Miasthenia gravis

The Anatomy of the Neuromuscular Junction

Motor neurone terminates as a bouton or pre-synaptic nerve terminal separated from the muscle by a thin synaptic cleft (Motor endplate)

The blood nerve barrier is relatively deficient at the NMJ (neuromuscular junction)

Nerve and muscle are kept in close proximity by bridging protein (laminin), with release zones and the crests of post synaptic folds aligned

The skeletal neuromuscular junction is the most studied and best understood synapse

Healthy Neuromuscular Junction

The Physiology of Neuromuscular transmission

Neuronal Action potential invades the pre-synaptic nerve terminal

Depolarisation triggers opening of VGCCs (voltage gate calcium channels)

Calcium influx triggers quantal release of ACh (acetil-choline)

ACh binds to post synaptic nAChRs (acetil choline receptor)

Ca and Na ions influx through nAChR triggering muscle membrane depolarisation via VGSCs- CMAP and muscle contraction (voltage gate sodium channels - compund muscle action potential )

Spontaneous and Nerve Evoked Endplate Responses

Myasthenia Gravis (MG)

MG is the most common disorder of neuromuscular transmission

Incidence 2-6 per 106 , prevalence 40 per 106 population MG is an acquired autoimmune disease characterised by

the formation of anti- nAChR antibodies MG is common in young women, and older men MG is characterized by fluctuating and fatigable weakness Weakness may be limited to a few muscles, such as the

extraocular muscles, bulbar, limb or be generalised in fashion

As the weakness is often worse with activity and improved

by rest, it is often worse in the evening

Myasthenia Gravis (MG)

Ocular features: ptosis, diplopia, ophthalmoplegia

Facial weakness esp ob oculi and oris (snarl)

Bulbar weakness: nasal speech, reduced gag, swallowing problems, aspiration (silent), weak neck (dropped)

Limb weakness: proximal, fatiguable Reflexes: normal Respiratory weakness: diaphragm and

intercostal Fatigue (palpebral ptosis) in MG

Myasthenia Gravis (MG)

MG is a defect of neuromuscular transmission with reduced efficacy of Acetyl Choline at the

post synaptic motor endplate due to pathogenic antibodies which

Block the nAChR, Down regulate the nAChR & cause complement dependent destruction

of the motor endplate

Myasthenia Gravis (MG)

The immunopathogenesis of MG is unclear but involves

Genetic factors (HLA B8) Thymus

Vast majority of young onset cases are autoimmune and associated with thymic hyperplasia

Around 10% of patients with MG, often older patients) have an associated thymic tumour (oft striated muscle Abs)

Seronegative (10% gen, 50% OMG) Neonatal MG

Myasthenia Gravis (MG) Diagnosis

Typical clinical picture Detection of anti-AChR

antibodies in serum (90%) Positive Tensilon test

(atropine) Repeptitive nerve

stimulation at low frequency leads to a decrement in compound muscle action potential amplitude

Tensilon test – before and after

Single fiber EMG – normal

Single fiber EMG – increased jitter

Repetitive Nerve Stimulation (Supramaximal

2Hz)

Myasthenia Gravis (MG)

Treatment Symptomatic (pyridostigmine often with

propantheline) Thymectomy

Hyperplasia (trans-sternal approach), Thymoma (locally invasive)

Immunotherapy steroids, and other agents including Azathioprine plasma exchange, IVIG

Lambert Eaton Myasthenic syndrome (LEMS)

A defect of neuromuscular transmission with reduced quantal release of Acetyl Choline from the presynaptic nerve terminal

Pathogenic antibodies directed against voltage gated calcium channels (VGCCS) expressed at the NMJ and autonomic ganglia

2/3 patients with LEMS have cancer, most commonly Small cell lung Ca (express VGCCs)

Lambert Eaton Myasthenic syndrome (LEMS)

Clinical features Dry mouth Fatigable weakness of proximal muscles

(like MG) Wasting of proximal muscles Depressed reflexes Ocular and bulbar weakness rare

Lambert Eaton Myasthenic syndrome (LEMS)

Diagnosis Typical clinical picture Detection of anti-VGCC antibodies in serum Positive Tensilon test (like MG) Repeptitive nerve stimulation at low frequency

leads to a decrement in compound muscle action potential amplitude (like MG)

