence of LMN signs) but are normal in PLS.

Although HSP can be distinguished by the presence of affected relatives, isolated patients with autosomal-recessive or X-linked recessive disease may be difficult to distinguish from patients with PLS.

Question 56

Primary lateral sclerosis diagnostic criteria

Answer 56