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For Neurology Residents Erin O’Ferrall Neuromuscular fellow Jan 13, 2010
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To describe the classification systems for myopathies
To describe how to elicit history & physical exam findings of myopathy
To briefly review the most common or important myopathies in each category
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Classification of Muscle Diseases ◦ Molecular ◦ Phenotype ◦ Etiology
History Physical exam The Myopathies: illustrated with cases ◦ Inflammatory
IBM, PM, DM ◦ Inherited: Muscular Dystrophies
LGMDs (Calpain, Dysferlin), Dystrophin, OPMD, FSHD, DM1&2 ◦ Metabolic Myopathies ◦ Channelopathies ◦ Toxic/Drug Myopathies
Conclusions
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The bad news: ◦ Myopathies cannot be covered in 1 hour! ◦ I will spend more time discussing the approach as
well as key points on the history and physical exam…the rest is up to you!
The good news: ◦ Myology is a neglected area of Neurology and is
not heavily emphasized on the Royal College Exam! ◦ Myology is cool
Today I will focus on the adult-onset presentations
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Molecular Phenotype Etiology
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Extracellular defects
Sarcolemmal defects
Myofibrillar and cytoskeletal defects
Myonuclear abnormalities
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Limb Girdle -LGMD -Inflammatory
Limb Girdle Plus -LGMDs -Inflammatory -Duchenne & Becker
Humeroperoneal -Emery-Dreifuss
Facioscapulohumeral -FSHD
Distal -distal myopathies
Ocluopharyngeal -OPMD
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Proximal/ Limb-Girdle Weakness ◦ Most common pattern for hereditary & acquired myopathies
Distal weakness ◦ Rule out neuropathy (look for sensory involvement) ◦ DMs, FSHD, OPMD, Emery-Dreifuss, IBM ◦ Miyoshi (dysferlin)
Proximal Arm + Distal Leg /Scapuloperoneal ◦ Scapular winging ◦ FSHD, Emery-Dreifuss, LGMD: Laminopathies, Calpain, sarcoglycans
Distal Arm + Proximal Leg ◦ IBM
Ptosis with or without ophthalmoplegia ◦ WITH: OPMD, oculopharyngodistal myopathy, Mitochondrial, NMJ (MG, Lambert-Eaton, Botulism) ◦ WITHOUT: DMs, Congenital Myopathies, Desminopathy
Prominent Neck extensor weakness/ Dropped head ◦ Inflammatory (PM< DM, IBM) FSHD, DM, Congenital (nemaline) myopathy, HyperPTH, Carnitine
deficiency, isolated neck extensor myopathy, HypoT, HypoK
Bulbar weakness: OPMD ◦ Think of motor neuron diseases or NMJ
Episodic weakness ◦ Metabolic myopathies, drugs/toxins, infections, trauma, DM/PM (rare), channelopathies,
Thyrotoxicosis
(NOTE: one disease may have several phenotypes; only a few examples are listed)
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Hereditary Muscular
Dystrophies* Myotonias Channelopathies Congenital Myopathies Metabolic
Myopathies Mitochondrial
myopathies
Acquired Inflammatory
myopathies Endocrine Associated with other
systemic illness Drug-induced and
Toxic myopathies
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Dystrophinopathies ◦ Duchenne MD ◦ Becker MD
Limb-Girdle MD: LGMD ◦ Many “__opathies” named based on the deficient or
defective protein Facioscapulohumeral MD Oculopharyngeal MD Distal MDs Emery-Dreifuss MD Congenital MDs (MD= muscular dystrophy)
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Symptoms depend on which muscles are involved > etiology Weak = loss of muscle power Patients may confuse this with ◦ Numb, SOB or generalized fatigue ◦ Always ask: for what specific movements or activities are you weak? Or
When do you notice weakness (i.e what are you doing)? ◦ Is there anything you can’t do now that you could do X months ago?
Differentiate weakness from from ◦ depression/ malingering (vague description) ◦ Tendon or joint contractures ◦ Weakness secondary to pain (may have pain with passive movement)
Course is KEY! When did the weakness start? Ask about infancy, childhood, adolescence, etc using both broad and specific
questions: EXAMPLES?
