Course: Myalgia, Neuralgia, and Arthralgia “Myalgia: Muscle Disorders and Pain” 1 W. David Arnold, MD AAPMR 2015.

Muscle impedance as a Therapeutic Biomarker of Spinal Muscular Atrophy

Course: Myalgia, Neuralgia, and Arthralgia

Myalgia: Muscle Disorders and Pain1W. David Arnold, MDAAPMR 2015

Muscle Disorders and PainOverview of the problemExamples of myopathies associated with painNon-muscle disorders associated with myalgiaApproach and diagnosis of the patient with myalgia

Acknowledgements:

I receive funding through the RMST program (NICHD 5K12HD001097-17)

John T. Kissels 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 fatigue95% of patients with chronic fatigue syndrome have myalgia

Myalgia: the problem..Pain is often an isolated symptomNo objective signs of disease (i.e. weakness) Myalgia may arise from many sourcesOrthopedic, rheum, endocrine, vascular, psychologicalMay not be related to muscle diseaseMany patients, despite extensive workup are not diagnosable

Myalgia TerminologyTypes of PainMay be useful to classify into types:Contractures StiffnessCrampsAching myalgia (after Layzer, 1985)Types of Muscle PainContractureLeast common myalgia, can be excruciatingForceful, sustained contractionLocalized hard nodule in muscleElectrically silent by EMG!Sudden onset with exercise (may be mild)May persist for hours & result in rhabdo.Hallmark of glycolytic dx. (eg McArdles)FET useful screen for these disordersOthers: Brodys disease, hypothyroidTypes of Muscle Pain CrampsIdiopathic (normal cramps)Exertional, post-exertional, nocturnalNeurogenic cramps MND, PN, radics, others.Cramps due to altered neural environmentPregnancyMetabolic disorders (renal or liver failure)HypothyroidismAdrenal insufficiencyElectrolyte disturbances/volume depletionCramps are related to nerve hyperexcitability, electrically active on EMG

Muscle StiffnessDifferential Diagnosis8Myotonic disordersDM 1 & 2MC and PMCHypothyroidismHypo PPBrodys diseasePMRFibromyalgia

Myotonic DystrophyTwo characterized typesDM1-more common and usually more severeDM2Multisystem diseaseMuscleEyes (cataracts)GICardiac-mainly arrhythmia (30% mortality)CNS (cognitive and personality)Pulmonary (restrictive and hypoventilation)

Autosomal DominantTriplet repeat disease associated with anticipationDM2 has been associated with fibromyalgia in case series and case reports --Auvinen et al. 2008

Periodic ParalysisNondystrophic myotoniaAndersen-Tawil syndrome

Hypokalemic PP

Hyperkalemic PP

Sodium Channel myotonia

Paramyotonia congenita

Myotonic congenitaKCNJ2

CACNA1S

SCN4A

CLCN1

Muscle ChannelopathiesDisease/Phenotype Gene

Stiffness, +/- painTreatment: medications and potential triggersMedicationParamyotoniaCongenitaMyotonia CongenitaSodium Channel MyotoniaHyperPPHypoPPATSAcetazolamideYes/NoNoYes/NoYesYesYesDichlorphenamideYes/NoNoYes/NoYesYesYesThiazidesNoNoNoYesNoYesMexiletine

YesYesYesYes/NoNoNoTriggersCold, exerciseCold, stress, pregnancyCold, exerciseRest after exertion, K rich foods, coldRest after exertion, carbsRest after exertionMeola 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 PainDeep Aching - Generalized Differential DiagnosisWith weaknessPM, DMHypothyroidismMitochondrial dx.Myotonic dystrophy 2Infectious myopathiesOther rare myopathies

Without weaknessInfectious myalgia (esp. viral)Toxic myopathies (eg statin)PMRFibromyalgia

Polymyalgia RheumaticaEpidemiologyTechnically not muscle disease per seCommon causes of myalgia600-1000/100,000 in patients >age 50Incidence of ~50/100,000 per yearMean age of onset 70 (90% > age 60)Female predominance of 3:1Polymyalgia RheumaticaTreatmentPrednisone (10-40 mg/day) causes immediate and dramatic improvementDiagnostic and therapeuticTreat symptoms and ESRTaper slowly when sxs. under controlUsually requires 1-2 years treatment10% require treatment for over 10 years!Diffuse MyalgiaInflammatory Muscle Disease*

*Myth: ALL PM/DM pts. have sig. myalgias (only ~25% do!)Examples of Focal Myalgia

Sarcoid Myopathy Diabetic Thigh InfarctYield of workup:Diagnoses in Myalgia PatientsMills and Edwards, 1983Diagnosis# Pts. % Enzyme defects1615%Inflammatory myopathy 8 7%Neurogenic disorders 7 6%Endocrine & metabolic 6 6%No diagnosis72 66%

Total 109100%18Filosto et al, Neurology 2007240 patients presenting with myalgiasExcluded statin patients; only 2 FM patientsBattery of tests done on each biopsyHistochem, biochem, immunohistochemistryNo genetic testingCorrelated findings with CK, EMG, clinical picture

Filosto et al, 2007Five groups of biopsies19% normal 81% abnormal BUT

Only 20% had diagnosisOnly 6% had muscle diagnosis (metabolic)Only 2% with normal strength had diagnosis!

NeuMitNlMyoMetFilosto et al, Neurology 2007Many myalgia patients DO have biopsy abnormalities, but they are usually non-specificThey usually do NOT lead to a diagnosis Routine biopsy NOT indicated in patients with isolated myalgia; careful patient selection is neededImportant info for referring doctors AND patients!The Patient with Muscle PainGeneral Approach Careful history attending to type of painConsideration of localization/pathogenesisAnalysis of disease possibilitiesExam. 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 PainFM/sfn? Tender points present?pmr,statins Tender points absent?NormalRepeat5x normal,other abnCK elevatedFET, GenetictestingWeak, abn EMG, CKMSK & neuro exam with particular attention to strength

Labs. CK, CBC, ESR, TFTs, lytes, Edx studiesBiopsyObjective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia.Oaklander et al. Pain. 154(11):2310-2316, November 2013.

Decreased nerve fiber density noted in large percentage of patients with FMMyalgia in non-muscle related disorders

Normal skin biopsyNormal innervation with arrows indicating small nerve fibers in epidermis.No small nerve fibers are seen in the epidermisSmall fiber neuropathyTAVEE J , ZHOU L 2009Other testing in myalgia: skin biopsy?25

Abnormal: reduced sweat response at foot

Normal sweat response at forearm

Testing in myalgia- Quantitative sudomotor axon reflex testingQSART: assesses the integrity of postganglionic sympathetic sudomotor efferents, which are activated via an axon reflex by controlled iontophoretic stimulation with acetylcholineConclusionsPain is a frequent reason for referral to the neuromuscular specialistPatients with myalgia infrequently have a primary muscle disorderMuscle biopsy is a low-yield evaluation in the absence of weakness or a CK >1000Non-muscle disorders are more often the cause of myalgia-like symptoms