Lower Motor Neurone

Question 1

3 primary anterior horn cell disorders affecting the ventral horn of the spinal cord

Answer 1

• amyotrophic lateral sclerosis

primary lateral sclerosis and progressive muscular atrphy

• spinobulbar musculat atrophy

Question 2

ALS:

Definition: progressive neurodegenerative disease that causes UMN and LMN symptoms. Ultimately fatal, primary laterla sclerosis and progressive muscular atrophy.

Epi: 2/100,000, most in ages 65– ____ is the greatest risk factor

Etiology: associated with __ gene (50%), and ___ gene (20%), idiopathic

Answer 2

Definition: progressive neurodegenerative disease that causes UMN and LMN symptoms. Ultimately fatal, primary laterla sclerosis and progressive muscular atrophy.

Epi: 2/100,000, most in ages 65– AGE is the greatest risk factor

Etiology: associated with c9orf72 gene (50%), and SOD1 gene (20%), idiopathic

Risk factors: AGE, Hamily history, usually AD inheritance, environmental factors (manual workers and athletes)

Symptoms and Clinical Features:

Combos of UMN and LMN signs

Quick progression

Typically earlier involvement of hands and bulbar musculature, leading to dysarthria and dysphagia, coexistence with FTD and some patients.

Investigations:

Clinical

EMG: objective evidence of muscle deinnervation (fibrillations (random depolarizations) and positive sharp waves)

Exclusion of other disorders with MRI, blood work (B12, Cu, VLCFA, HTLV1, genetics as indicated.

Diagnosis using El Escorial Diagnostic Criteria:

Diagnosis of ALS requires the presence of:

1. Signs of lower motor neuron degeneration by clinical, electrophysiological or neuropathological examination

2. Signs of UMN degeneration by clinical examination

3. Progressive spread of signs within a region or to other regions, together with the absence of :

Electrophysiological evidence of other disease processes that might explain the signs of LMN and UMn degenerates and

Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs.

***UMN and LMN signs must be present in 3 separate regions.

Question 3

El Escorial Diagnostic Criteria

Answer 3

Diagnosis of ALS requires the presence of:

• 1. Signs of lower motor neuron degeneration by clinical, electrophysiological or neuropathological examination
• 2. Signs of UMN degeneration by clinical examination
• 3. Progressive spread of signs within a region or to other regions, together with the absence of :

Electrophysiological evidence of other disease processes that might explain the signs of LMN and UMn degenerates and

Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs.

***UMN and LMN signs must be present in 3 separate regions.

Question 4

treatment of ALS

Answer 4

Treatment: Rilozole, multidisciplinary supportive care

Riluzole extends survival approximately 3 months. MOA is antiglutamatergic. Must monitor CBC and liver function. Does not improve QOL.

Question 5

Primary lateral sclerosis: causes ____ Degeneration (compared to ALS, which is LMN and UMN). is it associated with ALS genes?

Answer 5

PLS causes UMN degeneration and is DISTINCT FROM ALS (does not share genes)

prognosis: decades

Question 6

progressive muscular atrohpy causes ___ degeneration (unlike als which affects both umn and lmn). Does it share genes with ALS? What is the prognosis?

Answer 6

Definition: “Pure” LMN degeneration (7% of anterior horn cell disorders)

Most have subclinical UMN involvement

Association with ALS genes *unlike PLS

Probably on disease spectrum with ALS, but survival tends to be longer than ALS.

Question 7

Key finding in spinobulbar muscular atrophy (kennedy disease)

• method of inheridence?
• investigations

Answer 7

kennedy disease: X LINKED GENETIC DISORDER OF AR GENE (CAG REPEAT)

Epi; MEN ONLY

symptoms: LMN degeneration, muscle cramps, tremor, limb+ bulbar muscle atrophy, androgen insensitivty (gynecomastria, reduced fertility)
investigations: genetics ( CAG in AR gene), EMG (muscle de-innervation and subclinical sensory neuropathy)

Question 8

___ ___ ___: PEDIATRIC and RECESSIVE disease due to mutation of SMN1. Causes progressive death of LMN. The copy number of SMN 2 is a major phenotypic modifier.

Treatment: Antisense Oligonucelotide Therapy (Nusinersen): designed to bind to mRNA to achieve altered splicing or expression.

Adaptations for stability and penetration through cell membrane

Binds to SMA transcripts, to promote inclusion of exon 7 in SMN2 transcripts.

Most beneficial for types I and II.