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Ocular: ◦ Ptosis & Diplopia
Facial ◦ What do you ask to assess facial weakness? ◦ Drinking with a straw, whistling, blowing up balloons,
drooling; Facial expression reported by others; Photos for change over time ◦ Sleep with Eyes Open~ think FSHD
Chewing: ask about fatigue, discomfort Swallowing: choking, aspiration, nasal regurgitation Speech: ◦ What type of speech is heard with myopathies? ◦ Slurred, nasal, hoarse
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What questions can you ask to assess: Proximal upper extremity? ◦ painting the ceiling, shampooing or combing the hair, shaving,
lifting objects off high shelves Distal upper extremity? ◦ Difficulty with buttons, zipper then opening jars, turning faucet/
door knob/ car ignition, using keys, holding silverware, writing, opening car door
Proximal lower extremity? ◦ Rising from floor or low chair, Getting out of the bath, up from
toilet, Stairs (down=quads; up=hip extn) ◦ Gait: waddling
Distal lower extremity? ◦ Difficulty to stand on your toes, Tripping, footdrop /slapping (ask
partner), can’t stand still /poor balance
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Neck: ◦ Ask about braking or accelerating in a car, difficulty
lifting head off the pillow, need to use hands to lift head off chest
Diaphragm ◦ How do you ask about diaphragm weakness? ◦ SOB esp lying flat ◦ Hypoventilation, CO2 retentions: AM headaches, vivid
nightmares, daytime somnolence Axial ◦ Can you do a sit up? ◦ Do you have trouble standing up straight? (Bent spine
Syndrome)
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Define Cramps ◦ Painful; occur when a muscle contracts in a shortened
position; muscle becomes hard, well-defined; relieved by stretching ◦ Benign or abnormal ◦ Motor units firing at high frequency
Define Muscle Contracture ◦ Ex: metabolic myopathy ◦ Electrical silence
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Cranial Nerves ◦ Smooth, unlined face if weakness longstanding (in
an older person) ◦ Temporalis/ Masseter wasting: scalloped
appearance ◦ Jaw power ◦ lips: tented upper lip or straight line ◦ Don’t forget to check for dysarthria & phonation ◦ High arched palate: wk since childhood
Frontal balding is seen in which myopathy? ◦ What “special” cranial nerve test could you do?
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Posture ◦ Pectoral atrophy –upward sloping pectoral fold in FSHD
Muscle bulk ◦ Atrophy? Asses at rest & activated ◦ Hypertrophy?
Dystrophies, myotonic disorders
◦ Abnormal muscle movements? ◦ Rippling (Caveolin3)
Winged scapula: What Muscles? How to test? ◦ Trapezius hump in FSHD
Palpate muscles ◦ Fibrotic: rubbery or hard; Tender: inflammatory, rhabdo, viral myositis
Percuss: myotonia, rippling, myoedema Look for Bony deformities (scoliosis) & Contractures (Elbows for
Emery-Dreifuss)
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Can use 4+, 4, 4- for mild, moderate, & severe weakness
Grade 3+ “used when the muscle can move the joint against gravity and can exert a tiny amount of resistance but then collapses under the pressure of the examiner’s hand.”
Grade 3- ex: knee that can extend only to 30-40 degrees of horizontal
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neck flexion/ extension shoulder abduction, internal rotation, external rotation elbow flexion/ extension wrist flexion and extension finger abduction and adduction thumb abduction and flexion hip flexion and extension knee flexion and extension ankle dorsiflexion and plantar flexion; inversions & eversion dorsiflexion of the great toe Toe flexion Sit up Diaphragm (if indicated): counting seated and supine
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Walking ◦ What type of gait do you expect with limb girdle
weakness? ◦ Knee hyperextension is a sign of what? ◦ Steppage gait is a sign of what? ◦ Arm swing
Arising from Floor Sit up from lying supine Stepping on stool Squat from low chair Provocative/ Special tests are necessary when the
patient complains of weakness and you do not find it on confrontational testing!
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WHAT’S THE DIFFERENTIAL DIAGNOSIS??