Repeptitive nerve stimulation at high frequency leads to a increment in compound muscle action potential amplitude (X MG)

Repetitive Nerve Stimulation (Supramaximal

2Hz)

Lambert Eaton Myasthenic syndrome (LEMS)

Treatment Treating the underlying lung tumour

improves LEMS Treatment for LEMS per se

Symptomatic (mestinon, 3-4 DAP) Immunotherapy (steroids, plasma exchange,

IVIG)

POLYMYOSITISDERMATOMYOSITIS

CLASSIFICATION OF POLYMYOSITIS (PM) –

DERMATOMYOSITIS (DM)

Group I: Primary Idiopathic PM Group II: Primary Idiopathic DM Group III: DM or PM associated with

neoplasia Group IV: Childhood DM or PM associated

with vasculitis Group V: PM or DM with associated with

collagen diseases

POLYMYOSITIS - DERMATOMYOSITIS

Onset age: Usually > 20 years Progression: weeks-months Possibly preceded by upper tract infection Other possible trigger factors:

Anti hepatitis B vaccination Growth hormone administration Drugs: penicilamine Viral infections: Coxsackie B; Parvovirus; Echovirus HLA

Class II: antigens DQα1*0501 (88%) For DM: DMA*0103 si DMB*0102

Clinical Picture

Muscle weakness Proximal > Distal Symmetric Frequently starts at lower limbs Selective regions of weakness:

eophagus (dysphagia); Posterior neck; Quadriceps

Usually does not affect oculomotor muscles

Amiotrophies occur late in the evolution

Reflexes usually normal

Motor deficit

Most often proximal Distal: inclusion body myositis Lack of simmetry: inclusion body myositis cvadriceps: inclusion body myositis; PM with

mitochondrial diseases Extraocular muscles: extraoculary myositis Swallowing : inclusion myositis, granulomatous

myositis, scleroderma associated myositis Episodic: episodic miopathy with pipestem

capilaries Acute: infectious;

Skin lesions (DM) Heliotrope rash - reddish

violaceous eruption on upper eyelids +/- oedema

Diffuse/localised erythema over chest, neck, or over forehead, chin, malar area

Gottron’s sign - symmetric violaceous erythematous eruption over knuckles

Necrosis

Gottron sign

Pain

Pain 30%; Especially with associated connective tissue

disease Rule out: Polymyalgia; Arthritis; Fasciitis;

Rhabdomyolysis Muscle pain

Associated with contraction, muscle mass compression or spontaneous pain

Joint pain Arthrites or nondestructive arthralgia Anti-Jo1 or AntiARNt synthethasys antibody syndromes

Associated disorders Cardiac: Arhythmias; Inflammatory cardiomyopathy Pulmonary: Respiratory muscle weakess; Interstitial

lung disease Esophageal paresis: Upper 1/3 with muscle

weakness, Lower 2/3 with scleroderma Abdominal pain:

Gastro-intestinal mucosal involvement Marked by ulceration, hemorrhages & perforation Due to associated vasculopathy

Malignancy: Mild increased risk Autoimmune:Lupus, Sjoegren's, Anti-phospholipid

antibodies & syndrome: 5% to 8% Thyrotoxicosis: Rare

High CK: CK in hyperthyroid is usually low May resolve with anti-thyroid medication alone

Calcinosis (formation of calcium deposits in any soft tissue) in 1/3 of cases

Clinical forms (evolutive)

Acute: Important motor deficit, fast prograssion,

muscle pain, fever, inflamation signs, myoglobinuria

Possible death within weeks due to reapiratory destress, heart failure, kidney feilure

Subacute Cronic Focal forms – rare; sometimes evoluate

towards difuse type

Laboratory

Serum CK: High (3 to 30 times normal); elevated LDH, aldolase, AST, ALT

General inflamation signs (CRP) EMG: Irritative myopathy

Small amplitude, brief, polyphasic motor units

Fibrillations; Positive sharp waves spontaneous high frequency discharges

Antibodies: Disease specific & non-specific

EMG aspects

Long duration positive sharp waves: Initial positive deflaction followed by a negative component

Fibrilation: Short duration potentials (arrows) with positive and then negative component

