Toxic neuropathies

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TOXIC NEUROPATHIES

A B C D E F G H I L M N O P S T V Z

TOXIC NEUROPATHIES: CLINICAL & PATHOLOGICAL FEATURES

Axonal			Demyelinating	Mixed
Sensory	Sensory & Motor	Motor
Almitrine Bortezomib Chloramphenicol Dioxin Doxorubicin Ethambutol Ethionamide Etoposide (VP-16) Gemcitabine Glutethimide Hydralazine Ifosfamide Interferon-α Isoniazid Lead Leflunomide Metronidazole Misonidazole Nitrous oxide Nucleosides ddC; ddI; d4T; 3TC Phenytoin Platinum analogs Propafenone Pyridoxine Statins Thalidomide	Acrylamide Alcohol (Ethanol) Allyl chloride Arsenic Cadmium Carbon disulfide Chlorphenoxy Ciguatoxin Colchicine Cyanide Dapsone Dichloroacetate Disulfiram DMAPN Ethylene oxide Heroin Lithium Methyl bromide Nitrofurantoin Organophosphates Podophyllin PCBs Saxitoxin Spanish toxic oil Taxol Tetrodotoxin Thallium Trichloroethylene TOCP Vacor (PNU) Vinca alkaloids	β-bungarotoxin Botulism Dimethylamine Borane Gangliosides Latrotoxin Black widow Lead Mercury Misoprostol Tetanus Tick paralysis	Buckthorn Chloroquine Diphtheria FK506 (Tacrolimus) Hexachlorophene Muzolimine Perhexiline Procainamide Tellurium Zimeldine	Amiodarone Diethylene glycol Ethylene glycol 1,1'-Ethylidinebis [tryptophan] Gold Hexacarbons n-Hexane Na⁺ Cyanate Suramin

Also see:
Channel toxins
Muscle toxins
Snake venom toxins

Acrylamide

Toxicity
- Monomer
- Industrial settings
- Route: Skin contact; Occasionally inhalation or GI
- Prodrome: Dermatitis of hands
Neuropathy
- Onset: Numbness & sweating of hands & feet; Gait disorder
- Progression: Slow
- Sensory: Vibratory loss early; Stocking glove
- Autonomic: Sudomotor, distal; Hyperhidrosis or Hypohidrosis
- Tendon reflexes: Lost diffusely
- Distal weakness: Mild
- Recovery: Partial or complete after toxin removed
Other clinical features
- CNS
  - With acute high dose exposure
  - Encephalopathy; Sleep & Memory disorders
- Skin
  - Early in course
  - Focal irritation & desquamation
  - Abnormal sweating
Laboratory
- Electrodiagnostic: Distal denervation
- CSF: Normal protein
Nerve pathology
- Axonal loss; Large fibers
- Distal
- Accumulations of 10-nm neurofilaments: Especially paranodal & terminal
- Abnormal fast axonal transport
External link: NIEHS

Alcoholic (Ethanol) polyneuropathy⁷

Epidemiology
- Incidence
  - 9% of alcoholics with clinically manifest polyneuropathy
  - Female > Male
- Related factors
  - Alcohol abuse
    - Severe: > 100 grams of alcohol per day
    - Prolonged: Years; Higher total lifetime dose
  - Nutritional deficiency
    - Skipped meals
    - Diet low in: Meat & fish, Cereals, Fresh fruit, Vegetables
    - Weight loss: 30 to 40 lbs in 50%
    - ? Specific involvement of B1 deficiency
  - Family history: 40% to 50%
  - Age
Polyneuropathy: Clinical
- ~ 40% Asymptomatic
  - Muscles: Thin, Tender
  - Distal tendon reflexes: Reduced
  - Distal pain & temperature sensation: ± Reduced
- Pain: Dull ache & burning in feet ± legs; Occasional lancinating pains
- Distribution of signs: Distal; Symmetric
- Sensory
  - Panmodal loss: Variable involvement in individual patients
  - Hyperesthesia
- Weakness: Legs > Hands
- Tendon reflexes: Reduced at Ankle in 80%
- Autonomic
  - Hyperhidrosis: Feet & Hands
  - Reduced Parasympathetic cardiac responses
  - Esophageal dysmotility
- Cranial nerves: Hoarse voice
- Disease course: Slow improvement with reduced alcohol intake
- Electrodiagnostic: NCV changes
  - Axonal loss: Distal
  - Sensory & Motor: Small Sensory potentials & Mildly slowed CV
  - Legs > Arms
- Nerve Pathology: Distal axonal loss
CNS
- Cerebellar degeneration
- Wernicke-Korsakoff syndrome
Other systemic involvement
- Myopathy
- Skin changes
  - Stasis edema & pigmentation
  - Plantar foot ulcers: 1st > 5th metatarsal
  - Dryness & Scaliness: generalized
- Arthropathy: With severe polyneuropathy; 2° Repeated trauma
- Anemia
- Liver function changes

