Mehmet Ali Akalın V.ENG

Neuromuscular diseases (I)

Muscle and neuromuscular junction

Neuromuscular Diseases

• Group of miscellaneous diseases • Many are hereditary, some are not • Some are chronic, others progress very

rapidly

• Many share similar symptoms

Disorders of the Motor Unit (Classification of Neuromuscular Diseases)

• Motor neuron disease • Neuromuscular junction disease • Muscle disease • Peripheral nerve disorders

Motor Neuron Disease Diseases that can involve

1) Betz cells of the motor cortex, 2) the lower CN motor nuclei, 3) the CST, 4) and/or the anterior horn cells

– Amyotrophic Lateral Sclerosis (ALS) – Progressive bulbar palsy – Progressive muscular atrophy, spinal muscular

atrophy – Primary lateral sclerosis

ALS • Loss of motor neurons in the cortex,

brainstem and spinal cord • Mix of upper motor neuron and lower

motor neuron findings – Weakness, atrophy, fasciculations – Slurred speech, difficulty swallowing,

shortness of breath • Can start in any extremity or the bulbar

musculature • Relentlessly progressive

ALS

• 50 % dead in 3 years, 80% dead in 5 years, 5-10% live more than 10 years

• Death usually from respiratory failure • Etiology still only theoretical

– Excess glutamate – Oxidative stress – Free radicals – Mitochondrial dysfunction

• There is no therapy to date

Myopathies MUSCLE DISEASE

Largest group of neuromuscular diseases • Most diverse group • All show a loss of muscle fibers – Proximal

more than distal • No involvement of the anterior horn cell,

nerve axon, or neuromuscular junction

Subcategories

1. Muscular dystrophy 2. Endocrine disorders 3. Metabolic disorders 4. Myotonias 5. Periodic paralysis 6. Polymyositis

Endocrine Myopathies • Caused by some malfunction of the

endocrine system • Chronic • Respond to drug therapy (primarily

hormonal therapy) • Examples: –Addison’s Disease

–Cushing’s Syndrome (Steroid myopathy) – Thyrotoxic Myopathy

Metabolic Myopathies Myopathies characterized by a deficiency of a specific

enzyme resulting in muscle weakness Examples: • McArdle’s Disease

– Deficiency of the muscle enzyme myophosphorylase – Glycogen is thus stored in the muscles rather than being

used as a source of energy • Pompe’s Disease

– deficiency in acid maltase – Excess storage of glycogen in many different organs

Case • A 23-year-old man… • was found to have difficulty relaxing after

grasping since teenage.. • he has boldness and a thin neck.. • his school performance was poor.. • routine check-up showed cataract and diabetes.. • currently he also has problems with opening

eyes and swallowing.. • his mother shares the same disease.. • we heard dive-bomber sound on EMG

Myotonias • Characterized by: – Inability to relax a previously contracted muscle • Elicited by either voluntary contractions or some

external stimuli such as percussion • Worsened by cold • Lessened by light exercise • Examples: – Myotonic Congenita (Thomsen’s Disease) – Myotonia Atrophica (Myotonic dystrophy)

• Myotonic Congenita (Thomsen’s Disease)

– Children develop a characteristic hypertrophy of the:

• Neck • Deltoid • Biceps • Triceps • Quadriceps, and • Gastrocnemius muscles – Child appears to be a “Tiny Hercules”

Myotonic Dystrophy (Steinert’s Disease) – Most frequent neuromuscular disease although it is

relatively rare – It is a multisystem disease with major cardiac

involvement • Core features of myotonic dystrophy are • myotonia, • muscle weakness,

– involvement of the more distal muscles such as: – face – neck

– Tongue – Intrinsics of hands and feet

• cataract, and • cardiac conduction abnormalities Frontal baldness

Myotonic dystrophy (dystrophia myotonica, DM )

• The most frequently inherited neuromuscular disease of adult life

• It is a multisystem disease with major cardiac involvement

• Core features of myotonic dystrophy are myotonia, muscle weakness, cataract, and cardiac conduction abnormalities

Periodic Paralysis

• Relatively rare myopathy • Hereditary – Autosomal dominant • Characterized by: – Transient flaccid paralysis or paresis affecting

primarily the muscle of the proximal limbs – Attacks of weakness may last from a few

seconds to several weeks

Primary Periodic Paralyses

Sodium channel

Hyperkalemic PP Paramyotonia congenita Potassium-aggravated myotonias

Calcium channel Hypokalemic PP Potassium channel Andersen-Tawil syndrome

Hyperkalemic PP or hypokalemic PP*

* Hypokalemic periodic paralysis • where potassium leaks into the muscle

cells from the bloodstream.

