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Muscle Channelopathies Muscle Channelopathies Stanley Iyadurai, MSc PhD MD Assistant Professor of Neurology, Neuromuscular Specialist, OSU, Columbus, OH August 28, 2015 24 F 9 M 18 M 23 F 16 M 8/10 Occasional “Paralytic “Seizures at “Can’t Release Headaches Gait Problems Episodes” Night” Grip” Nausea Few Seconds Few Hours “Parasomnia” “Worse in Winter” Vomiting Debilitating Few Days Full Recovery Full Recovery Video EEG Exercise – Light- Worse Sound- 1-2x/month 1-2x/year Pelvic Red Lobster Thrusting 1-2x/day 3-4/year Dad? Dad? 1-2x/year Dad? Sister Normal Exam Normal Exam Normal Exam Normal Exam Hyporeflexia Normal Exam “Defined Muscles” Photophobia Hyper-reflexia Phonophobia Migraines Episodic Ataxia Hypo Per Paralysis ADNFLE PMC CHANNELOPATHIES DEFINITION Channelopathy: a disease caused by dysfunction of ion channels; either inherited (Mendelian) or acquired/complex (Non-Mendelian, e.g., autoimmune), presenting either in neurologic or non-neurologic fashion CHANNELOPATHY SPECTRUM CHARACTERISTICS Paroxysmal Episodic Intermittent/Fluctuating Bouts/Attacks Between Attacks Patients are Usually Completely Normal Triggers – Hunger, Fatigue, Emotions, Stress, Exercise, Diet, Temperature, or Hormones Muscle Myotonic Disorders Periodic Paralysis MUSCLE CHANNELOPATHIES Malignant Hyperthermia CNS Migraine Episodic Ataxia Generalized Epilepsy with Febrile Seizures Plus Hereditary & Peripheral nerve Acquired Erythromelalgia Congenital Insensitivity to Pain Neuromyotonia NMJ Congenital Myasthenic Syndromes Myasthenia Gravis Lambert-Eaton MS Cardiac Congenital long QT syndrome SOME OF THE IDENTIFIED GENES APPROACH Suspicion Evaluation Electrodiagnostics Gene Diagnosis Treatment PATIENT JM 16-year old young man referred for migraines and muscle stiffness Active high school wrestler Muscle stiffness started around age 11 Legs tighten up when start wrestling match but eventually loosen up, toes curl up, when holds opponents tight has trouble releasing Difficulty releasing pencils/doorknobs If he repeatedly flexes and extends hand it will cramp up and unable to open hand Severe migraines associated with right-sided numbness Exam well-defined musculature and grip myotonia PATIENT RM JM’s father – construction worker Reports muscle stiffness since high school in stressful situations or when nervous Describes warm-up phenomenon No change with cold Exam with grip myotonia (that improves with warm-up) EXERCISE-INDUCED STIFFNESS AND WARM-UP PHENOMENON EMG – MYOTONIC DISCHARGES THIS IS A CHANNELOPATHY! WHAT IS MYOTONIA? . Repetitive, autonomous muscle fiber depolarization which may be observed Clinically or Electrophysiologically . Clinical Myotonia: delayed muscle relaxation after a triggering stimuli (such as contraction or percussion) . Electrical Myotonia: needle electromyographic recording of a repetitive muscle fiber action potential of varying frequency and amplitude WHY DOES MYOTONIA OCCUR? Potassium accumulation in the T-system leads to a small transient after- depolarization at the end of muscular contraction This can trigger myotonia when exaggerated or sarcolemma is hyperexcitable Burge and Hanna Curr Neurol Neurosci Rep 2012 EMG: MUSCLE FIBER ACTION POTENTIALS . Positive Sharp Waves . Fibrillation Potentials = Single Muscle Fiber Depolarization (Spontaneous = Abnormal) Can Occur in Denervation and Myopathic Disorders GRIP MYOTONIA (CLINICAL MYOTONIA) MUSCLE MOUNDING HYPEREXCITABILITY INEXCITABILITY Periodic Myotonia Mixed Paralysis Disease/Phenotype Gene KCNJ2 Andersen-Tawil syndrome Periodic Paralysis Hypokalemic PP CACNA1S Hyperkalemic PP Nondystrophic Sodium Channel myotonia SCN4A Myotonia Paramyotonia congenita Myotonia congenita CLCN1 PARAMYOTONIA CONGENITA Characterized by myotonia and episodic weakness, aggravated by exercise and cold Mix autonomous action potentials and sodium channel inactivation Autosomal dominant Related to SCN4A mutations Percussion myotonia is present but not prominent Clinical paramyotonia is present in most patients (usually in at least the eyelids) Slowed inactivation of the Na channel with incomplete closure and associated “leaking” causing a shift towards depolarization MYOTONIA CONGENITA Characterized by muscle stiffness (myotonia) that is most pronounced after rest Myotonia improves with exercise - “warm up phenomenon” Mutations of the chloride channel gene, CLCN1 Autosomal dominant (Thomsen) and recessive (Becker) forms Myotonia is related to reduced Cl- channel conductance, causing a shift in membrane potential towards hyper- excitability (Wagner et al. 1998) SODIUM CHANNEL MYOTONIA Characterized by: clinical and electrical myotonia, occasional episodic weakness (Mix of autonomous action potentials and sodium channel inactivation) When episodic weakness is lacking….may closely mimic