Differential Diagnosis in Neurology

Topic 10. Differential Diagnosis of Peripheral Neuropathy

10.8. The Neuropathy of Heavy Metals and Industrial Agents

The criteria to establish the relationship of a neuropathy to a toxic exposure in the environment are:

  • A characteristic clinical picture
  • A definite dose related exposure
  • Its reproduction in experimental animals
  • Removal from exposure may lead to stabilization of the symptomatology or remission.

Heavy metals are often stored in bones and other organs such that a slow release from this compartment into the circulation after the cessation of the toxic exposure causes continued symptoms. Other agents may have a delay in onset of the clinical symptoms after exposure. Often the neurologic symptomatology involves both the central and peripheral nervous system and appears in the context of a systemic illness involving the hematopoietic, gastrointestinal, circulatory and renal systems.

Lead Exposure

  • Occurs in the smelting industry, battery manufacturing and disposal, auto production, paint ingestion, workers in indoor firing ranges and retained lead bullets in the body. Lead miners, plumbers and soldiers are exposed.
  • Pathogenesis: Lead is toxic to the nervous system in both organic and inorganic forms:
    • Organic tetra-alkyl derivatives are fat soluble and cross the blood brain barrier
    • Interacts with sulfhydryl, amino, phosphate and carboxyl groups': produces encephalopathy but not neuropathy
    • Inorganic salts produce neuropathy in adults
    • Absorbed by inhalation, dermal contact or through the GI tract
  • Systemic clinical features:
    • Intermittent abdominal pain
    • Hypochromic microcytic anemia; RBC stippling
    • Nephropathy
    • Gout
    • Bluish discoloration of the gums "lead line"
    • Weight loss, anorexia, fatigue, constipation
  • Neurologic features:
    • High level exposures in adults: CNS
      • Encephalopathy
      • Ataxia tremulousness, choreiform movements
      • Tremulousness
      • Choreiform movements
      • Seizures
      • Coma
  • Chronic exposure in adults:
    • Joints and muscle may be tender
    • Rare sensory symptoms
    • Early weakness of the proximal extensors of the middle and ring fingers; later weakness of the index, little fingers, thumb and wrist extensors
    • Weakness and atrophy can extend to the abductor pollicis brevis and interossei
    • May affect the arm that is dominant first
    • Arms affected earlier, and more severely than legs
    • Shoulder girdle, peroneal or laryngeal muscles may be focally involved
  • Usually a progressive motor peripheral neuropathy with generalized weakness and associated fasciculations
  • EMG: decreased motor and sensory NCVs; slight abnormalities of SNAPs, axonal demyelination is evidenced by fibrillation potentials and reinnervation
  • Laboratory evaluation:
    • Blood level of 40 μg/100 ml is abnormal
    • SEP may be abnormal
    • Neuropsychological testing; decreased attention; poor visual spatial processing; loss of short term memory

Differential Diagnosis

The constellation of abdominal pain and distal motor neuropathy with upper extremity predominance resembles AIP. The triggering event, speed of onset and more acute abdominal pain suggest AIP (low sodium is helpful). Both may preferentially affect the upper extremities as do some autoimmune neuropathies (GM1); and hypothyroidism.

Arsenic

  • Exposure occurs as a byproduct of copper and lead smelting; inhalant drugs contaminated by arsenic; contaminated well water, tainted illicit drugs and manufacture of integrated circuits or microchips
  • Pathogenesis:
    • Absorption is respiratory, GI or dermal
    • Affinity for thiol groups; binds with lipoic acid and blocks the conversion of pyruvate to Acetyl-CoA
    • Trivalent arsenic is toxic
  • Clinical features:
    • High dose acute exposure:
      • Abdominal pain, vomiting, diarrhea
      • Renal failure
      • Vascular collapse
      • Drowsiness, confusion and stupor
      • Less severe exposure:
        • Organic psychosis
        • Hallucination
        • Paranoid delusions
        • Delirium
      • Rarely with high dose exposure:
        • Respiratory depression, acute loss of reflexes that resembles AIDP
        • Dermatologic and bone marrow suppression may occur
      • Typical clinical picture after an exposure is gastrointestinal symptoms followed 7–10 hours later by distal paresthesia with distal muscle weakness:
        • Hyperkeratosis and sloughing of the skin soreness, redness and swelling of the hands and feet.
        • Areas of both increased and decreased pigmentation are seen axially.
        • Pale transverse bands are seen in the nails (Mee's lines). Multiple bands may be seen with multiple exposures.
        • Aplastic anemia with pancytopenia is characteristic of the chronic state

