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NEUROPATHIES: PAINFUL

Types   Acute onset   Diabetic amyotrophy   Hereditary   Idiopathic neuropathies   Immune   Local neuropathies   Metabolic   Mononeuritis multiplex   Motor   Small fiber     Erythromelalgia   Toxic Other   Axonal classifications   Nociceptors   Pain: General principles   Pain medications Also see   Itch   Muscle Pain     Principles

From Roxane Institute

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PAINFUL NEUROPATHIES: Differential Diagnosis

• Toxic
  • Alcohol
  • Metals: Thallium; Arsenic
  • Medications:
    cis-platinum; Disulfiram; Ifosfamide; Nitrofurantoin;
    Perhexiline; Taxol; Thalidomide; Vinca alkaloids
  • Mushroom: Clitocybe acromelalga
• Immune
  • Acute onset
    • Guillain Barré
      • Diffuse pain during acute course
      • Distal pain with incomplete recovery
      • Immobility
    • Acute panautonomic
  • IgM antibody associated polyneuropathies
    • TS-HDS
    • Sulfatide
  • IgG antibody associated polyneuropathies
    • Potassium channel-complex antibodies: CASPR2 & Other
    • Neuropathic pain: Plexin D1 antibody
    • FGFR3 antibodies
  • M-protein
  • Ganglionopathies
    • Sjögren's
    • Paraneoplastic (Hu)
  • Cryoglobulinemia
  • Connective tissue disease
  • HIV (DILS)
  • Vasculitis
• Hereditary
  • α-galactosidase (Fabry's)
  • GM2 gangliosidosis: Late-onset
  • Sensory Neuropathy I: Lancinating pains
  • Motor-Sensory Neuropathy I & II: Foot deformity
  • SCN9A (Nav1.7)
    • Burning feet syndrome
    • Small fiber neuropathy
    • Erythromelalgia
  • SCN10A (Nav1.8)
  • SCN11A (Nav1.9)
    • Congenital absence of pain perception (HSAN7)
    • Familial Episodic Pain 3 (FEPS3)
    • Neuropathy, Painful & Autonomic
  • Amyloidosis
    • Polyneuropathy: Pain & Paraesthesias in legs
    • Carpal tunnel syndrome: Pain in hands
  • Porphyria
  • Episodic pain syndromes, Familial (FEPS)
  • Restless legs syndromes: Some with PNS involvement
    • Hereditary (Acromelalgia) : 12q
    • HSN 1
    • HMSN 5
    • CMT 2
    • Huntington disease-like 1
    • Also: Renal failure
• Metabolic
  • Diabetic
    • Acute: Lumbar or Thoracic radiculopathy; Distal sensory
    • Chronic: "Small fiber" neuropathy
  • Alcoholic: Acute
  • Pellagra (niacin)
  • Beriberi (thiamine)
  • Strachan syndrome (Cuban neuropathy)
  • Post gastroplasty
  • Hypertriglyceridemia
  • Chronic mountain sickness
• Idiopathic
  • Distal sensory polyneuropathy syndromes
  • Erythromelalgia
• Mononeuritis multiplex
• Motor disorders with pain
  • Diabetic amyotrophy
  • Polio
• Infections
  • Polio
  • HIV
• Localized disorders
  • Nerve lesions:
    • Trigeminal
    • Brachial plexus
    • Lumbosacral plexopathy
    • Thoracic outlet syndrome
    • Median
    • Posterior tibial (Tarsal tunnel syndrome)
    • Radiculopathies: Upper & Lower Extremities
  • Burning mouth syndrome
  • Diabetic Amyotrophy
  • Reflex Sympathetic Dystrophy (Complex regional pain syndrome)
  • Infections: Herpes zoster
  • Neoplastic infiltration: Burning pain with dysesthesia in area of sensory loss
  • Post surgical localized pain syndromes
• Acute onset of pain & paresthesias
  • Acute porphyria
  • Toxic: Thallium; Arsenic; Perhexiline; Vinca alkaloids
  • Guillain-Barré
  • Acute sensory neuropathies
    
  • Spinal: Myelopathy; Radiculopathy

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Sensory polyneuropathy syndromes: Idiopathic