Answer 8

Spinal Muscular Atrophy

Subtypes:

• 1: Wednig Hoffmann Disease: 50% of patients, most severe with onset <6 months and death <2 years. Generalized hypotonia, no head control. Paradoxical breathing with tongue fasciculations and bulbar weakness.
• 2: onset 7-18 months, generally can sit unaided but cannot walk. Bulbar and generalized weakness with significant scoliosis because of weakness in axial muscles, respiratory complications usually cause of death in adolescence
• 3: Heterogenous group with onset >18 months but less than 10 years. Achieve major miulestones but eventually develop weakness and scoliosis
• 4: very late onset >10 years, also heterogenous group, normalish life expectancy

Treatment: Antisense Oligonucelotide Therapy (Nusinersen): designed to bind to mRNA to achieve altered splicing or expression.

Adaptations for stability and penetration through cell membrane

Binds to SMA transcripts, to promote inclusion of exon 7 in SMN2 transcripts.

Most beneficial for types I and II.

Question 9

3 key NMJ disorders

Answer 9

Myasthenia Gravis

Lambert- Eaton myasthenic Syndrome

Botulism

Question 10

Myasthenia Gravis

Definition: progressive autoimmune disorder due to anti-__ or anti-___ antibodies, resulting in early saturation at the NMJ and inadequate muscle activation with increasing nerve stimulation. Most common NMJ disorder.

Epi: bimodal age at 20 (F>M) and 60 (which gender is preferred); 85% have ___ hyperplasia and 15% have __ neoplasia

Answer 10

Myasthenia Gravis

Definition: progressive autoimmune disorder due to anti-AChR or anti-MuSK antibodies, resulting in early saturation at the NMJ and inadequate muscle activation with increasing nerve stimulation. Most common NMJ disorder.

Epi: bimodal age at 20 (F>M) and 60 (M>F); 85% have thymic hyperplasia and 15% have thymic neoplasia

Question 11

in myasthenia gravis, symptoms include:

• ___ symmetric or asymmetric weakness w/o reflex changes, sensory changes or coordination abnormalities
• ___ subtype (diplopia/ptosis), ___ (dysarthria/dysphagia) and/or __ limb weakness

Eye symptoms last 2+ years.

• ___ ___: exacerbation triggered by infection, surgery, anemia, electrolyte disturbance, drugs→ ___ failure (ICU)

15% chance after diagnosis

Triggers: infections, recent surgery, electrolye distrubances, anything that stresses the body and thus can aggravate the myasthenia.

Answer 11

• Fatigable symmetric or asymmetric weakness w/o reflex changes, sensory changes or coordination abnormalities
• Ocular subtype (diplopia/ptosis), bulbar (dysarthria/dysphagia) and/or proximal limb weakness

Eye symptoms last 2+ years.

• Myasthenic crisis: exacerbation triggered by infection, surgery, anemia, electrolyte disturbance, drugs→ respiratory failure (ICU)

15% chance after diagnosis

Triggers: infections, recent surgery, electrolye distrubances, anything that stresses the body and thus can aggravate the myasthenia.

Question 12

classes of drugs that can worsen myasthenia

Answer 12

Antibiotics (aminoglycosides, antimalarial chloroquine), anaestehtics (succinylcholine), antiarrhythmics (quinidine), antihypertensives (beta blockers and calcium channel blockers)

Note that alteration of therapy (steroids or AChE inhibitors can also cause myasthenic crisis

Question 13

Investigations for myasthenia gravis

Answer 13

• Edrophonium/Tensilon or Ice Pack Test: improves ptosis

• NCS: decremental response (supramaximal stimulation, 2-3Hz)

Normal, would see compound AP reaching the same peak every time. In MG, the more you stimulate, the lower the AP is, indicating a physiological fatigue.

• Single-fiber EMG: jittery motor units
• Antibody tests

Achr Ab positive in 50% of ocular MG, and 85% of generalized MG

• CT/MRI: thymoma/thymic hyperplasia

Question 14

nerve conduction study findings for myasthenia gravis

Answer 14

• NCS: decremental response (supramaximal stimulation, 2-3Hz)–> indicating fatigue

Normal, would see compound AP reaching the same peak every time. In MG, the more you stimulate, the lower the AP is, indicating a physiological fatigue.

Question 15

Management for myesthenia gravis

Answer 15

• Thymectomy: always in pt with thymoma and in any pt less than 60yo

MG is very associated with thymoma paraneoplastic syndrome

ALWAYS INDICATED TO PREVENT LOCAL SPREAD OF DISEASE

Remove thymus even without thymoma?–>Has shown a 34% remission rate… the evidence is uncertain and medical therapy has improved.