Polyphasic action potentials with small amplitude, short duration

Muscle biopsy

Myopathic Variation in size of muscle

fibers Necrosis + phagocytosis &

regeneration of muscle fibers Mild, patchy increase in

endomysial connective tissue Inflammation

Endomysial & perivascular inflammatory (mononuclear) cells

Macrophages & CD8+ T-cells Focal invasion of non-necrotic

muscle fibers

Muscle fiber necrosis

MAC (complement) deposits at the surface of the muscle fibers

Differential diagnosis

Myasthenia Gravis Electrolyte disturbances Metabolic, endocrine or toxic

myopathies Muscular dystrophy Guillain-Barre Syndrome

Tratament

Corticosteroids Good response to treatment if:

Clinical picture: proximal or diffuse motor deficit, disease duration <1 year; association with mialgia, cutaneous rash, connective tissue diseases

Lab: very high serum CPK, anti Jo-1antibodies Biopsy: perimisial inflammation, perifascicular atrophy, necrosis

and regeneration Poor response to therapy if:

Focal or asymetric motor deficit; acute or very slow form of evolution; family history

Lab: normal or low seric CK Biopsy: focal invasion of muscle fibers by inflammatory cells;

Prednisone 1-2mg/kg/day, tapered after strength improves and CK declines, often after 1-3 months.

TREATMENT

Cytotoxic agents introduced if severe disease, relapsing disease,

inadequate steroid response or steroid induced cx’s.

Azathioprina or methotrexate used with steroids

Cyclosporin, cyclophosphamide, tacrolimus and antiTNF are alternatives.

Intravenous immunoglobulin successful Child DM, esophageal dysfunction 1gram/kg/day

Muscular Dystrophy

What is Muscular Dystrophy?

(MD) Muscular Dystrophy: group of genetic disorders

that are characterized by progressive loss of muscle integrity, wasting, and weakness. Characterized by degeneration and regeneration of muscle fibers (in contrast with static or structural myopathies)

History and Physical Exam in the Newborn and Office

History Newborn – floppy infant, term or

preterm, poor head control, poor feeding, prolonged labor, maternal complications

Childhood development – delay in sitting, standing, walking, toe walking, difficulty stair climbing or running

Teen or adult – difficulty in self-care, swallowing, athletic/endurance activity

Family History Include enough of family tree to pick

up autosomal recessive disorders and X-linked or AD (autosomal dominant) disorders with variable penetrance

Many x-linked or AD represent new mutations

Past diagnoses in older family members may not be accurate

Review of Systems School functioning/cognitive

development Cardiac function/arrhythmias/syncope Respiratory

Physical exam findings Muscle mass: signs of wasting or

hypertrophy/pseudohypertrophy Muscle strength: power – generation of

force against resistance or gravity Observe reaching, getting up from floor Observe trunk and head/neck control Test specific proximal groups – position so

against gravity Tone: resistance to passive movement

Note hyper vs. hypotonia in weak areas Deep tendon reflexes: normal or

decreased Normal sensation: remember

proprioception Joint contracture: reduced passive range

of motion not due to tone

Dystrophinopathy: disorders involving dystrophin

Duchenne MD and Becker MD are the muscular disorders – the two most common and severe dystrophies

Dystrophin is a very large gene on the X-chromosome, ubiquitous in the human body

Dystrophin-Associated Protein (DAP) Complex – composed of the extracellular, transmembrane, and intracellular components

General Diagnostic Testing

Creatine kinase : Aids in narrowing the differential

diagnosis if greatly elevated (50 times normal)

Increased in Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, polymyositis, and rhabdomyolysis

Nonspecific if mildly elevated 2-3x normal

Lower late in MD course due to severely reduced muscle mass

Not helpful for carrier detection

Muscle biopsy Dystrophic changes include necrosis,

degeneration, regeneration, fibrosis and fatty infiltration, sometimes mild inflammation

Specific diseases may have inflammation, intracellular vacuoles, rods, and other inclusions on biopsy

Biochemical muscle protein analysis Useful for specific identified protein that

is missing and many specific mutations may cause the same deficiency

Immunohistochemical protein staining Western blot – quantitates percent of

normal protein present

Genetic analysis PCR for specific known defects Southern blot for nucleotide repeats