Acute onset Small fiber   Neuropathy, Chronic   Neuronopathy

• Epidemiology

  Axon loss: Especially small axons

  • Increased frequency > 50 years
  • Female > Male: 2 to 1
• Clinical syndrome: Chronic small fiber neuropathy syndrome, Common
  • Age: 40 to 84 years
  • Onset: Legs
  • Sensory loss: Small ± Large fiber
    • Pin loss: Distal; Most patients
    • Vibration: Commonly (50%) reduced
    • Sensory ataxia: Increased falling in some patients
  • Pain: Some patients
    • Distal > Proximal: May be prominent in proximal regions
    • ± Paresthesia
    • Burning
    • Increased at night
  • Motor: Fatigue; Occasional distal weakness in toes (Plantar flexion; Abduction)
  • Tendon reflexes: Generally preserved; ± Reduced distally
  • Autonomic disorders: Especially cholinergic ⁴
    • Pain
    • Vasomotor: Skin; Secretory
    • Hypertension
    • Impotence
    • Hypohidrosis: Distal
  • Progression: More proximally in legs; Hands in some
• Clinical syndrome: Acute onset small fiber neuropathy/neuronopathy
  • Age: 48 to 65 years
  • Sensory loss: Proximal & Distal
  • Pain: Burning & Hyperesthesia
  • Course: Slow partial recovery
  • NCV: Axon loss, Sensory or Normal
  • Pathology: Proximal & Distal axon loss in skin
• Clinical syndrome: Non-length dependent Small fiber polyneuropathy (SFPN) ¹⁸
  • Age
    • Range: 19 to 72 years
    • Mean 46 years
  • Epidemiology vs Length dependent SFPN
    • Younger
    • Females more common
  • Etiologies
    • Often idiopathic
    • Immune: Antibodies
      • TS-HDS
      • FGFR3
    • Associated immune disorders (14%)
  • Clinical
    • Strength: Normal
    • Sensory
      • Loss
        • Distribution: Diffuse; Patchy; Arms (50%), Legs (60%), Trunk (20%) & Face (20%)
        • Modalities: Pin; Light touch
      • Discomfort: Pain, Burning, Tingling, Myalgias
    • Tendon reflexes: Normal
  • Laboratory
    • NCV: Normal
    • Skin biopsy: Reduced intraepidermal axons, Proximal & Distal
    • Diabetes: Less common than Length dependent neuropathies
• Electrodiagnostic
  • NCV
    • Conduction velocity: Unremarkable
    • Sensory action potentials: Usually normal or reduced amplitude
    • Quantitative sensory testing: Abnormal in ~60%
  • EMG
    • Proximal muscles: Normal
    • Distal: Denervation in some patients
• Laboratory
  • Triglycerides: Higher than in controls
  • ? Increased frequency of abnormal glucose tolerance tests ⁶
    • Not clearly more common than in age matched controls
    • Abnomal GTT may be more common with painful polyneuropathy
    • ? Related to
      • Disuse of muscle
      • Metabolic syndrome
• Pathology
  • Skin biopsy: Reduced epidermal axon density
  • Nerve biopsy
    • ± Reduced numbers of small & large axons
    • Inflammation: Epineurial vessels in some patients with severe pain & absent SNAPs ¹⁰
• Epidemiology
  • ? History of exposure to environmental toxins: More common in neuropathy patients
  • Family history of neuropathy & foot deformity: More common in neuropathy patients
• Differential diagnosis
  • M-protein
  • Amyloid
  • Connective tissue disease
  • Diabetes
  • SCN9A mutations
  • TS-HDS antibodies

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Post surgical localized pain syndromes

• Postradical neck dissection:
  • Cervical plexus lesion
  • Drooped-shoulder syndrome
• Postmastectomy
  • Posterior arm, axilla, and anterior chest wall
  • Exacerbated by arm movement
• Postthoracotomy
  • In distribution of the incision with sensory loss
  • Point tenderness at most medial & apical points of scar
  • Reflex sympathetic dystrophy
• Postnephrectomy
  • Flank, anterior abdomen, and groin
  • Dysesthesias, numbness & heaviness
• Postlimb amputation
  • Phantom limb: Usually occurs after pain in the same site before amputation
  • Stump pain
    • At site of the surgical scar
      
    • Onset: Months to years after surgery
      
    • Burning dysesthesias exacerbated by movement
• Nerve tumors: Radiation-induced
  • Fibrosarcoma
  • Painful, enlarging mass in previously irradiated area
  • Especially with neurofibromatosis

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α-Galactosidase Deficiency (Fabry disease) ²⁰