Clinical Neuropathy of Arsenic Poisoning

  • General features:
    • The neuropathy characteristically beings 5–10 days after intoxication:
      • Pain, aching and burning that spreads proximally from fingers and toes; mild cases a stocking and glove sensory loss affecting all modalities is noted
      • Severe cases there is generalized weakness requiring ventilatory support
      • Reflexes are decreased in proportion to the degree of sensory loss
      • Massive exposure causes a demyelinating polyradiculoneuropathy
  • EMG:
    • Chronic patients have a distal axonopathy with absent SNAPs and reduced (MAPs)
  • Pathology:
    • Arsenic levels greater than 25 μg/24 hrs are toxic
    • CSF protein elevation is less than 200 mg/dL without pleocytosis
  • Differential Diagnosis:
    • Massive exposure may simulate AIDP with rapid onset of weakness and areflexia. Arsenic poisoning's seminal symptoms of nausea, vomiting, diarrhea and vascular collapse is characteristic. Long, low level exposure to arsenic may present with hyperkeratosis of palms and soles prior to the neuropathy. It may simulate the palmar keratosis of syphilis.

Mercury

  • Exposure:
    • The effects of mercury on the nervous system depend on the chemical state of the element. Elemental mercury is in thermometers. Metallic mercury is volatile at room temperature.
    • Organic mercury is used in disinfectants, latex paint, and as industrial catalysts.
    • Inorganic mercury salts and elemental mercury are used in dental amalgams (no relation to any neurologic disease) manufacture of chlorine and the natural gas industry. Exposure to levels above 0.1 μg/m3 is toxic for metallic mercury.
  • Pathogenesis:
    • Elemental mercury vapor is inhaled. Mercury salt is absorbed orally and through dermal contact. Organic mercury enters the body through the GI tract. There have been major mercury intoxications in Minamata Bay Japan and by organic mercury fungicide contamination of grain in Iraq.
  • Clinical features:
    • Intoxication with mercury affects the CNS > PNS
    • The chemical state of the element determines the effect of mercury on the nervous system and whether there are systemic affects
    • Elemental mercury:
      • Lipid soluble
      • Micro mercurialism (low level toxicity):
        • anorexia; weight loss; constipation
        • fatigue
        • tremor
        • personality change and insomnia
      • Predominant CNS symptoms
      • Larger exposure:
        • tremor that involves the face, head and eyelids
        • severe GI symptoms and the nephrotic syndromes
    • Organic mercury compounds:
      • Short chain compounds (methyl mercury):
        • tremor, hearing loss, dysarthria
        • constriction of visual fields
        • cognitive dysfunction and dysarthria
        • sensory ataxia (dorsal root ganglioneuritis); benign distal to proximal and may involve the tongue
      • Complex organic mercurials cause nephrotoxicity

Clinical Neuropathy of Mercury Poisoning

  • Mercury metal vapor:
    • Causes subacute diffuse motor peripheral neuropathy; if severe may mimic acute demyelinating poly neuropathy
    • Alkyl mercury intoxication; severe distal limbs paresthesias
    • Mercury metal vapor:
      • Peripheral neuropathy
      • CMAP decreased > SNAPs