Allyl chloride

Toxicity
- Uses: Manufacture of epoxy resin & glycerin
- Atmospheric exposure
- Outbreaks in Chinese
Neuropathy
- Distal
- Sensory > motor
- Axonopathy; Distal
- Recovery: Months; Following toxin withdrawal
- Pathology
  - Distal axonopathy
  - Multifocal neurofilament accumulations
  - CNS: Dorsolateral columns

Almitrine

Uses: Respiratory disorders
Clinical features
- Neuropathy
  - Burning pain; Distal; Pansensory; Axonal
  - Maximum severity: Moderate 2^o pain
  - Time course
    - Latency: Several months
    - Recovery after drug stopped: Over 2 to 12 months
  - Incidence: High
- Weight loss
Pathology: Axonal loss; Large > small axons

Amiodarone

Uses: Cardiac arrhythmias
Actions: Channel blocker
- Blocks repolarising K⁺ channel: Prolonged QT interval on EKG
- Also blocks Na⁺ & Ca⁺⁺ channels
- Non-competitive α & β-adrenoreceptor antagonist
General: Neuropathy
- Incidence: High
- Risk: Dose related; > 400 mg/day; > 1 year
Clinical features of toxicity
- Neuropathy
  - Onset: Aching pain & Myalgias (proximal & distal)
  - Motor: Distal weakness
  - Sensory: Large > Small fiber loss; Distal; Symmetric
  - Tendon reflexes: Reduced
  - Maximum disability: Severe
  - Time course: Partial recovery after reduced dosage
- Autonomic: Rare orthostatic hypotension
- CNS
  - Tremor (40%)
  - Encephalopathy; Ataxia (Gait)
  - Optic neuropathy
    - Frequency: 1.8%; 5x control population
    - Drug history: 3 months to 1 year
    - Onset: Slowly progressive
    - Distribution: Bilateral, asymmetric
    - Disk edema
    - Reduced visual acuity: Arcuate, Altitudinal or Nasal step defects
    - Course: Improvement after drug stopped
- Myopathy
  - Proximal weakness
  - Pathology: Autophagic vacuolation; Phospholipid inclusions
- Keratopathy (Dose related)
- Other: Dermatitis; GI; Bone marrow suppression; Pulmonary fibrosis; Thyroid (Hyper- or Hypo-)
- Prevention: Periodic ophthalmologic evaluation
Pathology: Nerve
- Axonal loss
- ± Demyelination: Variable from patient to patient
- Lamellar/crystalline lysosomal inclusions
  - Location: Endothelial cells, Smooth muscle, Schwann cells (non-myelinating)
  - Membrane-bound, osmophilic
  - Similar inclusions in perhexiline & chloroquine
External link: RxList

Arsenic (inorganic)

Toxicity
- Sources: Suicidal, Homicidal, Occupational, Environmental
  - Mining
  - Inorganic arsenic: Exposure to by-products of copper & lead smelting
  - Ingestion of trivalent arsenic
    - Suicide
    - Homicide
    - Food or water contamination: Endemic regions
      - Groundwater contamination
      - Locations: West Bengal, India; Bangladesh; Inner Mongolia
      - West Bengal, India
        
