Muscle pain

Home, Search, Index, Links, Pathology, Molecules, Syndromes,
Muscle, NMJ, Nerve, Spinal, Ataxia, Antibody & Biopsy, Patient Info

MUSCLE PAIN & DISCOMFORT

Generalized
Drugs
Myopathic
Non-muscle disorders
Polymyalgia
Localized
Cramps: Differential diagnosis
Pain medications
Principles
Pain
Muscle pain

Also see
Painful neuropathies

GENERALIZED MUSCLE PAIN: Differential Diagnosis

Myopathic pain: Usually with High CK & Abnormal EMG; Weakness common

Inflammatory
- Inflammatory myopathies
- Muscle infections
  - Viral myositis
  - Pyomyositis
  - Toxoplasmosis
  - Trichinosis
Rhabdomyolysis ± Metabolic disorder
Other myopathies with pain or myalgias
- Myoadenylate deaminase
- Myopathy with focal depletion of mitochondria
- Myopathy with tubular aggregates ± cylindrical spirals
- Myopathy with tubulin-reactive crystalline inclusions
- Myopathy with hexagonally cross-linked crystalloid inclusions
- Dystrophy-related: Dystrophin; α-sarcoglycan
- Neuromyopathy with internalized capillaries
- Myotonias: PROMM; Dominant myotonia congenita (Occasional)
- Selenium deficiency
- Toxic myopathy: Eosinophilia myalgia; Rhabdomyolysis
- Hypothyroid myopathy
- Mitochondrial disorders
- Camurati-Engelmann syndrome
- Vitamin D deficiency
Pain of muscle origin without chronic myopathy
- Muscle ischemia: Atherosclerosis; Calciphylaxis; Diabetes
- Cramps
- Muscle overuse syndromes
  - Drugs & toxins
  - Delayed onset muscle soreness (DOMS)
- Muscle injury (strain): External link-Iowa
Drugs & Toxins

Polymyalgia syndromes

Features
- Muscle pain without weakness: Pain may interfere with effort
- Pain: Present at rest; ± Increased with movement
- Muscle tenderness: Diffuse or Multifocal
- Serum CK: Normal
- No pathologic changes in muscle
Disorders
- Polymyalgia rheumatica
- Fibromyalgia
- Chronic fatigue syndrome
- Infections
  - Viral & post-viral syndromes
  - Brucellosis; Leptospirosis; Falciparum malaria
- Systemic connective tissue disorders: Sjögren's
- Drugs & Toxins
- Hereditary
  - Familial Mediterranean Fever (Febrile myalgia syndrome): MEFV
  - Familial Cold Autoinflammatory Syndromes: Episodic myalgias; Dominant
    - 1 (FCAS1) : NLRP3
    - 2 (FCAS2)
- Non-muscle pain with defined origin
- Polyneuropathy: Small fiber

Muscle Cramps

Clinical features
- Acute onset
- Short duration
- Muscle contraction: Strong & palpable
- Relief by stretching muscle
Etiologies
- Ordinary: Common in normal people
  - Distribution
    - Gastrocnemius
    - Frequent cramps in other muscles suggests neuromuscular disease
  - Onset
    - During or after exercise
    - Sleep
  - Provoked by
    - Contraction of shortened muscle
    - 10 Hz electrical stimulation
  - Neurogenic: ? Terminal region of peripheral nerve
  - Stretching muscle terminates cramp
- Familial
  - Becker Dystrophy
  - Phosphorylase deficiency (McArdle's)
    - Always provoked by ischemic exercise
    - Electrically (EMG) silent
  - Other familial cramp syndromes
  - Note: Myotonic cramps are not usually painful
- Systemic disorders
  - Hypothyroid
  - Electrolyte & metabolic disorders
    - Dehydration: Hidrosis; Diuretics; Hemodialysis
    - Metabolic: Low Sodium, Magnesium, Calcium, Glucose
- Neurogenic
  - ALS & Motor neuron disorders
  - Neural Overactivity Syndromes
  - Spinal Stenosis
- Drugs & Toxins
Also see: Cramps

Non-muscle disorders

Features
- Serum CK: Normal
- Serum EMG: Normal
Etiologies
- Connective tissue disorders: Fasciitis; Systemic
- Bone
  - Osteomalacia: Vitamin D deficiency; Oncogenic
  - Fracture (Hip)
  - Myeloproliferative
  - Fluorosis
- Endocrine
  - Thyroid: Hyper- or Hypo-
  - Parathyroid: Hyper- or Hypo-
- Vascular: Ischemia; Thrombophlebitis
- Polymyalgia syndromes
- Joint disease: Immune; Hypermobility syndromes; Gout; Degenerative
- Polyneuropathy
- CNS
  - Restless legs: Paresthesias; Hereditary (12q) or Renal failure
  - Dystonias (Focal)

MUSCLE DISCOMFORT ± MYOPATHY: DRUGS & TOXINS
Inflammatory Myopathy	Rhabdomyolysis & High CK ± Chronic myopathy	Painful myopathy ± Rhabdomyolysis	Myalgia ± Myopathy	Cramps
Definite Hydralazine Penicillamine Procainamide L-tryptophan (impurity) Possible Cimetidine Interferon-α Ipecac Leuprolide Levodopa Penicillin Phenytoin Propylthiouracil Proton pump inhibitors Sulfonamide	Alcohol e-Amino Caproic Acid Amphetamines Anti-Psychotics Loxapine Quetiapine Cocaine Cyclosporine Hypokalemia Isoniazid Lipid lowering agents Fibrates Bezafibrate Clofibrate Gemfibrozil Statins Lovastatin Simvastatin Pravastatin Fluvastatin Atorvastatin Cervistatin Red yeast rice Lithium Mibefradil Neuroleptic-Malignant Propofol Zidovudine	Colchicine Emetine Germanium Hypervitaminosis E Taxenes Zidovudine	All-Trans-Retinoic Acid Azathioprine Bryostatin 1 Captopril Ciguatoxin Corticosteroids Withdrawal Cytotoxics Danazol Enlapril Gemcitabine Gold Interferon α-2a Interferon α-2b Isotretinoin Ketorolac Labetalol Methotrexate Metolazone Mycophenolate mofetil Neuropathy: Small fiber Paclitaxel Retinoids Rifampin Spanish toxic oil Suxamethonium (Succinylcholine) Tyrosine kinase inhibitors Vinca alkaloids Zimeldine	Albuterol Anti-Cholinesterase Bergamot (bergapten) Caffeine Clofibrate Cyclosporine Diuretics Labetalol Lithium Nifedipine Terbutaline Tetanus Theophylline Vitamin A

Localized Muscle Pain

Trauma
Mass: Hematoma; Neoplasm; Infection
Vascular: Thrombophlebitis; Ischemia
Nerve: Neuropathy; Radiculopathy
Movement disorder: Restless legs; Moving toes
Adenosine, intraarteriolar: Ischemic-like pain
Cramps