* Hyperkalemic periodic paralysis • where potassium leaks out of the cells into

the bloodstream.

Hyperkalemic Form – Has increased serum K+ – Triggered by: • Stress • Fasting • Cold • Rest following intensive or prolonged muscular

exercise – Attacks minimized by: • Light exercise • Ingestion of carbohydrates

Hypokalemic Form – Has decreased serum K+ – Affects men more than women – Triggered by: • Stress • Fasting • Cold • Rest following intensive or prolonged muscular

exercise • Alcohol consumption • High carbohydrate diets

Polymyositis • Second most common myopathy in adults • Chronic inflammatory condition of muscle • If skin is involved >>>>>(Dermatomyositis) • Insidious onset, Moderately progressive • Clinical signs:

– Muscle weakness Flexors more than extensors

– Fatigue – – Difficulty swallowing – Joint pain – Mild fever – Weight loss – Very diffuse erythema of face and neck

Polymyositis • Presents with proximal muscle weakness

in 92% • Myalgias in 25% • Slightly increased risk of cancer

– Bladder, lung, lymphoma • Biopsy of muscle confirms diagnosis • Treatment with immunosuppression

– Prednisone – Methotrexate

Muscular Dystrophy

• Largest group of the myopathies • Group of inherited diseases • Characterized by: – Progressive muscle weakness • Examples: – Pseudohypertrophic Muscular Dystrophy

(Duchenne’s) – Becker-type Muscular Dystrophy – Facioscapulohumeral Muscular Dystrophy – Limb-girdle Muscular Dystrophy

Muscular Dystrophy Duchenne/

Becker Emery-Dreifuss,

Congenital Limb-Girdle,

Distal Myopathy Onset 2-6 years Childhood to early

teens, infancy Late childhood-middle

age

Muscle groups affected

Life expectancy Rarely beyond 20’s varies Middle age +

Inheritance X-linked recessive X-linked recessive, autosomal dom & rec.

Autosomal dominant & recessive

Genetic linkage Dystrophin Emerin, lamin, merosin, etc.

Calpain-3, Dysferlin, Caveolin-3, αβδγ-sargoglycans, etc.

Source: www.mdausa.org

Dystrophin connects the myofibrils to a complex of proteins in the muscle cell membrane. This in turn connects to the extracellular matrix protein laminin, stabilizing the membrane

Case

• A school boy , aged 10 yr…with • delayed development of walking since

childhood.. • and frequent falls.. • NE showed..

– proximal muscle weakness, waddling gait..toe walking..

– Gower’s sign..lordosis.. – enlarged and stiff calves..

• mental retardation seems obvious.

Duchenne's dystrophy (DMD) History and epidemiology

• Described in 1852.

• The most common X-linked, lethal disease.

• Occurs in 1: 3,500 male newborns.

Clinical features Skeletal muscle involvement • Onset usually between ages 3 and 5 years. • Proximal muscles and neck flexor muscles

(severely) are affected early. • Difficulty doing a sit-up. • Calf hypertrophy (pseudohypertrophy). • Contractures of heel cords and iliotibial bands. • Scoliosis • Cardiomyopathy (can be asymptomatic)

• Waddling gait with increased lumbar lordosis.

• Difficulty rising from floor; Gower's sign.

• Proximal leg muscles are the most severely affected by weakness and wasting. Proximal arm muscles are the next most severely affected.

Gower's sign

• Cranial nerve supplied muscles are relatively spared.

• Between ages 3 and 6 the child's function may improve due to growth and the normal increase in strength, which more than offset the loss of function.

