Pain Differential Diagnosis

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NEUROPATHIES: PAINFUL

Types
Acute onset
Diabetic amyotrophy
Hereditary
Idiopathic neuropathies
Immune
Local neuropathies
Metabolic
Mononeuritis multiplex
Motor
Toxic

Other
Axonal classifications
Nociceptors
Pain: General principles
Pain medications

Also see
Itch
Muscle Pain
Principles

From Roxane Institute

PAINFUL NEUROPATHIES: Differential Diagnosis

Toxic
- Alcohol
- Metals: Thallium; Arsenic
- Medications:
Immune
- Acute onset
  - Guillain Barré
    - Diffuse pain during acute course
    - Distal pain with incomplete recovery
    - Immobility
  - Acute panautonomic
- Anti-Sulfatide Antibody associated polyneuropathies
- Connective tissue disease
- HIV (DILS)
- M-protein
- Ganglionopathies: Sjögren's; Paraneoplastic (Hu)
- Cryoglobulinemia
- Vasculitis
Hereditary
- α-galactosidase (Fabry's)
- GM2 gangliosidosis: Late-onset
- Sensory Neuropathy I: Lancinating pains
- Motor-Sensory Neuropathy I & II: Foot deformity
- Burning feet syndrome
- Amyloidosis
  - Polyneuropathy: Pain & Paraesthesias in legs
  - Carpal tunnel syndrome: Pain in hands
- Porphyria
- 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
- Spinal: Myelopathy; Radiculopathy

Sensory polyneuropathy syndromes: Idiopathic

Epidemiology

Axon loss: Especially small axons
- Increased frequency > 50 years
- Female > Male: 2 to 1
Clinical: Common chronic syndrome
- Age: 40 to 84 years
- Onset: Legs
- Sensory loss: Small ± Large fiber
  - Pin los: 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 cholinergic⁴
  - Pain
  - Vasomotor: Skin; Secretory
  - Hypertension
  - Impotence
  - Hypohidrosis: Distal
- Progression: More proximally in legs; Hands in some
Clinical: Acute onset syndrome
- Age: 48 to 65 years
- Sensory loss: Proximal & Distal
- Pain: Burning & Hyperesthesia
- Course: Slow partial recovery
- Pathology: Proximal & Distal axon loss in skin
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 tests⁶
  - 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 SNAPs¹⁰
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

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

α-Galactosidase Deficiency (Fabry disease)

l α-Galactosidase

; Chromosome Xq22; Recessive

Genetics: Mutations¹²
- > 245 different mutations identified
- Missense point mutations: 75%
  - Two major types
    - Active site: Reduces enzyme activity; Hotspot for mutations
    - Folding: Reduces stability of α-Galactosidase by disrupting its hydrophobic core
  - Locations: All through molecule
    - Severe phenotype: Mutations buried deep in molecule
    - Milder phenotype: Less disruptive to hydrophobic core
    - D313Y: Exonic variant
      - 60% of wild-type activity in vitro
      - Reduced activity at neutral pH: Results in low plasma α-Gal A activity
- Deletions/Insertions: 15%
- Splice site mutations: 5%
- Most families have private mutation
α-galactosidase function
- Cleaves terminal galactose from ceramide trihexoside
- Fabry's: Ceramide trihexoside accumulates in
  - CNS neurons
  - PNS Ganglia
  - Systemic: Heart, Kidney
- Residual enzyme activity in Fabry's: 1% to 17%
- Disease severity correlates with residual enzyme activity
- Highest residual levels: Asymptomatic; Selective cardiac disease
Clinical features: Males with disease⁸

Fabry disease: Peripheral nerve
Loss of unmyelinated axons

From L Scott
- Onset: Late childhood or Early adolescence
- Prevalence
  - 1 in 366,000 males in UK
  - Birth frequency: 1 in 100,000
- Polyneuropathy
  - Onset
    - Burning pain
    - Palms & Soles of feet
    - Precipitated: Fever or Hot weather; Physical activity; Stress; Alcohol
    - Mean age at diagnosis: 21 years
    - Children: Painful feet during febrile episodes
  - Pain (77%)
    - Onset: 10 years
    - Location: Hands, feet, abdomen +...
    - Episodic severe
      - Attack duration: Minutes to Weeks
    - Chronic (89%)
      - Tingling & Burning
      - Life-long (90%)
      - Increases over time
    - Fatigue (60%)
    - Treatment
      - Neurontin
      - Poor response to carbamazepine or opiates
  - Sensory loss
    - Especially cold
    - Large fiber modalities spared
      - Unless renal failure present
  - Autonomic
    - Hypohidrosis
    - Impotence
  - Electrodiagnostic testing¹¹
    - NCV: Often normal; Some (25%) with carpal tunnel syndrome
    - Sympathetic skin responses: Preserved
    - QST: Abnormal thermal detection; Cold worse than warm
  - Pathology: Axonal loss
    - Small fiber: Early in disease
    - Pansensory: With renal failure
    - Osmophilic inclusions
- CNS
  - Strokes (24%)
    - Ectatic vessels
    - Especially posterior circulation
    - Onset: Mean ~40 years
    - High serum myeloperoxidase level¹⁷
      - Increased risk for developing cerebrovascular disease
      - No change after enzyme replacement therapy
    - May occur after enzyme replacement therapy
  - Personality: Passive; Depression
  - Dementia (18%): Associated with CVAs
  - Hearing¹⁶
    - 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%)
- Skin
  