PAIN: Principles ³

Pain
Categories
Definitions
Drugs
Modulation
Muscle
Sensitization

Painful neuropathies

Nociceptive system
Afferent neurons & axons
Primary (PNS)
Secondary (CNS)
Descending pathways
Pain perception
Sensory terminals
Nociceptor (axon) types
Stimulus types
Acid
Chemical
Temperature
Mechanical
Sensitization
TRP channels

Pain from noxious stimulation
of normal tissue

Definitions

Pain
- Subjective response to nociceptive input to brain
- Components
  - Motivational-Affective: Emotional
  - Sensory-Discriminative
Nociception
- Awareness of the stimulation of nociceptors by a noxious stimulus
- Pathway
  - Transduction: Noxious stimuli are converted to electrical impulses in sensory nerve terminals
  - Transmission: Conduction of impulses along axons to CNS
  - Modulation: Inhibitory & excitatory mechanisms; Occurs in PNS & CNS
  - Perception
    - Perception in thalamus
    - Cortex: Discrimination of specific sensory experiences
Pain categories
- Nociceptive pain
  - Elicited by noxious stimulation of normal tissue
  - Elicited when tissue is in pathological state (Hyperalgesia & Allodynia)
- Neuropathic pain: Elicited when sensory axons or cell bodies are damaged

Pain Categories

Nociceptive pain: Elicited by noxious stimulation of normal tissue

Stimulus: Tissue damage
Clinical relevance: Short term pain control may be needed
Perceptual categories
- Pricking (First pain)
  - Quality: Sharp
  - Temporal: Initial pain sensation; Brief
  - PNS axons: Aδ fibers
  - CNS pathway: Somatosensory to thalamus & cortex
- Burning (Second pain)
  - Qualities: Dull; Aching; Unpleasant
  - Temporal: Later, more long-lasting pain sensation
  - PNS axons: C fibers
  - CNS: Reticular formation; Periaqueductal gray; Hypothalamus; Central thalamus

Nociceptive pain: Elicited when tissue is in pathological state

Associated with inflamed or damaged tissue
May occur with stimulus or spontaneously
Nociceptive system may become more sensitive to stimuli
- Hyperalgesia
  - Definition: Noxious stimulus produces exaggerated and prolonged pain sensation
  - Types
    - Mechanical: May be associated with central sensitization
    - Heat: Associated with peripheral nociceptive sensitization
    - Secondary hyperalgesia: Painful stimulus produces pain experienced outside area of injury or input
      - May be due to enlarged receptive fields of CNS neurons
  - Mechanisms: May be associated with inflammation
  - Toxic models
    - Capsaicin
      - Induces burning sensation & Strong mechanical hyperalgesia
      - May be associated with central mechanisms
    - Melittin
      - Bee venom component
      - Induces heat hyperalgesia
- Allodynia
  - Definition: Pain induced by stimuli not usually causing pain
  - Pathways
    - Peripheral
      - Tactile: Via low threshold myelinated Aβ fibers
        
        Neuropeptide Y upregulation
        Na_v1.9 channel upregulation
        P2RX4 receptors
        
        Blockade reverses tactile allodynia
        
        Expression in ipsilateral spinal cord increased after nerve injury
      - Thermal: Via unmyelinated axons; Opioid receptors
        
        Associated with: SCN10A channels (Na_v1.8)
        
        Controlled by: HCN2 channels
      - Mechanical
        
        Na_v1.6 channel involvement
    - Central pain can be produced by
      - Spinothalamic tract axon activity: Deep; Nociceptive specific ¹⁹
        
        Change in threshhold after nerve injury: To innocuous tactile range
        
        Associated with
        
        Block of: K⁺ �Cl^- co-transporter 2 (KCC2; SLC12A5)
        
        Deregulation of intracellular Cl^- homeostasis
        
        Inhibited by stimulation of: KCC2
      - Activity in non-nociceptive primary sensory fibres: Lamina I relay pathway
- Referred pain: Pain in regions apart from damaged tissue
- CNS pathologic changes
  - Persistence of increased pain sensation: Depends on contionued peripheral input
  - Loci of central sensitization: Dorsal horn; Ascending sensory axons; Brainstem; Thalamus; Cortex
Pain may become chronic
- Hypersensitivity to pain signals
- Anti-nociception resistance

Neuropathic pain

Mechanisms
- Related to spontaneous activity of sensory axons
- Elicited when sensory axons or cell bodies are damaged
- Not related to damage in innervated tissue: Occurs without an inflammatory reaction
- Related disorder: Neuroma
Sensation qualities
- C-axon damage: Burning
- Aβ axon damage
  - Paresthesias: Abnormal, non painful sensation; Pins & Needles
  - Dysesthesias: Abnormal unpleasant, not necessarily painful sensation
  - Pain
- Also: Shock-like, shooting pain
Pain precipitants: May occur spontaneously or with stimulus
Temporal
- Continuous or Episodic
- Often chronic and difficult to treat
Associated with sensitization: Both central & peripheral mechanisms

Nociceptive system

Afferent neurons & axons
Primary (PNS)
Secondary (CNS)
Descending pathways
Pain perception
Sensory terminals
Nociceptor (axon) types
Stimulus types
Acid
Chemical
Temperature
Mechanical
Sensitization

Signalling mechanisms in afferent neurons: General
- Polymodal nociceptors: Use great diversity of signal-transduction mechanisms to detect stimuli
  - Single type of stimulus can interact with multiple detectors
  - Different signal-transduction mechanisms to detect physical and chemical stimuli
- Other primary sensory neurons (Smell; Light): Use single predominant ion channel & 2nd messenger system
Stimulation of nociceptive sensory terminals
- Types of stimulation
  - Activation
    - Transmits afferent messages to spinal cord dorsal horn & brain
    - Initiates neurogenic inflammation
  - Sensitization: Underlies spontaneous pain, hyperalgesia & allodynia
- Pain Stimuli
  - Mechanical
    - Stimuli: Direct pressure; Tissue deformation; Changes in osmolarity causing swelling (Stretch)
    - Channel activation: ENaC/DEG (ASIC2)
    - Stretch transmission: ? Associated with extracellular ATP & P2Y or P2X₃ receptors
    - Mechanical allodynia
      - Transmitted by sensitized Aβ axons
        
        Neuropeptide Y & Sodium channel (Na_v1.9) upregulation
        Sprouting of central terminals
      - Central pathway: To nucleus gracilis
  - Temperature
    - Heat, noxious
      - Threshold: ~45°C
      - Aδ & C axons
      - TRPV-channels: VR1 and VRL-1
    - Cold, noxious
      - Thresholds: ~4°C; <0°C activates more axons
      - Aδ & C axons: Minority
      - Associated with
        
        Up-regulation of TRPA1 receptors ¹²
        Due to NGF stimulation via p38 MAPK pathway
      - Na_v1.8 sodium channels
        