  ● α-Galactosidase ; Chromosome Xq22.1; Recessive

• Epidemiology: Prevalence
  • 1 in 366,000 males in UK
  • Birth frequency: 1 in 117,000
• Genetics: Mutations ¹²
  • > 600 different mutations identified
  • Missense point mutations: 75%
    • Two major types
      • Active site: Reduces enzyme activity; Hotspot for mutations
      • Folding
        • Disrupted hydrophobic core
        • Reduces stability of α-Galactosidase
    • Locations: All through molecule
      • Severe phenotype: Mutations buried deep in molecule
      • Milder phenotype: Less disruptive to hydrophobic core
  • Deletions/Insertions: 15%
  • Splice site mutations: 5%
  • Specific mutations
    • Most families have private mutation
    • Taiwan
      • Mutation: IVS4+919G>A
      • Frequency: 1:875 male & 1:399 female live births
      • Phenotype: Mild
    • D313Y: Exonic variant ²¹
      • 60% of wild-type activity in vitro
      • Reduced activity at neutral pH: Low plasma α-Gal A activity
      • Female carriers: Small fiber neuropathy in 75%; Pain; Sweating disorders
  • Incidence
    • Higher: Young stroke patients; Hypertrophic cardiomyopathy
    • Not frequent: Isolated small fiber neuropathy
• α-galactosidase function
  • Normal: Cleaves terminal galactose from ceramide trihexoside
  • Fabry's ²³
    • Ceramide trihexoside (globotriaosylceramide (GL-3; Gb3)) accumulates in
      • CNS neurons
      • PNS Ganglia
      • Systemic: Heart, Kidney
      • Smooth muscle
      • Skin
        • Frequency: Most in classic FD; Rare in late onset
        • Correlate with loss of skin innervation
    • Enzyme activity
      • Residual activity in Fabry's: 1% to 17%
      • Disease severity correlates with residual enzyme activity
      • Highest residual levels: Asymptomatic; Selective cardiac disease
    • Calcium: Increased levels in sensory neurons
    • Plasma
      • Deacylated globotriaosylceramide (lyso-globotriaosylceramide (lyso-GL-3)) increased
• Clinical features: Males with disease ⁸
  • General
    • Childhood: Neuropathic; Pain, Hypohidrosis, GI
    • Progression: Systemic features; Renal, Heart, Brain
  • Onset age: Late childhood to Early adult; Mean 21 years
  • Polyneuropathy ¹⁹
    • Onset
      • Age: Childhood or Adolescence; < 18 years; Mean Dx 21 years
      • Burning pain
        • Location: Palms & Soles of feet
        • Precipitated by: Fever or Hot weather; Physical activity; Stress; Alcohol
        • Children: Painful feet during febrile episodes
      • Hypohidrosis
    • Pain (77%)
      • Onset: 10 years
      • Locations: Hands, Feet, Abdomen +...
      • Episodic severe
        • Attack duration: Minutes to Weeks
        • Triggered by: Heat; Ethanol
      • Chronic & Continuous (89%)
        • Tingling, Shooting & Burning
        • Life-long (90%)
        • Increases over time
      • Fatigue (60%)
      • Course: Worst in 3rd or 4th decades
      • Treatment
        • Neurontin
        • Poor response to: Carbamazepine or Opiates
    • Sensory loss
      • Increased threshhold
        • Cold
        • Warm
        • Heat pain
      • Large fiber modalities: Spared
      • Length dependent
        • Unless renal failure present
      • Course: More with increased age
    • Autonomic
      • Hypohidrosis
      • Impotence
    • Course: Progressive with age
    • Electrodiagnostic testing ¹¹
      • NCV: Often normal; Some (25%) with carpal tunnel syndrome
      • Sympathetic skin responses: Preserved
      • QST: Abnormal thermal detection; Cold worse than warm
    • MRI
      • Dorsal root ganglion T2 signal: More common with Fabry PN with pain ²⁴
    • Pathology: Axon loss
      