Electromyography Useful if diagnosis not clear (biopsy

has mixed features) Differentiates neuropathic vs.

myopathic Characteristic myotonic discharges in

adults with myotonia – “dive bomber” sound

Perform after the CK

Duchenne Muscular Dystrophy

Presentation: 3-5 y/o with pseudohypertrophy of calf muscles, frequent falls, slow running, and waddling gait

Prevalence of 1:3500 Other organs affected

Heart – cardiomyopathy Respiratory Intellect - 30 % with impairment IQ <75

Testing Immunostaining with absence of dystrophin PCR testing available for common mutations

(X21.2)

Becker Muscular Dystrophy

Slowly progressive form with same gene affected as Duchenne MD

Muscle biopsy immunostaining for dystrophin with patchy staining

Disorder of function or decreased amount of dystrophin rather than absence of the protein

Congenital Muscular Dystrophy

Presentation: neonatal onset of severe weakness, delayed motor milestones, contractures

Merosin negative/CMD A1 White matter hypodensities on brain

scan but normal mental capacity Diagnosis by muscle biopsy

immunohistochemistry showing loss of α2-laminin (AR-chromosome 6q22-23)

FascioScapularHumeral Muscular Dystrophy

Presentation: Facial weakness with trouble

blowing up a balloon, sipping through a straw, whistling, trouble closing the eyes at night, scapular winging that may be asymmetric, pain

May have absence of pectoralis, biceps, or brachioradialis

Also affected: mild high pitched hearing loss, retinal abnormalities, mental retardation in early onset

Genetics/Testing Southern blot testing available

(chromosome 4q35) for decrease in repeats normally present

Muscle biopsy may show lymphocytic infiltrates

Limb Girdle Muscular Dystrophy

Presentation: variable age of onset with weakness and wasting of the limb-girdle

May have calf hypertrophy, involvement of scapular muscle and deltoid in sarcoglycanopathies

Many types involve dysfunctional sarcoglycans – transmembrane proteins of the DAP that interact with cytoplasmic proteins

Table 2 – types of LGMD

Oculopharyngeal Muscular Dystrophy

Presentation: mid-adult with ptosis, facial muscle weakness with difficulty swallowing, proximal muscle weakness, may have extraocular muscle weakness, more common in French-Canadian and Hispanic population

Genetics Muscle biopsy shows filamentous nuclear

inclusions and ubiquitin containing vacuoles

Affects poly A binding protein 2 (PABP2) by expansion of a GCG repeat without anticipation seen – Southern blot (chromosome 14q11-13)

Emery-Dreifuss Muscular Dystrophy

Scapuloperoneal MD Presentation: stiff joints, shoulder and

upper arm weakness, calf weakness, cardiac conduction defects and arrhythmias, contractures

Genetics X-linked type affects emerin

Diagnose by protein analysis of leukocytes or skin fibroblasts

DNA testing available (chromosome Xq28) AD affects lamin A or lamin C (chromosome

1q21) Nuclear membrane proteins

Myopathies

Central core disease: Ryanodine receptor, Ca channel that mediates

excitation/contraction coupling, (AD – chromosome 19q13)

Associated with Malignant Hyperthermia Myotubular myopathy

Myotubularin, important in myogenesis (Xq28) Nemaline Myopathy

Caused by many defects, disorder of thin filaments Rod-like stuctures on muscle biopsy

Inflammatory Juvenile Dermatomyositis Inclusion Body Myositis (usually distal) Adult Polymyositis (associated with malignancy)

Myotonic Muscular Dystrophy or Steinert’s disease

Presentation – adult with multiple systems affected

Primarily distal and facial weakness Facial features: frontal balding in men,

ptosis, low-set ears, hatchet jaw, dysarthria, swan neck, ^ shaped upper lip

Myotonia: worse in cold weather, after age 20

Heart: conduction block – evaluate syncope

Smooth muscle: constipation, care with swallowing, gallstones, problems with childbirth, BP lability

Brain: learning disabilities, increased sleep requirement

Ophthalmology: cataracts Endocrine: insulin resistance,

hypothyroidism, testicular atrophy

Thomsen’s miotonia

Genetics: Mothers can have adult or congenital onset

offspring; fathers can have adult onset offspring

Parents may not be aware of own diagnosis Myotonin gene is affected as well as adjacent

transcription factor gene SIX 5 by CTG repeat in noncoding region of chromosome 19q13.3, and anticipation seen with increased repeats