        Essential for sustained excitability of nociceptors when skin is cooled
        
        Inactivation properties of Nav1.8 are cold-resistant
        
        Allow perception of cold pain
    - Cold allodynia ¹⁶
      - General
        
        Experience of normally innocuous cooling as noxious pain
      - Clinical
        
        Associated with aching sensation
        
        Related disorders
        
        Posttraumatic neuralgias
        
        Small-fiber polyneuropathies: Some
        Chronic CRPS
        
        Oxaliplatin toxicity
        Cold injury
        Ciguatera poisoning
      - Mechanisms
        
        Axons involved
        
        Normally silent large diameter neurons
        
        Become sensitive to cooling with cold allodynia
        
        Respond to noxious mechanical stimuli
        
        Express nociceptor markers: Na_v1.8; CGRPα
        
        May be activated by blocking K_v1 K⁺ channels
        
        C-nociceptors
        
        Spontaneous discharge of cutaneous mechano-sensitive C-nociceptors
        
        Activation of CGRP-containing, mechano-insensitive C-nociceptors
        
        Possible involvement of TRPM8 (Menthol receptor)
        
        Menthol may sensitize axons to cold
        
        I_KD excitabilty brake current: Density reduced in ²¹
        
        Cold-sensitive neurons
        
        Polymodal nociceptors expressing TRPM8
        
        Cold injury related pain may be different mechanism
      - Variant: May be induced in normals by A-fiber block
    - Thermal allodynia
      - Unmyelinated axons
      - Opioid receptors
      - Associated with: SCN10A channels (Na_v1.8)
      - Controlled by: HCN2 channels
    - See
      - Temperature sensing channels
      - Oxaliplatin neuropathy
  - Chemical
  - Protons (Acidosis) and Pain
    - General
      - Local tissue acidosis: Common physiological response to injury
      - Degree of associated pain or discomfort is well correlated with the magnitude of acidification
      - Acid (pH 5) on skin stimulates 33% of polymodal nociceptors
    - DRG cellular effects: Sensory axons depolarized in 2 phases
      - Initial: Transient, rapidly inactivating current; Carried predominantly by Na⁺ ions
      - Secondary: Sustained non-selective cationic current
    - Candidate channels in afferent terminals
      - VR1: Sustained phase
      - ASIC family
        
        Single channel expression: Transient phase of current
        
        Co-expression of ASIC3 & ASIC2b
        
        Sustained component with non-selective cation permeability
        
        DRG afferents in heart: May be activated during cardiac ischemia (pH < 7)
- Polymodal nociceptors: DRG neurons that may express several channel types
  - TRPV1
  - TRPA1 (ANKTM1)
Primary afferent neurons: Activated by pain-producing stimuli
- Cell body & central
  - Size: Small
  - Location of cell bodies: Dorsal root or Trigeminal ganglion
  - CNS termination: Neurons in spinal cord dorsal horn
- Nociceptor types (in skin)
  - Aδ axons: Conduction velocities 5-30 m/s
    - Anatomy: Myelinated; Medium diameter
    - Subtypes
      - Type I: Mechanical (Intensive pressure) sensitive; Thermal threshold ~52°C; Insensitive to capsaicin
      - Type II: Thermal sensitive; Threshold ~45°C
  - C axons: Conduction velocities less than 1.0 m/s
    - Anatomy: Unmyelinated; Small diameter
    - Pharmacologic subtypes: ? Functional associations
      - Peptidergic: Contain Substance P; Express TrkA
      - P2X₃ receptor expression: Label with α-D-galactosyl-binding lectin IB₄
    - Other components
      - CGRP
      - PAR2
      - Sodium channels: TTX-resistant (Na_v1.8; Na_v1.9) & sensitive Na_v1.7
    - Stimuli
      - Most C axons are polymodal: Respond to noxious, thermal & mechanical stimuli
      - Some are mechanically insensitive, but respond to noxious heat
      - Most respond to noxious chemical stimuli, e.g acid or capsaicin
      - Thermal responses mediated by VR1 receptor
    - Toxin: Resiniferatoxin
  - Silent nociceptors: Responsive only when sensitized by tissue injury
    - Firing threshold decreased by inflammation
    - Role in hyperalgesia
  - Aβ axons
    - Anatomy
      - Myelinated; Large diameter
      - Project directly to supraspinal dorsal column nuclei
      - Send collaterals into laminas III and IV of spinal dorsal horn
    - Stimuli: May be associated with
      - Primary nociception
      - Allodynia (Mechanical)
- Nociceptor properties: Tissue variants
  - Cornea
    - Pain normally produced by innocuous tactile stimulation
    - Afferents can be activated by capsaicin & sensitized by inflammatory mediators
  - Teeth: Most stimuli produce pain
  - Viscera
    - No first (fast) and second (slow) components
    - Pain is often poorly localized, deep and dull
    - Tissue damage: Not required for visceral pain to occur
    - Pain can result from excessive distension (e.g. colon)
  - Ischemic pain
    - May reflect innervation of vasculature by acid-sensitive primary sensory nociceptors
- Transmitters
  - Glutamate: Predominant excitatory neurotransmitter in all nociceptors
    - Vesicles: Small electron lucent
    - Receptor: AMPA
    - Physiology: Fast synaptic potential in dorsal horn
    - Metabolism: Reuptake by presynaptic terminals
    - Action: On
      - Secondary afferent neurons: Post-synaptic membrane
      - Afferent terminals of primary sensory axons
    - See: Mechanisms of action
  - Neuropeptides
    - Types: Substance P; Calcitonin gene-related peptide (CGRP); VIP; Neurokinin
    - Vesicles: Large dense core
    - Synsthesis location: Dorsal root ganglion
    - Transport: To peripheral & central endings of axons
    - Metabolism: No reuptake mechanism
  - Transmitter release
- Peripheral receptors
  - Acid-induced pain
    - Acid-sensing ion channels: Amiloride sensitive; pH < 7.0
    - Vanilloid receptor subtype-1 (VR1): Capsazepine sensitive; pH < 6.0
  - Bradykinin: G-protein-coupled (BK₂) receptors
  - Serotonin (5-HT)
  - Prostaglandin E₂
  - ATP (Purinergic)
- Membrane channels: Sodium
  - Tetrodotoxin-sensitive
    - Na_v1.3: Groups I, II, III axons
    - Na_v1.7: Nociceptive DRG cells
  - Tetrodotoxin-resistant
    - Na_v1.8 & Na_v1.9: Group IV axons
Central pain pathways: Secondary afferent neurons & interneurons
- Termination of peripheral axons
  - C axons: Laminae I and II of dorsal horn
  - Transmitter: Glutamate
  - Synapse with: Secondary afferent neurons
  - Post-synaptic receptors
    - NMDA: Blocked by Magnesium
    - Central sensitization: Activity more with persistent than acute nociceptive stimuli
- Cell bodies: Secondary afferents
  - Location: Lamina V of dorsal horn
  - Types
    - Wide dynamic range: Respond to innocuous and noxious stimuli
    - Nociceptive-specific: Respond only to intense noxious stimulation in the periphery
- Axons: Central
  - Cross sides in spinal cord
  - Ascend: Especially in spinothalamic tract
  - Terminate: Thalamus (nucleus submedius); Brain stem
- Interneurons
  - Often inhibitory
  - Transmitter: γ-aminobutyric acid (GABA)
  - May be stimulated by Aβ axons
- Marker of activation: Expression of Fos protein
- Related disorders: Complex regional pain (Reflex sympathetic dystrophy)
Pain perception: ? Located in Thalamus & Cortex
- Psychophysical features
  - Components: Location; Intensity; Character; Duration
  - Location: 1° & 2° somatosensory cortex
- Affective features
  - Components: Unpleasantness & Rejection
  - Location: Limbic cortex (Cingulate & Insula)
  - Ascending pathway: Dorsal horn; Parabrachial nucleus; Amygdala
- Central mechanisms of nociception
  - Acute; Increased flow of action potentials
  - Chronic stimulation: May produce central sensitization
    - Central neurons have increased response to peripheral stimuli
    - Related to increased efficacy to synaptic transmission
    - Presynaptic mechanisms: Entry of Ca⁺⁺ ions through N-type & P-type Ca⁺⁺ channels
  - Transmitter system in cingulate & insular cortex
    - Transmitter: Glutamate
    - Receptors: N-methyl-D-aspartate (NMDA)
      - Enhance persistent chronic behavioral responses to tissue injury & inflammation
      - No effect on acute nociception in spinal cord
      - Susceptible to persistent pain & NR2B selective NMDA antagonists
    - Mouse models
      - Overexpression of NR2B NMDA receptors: Delayed behavioral responses; Greater mechanical allodynia
- Genetic components ¹⁴
  - Heat pain threshold (HPT)
  - Thermal burn
  - Punctate hyperalgesia: Secondary areas
  - Brush evoked allodynia
  - Pain during iontophoresis of adenosine triphosphate (ATP) & acid
Descending pathways ⁹
- Origins: Brain stem
  - Nucleus raphe magnus & Surrounding rostral ventromedial medulla
  - Perisylvian aqueduct grey matter
- Terminations: Trigeminal & Spinal relay areas (Lamina I)
- Functions
  - Inhibitory
    - Endogenous analgesia system
    - Enhanced after: Tissue injury with persistent noxious stimulation
    - Transmitter system: N-methyl-d-aspartate (NMDA); AMPA receptors
    - Associated with increased opioid sensitivity
  - Facilitatory
    - Contributes to persistent pain with secondary hyperalgesia & nerve injury
    - ? Associated with chronic deep pain