• Usually unable to walk by age 10 to 12. • Scoliosis develops following wheelchair-

dependency. • Death by age 20 in most without a ventilator • Steroids may delay time until wheelchair

bound

Cardiac involvement

• The heart develops fibrosis, mainly in the posterobasal part of the left ventricular wall.

• Congestive heart failure and cardiac arrhythmias occur in later stages.

• Congestive heart failure may develop in some patients who have adequate respiratory muscle function.

Smooth muscle of GI tract

• Acute gastric dilatation can cause episodic vomiting, abdominal pain, and gastric distension.

• May be mistaken for intestinal obstruction.

CNS involvement

• The average IQ of DMD patients is one standard deviation below the normal mean.

• The intellectual impairment is not progressive.

• Verbal IQ is affected more than performance IQ.

Case A young man,aged 20 years … was found to have problems with walking since age 12 years.. right now …he has waddling gait.. CK level was as high as 20 times normal..

EMG.. myopathic patterns.. Dystrophin stain showed a defective pattern

Becker's dystrophy Clinical features • Onset is usually between age 5 and 15

years. Sometimes, onset is much later. • • By definition, Becker patients walk past

the age of 15.

• Life expectancy is generally reduced.

Other phenotypes • Exertional cramps and myalgia. • Myoglobinuria. • Quadriceps myopathy.

Intermediate forms (outliers) • Recognized clinically as early as 3

years. • Preservation of anti-gravity strength in

neck flexor muscles. • Stair-climbing and walking to age 12 to

15.

• A 21-year-old young man …with.. • marked contractures of arms and • legs..his spine was rigid..he had • weakness of biceps and peroneal • muscles..he underwent pacemaker • implantation because of heart block

Emery-Dreifuss Muscular Dystrophy

• Genetics ... • X-linked recessive ( X q 28 ) • emerin defect • Features … • humeroperoneal weakness plus .. • early contractures , rigid spine • and heart block

Case

• A 19-year-old male … complaining of • progressive worsening of left arm for • a couple of years..his left arm shows • a Popeye appearance..in addition.. • he has difficulty blowing..slight ptosis.. • otherwise..he remains quite healthy

Facioscapulohumeral Muscular Dystrophy (FSH)

• Genetics AD , chromosome 4 • Features … • onset since adolescence • slowly progressive , life span unaffected • assymmetric weakness and wasting • of face,serratus anterior muscle ,biceps

muscles,etc. with deltoid spared … Popeye appearance

• CK : slightly elevated • EMG : myopathic patterns • Biopsy : myopathic patterns

Case

• A 52-year-old female …complaining • of progressive worsening of weakness • and wasting of both legs during the • past 6 years..recently she noticed • slight weakness in both arms too.. • N.E. showed weakness and atrophy • of leg and shoulder girdles...

Limb Girdle Muscular Dystrophy

• Genetics … • heterogenous pathogenesis • Features … • proximal weakness • legs early than arms • face and eye spared • knee jerk diminished early than • ankle jerk

Muscular Dystrophy Duchenne/

Becker Emery-Dreifuss,

Congenital Limb-Girdle,

Distal Myopathy Onset 2-6 years Childhood to early

teens, infancy Late childhood-

middle age Muscle groups

affected

Life expectancy

Rarely beyond 20’s

varies Middle age +

Inheritance X-linked recessive

X-linked recessive, autosomal dom &

rec.

Autosomal dominant & recessive

Genetic linkage

Dystrophin Emerin, lamin, merosin, etc.

Calpain-3, Dysferlin, Caveolin-3, αβδγ-sargoglycans, etc. Source: www.mdausa.org

Evaluation of the Patient with Suspected Muscle Disease

• Lab – Muscle enzymes (CPK, aldolase) – Erythrocyte sedimentation rate (ESR or

sed rate) if suspect inflammatory disease – Genetic test

• Duchenne’s • Myotonic dystrophy

• EMG/NCS • Muscle biopsy

• May provide a definitive diagnosis

Case for quiz

• A 49-year-old mother was examined • on the visit…she was found to have • lid ptosis, difficulty swallowing and • slight weakness in finger flexors and foot

drop.. • she also has diabetes and cataract.. • one of her sons shares the same illness...