        6 million people exposed to arsenic through drinking water
        
        300,000 people manifest signs of chronic arsenicosis
  - Chinese medicinal herbal preparations
    - Toxic agent: Arsenic sulfide
    - Chronic poisoning
  - Marine organisms: May contain large amounts of trimethylated organoarsenic, arsenobetaine
    - No known toxic effects
    - Well-absorbed
    - Excreted unchanged in urine
- Route of intoxication
  - Usually oral
  - Absorbed via GI tract
  - Accumulates in: Liver, Kidney, Lung, Spleen, Aorta, Skin, Hair, Nails
- Metabolism of inorganic arsenic
  - Methylation: Mainly in liver; To monomethylarsonic acid & dimethylarsinic acid,
  - Excretion: Urine; Along with residual inorganic arsenic
- External links: RAIS; Arsenic Project
Clinical syndromes: Dose related
- General: Garlic-like smell to breath & tissue fluids
- Massive overdose: Subacute neuropathy
  - Early
    - GI: Vomiting & Diarrhea; Probably 2° GI irritation
    - Autonomic: Tachycardia & Hypotension; 2° GI fluid loss
  - Neuropathy
    - Onset
      - Delayed: After 10 to 20 days
      - Distal paresthesias & numbness
    - Evolution
      - Over 2 to 5 weeks
      - Sensory > Motor
      - Large fiber sensory modalities
    - Systemic signs: Few
    - Pathology: Distal axonal loss ± Demyelination
    - Treatment: Chelation with BAL or penicillamine for months
    - Recovery: Slow over years
- Low level exposure: Slowly progressive; 3 stages
  - Chronic absorption > 500-1000 μg/d
  - Onset: Malaise; Anorexia; Vomiting
  - 2nd stage
    - Membrane irritation
    - Skin
      - Hyperkeratosis
        
        Feet & Hands
        
        Precancerous state
        
        Arginine variant of codon 72 of p53 gene: Homozygosity associated with development of keratosis
      - Dark (Gray) skin
      - Hypopigmentation ("Raindrop pattern")
    - Nails: White stria (Mees lines), May occur months after an acute episode
    - Pitting edema
    - Aplastic anemia
    - Renal damage
  - Polyneuropathy
    - Sensory loss: Stocking-glove; Large > Small fiber
    - Weakness: Mild
    - CSF: Protein mildly increased
    - Pathology: Axonal loss; Distal
    - Recovery: Better in mildly affected
    - More common in patients with skin hyperkeratosis
- Arsine gas: Hemolysis
- Long term: Carcinogen, Lung, skin, liver, kidney & bladder
Pathophysiology: Uncouples oxidative phosphorylation
- Trivalent As⁺⁺⁺ more toxic than pentavalent form
- Trivalent As⁺⁺⁺: ? Interaction with thiol on lipoic acid in pyruvate dehydrogenase complex
- ? Inhibits pyruvate ® acetyl CoA reaction: Substitutes for phosphate
Diagnosis: Arsenic levels
- Acute (< 6 weeks): Urine
- Chronic
  - Tissues: Hair (Pubic); Fingernails
  - Level: > 1μg/g
- False positive urine levels
  - 25 to 1,000 μg/24 hours
  - 2° to consumption of nontoxic organic arsenates in seafood (shellfish)
Treatment: Chelation
- BAL (Dimercaprol; IM; 100 mg/ml in peanut oil)
  - Mild poisoning: 2.5 mg/kg qid x 2d, bid x 1d, then qd
  - Severe poisoning: 3 mg q4h x 3d, qid x 1d, then bid
- D-penicillamine: May produce neurological complications
- ? 2,3-dimercaptopropanesulphate (DMPS): 5 mg/kg q 4 hours
- Treat until urine arsenic < 25 μg/24h

Black Widow Spider Venom (Latrotoxin)

From Crew

Black widow spider

Insect: Lactrodectus mactans (Female)
Toxin
- Homology with glucagon-like peptide-1 (GLP-1) family
  - Insulin secretagogic hormones
  - GLP-1, Glucagon, VIP, Secretin,
    Pituitary adenyl cyclase activating polypeptide
- Receptors
  - CIRL
    - Ca⁺⁺ independent receptor for latrotoxin (Latrophilin)
    - GTP-binding protein-coupled
  - Neurexin I-α : Binds latrotoxin in Ca⁺⁺-dependent manner
- Action mediated, in part, by
  - Increased Ca⁺⁺ flux into presynaptic nerve terminals ® Depolarization
  - Depolarization ® Spontaneous release of transmitter from nerve terminals
    - Acetylcholine from motor axons
    - Catecholamines from adrenergic terminals
- Late: Degeneration of nerve terminals
Neuropathy
- Onset: Severe local pain
- Spontaneous activity
  - Muscle spasms & Cramping: Generalized; Especially proximal
  - Fasciculations
  - Tremor
- Sensory
  - Pain: subsides within hours
  - Paresthesias
- Tendon reflexes: hyperactive
- General: Headache; Vomiting; Hypertension
- Pathology: Degeneration of very distal axon terminals
- Treatment: Anti-venoms; Calcium gluconate for muscle spasms