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Myopathies ◦ Polymyositis, IBM, ?DM, Fascioscapulohumeral dystrophy,
Myotonic Dystrophies (myotonic dystrophy with hypothyroidism, proximal myotpnic dystrophy) ◦ mitochondrial myopathy, acid maltase deficiency, carnitine deficiency ◦ hypokalemic periodic paralysis, congenital myopathy, nemaline
myopathy ◦ Endocrine: Cushing’s syndrome, Hyopthyroid myopathy,
hyperparathyroidism ◦ restricted non-inflammatory myopathy, focal myopathy -radiation
damage Motor neuron ◦ ALS, spinal muscular atrophy, postpolio
NMJ: MG CIDP
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DTRs: lost in proportion to weakness Sensory exam: normal except myofibrillar
myopathies (associated neuropathy), mitochondrial
Coordination: normal unless very weak No fasiculations After the Physical Exam… ◦ Return to the history if you have not
confirmed your hypothesis
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58 yr woman with a 6 wk history of muscle aching and weakness
Difficulty climbing stairs and rising from chairs; difficulty raising her arms above her head
Redness of face, neck & hands
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Cranial nerves: normal
Neck flexion 4-, Extension 5- Shoulder abduction 4- Elbow flexion 4-, extension 4- Wrist flexion 4+, extension 4+ Hip flexion 3-, extension 3-, abduction 3- Knee flexion 4-, extension 4+ Ankle dorsiflexion 4+, plantarflexion 5
Normal DTRs Normal Sensory exam
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Gottron rash
Heliotrope rash +/- edema
V sign, +/- Shawl sign
May also see Mechanic’s Hands
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Three main types: Dermatomyositis (DM), Polymyositis (PM), Inclusion Body Myositis (IBM)
Overall incidence of inflammatory myopathies is 1 in 100 000 per year (but estimates vary)
DM is most common overall but IBM is most common after age 50 yrs PM is rarely (if ever) seen in children PM & DM: slowly progressive limb-girdle
weakness, including neck extensors DM: activity-induced muscle pain IBM: finger flexor & quadriceps weakness
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Characteristic skin findings: (see prior slide) Dysphagia Multisystem disease can occur ◦ Pulmonary involvement (Interstitial lung disease) 10-20%, t-
histidyl transfer RNA Abs (Jo-1) ◦ Also GI, Cardiac, Joints ◦ Malignancy: 6- 45%, usually over 40 yrs; ovaries, GI tract, Lung,
Breast, Non-Hodgkin lymphomas ◦ Overlap with systemic sclerosis or other mixed connective
tissue diseases Variants ◦ No weakness: dermatomyositis sine myositis or amyopathic
dermatomyositis ◦ Transient or unrecognized rash: dermatomyositis sine dermatitis ◦ In Children: subcutaneous calcification, “Misery”: irritable,
uncomfortable child, red face, proximal weakness, tiptoe gait due to flexion contractures
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uncommon Diagnosis of exclusion This is NOT DM without the rash! ◦ Mediated by CD8+ T cells which attack
muscle fibers ◦ (DM: humorally mediated microangiopathy)
Occurs alone or in association with other autoimmune disorders
Controversial association with malignancy
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CK normal ANA positive 1:120 No anti-Jo1 antibodies Muscle biopsy: diagnostic for DM Treated with prednisone and methotrexate Mammogram reveals suspicious lesion,
biopsy shows cancer After surgery & chemotherapy she is able to
wean off the prednisone
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Usually >50 yrs Slowly progressive Dysphagia ◦ Later, in up to 2/3rds
Spares EOM CK: normal – 10X EMG: myopathic motor unit potentials, fibrillations, positive
sharp waves, long & high amplitude motor units DDx: ◦ Familial forms ◦ Hereditary: Inclusion Body Myopathy
(IBM1): Desmin, AD IBM2: GNE & non-GNE forms (LAMA2), AR IBM3: myosin heavy chain IIa, AD IBMPFD: IBM with Paget’s disease and frontotemporal
dementia; Valosin-containing protein