myotonia congenita Distinguishing features include associated muscle pain and symptomatic eyelid myotonia Numerous confusing and inconsistent clinical sub-phenotypes: Myotonia fluctuans-delayed onset of myotonia, aggravated with exercise and potassium Myotonia permanens-constant, severe myotonia which may cause ventilatory impairment Acetazolamide-responsive myotonia HYPERKALEMIC PERIODIC PARALYSIS . Characterized by episodic attacks of muscle weakness and myotonia . Triggers may include exercise, fasting, or cold exposure . Earlier age of onset (first decade) . AD, mutation of SCN4A . Milder but more frequent attacks of weakness . Electrical and +/- clinical myotonia . Blood potassium is inconsistently increased . Paralysis likely related to failed slow inactivation of Na channel HYPOKALEMIC PERIODIC PARALYSIS . Characterized by episodic attacks (hours to days) of muscle weakness usually sparing the muscles of respiration, deglutition, and ocular motility . Typically patients awake with paralysis hours after exertion or a meal rich in carbohydrates . Age of onset is within the second decade . Blood potassium at the beginning of an attack is usually below normal . Potassium chloride ingestion may hasten recovery . Mutation of the voltage gated calcium channel (CACNA1S) accounts for 70% of patients; SCN4A mutations account for about 10% ANDERSEN-TAWIL SYNDROME Characterized by Episodic skeletal muscle weakness (periodic paralysis) due to sodium channel inactivation Cardiac manifestations ranging from mild EKG abnormalities to ventricular rhythms and associated sudden death Rare: 1/500,000 K Channelopathy Kir2.1 (KCNJ2 gene on 17q23.1) (70%); Kir2.6 (KCNJ18) Affects skeletal and cardiac muscle Autosomal dominant disorder with significant clinical variability making diagnosis difficult DIAGNOSTIC STRATEGIES Clinical Provocative Genetic Electrodiagnostic Testing ELECTRODIAGNOSTIC PROTOCOL Standard testing Nerve conduction studies Needle EMG Exercise testing Short exercise test Long exercise test Cold Exercise test WHEN SHOULD AN EXERCISE TEST BE CONSIDERED? Any myotonic disorder in which a dystrophic myotonic disorder has been excluded or is not suspected. Any patient with episodic flaccid weakness, particularly of early age onset ***Unlikely to be helpful if description of weakness is more suggestive of fatigue, or if there is a change in alertness, ability to speak, etc ***Stiffness is not related to a channelopathy if there is no clinical or electrical myotonia THE EXERCISE TEST First described in 1986 (McManis et al. Muscle Nerve) Modified motor nerve conduction study recorded from abductor digiti minimi (ulnar) to assess muscle fiber excitability Numerous components/protocols Short and long versions (Exercise: 10 sec. vs. 5 min.) Specific patterns of abnormalities can help clarify phenotype and suggest which ion channel is affected BASIS OF THE EXERCISE TEST Non-specific EMG findings during acute bout of weakness include reversible findings of …. Myopathic motor unit action potentials Reduced CMAP amplitudes Blocking of action potentials of the motor unit action potential Triggers of bouts of weakness or myotonia Exercise COMPOUND MUSCLE ACTION POTENTIAL (CMAP) Wilbourn Weakness in periodic paralysis is associated with loss in amplitude and area (muscle fiber inexcitability) LONG EXERCISE TEST PROTOCOL Ulnar motor NCS recording setup Baseline CMAP measurements Isometric contraction for 5 minutes (max) with 1-2 seconds rest every 30 - 40 seconds Record: -CMAP after 5 min exercise -CMAP every 1 min for 5 minutes -CMAP amplitude every 5 minutes until amplitude stabilizes (up to about an hour) LONG EXERCISE TEST: INTERPRETATION . Normal controls 5.4% to 28.8% decrement (mean 15%) . Results: Abnormal if >40% CMAP amplitude reduction from baseline . About 70-80% sensitive for periodic paralysis (McManis et al. 1986) . 97% specific if all causes of periodic paralysis considered (Kuntzer et al. 2000) Example: Normal LET 140 120 100 80 Nor… 60 40 % Baseline CMAP%amplitude Baseline 20 0 0 10 20 30 40 50 60 70 80 Time (minutes) Example: Abnormal LET 140 120 100 80 Periodic… 60 40 % Baseline CMAP%amplitude Baseline 20 0 0 5 10 20 30 40 50 60 70 Time (minutes) LONG EXERCISE TEST LONG EXERCISE TEST SHORT EXERCISE TEST Examines short-term muscle fiber excitability after a brief 10” exercise, (Streib 1987) Useful to characterize patients with myotonia without episodic weakness Protocol: Ulnar motor NCS recording setup,Baseline CMAP measurements Isometric contraction for 10” Record: CMAP every 10” for 1 minute Immediately repeat for a total of three bouts of exercise/CMAP recordings Three described patterns SHORT EXERCISE TEST Pattern I: Progressive drop Expected in: Paramyotonia congenita Physiological correlate: Pattern
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