  Angiokeratoma
  
  Cornea verticillata
  
  Retinal vessels: Tortuous
  From L Scott
  - Angiokeratoma (90%)
    - Raised venous lesions
    - Bleeding tendency
    - Common in Navel & Scrotum
    - Onset: Mean 17 years; Umbilical rash may ocur at birth
  - Rash: Reddish purple; Abdomen & Sacral regions
  - Facial telangectasia
- Eye
  - Corneal opacity: Cornea verticillata
  - Tortuous conjunctival & retinal vessels
- Renal 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%)
  - Abdominal pain: Episodic; After meals
  - Episodic diarrhea; Nausea & vomiting
  - Fat intolerance: Most patients are thin
  - Treatment: Lipisorb
- Systemic, Other
  - Episodic fever: < 20 years
  - Edema (50%)
  - Dysmorphic faces (56%): Thickening of lips & nasolabial folds
- Prognosis
  - Survival
    - Median: 50 years; 20 year reduction
    - Decline starts at 30 to 35 years
    - Causes of death: Most commonly renal failure or CVA
  - Social: Reduced attendance at school, sports, social activity
  - Psychosexual difficulties: Genital angiokeratoma; Genital pain; Impotence
Clinical features: Female carriers⁹
- Peripheral pain (10% to 70%): Especially with fever or hot weather
- 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

Osmophilic Inclusions

From L Scott
- Proteinuria
- CSF: Normal
- MRI (T2)
  - Small lesions in grey or white matter
  - 37% symptomatic
  - Age: > 26
Pathology: Lipid inclusions
- Maltese cross birefringence
- EM: Osmophilic inclusions
- Tissue locations
  - Vessels (Small): Endothelial cells & Media
  - Kidney: Renal tubules &aqmp; Glomeruli
  - Cardiac: Muscle & conducting fibers
  - Perineurial cell
  - Spinal autonomic neurons
  - CNS: Cortical & brainstem structures
- Subcellular location: Initially in lysosomes
Diagnosis
- Measure α-galactosidase enzyme levels
  - Best in cultured fibroblasts
- Skin biopsy for inclusions
Treatment trials: Enzyme replacement

Burning Mouth Syndrome⁷

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
- Taste: Lost or Altered (Bitter, Metallic)
- Dry mouth
- No mucosal lesions
Causes & Associations: No strong relations
- Anemias: Pernicious; Megaloblastic; Iron-deficiency
- Diabetes mellitus
- 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

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
- Familial erythermalgia
  l SCN9A ; Chromosome 2q31-32; Dominant or Sporadic
  - Genetics
    - Mutations¹³
      - Missense
      - F216S, S241T, N395K, I848T, L858H,
        L858F, Pro610Thr, R1150W
      - Later onset (2nd decade) disease: Q10R; I136V
    - Sporadic case: Mosaic in father
    - Allelic with
      - Congenital inability to experience pain
      - Paroxysmal extreme pain disorder
  - SCN9A protein (NENA; PN-1; Na_v1.7)
    - 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
    - Function⁵
      - Slow closed-state inactivation
      - Amplify small depolarizations (generator potentials)
        
        Produces threshold currents
      - Role in inflammatory pain
      - Mutant protein: Gain of function
        
        Hyperpolarizing shift in channel activation
        
        Increased amplitude of response to slow, small depolarizations
        
        Cells expressing mutant protein are hyperexcitable
  - Onset: Childhood & Adolescence; Usually before age 6 years
  - Clinical: Burning pain
  - ? Related to: Burning feet syndrome
  - Rule out: Fabry; Raynaud's
- 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
    - Collagen vascular disease
    - Drugs
    - Other neuropathies
- Localized: ? ABC variant of complex regional pain syndrome
Onset age: Children & Adults
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
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: 1% Amitriptyline HCl + 0.5% Ketamine HCl in pluronic lecithin organogel¹⁵
  - Applied 4x to 5x daily
- ? Epidural anesthesia
- Treatment of associated disorder
Pathophysiology
- ? Hyperactive axon reflex in C-nociceptor fibers
- Skin pathology: Nonspecific; ? Reduction in autonomic plexi

Burning Feet Syndrome¹

l SCN9A

; Chromosome 2q24; 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

Reflex Sympathetic Dystrophy (Complex regional pain syndrome)

Tinel 1918

Causalgia after
median nerve lesion

General¹⁴
- 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
  - ? Medical conditions
Clinical Features²
- 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

Chronic Mountain Sickness³

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
- 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

Patient information

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4/18/2009