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IBM: Lancet Neurol 2007; 6: 620–31 PM, DM: Lancet 2003; 362: 971–82 AAN Continuum Jun 2006
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17 yr male At age 3: hyperactive, clumsy, speech delay At Age 4: weakness of face & shoulder girdle,
scapular winging, increased lumbar lordosis, waddling gait
Age 12: difficulty standing up from chair, bilateral foot drop
Currently sleeps with eyes open FHx: ◦ none
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CK mildly raised 683 U/L (N <150U/L) EMG normal Muscle biopsy: myopathy (may see
inflammation!) Bilateral hearing loss
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AD Prevalence 50 per million Variable penetrance; estimated that 30% of affected family members
are unaware Onset 3- 44 yrs (usually) FacioScapuloHumeral pattern of weakness, may be symmetric Trapezius lump Horizontal anterior axillary folds Popeye arms Abdominal muscle weakness Hypertrophic EDB Cardiac involvement in 4-60% Respiratory involvement rare Variants: ◦ Severe, rapid progressive infantile form (sporadic) ◦ Hearing loss, Coat’s disease (retinal telangiectasias) ◦ developmental delay, seizures
DX: deletion of Chr4q35, D4Z4 repeats
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AD, incomplete penetrance Onset usually 5th or 6th decade Progressive ptosis, dysphagia, proximal limb weakness Tongue: weak & atrophic First described in a French Canadian family (1915) but
found world-wide Prevalence 1:100 000 (1:1000 Quebec) Complications include aspiration pneumonia &
malnutrition Dx: PABN1 (poly(A) binding protein), GCG
trinucleotide repeats (usually 8-13; normal =6), Chr14
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Not just a myopathy: Multisystem RNA-mediated diseases!!
2 types: ◦ Type 1 or DM1: classical form, Steinert’s disease;
congenital form is reported ◦ Type 2 or DM1: new form; PROMM (Proximal
myotonic myopathy); No congenital form Define Myotonia?
Delayed relaxation after muscle contraction; patients often describe this as stiffness
EMG: spontaneous waxing and waning discharge of the muscle fiber; rate 20-150 Hz; reving engine sound
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AD, DMPK (myotonin protein kinase),Chr 19 ◦ CTG repeat expansion in 3’ UTR ◦ Mild: 50-80; Symptomatic: 80-2000
+anticipation Myotonia facial & limb weakness & wasting, frontal balding, bulbar weakness Cataracts (Christmas Tree), Tachyarrhythmias, cardiomyopathy, conduction defects Endocrine (hyperinsulin, adrenal atrophy, hypoT4, testicular
artophy) altered GI motility hypersomnia, low intelligence, hearing loss Respiratory weakness: especially after surgery & with narcotics
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maternal inheritance only, DM1 mothers Hypotonia at birth Facial diplegia Feeding and respiratory difficulties Skeletal deformities, such as clubfoot Mental retardation Absent clinical myotonia in infants and
neonates Ventriculomegaly due to brain atrophy
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PROM: proximal myotonic myopathy AD, Zinc finger protein 9,Chr 3 ◦ CCTG repeat expansion in intron ◦ Symptomatic: 75 to >10 000 repeats
Predominantly proximal weakness Cataracts (slit-lamp exam) Myalgias, Painful muscle cramps Fluctuating weakness & stiffness Calf pseudohypertrophy Multisystem: ◦ Deafness, DM or insulin resistance, Hypothyroidism,
Cardiac conduction defects, GI symptoms
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Muscular dystrophies with predominantly proximal distribution of weakness (at least early in the disease)
Recently defined group by the European Neuromuscular Group in 1995
Constantly expanding number of genes (see Neuromuscular Disorders, January issue for yearly update)
Important to note that one gene may have several phenotypes!
Type 1: AD Type 2: AR Usually childhood or adult onset & slowly progressive Some have cardiac involvement
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Extremely oversimplified table!