Pain Modulation: Central mechanisms

Gate control
- Aβ axons stimulate inhibitory interneuron
- Activity in central projection neuron is reduced
Descending brainstem pathways
Opiate-induced analgesia
- Opioid Receptors
  - Types
    - μ Receptor
      - Agonists: Morphine; [D-Ala²,N-Me-Phe⁴,Gly-ol⁵]-enkephalin (DAMGO)
      - Antagonist: H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP)
      - System stimulation: Reduces acute pain & hyperalgesia in most models
    - δ Receptor
      - Agonist: 4-[(^αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80)
      - Antagonist: Naltrindole
      - System stimulation: Reduces acute pain & hyperalgesia in inflammatory pain models
      - May have fewer side effects (Constipation, respiratory depression, physical dependence) than μ-agonists
    - κ Receptor
      - Agonist: (1S-trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cylcohexyl]-benzeneacetamide hydrochloride (U50,488)
      - System stimulation: No effect on chronic muscle pain
  - Locations: PAGM, Ventral medulla, Dorsal horn
- Transmitters: Endogenous opiod peptides
  - Enkephalins (m & d receptors)
  - Dynorphins (κ receptors)
  - Endorphins
- Actions
  - Opioids stimulate axons of inhibitory interneurons
  - Peripheral inflammation: Sensitivity to opioids in spinal cord is increased
  - Peripheral neuropathic pain Sensitivity to opioids is greatly reduced

Pain Sensitization

Peripheral sensitization
Central sensitization

Peripheral axons: Pain sensitization
- Physiological mechansims underlying sensitization
  - Threshold for firing (initial or subsequent) changed: By modification of voltage-gated channels
  - Modification of molecules (ion channels or other) underlying mechanical or thermal transduction
- Sensitization: Induction mechanisms
  - Repeated nerve stimulation: Lower level of depolarization required to initiate a subsequent action potential
  - Neurogenic inflammation
    - Definition
      - Secretion of factors by nerve terminals promotes release of factors
        from neighboring non-neuronal cells & vascular tissue
      - Factors produce spontaneous activity & sensitization in afferent axons
    - Factors involved in neurogenic inflammation
      - Source: Products of nerve, tissue damage and inflammation
      - Types: Molecules interacting with receptors or ion channels on sensory nerve endings
      - Molecules from tissue damage
        
        Extracellular protons, Lipid metabolites (Arachidonic acid), Serotonin, Bradykinin, Nucleotides, NGF
      - Nociceptor products
        
        Substance P, Calcitonin-gene-related peptide and ATP
    - Downstream neural effects & targets of neurogenic inflammation
      - Receptors: Na⁺ channels; VR1
      - Intracellular signal pathways
        
        Phospholipase C (PLC-γ; PLC-β)
        
        Hydrolysis of plasma membrane lipids
        
        Stimulation of protein kinase C isoforms: PKC_-e
      - Prostaglandins (PGE₂) and other inflammatory products: Enhance nociceptor excitability
        
        Activate adenylyl cyclase (AC) through Gs-coupled receptors
        
        Cyclic AMP-dependent protein kinase (PKA)-dependent phosphorylation of Na_v1.8 and/or Na_v1.9
    - Effects of factors produced during neurogenic inflammation
      - Vasodilation
      - Plasma extravasation: Leakage of proteins and fluid from postcapillary venules
      - Activation of many non-neuronal cells: Mast cells; Neutrophils
      - Stimulation of afferent axons
    - Drugs: Modulators of peripheral nociceptor excitability
      - Opiates; Cannabinoids
      - Activate G_i-coupled receptors
      - Counteract increases in excitability of nociceptors: Produce peripherally mediated analgesia
- Axon membrane: Channel mechanisms of activation & sensitization
  - Tetrodotoxin-sensitive (TTx-S) Na⁺ channels: Normal function
    - Function: Initiation of action potential
    - Location: All sensory neurons
  - Tetrodotoxin-resistant (TTx-R) Na⁺ channels
    - Na⁺ Channel subtypes: Na_v1.8; Na_v1.9
    - Location
      - Nociceptive neurons & axons
      - Accumulation in: Neuroma; Foci of axonal hyper-excitability & ectopic discharges
    - Physiology: Slow activation & inactivation kinetics.
    - Association: Pathologic pain, sensitization
  - α-adrenergic receptors
    - Damaged axons: Up-regulated
    - Normal axons: Not expressed
    - Associated pathology: Sprouting of sympathetic axons in dorsal root ganglia
    - Pain properties: Opioid-resistant; Not directly stimulus dependent