      Fabry disease: Peripheral nerve Loss of unmyelinated axons

      Osmophilic Inclusions From L Scott

      • Nerve
        • Small axon loss: Early in disease
        • Pansensory axon loss: With renal failure
        • Ganglion cells & Endothelium
          • Osmophilic (or Sudan black+) lipid inclusions
        • Skin biopsy: Loss of intraepidermal nerve fibers
      • Lipid inclusions
        • Inclusion staining
          • Sensory perikarya & Endothelial cells: Sudan black
          • Ultrastructure: Osmophilic
        • Maltese cross birefringence
        • Tissue locations
          • Vessels (Small): Endothelial cells & Media
          • Kidney: Renal tubules & Glomeruli
          • Cardiac: Muscle & conducting fibers
          • Perineurial cell
          • Spinal autonomic neurons
          • CNS: Cortical & brainstem structures
        • Subcellular location: Initially in lysosomes
  • CNS
    • Strokes (24%)
      • Onset: Mean ~40 years; Range 28 to 54
      • Frequency
        • General: 5.5�12.2-fold increased
        • Males 12x control population; Female 4x control
      • High serum myeloperoxidase level ¹⁷
        • Increased risk for developing cerebrovascular disease
        • No change after enzyme replacement therapy
      • May occur after enzyme replacement therapy
      • Vascular pathology
        • Early: Microvasculature dysfunction; Lipid in endothelial cells
        • Progression in medium-to-large vessels
          • Arterial remodeling
          • Intima-Media thickening
        • Ectatic vessels
        • Especially posterior circulation
      • CNS pathology
        • Common: Ischemia; TIA
        • Other: Hemorrhage, intracerebral or subarachnoid; Vein thrombosis
        • MRI
          • T2 white matter hyperintensities
            • Single, multiple, or confluent
            • 100% by age 54
          • Pulvinar sign (20%)
            • Bilateral T1 hyperintensity in thalamic posterior area
            • ? Related to calcification
            • Not specific
    • Personality: Passive; Depression
    • Dementia (18%): Associated with CVAs
    • Hearing ¹⁶
      

      Angiokeratoma

      • Loss (78%)
        • Sensorineural
        • All frequencies
        • Mild to Severe: Worse with
          • Neuropathy
          • Reduced renal function
          • White matter lesions: Cerebrovascular disease
        • Subclinical involvement: Early
        • Residual enzyme activity > 1.5%: Protective against hearing loss
      • Tinnitus (40%)
      • Course: Progressive
    • Vertigo
  • Skin
    • Angiokeratoma (90%)
      
      • Dilatated capillaries of dermal papillae overlying keratotic epidermis
      • Description
        • Papules: Raised
        • Red-Purple
        • Venous or Capillary lesions: Bleeding tendency
      • Locations: Navel & Lower abdomen; Scrotum & Buttocks; Thighs
      • Onset: Mean 17 years; Umbilical rash may ocur at birth
    • Rash: Red-purple; Abdomen & Sacral regions
    • Facial telangectasia
  • Renal
    • Proteinuria
    • Glomerular filtration rate: Progressive decline
    • Failure (30%): Onset 36 years
  • Cardiovascular
    • Cardiomyopathy
      • Left ventricular hypertrophy
      • Conduction disorders
      • Heart may be selectively involved
    • Vascular disease
      • Stroke
        • Ectatic vessels with clot
        • Embolic
        • Treatment: Aspirin; Coumadin
      • Hypertension
        • Treatment: ACE inhibitors
      • Myocardial infarction
  • GI (69%)
    

    Cornea verticillata Retinal vessels: Tortuous From L Scott

    • Abdominal pain: Episodic; After meals
    • Fat intolerance
      • Episodic diarrhea
      • Nausea & vomiting
      • Most patients are thin
    • Treatment: Lipisorb
  • Face dysmorphisms (60%)
    • Upper face: Periorbital fullness, Eyebrows bushy, Forehead recessed
    • Ears: Lobules prominent, Posteriorly rotated
    • Nose: Angle pronounced, Large nose/bulbous tip, Prominent supraorbital ridge & bridge
    • Lips: Full
  • Eye
    • Corneal opacity: Cornea verticillata
    • Conjunctival & Retinal vessels: Tortuous
  • Systemic, Other
    • Episodic fever: < 20 years
    • Edema (50%)
    • Hypothyroid
  • Prognosis
    • Survival
      • Median: 50 years; 20 year reduction
      • Decline starts at 30 to 35 years
      • Causes of death: Most common Renal failure or Cerebrovascular
    • Social: Reduced attendance at school, sports, social activity
    • Psychosexual difficulties: Genital angiokeratoma; Genital pain; Impotence
  • Diagnosis
    • Measure α-galactosidase enzyme levels
      • Best in cultured fibroblasts
    • Skin biopsy: Sudan+ inclusions
  • Treatment: Enzyme replacement
    • Agalsidase alfa: 0.2 mg/kg q 2 weeks
    • Agalsidase beta: 1.0 mg/kg q 2 weeks
    • Benefit: Slowed decline of renal disease; Some reduced pain
• Clinical features: Female carriers ⁹
  • Penetrance
    • 30% to 50% asymptomatic
    • Related partly to: X chromosome inactivation
  • Neuropathy
    • Small fiber modalities: Partially reduced
    • Peripheral pain (10% to 70%)
      • Especially with fever or hot weather
      • Less pain in some older patients (> 50 years)
  • Fatigue
  • Skin: Angiokeratomas, mild (10% to 35%)
  • GU
    • Renal dysfunction
    • Bladder dysfunction
  • GI symptoms
  • Long tract signs
  • Eye (70%): Cornea verticillata; Cataract, posterior lenticular
  • Hearing loss: Mild
  • Survival
    • Mean 70 years: Reduced 10 to 15 years
    • Death: Due to
      • Cerebrovascular disease: Most common
      • Renal failure
      • Cardiomyopathy
• Laboratory
  • Proteinuria
  • CSF: Normal
  • MRI (T2)
    • Small lesions in grey or white matter
    • 37% symptomatic
    • Age: > 26
  • Lyso-Gb3 (globotriaosylsphingosine): 50x high in blood

