Course: Myalgia, Neuralgia, and Arthralgia “Myalgia: Muscle Disorders and Pain” W. David Arnold, MD AAPMR 2015

Muscle Disorders and Pain Overview of the problem Examples of myopathies associated with pain Non-muscle disorders associated with myalgia Approach and diagnosis of the patient with myalgia Acknowledgements: I receive funding through the RMST program (NICHD 5K12HD001097-17) John T. Kissel’s expertise and input regarding content

Myalgia: the stats.. Common reason for referral in NM clinics ~50% of referrals (i.e. for muscle biopsy) 90% of myalgia patients have fatigue 95% of patients with chronic fatigue syndrome have myalgia

Myalgia: the problem.. Pain is often an isolated symptom No objective signs of disease (i.e. weakness) Myalgia may arise from many sources Orthopedic, rheum, endocrine, vascular, psychological May not be related to muscle disease Many patients, despite extensive workup are “not diagnosable”

Myalgia Terminology Types of Pain May be useful to classify into types: Contractures Stiffness Cramps Aching myalgia (after Layzer, 1985)

Types of Muscle Pain Contracture Least common myalgia, can be excruciating Forceful, sustained contraction Localized hard nodule in muscle Electrically silent by EMG! Sudden onset with exercise (may be mild) May persist for hours & result in rhabdo. Hallmark of glycolytic dx. (eg McArdle’s) FET useful screen for these disorders Others: Brody’s disease, hypothyroid

Types of “Muscle Pain” Cramps Idiopathic (normal cramps) Exertional, post-exertional, nocturnal Neurogenic cramps MND, PN, radics, others. Cramps due to altered neural environment Pregnancy Metabolic disorders (renal or liver failure) Hypothyroidism Adrenal insufficiency Electrolyte disturbances/volume depletion Cramps are related to nerve hyperexcitability, electrically active on EMG

Muscle Stiffness Differential Diagnosis Myotonic disorders DM 1 & 2 MC and PMC Hypothyroidism Hypo PP Brody’s disease PMR Fibromyalgia

Myotonic Dystrophy Two characterized types DM1-more common and usually more severe DM2 Multisystem disease Muscle Eyes (cataracts) GI Cardiac-mainly arrhythmia (30% mortality) CNS (cognitive and personality) Pulmonary (restrictive and hypoventilation) Autosomal Dominant Triplet repeat disease associated with anticipation DM2 has been associated with fibromyalgia in case series and case reports --Auvinen et al. 2008

Nondystrophic myotonia Muscle Channelopathies Disease/Phenotype Gene KCNJ2 Andersen-Tawil syndrome Hypokalemic PP Hyperkalemic PP Sodium Channel myotonia Paramyotonia congenita Myotonic congenita Periodic Paralysis CACNA1S Nondystrophic myotonia SCN4A CLCN1 Stiffness, +/- pain

Treatment: medications and potential triggers Paramyotonia Congenita Myotonia Congenita Sodium Channel Myotonia HyperPP HypoPP ATS Acetazolamide Yes/No No Yes Dichlorphenamide Thiazides Mexiletine Triggers Cold, exercise Cold, stress, pregnancy Rest after exertion, K rich foods, cold Rest after exertion, carbs Rest after exertion 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)

Study of Ranolazine in Myotonia Congenita and Paramyotonia Congenita Sponsor: Ohio State University and Gilead Sciences ClinicalTrials.gov Identifier: NCT02251457 This study is currently recruiting participants.

Types of Muscle Pain Deep Aching - Generalized Differential Diagnosis With weakness PM, DM Hypothyroidism Mitochondrial dx. Myotonic dystrophy 2 Infectious myopathies Other rare myopathies Without weakness Infectious myalgia (esp. viral) Toxic myopathies (eg statin) PMR Fibromyalgia

Polymyalgia Rheumatica Epidemiology Technically not muscle disease per se Common causes of myalgia 600-1000/100,000 in patients >age 50 Incidence of ~50/100,000 per year Mean age of onset 70 (90% > age 60) Female predominance of 3:1

Polymyalgia Rheumatica Treatment Prednisone (10-40 mg/day) causes immediate and dramatic improvement Diagnostic and therapeutic Treat symptoms and ESR Taper slowly when sxs. under control Usually requires 1-2 years treatment 10% require treatment for over 10 years!

Diffuse Myalgia Inflammatory Muscle Disease* *Myth: ALL PM/DM pts. have sig. myalgias (only ~25% do!)

Examples of Focal Myalgia Sarcoid Myopathy Diabetic Thigh Infarct

Yield of workup: Diagnoses in Myalgia Patients Mills and Edwards, 1983 Diagnosis # Pts. % Enzyme defects 16 15% Inflammatory myopathy 8 7% Neurogenic disorders 7 6% Endocrine & metabolic 6 6% No diagnosis 72 66% Total 109 100%

Filosto et al, Neurology 2007 240 patients presenting with myalgias Excluded statin patients; only 2 FM patients Battery of tests done on each biopsy Histochem, biochem, immunohistochemistry No genetic testing Correlated findings with CK, EMG, clinical picture

Filosto et al, 2007 Myo Five groups of biopsies 19% normal Mit Nl 81% abnormal BUT Only 20% had diagnosis Only 6% had muscle diagnosis (metabolic) Only 2% with normal strength had diagnosis! Mit Nl Neu Met

Filosto et al, Neurology 2007 Many myalgia patients DO have biopsy abnormalities, but they are usually non-specific They usually do NOT lead to a diagnosis Routine biopsy NOT indicated in patients with isolated myalgia; careful patient selection is needed Important info for referring doctors AND patients!

The Patient with Muscle Pain General Approach Careful history attending to type of pain Consideration of localization/pathogenesis Analysis of disease possibilities Exam. with attention to strength testing! Most common mistake we see (& make)!! Judicious lab tests Routine (e.g. CK and EMG) Specialized (biopsy, genetic testing)

Evaluation of Muscle Pain MSK & neuro exam with particular attention to strength Labs. CK, CBC, ESR, TFTs, lytes, Edx studies Normal CK elevated Weak, abn EMG, CK Tender points present? Tender points absent? FET, Genetic testing <5x nl No other abn >5x normal, other abn pmr,statins FM/sfn? Repeat Biopsy Biopsy

Myalgia in non-muscle related disorders Decreased nerve fiber density noted in large percentage of patients with FM Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Oaklander et al. Pain. 154(11):2310-2316, November 2013.

Other testing in myalgia: skin biopsy? Normal skin biopsy Small fiber neuropathy Normal innervation with arrows indicating small nerve fibers in epidermis. No small nerve fibers are seen in the epidermis TAVEE J , ZHOU L 2009

Quantitative sudomotor axon reflex testing Testing in myalgia- Quantitative sudomotor axon reflex testing Normal sweat response at forearm QSART: assesses the integrity of postganglionic sympathetic sudomotor efferents, which are activated via an axon reflex by controlled iontophoretic stimulation with acetylcholine Abnormal: reduced sweat response at foot

Conclusions Pain is a frequent reason for referral to the neuromuscular specialist Patients with myalgia infrequently have a primary muscle disorder Muscle biopsy is a low-yield evaluation in the absence of weakness or a CK >1000 Non-muscle disorders are more often the cause of myalgia-like symptoms