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Home , Channelopathy, Episodic ataxia, Erythromelalgia, Malignant hyperthermia, Myopathy, Myotonia

Muscle

Stanley Iyadurai, MSc PhD MD Assistant Professor of , Neuromuscular Specialist, OSU, Columbus, OH

August 28, 2015 24 F 9 M 18 M 23 F 16 M

8/10 Occasional “Paralytic “ 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 Episodic Hypo Per ADNFLE PMC

CHANNELOPATHIES DEFINITION

Channelopathy: a 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 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  MUSCLE CHANNELOPATHIES  Malignant CNS   Generalized Epilepsy with Febrile Seizures Plus Hereditary & Peripheral nerve Acquired   Congenital Insensitivity to NMJ  Congenital Myasthenic Syndromes   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 up and unable to open hand Severe migraines associated with right-sided numbness Exam well-defined musculature and grip 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 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 of varying frequency and amplitude WHY DOES MYOTONIA OCCUR? 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 . 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 myotonia SCN4A Myotonia

Paramyotonia congenita

Myotonia congenita CLCN1

PARAMYOTONIA CONGENITA Characterized by myotonia and episodic , aggravated by exercise and cold Mix autonomous action potentials and sodium channel inactivation Autosomal dominant Related to SCN4A 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 gene, CLCN1 Autosomal dominant (Thomsen) and recessive (Becker) forms Myotonia is related to reduced Cl- channel conductance, causing a shift in 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  -responsive myotonia HYPERKALEMIC PERIODIC PARALYSIS

. Characterized by episodic attacks of and myotonia . Triggers may include exercise, fasting, or cold exposure . Earlier age of onset (first decade) . AD, 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 channel (CACNA1S) accounts for 70% of patients; SCN4A mutations account for about 10%

ANDERSEN-TAWIL SYNDROME

Characterized by  Episodic 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 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 is affected

BASIS OF THE EXERCISE TEST

Non-specific EMG findings during acute bout of weakness include reversible findings of ….  Myopathic 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 CMAPamplitude%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 CMAPamplitude%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 of decrement mirrors paradoxical worsening of myotonia Tan et al. 2011 with exercise

SHORT EXERCISE TEST Pattern II: Initial drop Expected in: Myotonia congenita

Physiological correlate: Warming up phenomenon

Tan et al. 2011 SHORT EXERCISE

TEST Pattern III: No change

Expected in: . Sodium channel myotonia . Normal/control populations . Pattern 3 is the lack of a pattern….no change Tan et al. 2011 COOLING – ADDITION TO THE EXERCISE TEST PROTOCOL?

Multiple reports of modifying the exercise test with the addition of muscle cooling

May help reveal pattern two in AD myotonia congenita

May help confirm paramyotonia associated cold- sensitivity

PARAMYOTONIA: WITH COOLING

Tan et al. 2011 MYOTONIA CONGENITA: WITH COOLING

Tan et al. 2011 Clinical Paramyotonia Myotonia Sodium Hyperkalemic Hypokalemic Andersen- Phenotype Congenita Congenita Channel Periodic Periodic Tawil Myotonia Paralysis Paralysis Syndrome Ion Channel Na (SCN4A) Cl (CLCN1) Na Na Ca (70%) K (KCNJ2) Involved Na (10%) Na

Edx pattern1 I II III IV V Similar to IV

Myotonia Yes Yes Yes Yes No Yes

SET decrement >20%2 decrement Normal Normal Normal Normal >20%2

LET Normal Normal Normal >40% decrement >40% decrement >40% decrement

1 Fournier et al. 2004. SET: short exercise test; LET: long exercise test 2 Tan et al 2011. Fournier 2006 Tan et al. 2011 SCN4a Mutation TREATMENT

Treatment is usually determined by clinical phenotype or genotype

Comprised of combined lifestyle modification and strategies

Treatment: and potential triggers

Medication Paramyotonia Myotonia Sodium Channel HyperPP HypoPP ATS Congenita Congenita Myotonia