Thallium

  • Exposure: insecticide and rodenticide accidental exposure; suicide and homicide; consumption of contaminated food and water.
  • Pathogenesis:
    • Absorption occurs through the respiratory, GI tract or skin.
    • Complete with potassium for sodium potassium ATPase.
  • Clinical Features
  • Acute High Level Exposure (>29 grams)
    • Abdominal pain, nausea and vomiting may begin within an hour; may be delayed for 24 hours.
    • Cardiovascular shock with lethargy, coma and death reported within 24 hours
  • Moderate exposure:
    • Paresthesias occur distally within 24–48 hours; occasionally up to five days
    • Limb pain is more severe in the lower extremities-joint pain may be severe
    • Large and small fiber sensory modalities are affected
    • Alopecia usually begins within 15–39 days
    • Increasing distal to proximal extremity sensory loss, distal muscle weakness and atrophy supervene. Proximal loss of deep tendon reflexes occurs .
    • Weakness and sensory loss may involve the cranial nerves and respiratory muscles.
    • Ptosis is common.
    • Neuropathy may progress for several weeks after a single exposure (coasting effect)
    • Sensory loss greater than weakness
    • Central nervous system signs and symptom are directly related to dose and include:
      • Anxiety
      • Psychosis and behavioral changes
      • Tremor
      • Abnormal chewing movements
      • Fever; loss of sweating, hypertension, tachycardia
      • Chorea and ataxia
    • Mee's lines; hyperkeratosis and alopecia may occur concomitantly.
  • Chronic exposure (low level):
    • Extrapyramidal signs
    • Minimal sensorimotor neuropathy
  • EMG:
    • Mild slowing of motor conduction velocities; reduced SNAP amplitudes; evidence of motor axonal degeneration
  • Laboratory:
    • Thallium can be measured directly in blood, urine, hair and nails; potassium will cause a rise in urinary excretion
    • Negative CSF
  • Pathology: axonal neuropathy affecting larger > smaller fibers. Distal axons affected > proximal segments; small unmyelinated fibers may be affected.

Acrylamide

  • General features:
    • Exposure:
      • The agent is used to seal pipes, stabilizers in the paper industry; cosmetic additive, coating on paper products; engineering; polyacrylamide is used as a flocculate in waste water treatment plants.
    • Pathogenesis:
      • The monomeric form is neurotoxic; polyacrylamide is nontoxic. Industrial poisoning is usually through the skin, but it can be absorbed by inhalation or through the GI tract; greater than 0.3 mg/m2 is toxic. Its metabolite glycinamide is also neurotoxic. The toxin interferes with axonal transport that causes axonal swelling and accumulation of neurofilaments par anodally.
  • Pathology
    • Central peripheral distal axonopathy. Early exposure causes damage to the lungs peripheral axons. Continued exposure cause damage to the longest central axons of the corticospinal and cerebellar system.
  • Clinical Presentation:
    • The earliest symptoms are focal skin irritation, redness and desquamation.
    • Mild to moderate exposure causes loss of vibration, touch, paresthesias and depressed reflexes.
    • Severe exposure causes weight loss, muscle weakness and atrophy, areflexia, sensory ataxia, dysarthria and tremor; clumsiness and intention tremor in the upper extremities and gait abnormalities may be early signs.
      • Sensory ataxia
      • Dysarthria
      • Tremor
      • Clumsiness and intention tremor in the upper extremities
      • Gait abnormalities may be early signs
    • Acute high dose exposure:
      • Causes autonomic dysfunction with impairment of reflex changes in heart rate, blood pressure and dysregulation of the peripheral circulation.
      • Sleep disturbance, hallucinations and memory loss also occur with acute high dose intoxication.
      • The coasting phenomenon occurs.
  • EMG:
    • Normal motor NCV
    • SNAPs and CMAPs are reduced
    • CSF:
      • Protein may be elevated
  • Pathology:
    • Reduced numbers of large diameter thick myelinated fibers (αα and AB fibers).
    • Severe poisoning central and small fiber demyelination is seen.

Ethylene Oxide

  • Exposure:
    • The compound is utilized in sterilizing heat sensitive biomedical equipment. Exposure occurs during sterilization procedures or handling sterilized hospital gowns.
  • Pathogenesis:
    • FDA limits for toxic exposure are 250 ppms.
  • Clinical presentations:
    • Acute exposure:
      • Causes confusion
      • Memory loss and encephalopathy.
      • This is followed by distal extremity numbness and weakness. Tendon reflexes are depressed and ankle jerks are absent.
    • Chronic exposure causes:
      • Loss of vibration sensitivity
      • Decreased IQ
      • Depressed speed of cognitive processing
      • Neurologic symptoms are often preceded by a rash.
      • Encephalopathic symptom and signs may accompany the neuropathy
  • EMG:
    • Motor NCVs are mildly decreased