Pain sensitization: Central mechanisms
- Acute pain (Normal): AMPA-associated fast EPSPs & Rapid depolarization
- Wind up: Afferent central nociceptive axons stimulated with less peripheral input
- Long term changes in DH: Similar to long-term potentiation

Chronic pain: Underlying mechanisms

Stimulation of peripheral nociceptors
- Persistent activation
- Sensitization: Up-regulation of
  - Sensory neuron-specific Na⁺ channels
  - Substance P
- Ectopic discharges along axons
- Phenotype switch: Aβ axons
  - Secretion of BDNF, Substance P & CGRF doesn't normally stimulate pain
  - Increased nociceptor drive: Aβ input stimulates spinal pain pathways
  - Low threshold tactile stimuli may produce pain sensation & hyperaesthesia
- Sympathetic stimulated pain: Via newly expressed α-adrenoceptors on axons
- Sprouting of nociceptors
  - May occur after nerve injury
  - Growth of Aβ terminals into superficial layers of dorsal horn: May produce allodynia
Persistent central sensitization
- Increased response of central neurons to peripheral input
- Altered synaptic connections in dorsal horn (Sprouting)
Loss of inhibition
- Segmental: Loss of inhibitory interneurons, ? due to excitotoxicity
- Descending pathways

Drug treatment of pain: Principles

Mechanism	Symptom	Molecular targets	Drugs
Na⁺ channels Accumulation Redistribution Altered expression	Spontaneouspain Paresthesias Neuroma sign	Na⁺ channels TTX-sensitive TTX-resistant	Carbamazepine Lamotrigine Mexilitine Tricyclic antidepressants
Central sensitization	Hyperalgesia Tactile Cold Pin-prick	NMDA receptors Neurokinin-1 receptors nNOS Protein kinase γ	NMDA antagonists Ketamine Dextramethorphan Amantidine
Peripheral sensitization	Hyperalgesia Pressure Thermal Spontaneous pain Neurogenic inflammation	Vanilloid receptor-1-desensitization Neurokinin 1 Na⁺ channels: TTX-resistant Nerve growth factor	Capsaicin
Sympathetic stimulation	Spontaneous pain	α-receptor antagonists Nerve growth factor/trKA	Phentolamine Guanethidine
Increased transmission Reduced inhibition	Spontaneous pain Hyperalgesia	Calcium channels, N-type Receptors	Conotoxin Opiates Gabapentin Clonidine Tricyclic antidepressants SNRIs

MUSCLE PAIN: Principles

Causes
Drug-induced
Features
Basic
Clinical

Muscle Pain: Basic Features ⁵

Neural Anatomy
- Sensory afferent pathways
  - Mechanical: Thinly myelinated (Group III or A δ) axons
  - Noxious: Unmyelinated (Group IV or C) axons
  - Also see: Dorsal root ganglion cells
- Nerve Terminals
  - Type
    - Freely branching, Unencapsulated
    - Terminals of Aδ & C axons
  - Location
    - Tissues: Tendons; Fascia
    - Near arterioles & venules: Increased density with inflammation
    - No contact with muscle fibers
  - Schwannn cell processes: Surround axons except at terminal
  - Anatomy
    - Diameter: 0.5 μm
    - Varicosities (expansions) contain neuropeptides
Electrical properties of pain-related axons
- Not electrically excitable
- Stimulation produces
  - Graded receptor potential: Amplitude depends on strength of stimulus
  - Receptor potential: May elicit an action potential if threshold is reached
  - Threshold for Group IV axons is 100x higher than for Group I axons
- Conduction velocities
  - Group III axons: 3.1 to 13.5 m/s
  - Group IV axons: 0.6 to 1.2 m/s
- Molecular properties of nociceptors: Not specifically studied; See General pain mechanisms
Associated algesic substances in muscle
- Glutamate: Pain stimuli (DOMS; Hypertonic saline) associated with glutamate release in muscle
- Peptides: ? Association with muscle pain
- See: Experimental muscle pain stimuli
Functional properties of pain
- High threshold mechanosensitive terminals
  - Pain types
    - Acute muscle pain
    - Deep hyperalgesia
  - Axon type: Aδ (Group III)
    - Probably belong to polymodal nociceptor group: Also present in skin
    - Many axons respond to one or subgroup of stimulus types
    - Axon Na+ channels: Tetrodotoxin-sensitive
  - Stimuli: Strong deformation of muscle; Chemical stimuli; High temperature
  - Sensitization
    - Definition: Lowering of threshold for activation into innocuous range of stimuli
    - Inducing factors: Muscle damage; Repetitive stimulation
- Muscle nociceptors
  - Axon type: C (Group IV)
  - Pain type: Burning (Second pain)
  - Axon Na+ channels: Tetrodotoxin-resistant
- Peripheral mechanisms of hyperalgesia: Sensitization of muscle nociceptors
  - Sensitization by one chemical stimulus to another
    - PGE₂ plays more role in sensitization than in direct pain stimulation
    - 5-HT sensitizes to Bradykinin
  - Sensitization by algesic substance to mechanical stimuli
    - Associated with: 5-HT; Bradykinin
  - Desensitization of muscle nociceptors: Leukotriene D4
- Central modulation of muscle pain
  - Opioid receptors: μ & δ; Not κ
  - Other: See general mechanisms
Experimental muscle pain stimuli
- Algesic substances
  - Drugs: Capsaicin; Bradykinin; 5-HT; KCl; Levoascorbic acid; Hypertonic saline
  - Substance P and CGRP: IM injection does not induce muscle pain
- Electrical stimulation: First elicits non-nociceptive input
- Ischemia: Pain related to algesic compounds, not lactate
- Axon reflex: May spread pain from injured area
- DOMS
- Injection of hypertonic saline
  - Mimics clinical muscle pain
  - Muscle morphology: Minimal change
  - Mechanism of pain: ? Activation of muscle nociceptors
- Acidification