Acetazolamide Yes/No No Yes/No Yes Yes Yes

Dichlorphenamide Yes/No No Yes/No Yes Yes Yes

Thiazides No No No Yes No Yes

Mexiletine Yes Yes Yes Yes/No No No

Triggers Cold, exercise Cold, stress, Cold, exercise Rest after Rest after Rest after pregnancy exertion, K exertion, exertion rich foods, carbs cold

Meola et al 2008. Tawil et al 2000. Matthews et al 2011. Trip et al 2011. Barohn et al. Clinical Investigation of Neurological Channelopathies (CINCH) JM EMG/NCS – SHORT EXERCISE TEST

LONG EXERCISE TEST

Pattern 3 CASE RESOLUTION

Acetazolamide-responsive Paramyotonia Congenita

Mutation in a Conserved Sequence in SCN4A gene SUMMARY

1. Episodic neurologic disorders cause symptoms in discrete attacks. Between attacks, patients appear to be normal. 2. Attacks are often triggered by commonplace stimuli such as hunger or emotional stress. For most disorders, we do not understand how these stimuli trigger attacks. 3. Episodic neurologic disorders can be caused by a mutation in a single gene (Mendelian). Alternatively, they may be genetically complex: influenced primarily by environmental factors, with some polygenic genetic contribution. The four common complex disorders are transient ischemic attack, , epilepsy, and migraine. 4. Many rare complex episodic neurologic disorders exist. For example, autoimmune episodic disorders are caused mostly by against ion channels or channel-related proteins. 5. Many Mendelian episodic neurologic disorders exist, each of which is rare. Most affect a single anatomical location: skeletal muscle, cardiac muscle, , peripheral nerve, or CNS. 6. Most Mendelian episodic disorder genes encode ion channels. Mutant channels are dysfunctional, and ensuing alterations in membrane excitability cause disease. 7. Investigators have recently identified many causative genes that do not encode ion channels. Some alter expression, localization, or function of channels. However, for many others we do not know yet how the mutant gene leads to changes in excitability. 8. Recent progress indicates that episodic neurologic disorders may also be caused by dysfunction at the synaptic and neuronal circuit levels, suggesting an expansion of the channelopathy spectrum. Thanks SODIUM CHANNEL MUTATIONS

-over 30 missense mutations identified SPECTRUM OF MUSCLE CHANNELOPATHIES Fournier 2006 Fournier 2006 Current-voltage relationships in normal and HypoPP: Net current

A small reduction in eternal K is sufficient to flip the to depolarized state. K+ -rectifying current muscle fibers become inexcitable

Burge and Hanna Curr Neurol Neurosci Rep 2012 TABLE 1. MYOTONIC DISORDERS AND THEIR MIMICS. MYOTONIA-LIKE SYMPTOMS WITHOUT ELECTRICAL MYOTONIA

Stiff-person syndrome Neurogenic muscle Schwartz-Jampel syndrome Hereditary familial episodic ataxia type 1 Brody disease TABLE 1. MYOTONIC DISORDERS AND THEIR MIMICS. CLINICAL AND ELECTRICAL MYOTONIA*

Myotonic dystrophy type 1 Hyperkalemic periodic paralysis with paramyotonia type 2 Myotonia fluctuans Paramyotonia congenita Myotonia permanens Thomsen disease Acetazolamide-responsive myotonia Fluctuating myotonia congenita Hyperkalemic periodic paralysis Becker disease Myotonia levoir

TABLE 1. MYOTONIC DISORDERS AND THEIR MIMICS. ONLY ELECTRICAL MYOTONIA* Myotubular Malignant hyperpyrexia Hypothyroidism Acid maltase deficiency Severe denervation Caveolinopathy

Medications: HMG-CoA reductase inhibitors, , Clofibrate, Propranolol, Fenoterol, Terbutaline, , Diazocholesterol, Monocarboxylic acids, Cyclosporine, Anthracene-9- carboxylic acid, 2,4-dichlororophenoxyacetic acid