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Burning Mouth Syndrome ⁷

• Epidemiology
  • Females (88%) > Males
  • Age: Middle aged & Elderly; Median 60 years; Range 30 to 82 years
• Clinical
  • Onset: Spontaneous or with precipitating factor
  • Pain: Burning & Painful sensations in mouth
    • Location: Tongue (100%); Hard palate (Anterior) & Inner lip
    • Bilateral (85%)
    • Not in distribution of single peripheral nerve
    • Temporal
      • Reduced in morning
      • Increases through day
      • Not aggravated by eating or drinking
      • No effect on sleep
  • Taste: Lost or Altered (Bitter, Metallic)
  • Dry mouth (Xerostomia): May be transient
  • No mucosal lesions
• Causes & Associations: No strong relations
  • Anemias: Pernicious; Megaloblastic; Iron-deficiency
  • Endocrine: Diabetes mellitus; Thyroid
  • Menopause
  • Medications: Diuretics; Antidepressants; Clonazepam
  • Smoking
• Laboratory: Some abnormality in electrophysiology in 89%
  • Blink reflex
    • Brainstem pathology, or Peripheral trigeminal neuropathy: 20%
    • Increased excitability: 20%
  • Quantitative sensory threshhold
    • Small fiber abnormality: Abnormal sensory threshhold; 76%
    • Thermal hypoesthesia (15%)
  • Pathology: Small fiber neuropathy
    • Increased TRPV1 & NGF positive axons
    • Reduced intra-epidermal axons

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Erythromelalgia (Erythermalgia) ⁵

