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Erythromelalgia - Comprehensive Review

Definition & Etymology

• Erythros = red
• Melos = extremities
• Algos = pain

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Epidemiology

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Classification

1. Primary (Idiopathic) Erythromelalgia

2. Familial (Hereditary) Erythromelalgia

• Autosomal dominant inheritance
• Onset in childhood or adolescence
• Caused by a mutation in SCN9A (the gene encoding the Nav1.7 voltage-gated sodium channel)

3. Secondary Erythromelalgia

• Polycythemia vera
• Essential thrombocythemia / thrombocytosis
• Thrombotic thrombocytopenic purpura (TTP)

• Calcium channel blockers (nifedipine, verapamil, felodipine, nicardipine)
• Ergot derivatives (bromocriptine, pergolide)
• Cyclosporine
• Romiplostim (thrombopoiesis-stimulating protein)

• Peripheral neuropathy
• Myelitis
• Multiple sclerosis
• Autoimmune small-fiber axonopathy
• Diabetes mellitus

• Topical isopropyl alcohol exposure
• Mushroom poisoning (Clitocybe acromelalga, C. amoenolens)
• Chronic vibration, tobacco use

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Etiology & Pathogenesis

Primary / Neurogenic Mechanism

1. Arteriovenous shunting theory: Precapillary sphincters constrict while arteriovenous shunts remain open, increasing total perfusion but reducing nutritive capillary flow. Local hypoxia generates vasoactive substances that cause warmth, redness, and pain.
2. Small-fiber neuropathy (sodium channelopathy): Gain-of-function mutations in SCN9A encoding Nav1.7 - a voltage-gated sodium channel expressed in dorsal root ganglion and sympathetic ganglion neurons, especially nociceptors. These mutations:
   • Cause a hyperpolarizing shift of activation, allowing Nav1.7 to open at lower membrane potentials
   • Enhance neuronal excitability ("gain of function")
   • Are worsened by high temperatures (which cause a depolarizing shift in mutant channels)
   • Increased C-fiber activity-dependent slowing has been demonstrated

Secondary / Platelet-Mediated Mechanism (Myeloproliferative)

Autoimmune Mechanism

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Signs and Symptoms

The Diagnostic Triad

Distribution

• Feet (90% of cases) - toes, soles, dorsum, or entire foot
• Hands (25%) - fingers, dorsal hands
• Usually bilateral and symmetric (asymmetric in secondary EM)
• Rarely: face, ears

Episodic Nature

• Attacks last minutes to several days (average 1-2 attacks/week; can be more frequent)
• Between flares: extremities may appear normal
• Constant use of ice water leads to maceration, secondary infection, ulcers, necrosis

• 20% of patients show evidence of cold injury; >1% develop gangrene or require amputation

Triggering Factors

• Increased environmental temperature or exercise (most common)
• Dependent posture of limbs
• Wearing socks or tight shoes
• Ingestion of alcohol, spicy foods
• Certain drugs (pergolide, bromocriptine, calcium channel blockers)

Relieving Factors

• Cooling the affected extremity (fans, cold water, ice water)
• Limb elevation
• Cold floor exposure
• Ice-cold water immersion (though this causes chronic maceration)

Additional Symptoms

• Itching, tingling, pins and needles
• Swelling, sweating
• Raynaud phenomenon co-exists in up to 80% of patients (both conditions reflect vasomotor dysregulation)

Physical Examination

• During attacks: warm, red, extremely sensitive extremities
• Peripheral pulses: normal or bounding (distinguishes from vascular occlusion)
• Between attacks: examination may be entirely normal
• In secondary EM: signs of the underlying disorder may be present

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Investigations

Basis of Diagnosis

Practical Diagnostic Strategies

Laboratory Investigations

• Bone marrow aspiration and biopsy - to confirm myeloproliferative disorder
• JAK2 mutation testing (polycythemia vera)