Muscle Pain: Clinical Features

Muscle pain: Sensory manifestations
- Cramp
- Diffuse ache
- Referred pain
- Superficial pain modalities: Poorly localized
Muscle pain: Subtypes
- Pain onset: During exercise
  - Exhaustion of fuel supply in muscle
    - Features
      - Normal exercise may not be painful
      - Serum CK: High
    - Types
      - Vascular ischemia
      - Metabolic defect
      - Sustained muscle contraction
  - Other
    - Features
      - Normal exercise often painful
      - Serum CK: Normal
    - Types
      - Structural damage: Muscle; Tendon; Joint; Bone
      - Polymyalgia syndromes
- Pain onset: Hours after exercise
  - Muscle
    - Onset: Hours after exercise
    - Serum CK: High
    - Time course: Persists up to 5 days
    - Predisposing factors
      - Unaccustomed exercise
      - Eccentric contraction: Contraction while muscle is being stretched
    - Disorders: Myopathy, especially disorders associated with rhabdomyolysis
  - Non-muscle: Structural damage; Polymyalgia syndromes
- Pain unaffected by exercise
  - Polymyalgia
  - Drugs & Toxins
  - Small fiber or painful polyneuropathy
- Cramps
- Pain with prolonged immobility
- CNS related: Restless legs; Upper motor neuron disorders; Dystonias
- Fatigue syndromes: Chronic fatigue; Depression
Typical evaluation for generalized muscle pain or discomfort
- History: Precipitating factors; Nature & Location of pain
- Examination: Strength; Sensory loss; Trigger & tender regions; Endurance
- Laboratory
  - Blood: CBC; Sedimentation rate; CK; K⁺; Ca⁺⁺; Phosphate; TSH & T₄; ANA & ENA
  - EMG & Nerve conduction studies
  - Muscle biopsy: If weakness, abnormal CK or myopathic EMG
  - ? Exercise testing
    - Glycogen & AMPDA pathways: Ischemic lactate & Ammonia
    - Mitochondrial testing: Lactate after mild exercise

Other myopathies with pain

Myoadenylate Deaminase Deficiency (MMDD)

● Adenosine monophosphate deaminase 1 (AMPD1; Myoadenylate deaminase)

; Chromosome 1p13.2; Recessive

Genetics
- C-to-T mutation at nucleotide 34 (Glu12Ter)
  - Produces stop codon
  - Caucasians & African-Americans: 20% heterozygous; 2% homozygous
  - No clear correlation with severity of clinical phenotype
  - Alternative splicing of exon 2: May provide phenotypic rescue & explain clinical variability
  - Heterozygotes with heart failure may have better prognosis
- Other mutations with consistent severe reductions in AMPD1 function: Produce symptomatic phenotype
- C34T polymorphism: Athletics predisposition
AMPD1 protein
- Component of multi-gene family: Several tissue & development stage specific isoforms
  - AMPD2
    - Widespread expression; Type I & Smoth muscle fibers; Nerve
    - Disease: SPG 63
  - AMPD3: Widespread expression; Not in muscle fibers; Mutations cause AMPDA deficiency in erytthrocytes
- High levels of expression of AMPD1 in skeletal muscle
  - 100x higher than other tissues
  - More abundant in type 2 muscle fibers
- Catalyzes deamination of AMP to IMP
- Component of purine nucleotide cycle: Purine nucleotide interconversion
- AMPD activity can be determinant of adenylate energy charge & energy metabolism in cells
- Severe reductions in protein function (< 1%) produce symptomatic phenotype
Clinical features
- Rhabdomyolysis
- Exertional myalgias
  - Worsen steadily during intensive exercise
  - No second wind
  - Location: Legs & hands
- Some patients: Asymptomatic
  - Especially with 34C>T mutation
  - ? More often when > 1% to 2% residual enzyme activity
Laboratory
- Serum CK: Normal or Slightly increased
- EMG: Normal
- Ischemic exercise
  - Ammonia: Reduced rise
  - Lactate: Normal rise
- Muscle pathology
  - Morphology: Normal
  - AMPDA histochemistry: Absent staining in all muscle fibers
  - Biochemistry with reduced staining: Activity reduced to < 10%

Myopathy with focal depletion of mitochondria

²⁰
● CHKB; Chromosome 22q13.33; Recessive

Epidemiology: 2 families; 3 patients
Genetics
- Mutations: c.263C>T (p.Pro88Leu); c.950T>A (p.Leu317Gln)
- Allelic disorder: Megaconial myopathy
Clinical
- Onset age: Adolescence
- Weakness: Mild; Proximal
- Myalgias: Especially after exercise
Laboratory
- Serum CK
  - High (1,000)
  - Increases (Up to 10,000) after exercise
- Muscle Mitochondria
  - Focal depletion: Especially type II muscle fibers
  - Remaining mitochondria enlarged
  - Phosphorylation potentials: Low

Delayed Onset Muscle Soreness (DOMS) ⁶

Clinical
- Produced by
  - Exercise type: Eccentricmuscle contraction
    - Downhill running or skiing
    - Weights: Lowering
  - Unaccustomed exercise
- Time course
  - Onset: 1/2 to 2 days after exercise
  - Peak: 1 to 3 days
  - Duration: Hours to 1 week
  - No long term damage
- Clinical
  - Discomfort & Pain in skeletal muscles
    - More with muscle contraction than at rest
    - Also evoked by muscle palpation
    - Location
      - Over muscle
      - Especially: Distal, or Myotendinous junction
  - Temporary weakness: ? Related to pain
  - Joints: Reduced range of motion
  - Greater with more duration or intensity of exercise
- Prevention: Partial
  - Previous exercise of same muscles: Eccentric; Progressive
  - Eating after exercise
- Treatment
  - Analgesics: Nonsteroidal anti-inflammatory drugs
  - No benefit
    - Massage, Cryotherapy, Stretching, Homeopathy,
      Ultrasound, Electric current
Laboratory
- Serum CK: High, or Elevated over resting levels
- Serum lactate
  - Elevated over resting levels: Returns to normal by 24 hours
  - Probably not related to pain syndrome
- Muscle pathology
  - Muscle fibers: Enlarged; Scattered necrosis
  - Inflammation: 1 to 3 days after exercise
  - Intramuscular fluid pressure: Elevated
  - Structural abnormalities in Z band
- MRI
  - Increased signal intensity on T2-weighted image
    - Often uniform through muscle
  - Muscle swelling: Directly after exercise
  - External link: MRI image
Experimental
- Sensory physiology: ? Pain influenced by large diameter axons (Allodynia)
  - Pain increased by vibration or pressure
  - Pain reduced by blockade of large diameter axons (mechanoreceptors)
- Algesic substances in muscle: Pain associated with release of glutamate
- Similar to syndrome induced by injection of muscle with hypertonic (5%) saline

From: Georges Y. El-Khoury, M.D.

DOMS
One day after exercise
Increased signal (Arrow) in
biceps & part of brachialis
muscles (MRI: T2)

Myopathy with Tubulin-reactive crystalline inclusions ⁴

Epidemiology: Single case
Onset

6th decade
Myalgias
Exercise intolerance

Clinical
- Strength
  - Normal at onset
  - Proximal & Distal
- Muscle aches
  - Persistent
  - Exacerbated by: Exercise; Heavy meals
- Fatigue
Laboratory
- Serum CK: High, 2x to 5x normal
- EMG: Myopathic; No spontaneous activity
- Lactate: Normal elevation with exercise
Muscle pathology
- Inclusions in type 2 muscle fibers
  - Eosinophilic
  - Red with Gomori trichrome
  - Stain with antibodies to tubulin
  - Ultrastructure: Crystals, small < 5μm, not membrane bound
- Atrophic muscle fibers: Rare
- Abnormal 65 kd band in muscle homogenates

Myopathy with hexagonally cross-linked crystalloid inclusions ¹⁷
● Sporadic or Recessive