General definition: Intermittent burning pain in distal extremities Especially hands and feet In response to warm stimuli or exercise Described & named by S. Weir Mitchell in 1878 Classifications Primary idiopathic Secondary Familial Polyneuropathy & Erythromelalgia Familial erythermalgia   ● SCN9A ; Chromosome 2q24.3; Dominant or Sporadic Genetics Mutations 13 Missense F216S, S241T, N395K, I848T, L858H, L858F, Pro610Thr, R1150W Later onset (2nd decade) disease: Q10R; I136V Sporadic case: Mosaic in father Allelic disorders Recessive Congenital insensitivity to pain (CIP) Hereditary sensory & autonomic neuropathy IID (HSAN 2D) Dominant Erythromelalgia Paroxysmal extreme pain disorder Burning feet Epilepsy Febrile seizures, familial, 3B (FEB3B) Epilepsy, generalized, + Febrile seizures plus, type 7 (GEFSP7) Polymorphisms Small fiber neuropathies Chronic pain: Increased sensitivity to pain (R1150W) Dravet syndrome (EEIE6) modifier SCN9A protein (NENA; PN-1; Nav1.7) Sodium channel Type 1: α-subunit Tetrodotoxin-sensitive Locations Peripheral nerve Nociceptive dorsal root ganglion cells Distal neurites May accumulate in neuromas Sympathetic neurons Not muscle or brain Molecular Functions 5 Slow closed-state inactivation Amplify small depolarizations (generator potentials) Produces threshold currents Mutant protein: Gain of function Hyperpolarizing shift in channel activation Increased amplitude of response to slow, small depolarizations Cells expressing mutant protein are hyperexcitable Associated sensory modalities 22 Pain C-low threshold mechanoreceptors (C-LTMR) Sensory modalities Mechanical threshhold Affective touch Non-noxious cooling Axon properties Respond to low threshold punctate indentations Conduction velocities in C-fibre range Molecular: Tyrosine hydroxylase 10% of dorsal root neurons Skin: Longitudinal lanceolate endings surrounding hair follicles. Inflammatory pain Secondary to associated disease Onset: Middle age Associated disorders Thrombocythemia (Myeloproliferative disorders) Most typical ? Related to intravascular platelet aggregation Thrombotic occlusions of arterioles & small arteries Platelet-mediated Arteriolar inflammation Fibromuscular intimal proliferation Diabetes Systemic autoimmune Rheumatoid arthritis Sj�gren syndrome Systemic lupus erythematosus Vasculitis Drugs Iodine contrast Calcium channel blockers Bromocriptine Cyclosporine Norephedrine Isopropranolol, topical Pergolide Statins (rosuvastatin; simvastatin) Other neuropathies Fabry Hematologic Infections Clitocybe acromelalga mushroom poisoning Localized: ? ABC variant of complex regional pain syndrome Clinical Onset age: Children & Adults; Usually before age 6 years Pain Location Early: Distal extremities; Legs > Arms; Relative sparing of toes Bilateral; Symmetric May spread to hands, ear lobes & nose tip Quality: Burning & Hot Dysesthesias with touch Environmental factors: Opposite responses to Raynauds Exacerbated by: Heat; Standing; Exercise Relief by: Cold; Elevation of extremity Associated with warmth & flushing of extremity Skin Red & Warm in limbs Initially: During attacks May become constant Itch: Episodic; May be followed by pain Skeletal: Short toes & toenails Disease course Episodic Severity of attacks may increase with age Area involved by attacks may increase Treatment Aspirin may produce rapid (1 hour) short-lived improvement: 2° syndromes Pain control: Capsaicin + Systemic analgesia Cooling of affected limbs Combination Gel 15 1% Amitriptyline HCl + 0.5% Ketamine HCl in pluronic lecithin organogel Applied 4x to 5x daily ? Epidural anesthesia Treatment of associated disorder Rule out Fabry Raynaud's NMNAT2 Laboratory Skin biopsy: May be normal Pathophysiology ? Hyperactive axon reflex in C-nociceptor fibers Skin pathology: Nonspecific; ? Reduction in autonomic plexi

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Burning Feet Syndrome ¹

  ● SCN9A ; Chromosome 2q24.3; Dominant

• See: Erythermalgia
• Clinical
  • Onset: 12 to 40 years; Mean 27 years
  • Pain
    • Distribution
      • Symmetric
      • Soles & toes of feet: Progresses to ankles & lower legs
    • Burning & Dull ache
    • Increased with warm; Reduced with cold
  • Normal touch, pain, temperature,and vibration & position sense
  • Normal strength; No wasting
• Laboratory
  • Electrophysiology: Normal, or mildly abnormal, nerve conduction studies
  • Nerve biopsy
    • Unmyelinated axons: Markedly reduced
    • Myelinated axons: Mildly reduced
    • Regeneration

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Small Fiber Neuropathy ⁵

  ● SCN9A ; Chromosome 2q24.3; Dominant

• Epidemiology
  • Some patients with definite small fiber neuropathy
  • Positive family history: Usual
• Genetics
  • Mutations: Heterozygous; Gain-of-function
  • Most true mutations: Patients with a positive family history
  • "Mutations" in spontaneous cases: Often polymorphisms; Frequent occurrence in genetic databases
  • Allelic disorders
• Clinical
  • Onset age: Adult; 14 to 68 years
  • Sensations reduced: Pain; Temperature
  • Pain
    • Distal > Proximal
    • Legs > Arms
    • Other: Some patients
      • Myalgias
      • Jaw
      • Diffuse
    • Exacerbation by warmth: 35%
  • Autonomic symptoms
    • Orthostatic dizziness
    • Palpitations
    • Dry eyes & mouth
    • Other (Few patients): Blurred vision, Constipation/Diarrhea, Hyperhydrosis
  • Strength: Normal
  • Tendon reflexes: Normal
  • Vibratory sense: Normal
  • symptom duration: 1 to 37 years
• Laboratory
  • Nerve conduction studies: Normal
  • Quantitative sensory testing (QST): Abnormal
  • Intraepidermal nerve�fiber density (IENFD): Reduced

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Episodic pain syndrome, Familial 1 (FEPS1)

  ● Transient receptor potential cation channel, Subfamily A, MEMBER 1 (TRPA1) ; Chromosome 8q13.3; Dominant

