Myopathy Primary Muscle Disease Functional Structural

Lower vs. Upper Motor Neuron Weakness (Brain to corticospinal tract) Lower Motor Neuron (Anterior horn cells to peripheral nerves) Reflexes Hyperactive +/- clonus Diminished or absent Atrophy Absent* Present Fasciculations Absent Tone Increased (spasticity) Decreased or absent Toes Up-going (Babinski’s sign) Down-going *Disuse atrophy can develop after initial presentation 25

Distinguishing Lower Motor Weakness from Muscle Weakness Neuropathy Myopathy Distribution Distal > proximal Proximal > distal Fasciculations May be present Absent Reflexes Diminished Often preserved Sensory signs/symptoms Weakness due to neuropathy: lower motor neuron disease. Weakness due to myopathy: nerve function intact. 25

Symptoms of Muscle Disease Negative Weakness Proximal and symmetric Waddling gait; difficulty of rising from sitting, climbing stairs; getting up from a squatted position, Gower’s sign Fatigue; exercise intolerance Metabolic, mitochondrial Atrophy Positive Myalgia Cramp Contractures Increased lordosis, scoliosis Myotonia Impaired relaxation of muscle after forceful voluntary contraction Due to repetitive depolarization of the muscle membrane Myoglobinuria Dark colored urine Excessive release of myoglobin from muscle Metabolic-toxic-idiopathic Pseudohypertrophy Tendon reflexes are normal or depressed                          from A Kornberg MD

Gower’s Sign

Key questions Constant or episodic symptoms Age at onset Is there a family history Acute,subacute, chronic Life long Congenital Progressive or non-progressive Proximal-distal symptoms Cranial involvement Triggering factors Exercise Carbonhydrate Relieved by exercise Systemic signs Rash, dark/red urine, cardiac, cataract, neuropathy, mental retardation

Differential Diagnosis Lab CK Electrolytes Serum myoglobin Serum kreatinin, BUN Complete Blood Count ESR Thyroid function tests AST Urinalysis Myoglobinuria

Diagnosis of muscle diseases Creatinine kinase levels increased in many myopathies sign of muscle fiber necrosis ENG / EMG: differentiation between neurogenic and myogenic weakness Muscle biopsy: signs of muscle fiber abnormality, inflammation, immunostaining of muscle constituents Genetic testing EKG-Echocardiography

Classification of Myopathies Hereditary muscle diseases Muscle dystrophies Myotonias and Channelopathies Congenital Myopathies Metabolic myopathies Mitochondrial myopathies Acquired muscle diseases Inflammatory myopathies Idiopathic, infectious Endocrine myopathies Myopathies associated with other systemic illness Drug induced/toxic myopathies

Muscular Dystrophies Hereditary Progressive Pseudohypertrophy +++ Muscles replaced by fat Very High CK Genetic defect of proteins constituting the sarcolemma-associated cytoskeleton system Dystrophinopathies and others

Muscular Dystrophies Dystrophinopaties Limb Girdle dystrophies Duchenne, Becker Limb Girdle dystrophies Fascioscapulohumeral dystrophy Oculopharyngeal dystrophy Distal muscular dystrophies Myotonic dystrophies

Muscular Dystrophies-Duchenne X linked recessive Absence of dystrophin protein Slow to reach motor milestones Symptoms by age 5 All walk, may never run End up in wheelchair by age 12 Frequently mildly mentally retarded Life expectancy < 20 years with death related to respiratory failure or cardiomyopathy Dx- Genetic, muscle biopsy

Duchenne muscular dystrophy Normal Duchenne dystrophy Diagnosis: Lack of immunostaining of dystrophin in muscle biopsy specimen Demonstration of deletion in the dystrophin gene

Muscular Dystrophies-Becker Less common than Duchenne X-linked recessive Later Onset 10 years Most patients ambulant until 3rd-4th decade Death from heart failure due to dilated cardiomyopathy-late 40’s Mental retardation is rare

Management of DMD/BMD Annual echocardiography Cardiomyopathy ACE inhibitor and/or beta blocker....digoxin Cardiomyopathy and decreased pulmonary function + Pneumoccal vaccine Annual influenza vaccine Anesthesia complications...... Consider TIVA Susceptibility to malign hyperthermia Rhabdomyolisis, hyperkalemia, cardiac arrest Succinylcholine, halothane, isoflurane, sevoflurane Reaction to inhaled anesthetics, muscle relaxants, hypoventilation, atelectasis, cardiac arrhytmias, heart failure, difficulty weaning from mechanical ventilation, Deflazacort derivative of prednisone dose 1,3 mg deflazacort = 1 mg prednol

Management of DMD/BMD Low dose daily prednol - deflazacort in DMD İncrease of muscle strength-maximum at 3 months Prolongs independent ambulation İmprovement of FVC Preserves cardiac function Increases osteoporosis AAN recommendations Prednol 0,75 mg/kg/day for patients over the age of 5 years Watch for weight gain, cushingoid appearance, fractures, gastrointestinal symptoms..... Decrease to 0,5 then 0,3 mg/kg/day if weight gain occurs Deflazacort 0,9 mg/kg/day Watch for weight gain and cataracts

Management of DMD/BMD Vitamin D supplement Nutritionist If serum vitamin D level less than 20ng/ml Nutritionist Avoid obesity Physical Therapy, orthopedic devices Gene Therapy Aminoglycosides, PTC124, Creatine

Facioscapulohumeral dystrophy Prevalence: 1 in 20,000 Most common after DMD and BMD Autosomal dominant Age of onset: before 20 Sensorineural hearing loss