Epidemiology: 10 patients
Clinical
- Onset age: 13 to 56 years
- Exercise intolerance
- Discomfort: Exercise induced (15 minutes)
- Symptoms may be worse in cold
- No rhabdomyolysis
- Strength: Normal or Mild proximal leg weakness
Laboratory
- Muscle
  - Inclusions
    - H&E: Eosinophilic
    - Gomori�s trichrome: Bright red
    - NADH: Negative staining
    - PAS: Positive surrounding inclusions
    - Present in type 2 fibers
    - Immunoreactivity: Caveolin-3; Junctin; Calsequestrin
    - Ultrastructure: Highly organized, hexagonally cross-linked crystalloid structure
  - Fiber size variation: Mild
- Serum CK: Normal to 5x elevated
- EMG: Normal or Myopathic

POLYMYALGIA RHEUMATICA ¹¹

Diagnostic Criteria
(Healy)

Persistent pain (> 1 month) involving two of : neck, shoulders, pelvic girdle
Morning stiffness (> 1 hour in duration)
Abrupt onset of illness (< 2 weeks)
Age: ≥ 50 years
Erythrocyte sedimentation rate > 40 mm/hr
Rapid response to prednisone (≤ 20 mg/day)
Absensce of other disorders

General features
- Epidemiology
  - Female > Male: 2:1
  - White > African-American
  - Northern hemisphere: Higher latitudes; Scan
  - Frequency
    - 12 to 65 per 100,000 in patients > 50 years
    - England: Up to 400 per 100,000 in patients > 65 years
    - Correlates with frequency of giant cell arteritis
  - Genetic associations
    - HLA-DRB1*04 & DRB1*01 alleles
    - Polymorphisms: ICAM-1 (Risk of recurrence), TNF, RANTES
- Onset
  - Age
    - Most > 50 years old
    - Average 70 years
  - Rapid: < 2 weeks
  - Discomfort: Proximal joints; May be bilateral or unilateral
- Systemic features: Fever; Malaise; Fatigue; Night sweats
- Pain
  - Symmetrical
  - Proximal: Involves shoulder, neck, and hip girdle
  - Greatest after inactivity & sleeping
  - May be unilateral at onset
  - Worse with joint movement: Active or Passive
  - May be severe and disabling
- Joints: Limitation of movement in some patients
- No weakness: Strength limited by pain
- Distal features (50%)
  - Non-erosive, self-limiting, asymmetric peripheral arthritis (knee and wrist)
  - Carpal tunnel syndrome
  - Distal extremity swelling with pitting edema: Dorsum of the hands and wrists ± ankles & tops of feet
- Associated arteritis (15%)
  - Visual loss
  - Cerebral ischemia
  - Aortic arch syndrome
- Lab
  - ESR: > 40 (80% to 93%); Often > 100
  - Acute phase response
    - C-reactive protein: High in serum; Sensitive indicator of disease activity
    - Interleukin-6 (IL-6): High in serum
      - Reduced by corticosteroid treatment
      - Persistent elevation: May need higher steroid doses; More risk of relapse
  - Serum CK & aldolase: Normal
  - Anemia of chronic disease: Mild; Normochromic & Normocytic
  - Thrombocytosis
  - Liver function tests: Alkaline phosphatase may be high with arteritis
  - Adrenal hormones (cortisol, dehydroepiandrosterone sulfate): Reduced production
  - Negative: ANA & Rheumatoid factor
  - Temporal artery: Elevated cytokines IL-1, IL-2, IL-6 & TGF-β1
  - Anatomical studies (MRI & Ultrasound)
    - Subdeltoid & subacromial bursitis
    - Synovitis in proximal joints & periarticular structures: Less severe than in RA
- Muscle pathology
  - Type II fiber atrophy
  - Increased number of capillaries per muscle fiber
- Synovitis: Mild; Predominance of macrophages and CD4⁺ T lymphocytes; Few B-cells
Associated disorders
- Giant cell (Temporal) arteritis in 15% to 21% of PMR ¹³
  - Lower frequency without: Headache, Symptoms of claudication, or Abnormalities of temporal arteries
  - GCA clinical: Eend organ ischemia
    - Eye: Blindness
    - Jaw claudication
    - CNS: Headaches, Stroke
    - Aortic arch syndrome
  - GCA lesions
    - Granulomas in vessel wall
    - Smooth muscle cell apoptosis
    - Endothelial cell nitration
    - Arteries affected: Well-developed wall layers separated by elastic laminae
- PMR in 40% to 60% of GCA
Treatment
- Non-steroidal anti-inflammatory drugs (NSAIDs): May be tried for 2 to 4 weeks at disease onset
- Prednisone
  - Doses
    - Initial
      - 10 to 15 mg: For 1 month
      - < 20 mg in 75%
    - Taper: Very slowly (1 mg/day/month)
  - Rapid response
  - Prednisolone may be effective if no response to prednisone
  - Use Ca++ & Vitamin D ± Anti- resorptive medication (alendronate or risedronate)
- Better response & fewer relapses with
  - Short disease course
  - Lower ESR (pre-treatment < 50 mm/h)
  - Lower IL-6 (post-treatment < 10 pg/ml)
  - Corticosteroid treatment
    - Lower initial dose
    - Slow tapering
- Possible steroid sparing agents
  - Methotrexate
  - Anti-TNFα medications
Course
- Self-limited: 50%; Often to 18 to 24 months
- Chronic-Relapsing: Some patients require chronic treatment over years
- Mortality rate: Similar to general population

CHRONIC FATIGUE SYNDROME

CDC DEFINITION
Both major criteria, and either 8 minor symptom criteria, or 6 minor symptom criteria and 2 examination criteria

Major criteria

Fatigue: Relapsing or easily evoked
- No resolution with bed rest
- Severe: Reduced daily activity by 50% for > 6 months
Exclusion of other illnesses: Especially psychiatric

Minor symptom criteria

Fever or chills: Mild
Sore throat
Lymph node pain
- Cervical or axillary
Muscle discomfort or myalgia
Muscle weakness
- Unexplained; Generalized
Fatigue: Generalized
- After previously tolerated levels of exercise
- Prolonged: > 24 hours

Headaches: New; Generalized
Arthralgias: Migratory; Non-inflammatory
Neuropsychiatric
- Visual: Photophobia; Transient scotoma
- Behavior: Forgetfulness; Irritablilty; Depression; Confusion
Sleep disturbance: Hyper- or Insomnia
Onset: Acute or subacute

Physical examination criteria

Low grade fever
Pharyngitis: Non-exudative
Lymph nodes: < 2 cm in diameter
- Palpable or tender
- Cervical or axillary

COMMON SYMPTOMS & SIGNS

Systemic
- Fever & Night sweats
- Weight loss or gain
- Lymph nodes: Swollen in neck
Respiratory
- Onset: Sudden with flu-like illness
- Sore throat
- Cough
Musculoskeletal
- Myalgias
- Malaise: Postexertional
- Arthralgias
- Generalized subjective weakness
- Morning stiffness