• Epidemiology: Colombian family, 21 members
• Genetics
  • Mutation: Asn855Ser
• TRPA1 Protein
  • Cation channel
  • Expressed in primary afferent nociceptors
  • Mutation: 5-fold increase in inward current when stimulated by agonist cinnamaldehyde
• Clinical
  • Onset age: Infancy
  • Triggers
    • Types: Fasting, Fatigue, Cold, Illness, Physical exertion
    • Combination of factors more likely to precipitate episodes
  • Episodes
    • Upper body pain: Severe
    • Breathing difficulties
    • Tachycardia
    • Sweating
    • Pallor generalized pallor
    • Peribuccal cyanosis
    • Abdominal wall stiffness
    • Duration: 1.5 hours
    • Prodrome: Episode may be aborted
    • Post episode: Exhaustion & Deep sleep
  • Between episodes
    • No altered pain sensitivity
    • Neurologic exam: Normal
• Laboratory
  • Skin biopsies: Normal
  • Quantitative sensory testing: Normal
  • Mustard oil (Activates TRPA1 receptors): Higher flare responses & secondary hyperalgesia
• Differential diagnosis: Episodic pain syndromes
  • FEPS1: TRPA1
  • FEPS2: SCN10A
  • FEPS3: SCN11A
  • FEPS4: SCN9A

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Reflex Sympathetic Dystrophy (Complex regional pain syndrome)

Tinel 1918 Causalgia after median nerve lesion

• General ¹⁴
  • Features
    • Discomfort: Spontaneous pain or hyperalgesia/hyperesthesia
      • Distribution: Not limited to single nerve territory
      • Disproportionate to inciting event
    • Other associated features on affected limb, especially distal
      • Edema
      • Skin blood flow (temperature) or sudomotor abnormalities
      • Motor symptoms
      • Trophic changes
    • Other diagnoses are excluded
  • Types
    • I: No definable nerve lesion
    • II: Nerve lesion present
• Epidemiology
  • Patient features
    • Female:Male 2:1
    • Age: Mean 50 years; Range 15 to 80 years
  • Associated features
    • Serious life event (40%)
    • History of chronic pain (40%): Back; Headache; Multiple
    • ? Genetic susceptibility
    • ? Precipitating events
      • Limb fractures
      • General surgery
      • Soft tissue injury
      • Carpal tunnel surgery
      • Radiculopathy
    • ? Drugs
      Phenobarbital; Phenytoin; Isoniazid;
      Cyclosporin; Tacrolimus; Rapamycin
    • ? Medical conditions
      Diabetes mellitus; HyperThyroid;
      HyperParathyroid; Type IV hyperlipidemia
• Clinical Features ²
  • Onset: Weeks after precipitating event
  • Location
    • Distal extremity
    • Hands > Feet; Knees
    • Asymmetric or Unilateral most commonly
  • Pain
    • Character: Burning; Pricking
    • Continuous
    • Deep 2x more common than superficial
    • Hyperalgesia (100%)
      • Stimulus
        • Mechanical impact (Pin) stimuli
        • May be associated with central sensitization
        • Thermal hyperalgesia: Less common
      • Position dependent amplification
    • Allodynia: More in chronic syndromes
    • Exacerbated by
      • Movement: Especially lowering limb
      • Cutaneous stimulation
      • Stress
      • Temperature change
    • Cold pain
      • More common with nerve lesions
      • Sympathetically-maintained
  • Sensory loss
    • Distribution: Glove or Stocking
    • Modalities: Pain; Touch
  • Autonomic
    • Skin temperature
      • Increased (80%) or Decreased (20%)
      • Temperature difference between extremities: > 1°C
    • Hyperhidrosis (50%)
    • Edema (81%): Distal limb; More common early
    • Skin color change
      • Reddish: Early in course
      • Cyanotic: Chronic syndromes
    • Norepinephrine in RSD extremity: Reduced
  • Motor disorders
    • Sense of weakness with complex motor tasks (79%): "Give-way"
    • Difficulty initiating movements
    • Limited range of motion: Wrist; Ankle
  • Involuntary movements
    • More common with nerve lesions
    • Tremor (48%)
    • Irregular myoclonic jerks, dystonia or muscle spasm (30%)
  • Tendon reflexes: Increased, On affected side 46%
  • Trophic changes (50%)
    • "Plus"
      • Early: Days after injury
      • Increased hair- & nail growth
    • "Minus"
      • Late
      • Reduced hair- and nail growth
      • Atrophy of skin & muscles
      • Contractures
  • Late features
    • Skin: Atrophic; Red
    • Bone: Sudek's atrophy
    • Extremity: Cold; Pallor; Cyanosis; Hair loss
    • Pain: Hyperalgesia in anesthetic skin
• Laboratory
  • HLA-DQ1 association: 69% vs 42% in controls
  • Quantitative sensory testing: Patients with sympathetic maintained pain
    • Warm thresholds: Increased
    • Hyperalgesia to painful cold stimuli
  • X-ray: Osteoporosis
    • Patchy
    • Time: After 4 to 8 weeks
    • Frequency 40%
  • Bone scintigraphy: Increased metabolism
  • MRI: "Edema" in deep tissues
  • Serum CGRP: Increased in acute syndromes
  • Sympathethetic nervous system disorders: ? Central
    • Vasoconstrictor activity altered: Decreased early; Increased late
    • Sudomotor abnormalities
• Pathology
  • Nerve
    • C-fibers: Loss (50% of patients)
    • Myelinated axons: Normal
  • Muscle
    • Capillaries: Increased basement membrane thickness; Necrosis
    • Type 1 muscle fibers: reduced
• Treatments
  • Corticosteroids: Early in disease course
  • Glutethimide & sympathetic blocks: Early in 1st few months
  • Pain management: Analgesics often provide little benefit
    • Antidepressants: Amitriptyline; Venlafaxine; Fluoxitine
    • Local anesthetic type antiarrythmics: Flecainide
    • Opiates: Morphine
    • Other drugs
      • Ca⁺⁺ blocking agents: Nifedipine
      • Phenoxybenzamine
      • Corticosteroids: Prednisone; Solumedrol
      • Calcitonin
      • Biphosphonates
      • Gabapentin
      • Baclofen
        • Intrathecal
        • Mainly beneficial for predominantly arm syndromes
  • Topical DMSO: Early in disease course
  • Physical therapy: Reduce contractures
  • Limb amputation rarely reduces pain
• Possible pathogenetic factors
  • ? Upregulated sensitivity of α-adrenooceptors for catecholamines
  • ? Regional inflammatory response 2° O₂ derived free radicals or neuropeptides
• Variants
  • Erythralgia (ABC Syndrome):
    • Spontaneous pain
    • Hyperalgesia: Thermal & Mechanical
    • Pathophysiology: Related to sensitized C nociceptors
      • Ectopic activity
      • Antidromic secretion of vasoactive substances
      • Related general syndrome: Erythromelalgia
  • CCC Syndrome: Defective Aδ cold specific input
    • Cold hypoesthesia
    • Cold hyperalgesia
    • C-nociceptor pain with paradoxical burning character
    • Cold skin
    • Related to partial sympathetic denervation supersensitivity & vasospasm