Facioscapulohumeral dystrophy myopathic face, İnability to smile, whistle or close eyes Life span is not significantly affected                          Charcot

Facioscapulohumeral dystrophy Progressive muscular weakness and atrophy involving the face, scapular, proximal arm and peroneal muscles winging of the scapula

Oculopharyngeal Muscular Dystrophy 5’th-6’th decade Extraocular muscle weakness Ptosis Dysphagia Later facial and proximal muscle weakness Autosomal Dominant

Emery Dreifuss Muscular Dystrophy EDMD Childhood- adolescence Slowly progressive Contractures before weakness Neck extansors, elbows, ankles Cardiomyopathy Atrial arrhythmias and syncope                                From: A Kornberg Emery-Dreifuss: Rigid spine

Limb-girdle dystrophies Autosomal Dominant (10%) LGMD-1 Autosomal Recessive (90%) LGMD-2 Symptoms between 2-40 High CK Slow progressive proximal muscle weakness Onset variable Spares the face

Limb-girdle dystrophies Causes: Sarcoglycanopathies α, β, γ, δ sarcoglycans Clinically often indistinguishable from Duchenne-dystrophy scapular winging more pronounced, hamstrings and quadriceps equally affected Calpain - 3 mutation Dysferlin deficiency etc. Caveolin deficiency (AD)

Sarcoglycanopathies Sarcoglycanopathy Normal

Myotonic dystrophy Prevalence: 1 in 8000 Cause: CTG repeat expansion in a gene on chr. 19 Autosomal dominant inheritance, with anticipation Multisystemic disease: Myotonia: hyperexcitability of muscle membrane  inability of quick muscle relaxation Progressive muscular weakness and wasting, most prominent in cranial and distal muscles Cataracts, frontal balding, testicular atrophy Cardiac abnormalities, mental retardation, endocrinopathy

Myotonic dystrophy

Myotonic dystrophy

Muscle channelopathies

Periodic paralysis Characterized by episodes of flaccid muscle weakness occurring at irregular intervals Strength is normal between attacks General characteristics : Hereditary; Most are associated with alteration in serum potassium levels; Hypokalemic, hyperkalemic, normokalemic Myotonia sometimes coexists; Both myotonia and PP result from defective ion channels.

Periodic paralysis The physiologic basis of flaccid weakness is inexcitability of the muscle membrane (ie, sarcolemma). Sodium channel Hyperkalemic PP (HyperPP) Hypokalemic PP (HypoPP2) Paramyotonia congenita Potassium-aggravated myotonia Calcium channel Hypokalemic PP (HypoPP1) Potassium channel Andersen-Tawil syndrome Hyperkalemic PP or hypokalemic PP*

Myotonia congenita Mutation in the muscle Cl gene Autosomal dominant Thomsen Autosomal recessive Becker Symptoms: Myotonia (hyperexcitability of the muscle membrane): muscle stiffness and abnormal muscle relaxation, warm-up phenomenon Hypertrophied muscles Therapy: phenytoin, mexiletin

Myotonia congenita

Characteristic Myotonia Congenita Myotonic Dystrophy Onset Infancy or early childhood Severe infantile form, late childhood to adult life Myotonia Severe, generalized Moderate or slight Weakness Slight, nonprogressive Variable, may be severe and progressive Cardiac and smooth muscle involvement No Yes Cataract Absent Present Inheritance Autosomal Recessive Autosomal Dominant

Idiopathic Inflammatory Myopathies Clinical Classification Polymyositis (PM) Dermatomyositis (DM) Inclusion Body Myositis (IBM) Juvenile Dermatomyositis Myositis associated with malignancy Myositis associated with collagen vascular disease Bohan & Peter (1975). NEJM. Tanimoto et al. (1995). J Rheumatology.

Polymyositis / Dermatomyositis Diagnostic criteria Proximal muscle weakness Elevated serum CK Myopathic changes on EMG Muscle biopsy demonstrating lymphocytic inflammation Dermatomyositis: Skin rash as well as criteria above Definitive diagnosis with four criteria having been met Bohan & Peter (1975). NEJM.

Polymyositis-Dermatomyositis Painful muscles (60%) Polymyositis: Cell-mediated immune response against muscle fibers Less often paraneoplastic than DM Cardiac abnormalities Dermatomyositis: Humorally mediated autoimmune microangiopathy affecting the muscles and skin Rash on the face, neck Periorbital oedema Dysphagia Cardiac abnormalities, interstitial lung disease May be paraneoplastic

Dermatomyositis

Treatment for DM, PM Immunosuppression long-term treatment with corticosteroids (1 mg/day) Mtx-Imuran...

Inclusion Body Myositis Mainly affects older males Symptoms begin insidiously and progress slowly Symptoms are often present 5-6 years before diagnosis Finger flexors-quadriceps May include focal, distal or asymmetric weakness Neurogenic or mixed neurogenic / myopathic changes on EMG Dysphagia is noted in more than 20% of patient Wortmann RL. Primer on Rheum Dis. 12th edition. 2001:369–376.

Muscle Biopsy: Histology and Immunochemistry Dermatomyositis B cells, macrophages CD4 T cells Decreased capillaries Perifascicular atrophy Perivascular infiltrate IBM Same as PM; also: Rimmed vacuoles Eosinophilic cytoplasmic inclusions Polymyositis Mononuclear cells CD8 T cells Endomysial infiltrate Myonecrosis Patchy, focal Rolak LA. Neurology Secrets. 2005: 63-7.