Carbon Disulfide

  • General features:
    • Exposure:
      • Carbon disulfide vaporizes at room temperature and may be inhaled. It is a metabolic breakdown product of disulfiram that is used in the treatment of alcohol abuse. The chemical is used in viscose and cellophane; film; rayon manufacture, pesticides and in chemical laboratories. 4 mg/M3 is toxic.
    • Pathogenesis:
      • The chemical is usually absorbed by dermal contact, but patients have been seen with inhalation and GI exposure. It reacts with amino sulfhydryl and hydroxyl groups. P-450 cytochrome enzymes are affected due to the formation of reactive sulfur atoms. They may inactivate metalloproteinase; the compound is metabolized to isothiocyanate which may link cytoskeletal proteins.
  • Clinical presentation:
    • Massive exposure:
      • Psychiatric and extrapyramidal manifestations.
    • Chronic exposures:
      • Distal paresthesias, sensory loss, weakness and hyporeflexia. Retinopathy, microaneurysm and hemorrhage are seen.
      • Rarely, optic neuropathy and loss of the corneal reflex occurs.
      • Extrapyramidal signs are tremor bradykinesia and cogwheel rigidity.
      • Rarely chronic exposure leads to spasticity and hemiparesis. The coasting phenomenon occurs after exposure has ceased.
  • Laboratory:
    • Urinary level of 2-triothiazolidine-4-carboxylic acid a metabolite of CS2 measures the degree of exposure
    • CSF is normal
  • EMG:
    • Distal motor and sensory NCVs; some evidence of denervation. Prolongation of the motor and sensory latencies.
  • Pathology:
    • Giant axonal swellings are noted. Primarily a severe axonal degeneration is present.
    • CSF is normal.

Hexacarbons (N-Hexane, Methyl n-Butyl Ketone; Mn BK)

  • General features:
    • Exposure:
      • Both toxins are metabolized to 2,5-hexane etiane (2,5-HD) which is responsible for the toxic effects of the compounds.
      • N-Hexane is widely used as a solvent and is a component of lacquers, glues and glue thinners. Industrial exposure and inhalation abuse occur (glue sniffers).
      • Methyl n-butyl ketone is more common. Cluster epidemic resulted from the substitution of Mn BK form ethylethyl ketone and methyl butyl ketone during the process of color and plastic coated fabrics.
      • High level exposure occurs with glue sniffing. Methyl ethyl Ketone (MN BK) may potentiate the toxic effects of n-hexane.
    • Pathogenesis:
      • Compounds are absorbed most often by inhalation and dermal contact. The distinctive pathology of giant axonal neuropathy occurs by disruption of axonal transport and accumulation of neurofilaments at para nodal aerosis.
  • Clinical Presentation:
    • Severe exposure causes anorexia, abdominal pain, weakness and cramps in the lower extremities.
    • Acute high level exposure causes narcosis and coma.
    • Repeated high level exposure that occurs with glue sniffing causes a subacute predominately motor and cranial neuropathy. There is the insidrosis onset of distal sensory paraesthesias, followed by distal weakening, calf pain, atrophy and loss of ankle deep tendon reflexes.
    • The intrinsic muscles of the hands and long extensors or flexors of the digits are affected, which progresses to involve proximal muscles.
    • Glue sniffers may suffer bulbar and phrenic nerve paralysis.
    • The neuropathy usually progresses for 1–4 months after exposure is terminated (coasting phenomenon) in severely affected patients.
    • Autonomic dysfunction with hypo or hypertension impotence and bowel and bladder abnormalities are frequent.
    • Chronic low level exposure:
      • Central peripheral axonopathy with involvement of the longest central fibers (spinocerebellar, dorsal column and corticospinal).
      • Pin prick, temperature are initially impaired with gradual proximal sensory loss.
      • Some glue sniffing abuse patients suffer a subacute distal to proximal progressive weakness early in the course of the illness.
      • Severely affected patients may develop signs of spasticity several years after exposure which reflects spinal cord damage.
  • Laboratory Evaluation:
    • Measurement of 2,5-hexanedione in the urine
  • EMG:
    • Severe slowing of motor nerve conduction velocities and distal latencies
    • Prolonged somatosensory, auditory and visual evoked potentials
  • Cerebral spinal fluid (CSF):
    • Protein is elevated in severe intoxications without pleocytosis
  • Pathology:
    • Giant axonal swelling. This pathology is also seen with CS2, acrylamide intoxication and congential giant axonal neuropathy. The paranoidal regions accumulate neurofilaments.