• Symptomatic relief: ACh-esterase inhibitors (pyridostigmine)–> Inhibits ACh breakdown.
• Disease-modifying: steroids (can cause myasthenia gravis crisis), immunosuppression via azathioprine, methotrexate, myocophenolate

Steroids can caue a myasthenic crisis because it can first trigger a degranulation of the antibodies, initially increasing the number of antibodies and thus increasing the progression of disease at the beginning on initiation

Question 16

myasthenic crisis management

Answer 16

plasma exchange, IVIg + ventilatory support

Prognosis: 30% have remission with therapy. Good prognosis in early onset pt, mild symptoms and ocular myasthenia; poor prognosis with MuSK +ve

Question 17

Key symptom finding differences in LEMS vs MG

Answer 17

• Symptoms in LEMS spread UPWARDS (Legs to arms to bulbar), compared to MG which stars Bulbar to arms to legs.
• Ocular involvement isn’t usually present, or have minor ocular symptoms, compared to MG which can have ocular subtypes or significant ptosis.

Question 18

LEMS:

• Symptoms in LEMS spread UPWARDS (Legs to arms to bulbar), compared to MG which stars Bulbar to arms to legs.
• Ocular involvement isn’t usually present, or have minor ocular symptoms, compared to MG which can have ocular subtypes or significant ptosis.
• Definition: autoimmune disorder due to antibodies against __ __-__ calcium channels→ decrease __ released at the NMJ.

Etiology: paraneoplastic syndrome (__ __ __ __ cancer, predominantly in __ age 60); non-tumour (autoimmune HLA association, predominantly in F).

Symptoms: __ weakness with __-__ __ (spread legs→ arms→ bulbar) + autonomic dysfunction (ED, dry mouth, orthostatic dysregulation, constipation) + __

Investigations: antibodies to __, NCS show >10% __ at low frequency (5Hz) but >100% __ at high frequency (10Hz)

Management: __ screen (look for small cell lung cancer), ___ (increase ACh release therefore improving presynaptic Ach function), ACh-__ ___, immunosuppression (In non-tumor LEMS)

Answer 18

Definition: autoimmune disorder due to antibodies against presynaptic voltage-gated calcium channels→ decrease ACh released at the NMJ.

Etiology: paraneoplastic syndrome (small cell lung cancer cancer, predominantly in Men age 60); non-tumour (autoimmune HLA association, predominantly in F).

Symptoms: proximal weakness with post-exercise facilitation (spread legs→ arms→ bulbar) + autonomic dysfunction (ED, dry mouth, orthostatic dysregulation, constipation) + areflexia

Investigations: antibodies to VGCC, NCS show >10% decrement at low frequency (5Hz) but >100% increment at high frequency (10Hz)

Management: malignancy screen (look for small cell lung cancer), 3,4-DAP (increase ACh release therefore improving presynaptic Ach function), ACh-esterase inhibitors, immunosuppression (In non-tumor LEMS)

Question 19

compare and contrast LEM and MG

Answer 19

Question 20

Botulism

Definition: NMJ disease caused by the neurotoxin of clostridium botulinum→ inhibits ACh release from motor neurons

Etiology: inoculation with clostridium botulinum via ingestion or wounds

Symptoms: rapidly __ weakness, (similar to MG), fixed __ __ (due to autonomic dysfunction)

Management: supportive management + botulinum Ig

Answer 20

Botulism

Definition: NMJ disease caused by the neurotoxin of clostridium botulinum→ inhibits ACh release from motor neurons

Etiology: inoculation with clostridium botulinum via ingestion or wounds

Symptoms: rapidly descending weakness, (similar to MG), fixed dilated pupils (due to autonomic dysfunction)

Management: supportive management + botulinum Ig

Question 21

Gowers sign is an indication of:

Answer 21

Ducehenne Muscular Dystrophy: child uses handson legs to push themsevlves from sitting to standing position

Duchenne Muscular Dystrophy (DMD)

Epi: onset <5yo, will continue to gain motor milestones until they reach 7yo then begin to decline

Mechanism: missing structural protein dystrophin→ muscle fiber fragility→ fibre breakdown→ necrosis and regeneration of muscle

Symptoms: abnormal gait (toe walking, tight heel cords), proximal weakness (Gower sign- child uses hands on legs to push themselves from sitting to standing position), cognitive impairment, muscular pseudohypertrophy in calf, scoliosis, cardiomyopathy

Question 22

CK levels in Duchennes Muscular Dystrophy

Answer 22

Investigations:

Genetic testing

CK is >10x normal

Muscle biopsy: necrotic/regenerating fibers, fiber size variability, fatty/fibrous replacement, absence of dystrophin staining

Management: steroids (might be due to reduction of inflammatory response– it does help but it does not slow progression), clinical trials for antisense oligonucleotide therapy (Drisapersen, Eteplirsen)

Prgnosis: in untreated → wheelchair by 12 yo, cardiomyopathy by 18yo, death by 20yo.

Question 23

management of DMD, prognosis–> key systemic complication?