• ANA, anti-dsDNA, complement levels (SLE workup)
• Nerve conduction studies / skin punch biopsy for intraepidermal nerve fiber density (IENF) to document small-fiber neuropathy

Genetic Testing

• SCN9A gene sequencing - for familial/primary cases, especially with childhood onset
• Identifies specific mutations that may predict treatment response (e.g., carbamazepine responsiveness in certain Nav1.7 mutations)

Specialized Testing

Differential Diagnosis

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Treatment

1. Behavioral/Non-Pharmacological Measures

Warning: Prolonged ice water immersion provides temporary relief but leads to maceration, secondary infection, gangrene, and even amputation in >1% of patients.

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2. Topical Therapies

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3. Pharmacological Therapy - Primary/Neuropathic EM

No more than 50% of patients respond to any single medication - combination therapy is often needed.

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4. Pharmacological Therapy - Secondary EM (Myeloproliferative)

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5. Interventional / Surgical

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6. Novel/Emerging Therapies

• PF-05089771 and TV-45070 (Nav1.7-selective blockers) - promising for primary EM in clinical development
• Mepyramine (antihistamine with Nav1.7-blocking properties) - 2025 study shows relief of pain and erythema in primary EM patients with specific mutations
• Mutation-guided pharmacotherapy - specific SCN9A mutations may predict carbamazepine responsiveness; genomic profiling can guide drug selection

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Orthopedic Relevance

1. Confusion with CRPS (Complex Regional Pain Syndrome / reflex sympathetic dystrophy) - both present with burning limb pain, erythema, and warmth following extremity injury or surgery
2. Post-traumatic or post-surgical onset - erythromelalgia can be triggered by orthopedic procedures, with corticosteroids potentially effective if started early
3. Chronic cold-water immersion complications - maceration, ulceration, infection, potential need for orthopedic/surgical management
4. Mobility impairment - severe cases result in inability to bear weight or ambulate
5. Differential in foot/ankle pain - must be distinguished from tarsal tunnel syndrome, compartment syndrome, and vascular claudication

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Prognosis

• 32% - symptoms worsen over time
• 27% - unchanged
• 31% - improve
• 10% - complete resolution

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Summary Algorithm

Suspected Erythromelalgia
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    Clinical Triad: Burning pain + Erythema + Warmth
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    Rule out Secondary Causes
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         ├── CBC/Peripheral smear/Flow cytometry
         │        ↓
         │   Abnormal → Myeloproliferative workup
         │         → Low-dose ASPIRIN first
         │
         ├── Family history / Childhood onset
         │         → SCN9A genetic testing
         │         → Mutation-guided therapy (carbamazepine/mexiletine)
         │
         └── Neurologic evaluation
                   → Skin punch biopsy (IENF density)
                   → Small-fiber neuropathy confirmed
                   → Gabapentin / Pregabalin / TCAs

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Fibromyalgia Syndrome (FMS) - Comprehensive Orthopedic Review

Definition

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Epidemiology

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Etiology and Risk Factors

Genetic Predisposition

• First-degree relatives of FM patients have an 8-fold higher risk
• Polymorphisms in serotonin transporter gene (5-HTT), COMT (catechol-O-methyltransferase), and dopamine receptor genes have been implicated
• Symptom clustering within families suggests heritable neurobiological traits

Triggering Factors (Environmental Stressors)

Classification of Pain Mechanisms (Orthopedic Context)

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Pathology and Pathophysiology

1. Central Sensitization - The Hallmark

• Decreased activity of descending analgesic pathways (reduced serotonin and norepinephrine in the spinal cord)
• Increased excitatory neurotransmission - elevated CSF glutamate, substance P (3-fold elevated), and nerve growth factor
• Wind-up phenomenon - temporal summation of repeated painful stimuli causing progressive amplification
• Diffuse sensitization - not just pain, but all sensory stimuli (sound, light, smell) are amplified