Muscle biopsy with internalized nuclei, type 1 fiber atrophy, ring fibers, and sarcoplasmic masses

Congenital: severe form, initial respiratory distress after birth with ventilatory requirement or apnea, feeding difficulty, mental retardation, club feet, scoliosis, strabismus

Treatment - Medications Steroids

Briefly increase strength, slow progression in dystrophinopathy for walking, arm use, and respiratory function

Weekend or 15-20/month as well as prednisolone/deflazacort may minimize SE

Dilantin and Tegretol raise the repolarization threshold and improve myotonia

Methylphenidate improves daytime somnolence in DM

Albuterol may help in FSH MD Creatine and glutamine may help delay

progression/improve energy in youngest with DMD

Treatment – future therapies

Genetic therapies Repairing the mutated sequences

Using cell’s own repair mechanisms but adding template

Gentamicin trial for relaxation in stop codon recognition for DMD has not worked

Replacing the mutated sequences Inserting truncated genes or whole gene with vector

Upregulation of similar functioning proteins Utrophin in DMD

Therapy

Contracture prevention Stretching exercises and postural

changing Stretch the most contracture prone

groups (gastrocnemius, hip flexors, iliotibial bands, hamstrings)

AFO at night to supplement (ankle foot orthosis)

Strengthening/conditioning/endurance Goal is to maintain or improve muscle

strength and maximize functional ability – slight improvement is possible

Additional goal is to avoid muscular damage by overwork or injury

No eccentric contraction or delayed soreness

Voluntary active exercise such as swimming/hydrotherapy or cycling in ambulatory children currently recommended

Mobility aids Walking orthoses – KAFO (knee ankle foot

orthosis) Standing frames, standing wheelchairs,

swivel walker occasionally used Walkers where arm strength less affected Transfer board Wheelchair – power needed for independence Plan for indoor lift, van with lift, roll in shower

Improving daily activities of daily living Physical and Occupational Therapy – teaching

modified techniques Antigravity orthoses are being developed to

assist in daily living activities Splinting and therapy to prevent hand

contractures

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Surgery note the risk inherent to surgery –

malignant hyperthermia Palliative vs. rehabilitative Tendon releases

Achilles Need KAFO to walk post-op Relieves pain and allow shoe wear

Hamstring and iliotibial band Relieves hip and knee pain or contracture Allows better gait compensation

Scoliosis – spine stabilization Bracing is not effective with

progressive neuromuscular disease Timely correction of scoliosis is

important for patient comfort and respiratory ability

Spine and scapular stabilization may aid function of arms

Ophthalmology Deficient eye closure

oculomaxillofacial MD and FSH MD may require artificial tears or tarsorrhaphy

Treatment for cataracts in Myotonic MD

Respiratory Patients with morning headache,

nightmares, excessive daytime somnolence, mental dullness, difficulty concentrating, increased colds, coughing, or pneumonia should undergo evaluation

Influenza vaccine and pneumococcal vaccine

In-exsufflator for airway clearance, cough assist

Pulmonologist, pulmonary function testing

Assisted noninvasive ventilation Oxygen alone does not ventilate! Positive pressure ventilation vs. volume

ventilation with pressure limit Assisted ventilation with tracheostomy

Talk to patient about degree of desired intervention when respiratory status first starts to decline and before an acute event

The goal is home ventilation Cardiology

EKG – pacemaker for conduction defects and arrhythmias

Echocardiogram – afterload reduction, digoxin for cardiomyopathy

Nutrition/GI Overweight and underweight are

common problems Overweight impairs mobility Underweight decreases strength &

health Protein and calorie supplements Assess for dysphagia Intestinal hypomotility in DMD,

CMD, and myotonic dystrophy can require a bowel regimen to prevent constipation

Osteopenia/Osteoporosis Begins before walking stops, fractures

may end walking Worsened by steroids Calcium supplements, Miacalcin may

help Psychology/Neuropsychological

Education – aid in planning Special education may not be needed

with accomodation and modifications Progressive loss of function affects

patient and family