1. Miasthenia gravis

2. 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

3. Healthy Neuromuscular Junction

4. 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 )

5. Spontaneous and Nerve Evoked Endplate Responses

6. 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

7. 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

8. 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

9. 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

10. 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

11. Repetitive Nerve Stimulation (Supramaximal 2Hz)

12. 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

13. 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)

14. 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

15. 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)

16. Repetitive Nerve Stimulation (Supramaximal 2Hz)

17. 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)

18. POLYMYOSITIS DERMATOMYOSITIS

19. 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

20. 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

21. 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

22. 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;

23. 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

24. Pain Pain Muscle pain Joint 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

25. 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

26. 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

27. 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

28. EMG aspects
Polyphasic action potentials with small amplitude, short duration
Long duration positive sharp waves:
Initial positive deflaction followed by a negative component
Fibrilation:
Short duration potentials (arrows) with positive and then negative component

29. Muscle biopsy Myopathic Inflammation
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

30. Differential diagnosis
Myasthenia Gravis
Electrolyte disturbances
Metabolic, endocrine or toxic myopathies
Muscular dystrophy
Guillain-Barre Syndrome

31. 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.

32. TREATMENT Cytotoxic agents Intravenous immunoglobulin successful
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

33. Muscular Dystrophy

34. 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)

35. History and Physical Exam in the Newborn and Office
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

36. Family History Review of Systems
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

37. 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

38. 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

39. 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

40. Biochemical muscle protein analysis
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

41. Genetic analysis Electromyography 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

42. 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)

44. 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

45. 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)

46. 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

47. 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

48. 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)

49. 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

50. Myopathies Central core disease: Myotubular myopathy Nemaline Myopathy
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)

51. 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

53. Thomsen’s miotonia

57. 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

58. 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

59. 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

60. 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)

61. 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

62. Improving daily activities of daily living
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

63. comfysplints.com

64. Surgery Palliative vs. rehabilitative Tendon releases
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

65. 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

66. 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

67. Cardiology 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

68. 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

69. 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