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Most prevalent LGMD (?) Onset: any but usually 2nd – 3rd decade Weakness: Limb girdle, L/E >E/U, Scapular winging ◦ Predominant involvement of glutei & hip adductors/ posterior
compartment of the thigh, Hip abductor sparing ◦ Biceps > triceps
Gait: Tip-toe walking, waddling gait Contractures, calf hypertrophy No cardiac involvement or facial weakness CK normal to 50X Dx: Calpain reduced on Western Blot (from muscle biopsy tissue) ◦ Caution: secondary reduction in dysferlin, dystrophin, FSHD, Titin, FKRP
& calpain levels may be normal (missense mutations) Genetics: Many mutations (24 exons, 50kb) Clinical Variants: ◦ Eosinophilic myositis, Pseudometabolic pstn, Calf hypertrophy,
Ventilatory insufficiency, Asymptomatic/ pre-symptomatic, Intra-familial variability
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2 phenotypes for the same gene: ◦ LGMD2B (limb-girdle weakness) ◦ Miyoshi myopathy (distal myopathy, esp gastrocs)
Onset: late teens, early twenties (usually), slowly progressive
Weakness: Lower extremities >upper CK may be very elevated Variants: ◦ Distal myopathy with anterior compartment
involvement; proximo-distal variant; subacute painful calf swelling; inflammation on muscle biopsy; etc.
Usually No scapular winging, cardiac or respiratory involvement
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X-linked recessive Duchenne Muscular Dystrophy (DMD): ◦ most common form of muscular dystrophy ◦ Incidence 1:3300 live male births ◦ Age of wheelchair confinement: by 13 yrs
Becker Muscular Dystrophy (BMD): ◦ Similar phenotype to Duchenne but MILDER clinical course ◦ Incidence 1 in 18 000 to 31 000 male births ◦ Age of wheelchair confinement 16 yrs or later
Other Dystrophinopathies: ◦ Manifesting DMD/BMD female carriers ◦ X-linked dilated cardiomyopathy ◦ Isolated quadriceps myopathy ◦ Muscle cramps with myoglobinuria
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May be evidence of myopathy at birth but usually not discovered until 2-5 yrs of age
Difficulty running, jumping, stairs Waddling gait, lumbar lordosis, calf
enlargement, may have leg pain Cardiomyopathy Cognitive impairment Intestinal hypomotility Scoliosis, decline in pulmonary function
usually develops after wheelchair confinement
Mean age of death = 20 yrs +/- 3.9 yrs
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Onset later: 5-15 yrs or even later Milder phenotype Less cardiac & cognitive involvement Much less GI symptoms Neck flexor power relatively preserved Death between 30-60 yrs from
respiratory or cardiac causes
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FSHD: AAN Continuum, Jul 2006 OPMD: Biochimica et Biophysica Acta
1772 (2007) 173–185 DM1+2: Muscle Nerve 32: 1–18, 2005 LGMDs: Neurology India. July-September,
2008; 56(3) Duchenne & Becker Muscular
Dystrophies: AAN Continuum, Jul 2006
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55 yr Female with gradually progressive difficulty walking
Onset: 37 yrs; difficulty getting onto a bus, needed to use her arms
Difficulty arising from chairs, stairs Trouble lifting heavy objects No family history
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Mild weakness for eye closure 3/5 muscle weakness for proximal
muscles in arms and legs Waddling gait sensory exam normal DTRs: 1+ Ankle jerks, otherwise 2+ CK 800 EMG: small amplitude, brief, polyphasic
myopathic potentials; myotonic discharges
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Biopsy shows nonrimmed vacuoles with increased deposition of PAS-positive material
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Acid maltase deficiency ◦ Pompe’s Disease, Glycogen storage disease type
II, a Lysosomal storage disease Due to deficiency of the lysosomal enzyme
acid alpha-glucosidase ◦ Responsible for intralysosomal degradation of
glycogen Gene: GAA, Chromosome 17, AR Affects cardiac, skeletal & smooth muscle Pompe’s –infantile onset: 1 in 33-138 000 Adult onset: 1in 40 000
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Infantile ◦ Onset in first year of life, Rapid progression, Cardiomegaly,
hypotonia, death due to cardiorespiratory failure, often death <1 yr
Adult form: ◦ Weakness: Limb-girdle distribution (pelvic>shoulder)
Mild forms are reported (myalgia without weakness) ◦ Respiratory involvement (but no cardiac, although this is
controversial) ◦ Pain and Fatigue may be highly prevalent (experienced by 46% &
75% of patients in some studies, respectively) ◦ Cognition, Sensory and cerebellar functions are normal ◦ CK: 1-15X normal ◦ EMG: abnormalities may be isolated to paraspinals ◦ ABSENT clinical myotonia (present on EMG) ◦ Muscle biopsy may be normal ◦ Consider Dot Blot test (here)