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Chronic Mountain Sickness ³

• Epidemiology
  • Andean natives living at high altitude
  • Sex & Age predominance: Males; Ages 20 to 50 years
  • Occupation: Miners in Cerro de Pasco, Peru
• Clinical
  • General: Malaise; Depression
  • Headaches (Migraine-like) (100%)
  • Dizziness (50%)
  • Fatiguability; Somnolence; Coma (occasional)
  • Paresthesias: Burning feet-Burning hands syndrome
  • Burning pain: Distal; Hands & Feet
  • Distal sensory loss: Mild; 30%; Lower extremities
  • Tendon reflexes: Reduced (30%)
  • Hyperaesthesia (30%)
  • Relation to altitude
    • Resolves after 1 to 14 days at sea level
    • Recurs with return to high altitude in hands, then legs
  • Strength: Normal
  • Ataxia: 20%
  • Circulatory
    • Cyanosis
    • Suffused conjunctiva, cheeks & earlobes
    • Peripheral edema
    • Clubbing of fingers & toes
    • Splinter hemorrhages
    • Heart failure: Congestive; Especially right sided
• Laboratory
  • Polycythemia (Hct > 64)
  • Red cell mass increased: Hemoglobin > 21.3 mg/dl
  • O₂ saturation reduced: 70% or less
• Respiratory function
  • No hyperventilation: Failure of respiratory centers to respond to CO₂ stimunation
  • Ventilatory response to hypoxia: Reduced
  • Disordered respiration during sleep: Episodic hypopnea & Apnea
• Neuropathy: Pathology
  • Vessels: Reduced basal lamina thickness
  • Demyelination: Thin myelin sheaths
  • Axons: Myelinated & unmyelinated axon number most often normal

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Patient information

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9/13/2024