Myasthenia Gravis • An autoimmune disease of the neuromuscular junction

caused by autoantibody directed at nicotinic acetylcholine receptors

• Can be seen at any age, rare before 10 • Usual Onset : female(20-30 years), male(50-60 years) • F/M = 6/4 • Old/Young = F/M

Model of normal neuromuscular junction. Nerve action potential invades the nerve terminal, resulting in enhanced release of acetylcholine.

Model of normal neuromuscular junction on left compared with myasthenia neuromuscular junction on the right.

Onset

Presenting symptoms – Ocular (50%): Ptosis; Diplopia – Weakness (35%): Bulbar; Legs; Arms – Fatigue (10%) – Respiratory failure: Rare

Progression: Generally insidious over weeks to months

Classification after Osserman & Genkins 1. Adult MG

– Group I: Ocular (20%) – Group IIA: Mild generalized (30%) – Group III: Acute fulminating (11%), rapid

onset, early respiratory involvement, high mortality.

– Group IV: Late Severe (9%), > 2 years after onset.

2. Transient Neonatal MG: 1/6 born to MG mother. Last a few weeks.

3. Congenital Myasthenic Syndrome

Symptoms & Signs 1- Weakness • Variable:

• increses through the day or • with prolonged physical activity

• Onset: • Diplopia or ptosis 2° to extraocular muscle or levator

palpebrae weakness

• Most patients develop weakness in other muscles

• Weakness remains limited to ocular muscles during entire course of the illness >>>Ocular myasthenia

A- Ocular weakness • Ptosis & Ophthalmoplegia • Usually asymmetric & bilateral • Pupils: Normal • Rule out focal neural lesions

III or VI nerve lesion; Internuclear ophthalmoplegia Especially when unilateral signs

B - Facial vweakness : > 95%

C- Bulbar weakness Symptoms: Dysarthria, Dysphagia, Weak mastication Signs:

– Poor gag reflex & palate elevation; – Weak tongue – May result in aspiration pneumonia

Considered life-threatening – Usually an indication for rapidly-acting therapeutic

intervention – Plasma exchange most commonly used

D- Respiratory muscle weakness

Usually due to Diaphragmatic and Intercostal muscle weakness

•Strong indication for rapidly-acting therapeutic intervention •Pyridostigmine & Plasma exchange most commonly used

May be due to vocal cord paralysis1 •Vocal cords in adductor position: Produces stridor •May require intubation Considered life-threatening

E- Systemic muscle weakness

Typical: Proximal > Distal; Arms > Legs; Symmetric

• Weakness in selective areas • Posterior neck (head ptosis) • Triceps • Quadriceps • Occasionally: Distal musculature

• 3- Fatigue – Induced by repetitive muscle strength testing or

prolonged tonic contraction – Quantitation: Timed upward gaze; Forward arm

abduction • 4- Muscle wasting: Uncommon, except

when MG is chronic & untreated • 5- Deep tendon reflexes: Usually preserved;

May be somewhat brisk in clinically weak muscles

• 6- Sensory: Normal

Other Symptoms & Signs

Testing

• Anti-acetylcholine receptor Ab: – Present in 80% of patient

Tindall: – Ocular 55% positive – Mild Generalized 80% positive – Moderately severe or acute 100% positive – Chronic severe 89% – In remission 24%

Antibodies to striated muscle (StrAb)

• Positive in 30% of all adult onset MG. • Highly associated with thymoma

– Positive in 80% of MG patients with thymoma – Positive in 24% of patients with thymoma

without MG. – Seronegativity does not exclude thymoma. – Most useful as a marker of thymoma in

patients with MG onset before age 40. – A progressive rise in StrAbs titer after

resection of thymoma is a good indicator of tumor recurrence.

Thymoma

• 15% of patient has thymoma, 50% has thymic hyperplasia.

• Antiskeletal muscle Ab are detected in 90% of patients with thymoma.