Neuropsychological
- Awakening unrested
- Concentration: Poor
- Headaches
- Forgetful
- Depression or anxiety
- Alcohol: Exacerbates symptoms
- Tingling/Numbness in extremities
- Photophobia
Functional status: Intermittently bedridden

ASSOCIATED DISORDERS

Fibromyalgia
- Prevalence: 1% to 5% in Western countries
- Pain
  - Widespread: Multisystem
  - Bilateral; Truncal; Above & below waist
  - Duration: > 3 months
  - On palpation of tender point sites
  - Probable cause: Spontaneously firing nociceptive C-fibers
- Other symptoms
  - Fatigue
  - Exercise intolerance
  - Gastrointestinal symptoms
  - Cognitive concerns
- Small fiber neuropathy in > 50%: Especioally with ²²
  - Paresthesias: More severe
  - Autonomic symptoms
Sleep disorders
Lactate response to exercise
- Increased: In patients with fewer type I fibers

Fatigue & Exercise Intolerance: Differential diagnosis

Neuromuscular
- Chronic fatigue
- Fibromyalgia
- Neuromuscular junction disorders
- Myopathy
  - Childhood: PACSIN3
  - Metabolic ²³
    - Fatty acid: Intolerance to sustained low intensity exercise
    - Glycogen: Intolerance high intensity exercise
- Mitochondria
- Polyneuropathies, Small fiber
- Rhabdomyolysis syndromes
Systemic
- Connective tissue diseases
- Drug or Alcohol abuse
- Endocrine diseases
- Heart failure & Circulatory
- Hypouricemia
- Infections
- Malignancy
- Medications
- CNS
  - Psychiatric disorders
  - Sleep disorders

All-Trans-Retinoic Acid (ATRA) ¹

Uses: Induction therapy for acute promyelocytic leukemia
Muscle syndrome
- Myalgias
  - Legs > Arms
  - Reduced by corticosteroid treatment or Lowered ATRA dose
- Serum CK: Normal or mildly elevated
- MRI: High T2 signal in fascia & muscle
CNS: Intracranial hypertension; Headache
Systemic side effects
- Fever
- Dyspnea
- Weight gain
- Effusions: Pleural; Pericardial
- Hypotension
- Sweet's syndrome: Acute neutrophilic dermatosis

Myalgia Syndromes with No muscle pathology

Immunosuppressant Medications
- Drugs
  - Azathioprine
  - Mycophenolate mofetil ⁷
- Onset: Days to weeks after drug initiation
- Clinical
  - Fever
  - Myalgias
  - Arthralgias
- Course
  - Resolves within days to weeks after stopping drug
  - Reinstitution of drug
    - Syndrome usually recurs
    - 2nd episode is often more severe
Polyneuropathy: Small fiber
Statins
Tyrosine kinase inhibitors (TKI) ¹⁸
- Drugs
  - Imatinib (Glivec)
  - Nilotinib (Tasigna)
- Clinical
  - Onset: 1 to 12 months after drug initiation
  - Pain: Myalgias; Especially thighs
  - Muscle spasms: Quadriceps
  - Course
    - Resolves within weeks to months after stopping drug
    - Reinstitution of drug: Discomfort usually recurs
- Muscle biopsy: Normal
- Other TKI neuromuscular syndromes
  - Sensory-motor neuropathy, Distal: 1 patient with Imatinib
  - GI toxicity → Weight & Muscle loss (40%)
  - Mitochondrial disorders (Cardiac myoblasts)

Exercise Intolerance with High CK & Renal Injury ²⁴
● Solute carrier family 2 (Facilitated glucose transporter), Member 9 (SLC2A9)

; Chromosome 4p16.1; Recessive

Epidemiology: 3 patients, 2 families
Genetics
- Mutations: Missense; G216Arg, Leu75Arg
- Alleic disorder: Hypouricemia, renal, 2 (RHUC2), Dominant or Recessive
- Similar disorder: RHUC1 ; SLC22A12
SLC2A9 protein
- Urate transporter, High-affinity
Clinical
- Onset age: Late 2nd decade
- Episodes
  - Trigger: Exercise, strenuous
  - Myalgias
  - Back pain
  - Vomiting
Laboratory
- Serum Uric acid: Low
- Serum CK: Mildly high between episodes; 330 to 10,000 during episodes
- Episodes: Creatinine & Urea high
- Urolithiasis

Bergamot oil ⁸

Bergapten

Intoxication
- Ingredient in Earl Grey tea
- Syndrome occurs with ingestion of large amounts of tea
Toxic agent: Bergapten (5-methoxypsoralen)
- Selective axolemmal potassium channel blocker
- Reduces potassium permeability at nodes of Ranvier in a time-dependent manner
- May lead to: Hyperexcitability of axonal membrane; Phasic alterations of potassium currents
- Hyperexcitability may be enhanced by prolonged opening of voltage-gated sodium-channels due to bergapten
Clinical syndrome
- Fasciculations
- Muscle cramps: Distal; Hands & Legs
- Paresthesias
- Ocular: Pressure sensation in eyes; Blurred vision, particularly in darkness
- EMG & NCV: Normal other than fasciculations
- Course: Resolution of symptoms 1 week after stopping Earl Grey tea
Other effects
- UVA-induced Photosensitizer: Used therapeutically in psoriasis, vitiligo, mycosis fungoides, and cutaneous lymphoma
- Banned as an ingredient in cosmetics and tanning products
- Hepatotoxicity
- Contact-allergy
See: K⁺ channel disorders

Return to Neuromuscular home page
Return to Myopathy & NMJ Index

References
1. Am Jour Hematol 2000;63:94-98
2. Balliere's Clinical Rheumatology 2000;14:797-811
3. Nature Neuroscience 2001;4:9-10,72-77,Nature 2001;203-210, Trends Neurosci 2003:26;643-645
4. Neurology 2001;57:149-152
5. Clin J Pain 2001;17:2-10
6. Inflamm Res 2002;51:393�402, Sports Med 2003;33:145-164
7. Nephrol Dial Transplant 2002;17:923-926
8. Lancet 2002;359:1484
9. Pain 2002;100:1-6
10. Nature Medicine 2001;7:821-826
11. Best Pract Res Clin Rheumatol. 2004;18:705-722, J Rheumatol 2005;32:65�73, Geriatrics 2004;59:39-44
12. J Clin Invest 2005;115:2393�2401
13. Autoimmunity Reviews 2004;3:46�53
14. Brain 2007 Oct 11
15. J Neurochem 2007 Oct 18
16. Pain 2009 Online August, Brain 2021 Mar 9
17. Neuromuscular Disorders 2010;20:701-708
18.Leukemia Res 2012; Online June
19. Brain 2013; Online Dec
20. Neuromuscul Disord 2016;26:160-164
21. J Neurosci 2017 Feb 8
22. Muscle Nerve 2018 Jun 25
23. Muscle Nerve 2023;68:250-256
24. Neuromuscul Disord 2024;34:49-53

12/20/2024