Answer 23

Management: steroids (might be due to reduction of inflammatory response– it does help but it does not slow progression), clinical trials for antisense oligonucleotide therapy (Drisapersen, Eteplirsen)

Prgnosis: in untreated → wheelchair by 12 yo, cardiomyopathy by 18yo, death by 20yo.

Question 24

Compare and contrast Duchenne vs Becker

Answer 24

Becker Muscular Dystrophy

Definition: less severe form of DMD due to less severe mutation

Symptoms: symmetric proximal weakness, calf hypertrophy, preservation of neck flexor strength

Management: no evidence for steroid usage, cardiac transplant in some patients.

Prognosis: wheelchair in 20yo+, cardiomyopathy by 18yo (same as ,duchenne) death by 40yo

Question 25

Myotonic Dystrophy Type I

Definition: an autosomal dominant disease of __ gene

Founder disease in __ __.

Etiology: trinucleotide repeated expansion in DMPK gene, the number of repeats predicts disease onset; indirectly affects chloride channels.

Epi: founders effect in Quebec (1:500 in Saguenay), tends to get worse with each generation– ___ ___

Symptoms: distal + facial weakness, myotonia by age 5 (inability to relax muscles), frontal balding, facial atrophy leading to narrow face, cognitive impairment (10-20%), cataracts, endocrine dysfunction (diabetes, thyroid, hypogonadism), respiratory suppression, hypersomnolence

• Congenital Myotonic Dystrophy (due to very large expansion in mother)

o Before birth: ___ + reduce fetal movements

o After birth: hypotonia, diffuse weakness, resp failure, tented mouth

o Childhood: motor function improves, cognitive + motor delay, __ __, death from __-___ complications in 30s-40s

Investigations: Genetic testing of DMPK expansion size (normal <35; disease >50; congenital >4000)

Answer 25

Myotonic Dystrophy Type I

Definition: an autosomal dominant disease of DMPK gene

Founder disease in french canadians.

Etiology: trinucleotide repeated expansion in DMPK gene, the number of repeats predicts disease onset; indirectly affects chloride channels.

Epi: founders effect in Quebec (1:500 in Saguenay), tends to get worse with each generation– Anticipation Effect

Symptoms: distal + facial weakness, myotonia by age 5 (inability to relax muscles), frontal balding, facial atrophy leading to narrow face, cognitive impairment (10-20%), cataracts, endocrine dysfunction (diabetes, thyroid, hypogonadism), respiratory suppression, hypersomnolence

• Congenital Myotonic Dystrophy (due to very large expansion in mother)

• Before birth: polyhydramnios + reduce fetal movements
• After birth: hypotonia, diffuse weakness, resp failure, tented mouth
• Childhood: motor function improves, cognitive + motor delay, cerebral atrophy, death from cardio-resp complications in 30s-40s

Investigations: Genetic testing of DMPK expansion size (normal <35; disease >50; congenital >4000)

Question 26

Read about: Muscular Disorders-Metabolic/Mitochondrial Myopathy:

Definition: energy insufficiency from the mitochondria→ various syndromes

Etiology: genetic mutation in either mtDNA (point mutation + large scale rearrangements) or nDNA (leading to disordered mtDNA maintenance)

Symptoms: multisystem dysfunction (because all systems require ATP), CNS/muscle commonly affected

• • CNS: ataxia, movement disorder, spascitiy, seizures, migraines
• • MSK: skeletal muscle ocular >proximal> bulbar> distal; cardiomyopathy; dysphagia Investigations:
• • Genetic Testing:
• mtDNA lesions→ heteroplasmic. Large scale rearragnements and point mutations
• nDNA lesions → causing disordered mtDNA maintenance, or mitochondrial dysfunction
• • Muscle biopsy: ragged red fibers (ineffective mitochondiral aggregates), COX negative fibers, respiratory chain enzyme analysis
• • Skin biopsy: respiratory chain enzyme analysis

Question 27

In this condition, the symptoms include derm features (heliotropic periorbital edema, Gottron papules, erythematous rash face/neck/chest with V sign) +/- interstitial lung disease.

Which antibodies are involved?

How is CK affected?

How do you treat it?

Answer 27

Dermatomyositis (idiopathic inflammatory myopathy)

Antibodies: ANti-Mi2; Anti-Jo1

CK: 2-10x normal

Management: high dose steroids to induce remission +/- IVIG

Question 28

myositis symptoms of dermatomyositis + ILD + associated connective tissue disease (scleroderma, Sjorgen, lupus) +/- cardiomyopathy/arrythmias

this condition?

Answer 28

Polymyositis (idiopathic inflammatory myopathy)

Investigations:

• Clinical symptoms: non-specific
• Antibodies: anti-Jo1
• Muscle biopsy: endomysial inflammation with CD8 T-cell Management: high dose steroids to induce remission +/- IVIg