2. Neuroimaging Evidence

• In FM patients, mild pressure or heat that normal individuals perceive as touch is processed as pain
• Posterior insula is consistently hyperactive - a key region for sensory integration and emotional processing of pain
• Machine learning paradigms using fMRI data can distinguish FM patients from controls with >90% accuracy
• Increased connectivity between pain-transmission brain regions and non-pain neural networks
• Decreased connectivity between antinociceptive regions

• Elevated brain glutamate concentrations in the insula - levels predict pregabalin responsiveness
• Pregabalin therapy normalizes fMRI findings when effective

• Decreased mu-opioid receptor availability in FM (possibly due to increased endogenous opioid release) - explains why opioids are ineffective
• Increased substance P in CSF
• Reduced serotonin and norepinephrine (basis for SNRI treatment)

3. Peripheral Mechanisms

• Autoantibodies directed to satellite cells within dorsal root ganglia (DRG) can increase peripheral nociceptor sensitivity
• Binding of antibodies to Fc receptors on peripheral sensory neurons increases sensitivity
• Widespread small fiber neuropathy - demonstrated in skin punch biopsies of FM subgroups
• Ongoing peripheral nociceptive input from comorbid OA, myofascial pain, or obesity can drive or worsen central sensitization

4. Neuroendocrine and Autonomic Dysfunction

• HPA axis dysregulation - low-grade hypothalamic-pituitary-adrenal response
• Autonomic nervous system imbalance - increased sympathetic tone, reduced parasympathetic activity
• Abnormal growth hormone secretion (reduced somatomedin C/IGF-1)

5. Sleep Pathology

• Alpha-delta sleep anomaly - intrusion of alpha (awake) rhythms into Stage 3/4 (delta) NREM sleep
• Subjects experimentally deprived of Stage 4 sleep develop musculoskeletal pain and tenderness resembling FM

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Signs and Symptoms

Core Clinical Features

1. Musculoskeletal Symptoms (Primary - Orthopedic)

2. Sleep Disturbance

• Non-restorative sleep (wake up feeling unrefreshed)
• Sleep onset insomnia, frequent awakening
• Alpha-delta sleep anomaly on polysomnography
• Associated with restless legs syndrome

3. Fatigue

• Profound, disproportionate fatigue - the overlap with chronic fatigue syndrome is substantial
• Worsens with minimal activity
• "Fibro fatigue" - distinct from depression-related fatigue

4. Cognitive Dysfunction ("Fibro Fog")

• Difficulty concentrating, memory lapses
• Reduced processing speed
• Cognitive impairment worsens with pain flares and poor sleep

5. Associated Comorbid Conditions

6. Sensory Amplification

• Hyperacusis (sound sensitivity)
• Photophobia (light sensitivity)
• Chemical sensitivity
• Skin hypersensitivity

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Tender Points - Historical Diagnostic Criteria

1. Occiput - suboccipital muscle insertions
2. Low cervical - anterior intertransverse spaces C5-C7
3. Trapezius - midpoint of upper border
4. Supraspinatus - above medial scapular spine border
5. Second rib - second costochondral junctions
6. Lateral epicondyle - 2 cm distal to epicondyle
7. Gluteal - upper outer quadrant of buttock
8. Greater trochanter - posterior to trochanteric prominence
9. Knee - medial fat pad proximal to joint line

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Diagnostic Criteria

ACR 2010/2016 Updated Criteria (Current Standard)

Symptom Severity Scale (SS) Components

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Investigations

Routine Laboratory Tests (Harrison's 22E Table 385-2)

Guided by History and Examination

Key Point:

• All routine labs are typically NORMAL in FM - normal ESR, CRP, and CBC help confirm the FM diagnosis
• Elevated inflammatory markers suggest an alternative or comorbid inflammatory diagnosis

Specialized Investigations (Selected Cases)

Differential Diagnosis

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Treatment

Key principle from Harrison's 22E: Glucocorticoids and NSAIDs are NOT effective for FM-related symptoms. Strong opioids have NO demonstrated efficacy and worsen outcomes.

