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Miasthenia gravis
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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
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Healthy Neuromuscular Junction
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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 )
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Spontaneous and Nerve Evoked Endplate Responses
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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
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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
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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
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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
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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
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Repetitive Nerve Stimulation (Supramaximal
2Hz)
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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
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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)
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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
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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)
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Repetitive Nerve Stimulation (Supramaximal
2Hz)
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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)
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POLYMYOSITISDERMATOMYOSITIS
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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
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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
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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
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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;
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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
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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
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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
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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
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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
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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
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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
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Differential diagnosis
Myasthenia Gravis Electrolyte disturbances Metabolic, endocrine or toxic
myopathies Muscular dystrophy Guillain-Barre Syndrome
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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.
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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
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Muscular Dystrophy
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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)
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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
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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
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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
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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
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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
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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
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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
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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)
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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
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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)
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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
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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
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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)
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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
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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)
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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
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Thomsen’s miotonia
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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
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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
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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
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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)
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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
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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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comfysplints.com
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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
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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
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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
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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
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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
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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