• CT Chest detect over 85% of thymoma. • Removal of thymoma produces a delayed

improvement of MG 6 - 24 months later. Sustained improvement in > 50%, probably less in older patients. No known long-term side effects.

Tensilon test (Edrophonium) Given in incremental doses. Start with 2 mg, observe the

response for 45 to 60 seconds, followed by doses of 3 and 5 mg and observation for a clinical response for 1 to 2 minutes following each dose.

During the injection, patients often experience 1 to 3 minutes of increased salivation, mild sweating, perioral fasciculations and mild nausea.

Hypotension and bradycardia are extremely rare but

precautions should be taken. Atropine sulfate (0.6 mg intramuscular or intravenously) should be available in case of an emergency.

Tensilon test cont’d

• Positive means unequivocally improvement of weakness. • Slight to moderate improvement in muscle strength

must be interpreted with extreme caution. • Mild to moderate clinical improvement after tensilon

has been reported in: – brain stem lesions, – oculomotor palsy due to cerebral artey aneurysm, – diabetic abducens paresis and – even in normal control subjects.

Electrophysiology 1. Repetitive stimulation at 3 hertz.

>10% decrement of compound action potential.

2. Single fiber EMG: Increased jitter: jitter is the varying time interval between the triggered muscle action potential in 2 muscle fibers within the same motor unit.

• Positive in over 90%.

Principles of treatment

• Onset before age 60 – Thymectomy, pretreat with

plasmapheresis, cholinesterase inhibitors – If response unsatisfactory before or after

thymectomy, consider high dose daily prednisone and/or other immunosuppressive agents

Principles of treatment

• Onset after age 60 – Cholinesterase inhibitors with prednisone,

azathioprine or other immunosuppressant – Plasmapheresis for severe exacerbations – Consider thymectomy

Principles of treatment • Anticholinesterase useful in all forms • For patient with thymoma, thymectomy is

indicated in all ages. They may spread in the mediastinum.

• Plasmapharesis is effective, but practical only on a short term basis.

Pyridostigmine (Mestinon)

Tab: 60 mg, – half life 4 hrs, – take 1 q 4 while awake

– Side effect:

– diarrhea, – fasciculation, – hypersecretion

» treat with Lomotil or Motilium

Steroid treatment • Indications:

– Insufficient control with Mestinon – Diplopia rarely respond to Mestinon alone – Older male

• Start at 100 mg to avoid treatment failure.

After remission obtained, switch to alternate day dose, slow taper over 6 to 12 months. Patient may get weaker initially.

• Exacerbation is common.

Azathioprine (Imuran) – Initial dose 2-3 mg/kg/day.

• Complete remission 40%, • partial remission 51%, • minimal improvement 6.4%, • no effect in 2.6%.

• Improvement begins in 2-3 months, peaks in 6-15 months.

• Keep WBC above 3000/ml. • Monitor liver function weekly X 3 months,

then 2x/month. • Sometimes used in combination with

steroid.

If treatment fails, consider 1. Cyclosporine (Sandimmune)

– 5 mg/kg/day, in bid dose. Monitor BP, renal function, Cyclosporine level, Amylase, Cholesterol.

– May cause nephropathy, hypertension, hirsutism, liver function abnormality, opportunistic infection, may increase risk of malignancy.

2. Plasma Exchange: short term improvement

3. Human Immune Globulin: Effective but short term improvement

Drugs that may adversely affect MG 1. Antibiotics

– Aminoglycosides: Neomycin, Gentamycin – Peptide: Polymyxin B, Colistin – Other: tetracycline, Clindamycin,

Erythromycin, Ampicillin 2. Neuromuscular blockers:

– Botulinum Toxin 3. Cardiac drugs:

– Quinine, Quinidine, Procanamide, Lidocaine, Beta blockers, Calcium Channel Blockers

Drugs that may adversely affect MG cont’d

4. Miscellaneous: – Epdantion, Oxytocin, Lithium,

Magnesium, Diazapam, D penicillamine, Cloroquine, Interferon

5. Corticosteroids may initially produce worsening of MG.

Other causes of exacerbation

• Febrile illness • Thyroid disease • Heat • Pregnancy • Major Physical Stress