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1. Patient Education and Psychosocial Support

• Explaining the genetics, triggers, and physiology of FM reduces anxiety and healthcare resource use
• Validate the reality of pain (fMRI provides objective evidence)
• Set realistic expectations - focus on function, not pain elimination
• Discourage illness behaviors (frequent physician visits, excessive rest)

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2. Non-Pharmacological Treatment (First-Line)

Exercise (Most Effective Single Intervention)

Physical Therapy

Cognitive and Behavioral Therapies

• Cognitive Behavioral Therapy (CBT) - most evidence for psychological comorbidities
• Sleep hygiene interventions - critical given the alpha-delta sleep anomaly
• Biofeedback, hypnosis - pain rehabilitation adjuncts
• Mindfulness-based stress reduction (MBSR) - evidence for quality of life improvement

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3. Pharmacological Treatment

FDA-Approved Agents for Fibromyalgia

Evidence-Based Non-FDA-Approved Agents

Drug Selection by Symptom Complex

AVOID: Strong opioids (no evidence, worsen outcomes), glucocorticoids, NSAIDs (no FM-specific benefit), benzodiazepines long-term.

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4. Treatment of Comorbid Conditions

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5. Diet and Lifestyle

• Anti-inflammatory, Mediterranean-style diet
• Avoid caffeine, alcohol, processed foods (may worsen sleep and pain)
• Weight management - obesity drives peripheral nociceptive input
• Vitamin D supplementation (often deficient)

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Orthopedic Relevance

1. Arthroplasty outcomes: Fibromyalgia predicts worse pain outcomes after total knee/hip replacement compared to patients without FM, though significant functional improvement still occurs. Pre-operative FM screening is recommended.
2. Post-traumatic FM: Physical trauma (fractures, surgeries, MVA) can act as a trigger for FM onset in genetically predisposed individuals.
3. Masquerade as orthopedic conditions: Widespread joint and muscle pain mimics polyarthralgia, early RA, OA, and ankylosing spondylitis. FM must be excluded before attributing symptoms to structural disease.
4. Increased sensitivity to post-operative pain: FM patients have amplified pain processing. Peri-operative pain management must anticipate higher analgesia requirements; opioids are particularly problematic.
5. Comorbidity with inflammatory arthritis: 15-25% of spondyloarthropathy patients have comorbid FM; FM score is more predictive of pain/disability than objective inflammation markers in many patients.
6. Soft tissue pain diagnosis: Tendinopathies, bursitis, and myofascial pain syndromes coexist with or mimic FM and must be carefully separated.

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Prognosis

• FM rarely resolves completely but follows a waxing-and-waning course
• With education and multimodal therapy, significant functional improvement is achievable
• Predictors of poor outcome: high baseline pain, psychiatric comorbidity, low socioeconomic status, litigation/work disability claims
• FM is associated with significant healthcare utilization and work disability

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Treatment Algorithm Summary

Suspected FM: Widespread pain ≥3 months + fatigue + sleep disturbance
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               Exclude organic disease
           (CBC, CRP, ESR, TSH, CPK, ANA)
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              Apply 2016 ACR Criteria
          (WPI + SS score; ≥4 body regions)
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              FIRST LINE THERAPY
          ┌────────────────────────────┐
          │  Patient Education         │
          │  Aerobic Exercise          │
          │  Sleep Hygiene             │
          │  Low-dose Amitriptyline    │
          └────────────────────────────┘
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              ADD AS NEEDED (based on symptoms)
       ┌──────────────┬───────────────┬────────────┐
       │Pain+Fatigue  │Pain+Sleep     │Pain+Anxiety│
       │Duloxetine/   │Pregabalin/    │Pregabalin  │
       │Milnacipran   │Cyclobenzaprine│            │
       └──────────────┴───────────────┴────────────┘
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              REFRACTORY / SEVERE CASES
          CBT + Physiotherapy + Pain Clinic referral

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