Organophosphates

These are also utilized as flame retardants, antioxidants and lubricants. Agricultural exposure is the most common form of intoxication. Dermal contact from sitting on bags of the chemical in hot climates also occurs as does exposure during preparation of the compounds for spraying.

  • General features:
    • Exposure: The three major industrial applications of these compounds are:
      • Insecticides
      • Petroleum additives
      • Plastic modifiers
  • Clinical Presentation:
    • Most organophosphorus (OP) esters inhibit acetylcholinesterase
    • DEP/TEPP, sarin and their derivatives are extremely potent. They cause irreversible inhibition of acetylcholinesterase in both erythrocytes and in the central nervous system (CNS) which induces excess stimulation of muscarinic receptors in the CNS and nicotinic receptors in the PNS.
    • The acute type I OP syndrome:
      • Stimulation of CNS muscarinic receptors
      • Commences hours after exposure
      • Nausea and vomiting, increased salivation micturition, sweating, and cardiac rhythm abnormalities (brady or tachycardia)
      • High toxic exposure is dominated by CNS manifestations:
        • Emotional lability
        • Cognitive impairment
        • Convulsions
        • Coma
        • May be the only manifestations

Intermediate Type II Organophosphorus Syndrome

  • Onset is within 12–96 hours of exposure
  • Activation of nicotinic Ach receptors on skeletal muscle
  • Respiratory insufficiency
  • Weakness of neck flexors and proximal muscles
  • Rare cranial muscle involvement
  • Distal muscles are spared
  • Dystonic posturing
  • Sensation is intact
  • Recovery starts 5–15 days after exposure

Organophosphate-induced delayed polyneuropathy (OIDP)

  • Occurs most often with chronic low level exposure
  • Phosphates, phosphoramidites and phosphonates inhibit neuropathy target esterase
  • These effects do not involve inhibition of acetylcholinesterase
  • The neuropathy has a delayed onset following a single exposure; usually between 10–20 days
  • Related compounds that inhibit neuropathy, target esterase (NTE) are: mipofox, leptazol, trichlorfon, Trichlormate, dichlorovos; methmetaphase
  • Clinical Presentation
    • Most OP in pesticides do not cause CIDP
    • Maximal deficit occurs by 14 days of exposure
    • Initial manifestations are cramping, pain in the calves and painful leg paraesthesias
    • Early foot drop; later weakness of intrinsic hand muscles
    • Proximal muscles spared until late
    • Prominent gait ataxia
    • Ankle jerks depressed or lost; other deep tendon reflexes reflect CNS damage
    • Rare CN or ANS involvement

Triorthocresyl Phosphate (TOCP)

  • General features:
    • Produced the most cases of neuropathy
    • Mild cholinergic symptoms in humans
    • Exposure:
      • Softeners in the plastics industry
      • High temperature lubricant
  • Clinical presentation:
    • Early mild cholinergic response with diarrhea, perspiration and fasciculation for 24 hours
    • Asymptomatic interval for 7–21 days
    • Cramping calf pain
    • Tingling and burning sensations in hands and feet
    • Weakness of the feet and hands that may involve proximal muscles in severe cases
    • Weakness and flaccidity may be prominent early in addition to the paraesthesias
    • TOCP is predominantly a motor neuropathy although some sensory loss is invariant
    • Other organophosphorus ester intoxications cause progressive weakness of legs greater than arms which may be proximal greater than distal.
    • Gait ataxia, loss of reflexes and signs of hyper reflexa are late features
    • RBC acetylcholine is depressed early in the intoxication
    • Reduced lymphocyte NTE may predict later development of delayed peripheral neuropathy
  • EMG:
    • Axonal neuropathy and may improve if there is no super composed myelopathy

Differential Diagnosis of Organophosphate Poisoning

  • GBS
  • MG
  • Solvent neuropathies
  • Carbon disulfide intoxication
  • Acrylamide poisoning
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