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Aka Type V glycogenosis Onset: childhood Exercise intolerance, cramps, myalgia, fatigue, poor endurance,
muscle swelling Later: fixed weakness Triggered by brief intense exercise or long low-intensity Second wind phenomenon: ◦ Specific feature of McArdle’s ◦ Patients become symptomatic (ex: cramps) after beginning a physical
activity ◦ If the patients rest briefly then resume exercise they can continue
without symptoms Episodes of myoglobinuria +/- renal failure CK: usually elevated Forearm exercise test: flat venous lactate curve EMG: normal or myopathic with fibrillations or myotonic discharges ◦ Can see decrement on repetitive stimulation
Muscle biopsy: loss of myophosphorylase activity is diagnostic
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Mitochondrial disease is caused by nuclear or mitochondrial DNA mutations
Mitochondrial defects cause multisystem disease Myopathies are often seen with mitochondrial disease
Myopathy with exercise intolerance With respiratory failure or cardiomyopathy EOM abnormalities (CPEO), ptosis
When to suspect mitochondrial disease? ◦ Hearing, short stature, lactic acidosis, cardiomyopathy or
conduction defects, diabetes mellitus, hypoparathyroidism, pigmentary retinopathy, cataracts, renal dysfunction, multiple lipomas, etc ◦ Seizures, sensorineural hearing loss, ataxia, cognitive, dystonia,
peripheral neuropathy, optic neuropathy, GI dysmotility ◦ Maternal inheritance
Dx? ◦ Muscle biopsy: COX negative fibers; Ragged red fibers ◦ Genetics
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29 yr Female ◦ Had an EMG for numbness and tingling of the
first 3 digits of her right hand, Myotonic potentials were seen on EMG
Had muscle stiffness all her life Cramps with physical activity but did not
bother her Rarely difficulty releasing the handle on
her briefcase Sister and father with similar symptoms
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Normal muscle bulk and motor power Sensation and reflexes are normal How do you test for myotonia? Mild eye opening myotonia, diminishes
with repeated attempts ◦ Warm up!
Percussion myotonia is present No handgrip myotonia
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EMG: CTS right, myotonia in all muscles Genetic tests for DM1 & 2 negative Dx? Likely myotonia congenita
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Ann Rev Neurosci 2006. 29:387-415
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Drugs/ Toxins may induce several types of myopathies:
Necrotizing ◦ Statins
Inflammatory ◦ D-penicillamine
Type I fiber atrophy ◦ Steroids
Mitochondrial ◦ AZT
Other types…(emetin can cause a myofibrillar myopathy)
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J Neurol Neurosurg Psychiatry 2009;80:832–838.
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Statins: HMG CoA reductase inhibitors Appear to cause mitochondrial dysfunction, possibly
due to depletion of ubiquinone (electron transport) Order of myotoxicity:
Ceriva > simva > lovo > prava > atorva > fluva
Several clinical syndromes ◦ hyperCK in asymptomatic patients ~5% ◦ Myalgia with or without hyperCK ~9-25% ◦ Weakness with elevated CK ~least common
Did the statin cause the myopathy? Coincidence? Unmask pre-existing condition?
◦ Rhabdomyolysis High CK, myalgia, weakness, myoglobinuria +/- renal failure Incidence: <1 per 100 000, but higher if statin in combined with
amiodarone, gemfibrozil, ciclosporin
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Some metabolic: see Carnitine disorders (esp CPT2)
Distal myopathies Congenital myopathies and muscular
dystrophies: ◦ Will cover these briefly during next week’s
muscle pathology session Endocrine myopathies ICU myopathy Steroid myopathy
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Hereditary Muscular
Dystrophies* Myotonias Channelopathies Congenital Myopathies Metabolic
Myopathies Mitochondrial
myopathies
Acquired Inflammatory
myopathies Endocrine Associated with other
systemic illness Drug-induced and
Toxic myopathies
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The key to the diagnosis is a good history & a careful physical exam ◦ Use the pattern of weakness to help
determine further investigations and diagnosis There are a lot of myopathies ◦ Not everything is an inflammatory myopathy!
Next Week: ◦ Muscle pathology ◦ More about the diagnosis of muscle disease ◦ More pediatrics (only a little!)
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