Bortezomib (Velcade)³¹

Drug type: Boronic acid dipeptide
Uses: Anti-neoplastic (Multiple myeloma; POEMS)
Actions
- Proteasome (26S) inhibitor, reversible
- Sensitizes malignant cells to apoptosis
- Down-regulates expression of adhesion molecules
  - Inhibits cell-adhesion�mediated drug resistance,
  - Decreases transcription and secretion of cytokines in bone marrow
- Enhances oxidative stress: Upregulation of p53, p21, p27 & p38 MAPK & JNK
Neuropathy
- Risk
  - Cumulative dose related
  - Pre-existing neuropathy
    - ? Increased severity
    - No increased frequency of neuropathy
  - Increasing age: 23% < 50 years; 64% > 60 years
  - Diabetes mellitus
  - Pain: More common & prolonged with recurrent treatment
- Frequency
  - Pain: 30% to 46%
  - Severe neuropathy: 15%
- Time to occurrence: Mean 69 days of treatment; Range 21 to 184 days
- Clinical
  - Sensory loss
    - Subjective numbness
    - Small fiber (C & Aδ): Pain, Sharpness & Temperature
    - Aβ fiber: Touch
    - Distal
    - Legs > Arms
  - Pain⁴¹
    - Type: Burning (50%), Sharp, Cold or Electric
    - Skin dysesthesias
    - Worsened by: Activity; Cold pain stimuli
    - Common cause for drug dose modification
  - Motor
    - Normal: Most patients
    - Weakness: Occasional patients with more severe neuropathy
  - Course
    - Severe neuropathy: 12% to 15%
    - May be difficult to treat with analgesics
    - Improvement: After treatment stopped; Often (71%) to baseline
    - Persistent: 10%
- Electrophysiology
  - Sensory: Reduced SNAP amplitude
  - Axon loss
  - May be normal
- Dose modification with polyneuropathy³¹
  - Paresthesias or loss of reflexes) without pain or loss of function: Continued treatment
  - Pain ± interfering with function: Reduce dose to 1.0 mg/m2
  - Pain interfering with activities of daily living
    - Withhold treatment until toxicity resolves
    - Then reinitiate treatment at 0.7 mg/m2 once weekly
  - Permanent sensory loss that interferes with function: Discontinue treatment
Other side effects
- Postural hypotension
- Rhabdomyolysis: 1 patient

Buckthorn fruit

Toxicity
- Exposure: Ingestion
- Toxic agent: T-544 (Tullidinol)
- May uncouple oxidative phosphorylation
Epidemiology
- Ingestion of buckthorn fruit: Karwinskia humboldtiana
- Distribution: Southwestern U.S. & Mexico
- Children, cattle & goats most commonly affected
  - Animal disease called "Limberleg": Incoordination & Ataxia
  - Cattle most susceptible
- Severity of toxicity proportionate to amount of fruit ingested
- External links: Medicinal Plants; NatureServe
Neuropathy
- Onset
  - Latent period: 5 to 20 days after ingestion
  - Rapidly progressive
  - General features: Fever; Cramps; Diarrhea; Headache
- Weakness
  - Early: Legs > Arms
  - Progression: Severe quadriparesis; Bulbar & respiratory involvement
  - Cranial nerves: Normal
- Sensory loss: Mild; Distal
- CSF: Normal
- Course
  - May improve spontaneously if supported through paralysis
  - Over 3 to 12 months
- Pathology
  - Segmental demyelination ± Axonal swelling & loss
  - Experimental: Axonal loss (Motor) more prominent with systemic administration
- Diagnosis: History of ingestion of fruit; Exclusion of other causes
Systemic features
- Liver necrosis
- Occasional degeneration of skeletal & cardiac muscle fibers
- Micturition difficulty
- Muscle: Cramps; Cardiac change

Cadmium⁴

Toxicity: External link
Sources
- Occupational
  - Inhalation of dust
  - Often associated with lead or zinc exposure
- Cigarette smoke
- Exposure is cumulative with long half-life (> 15 years)
Onset: Late; After cadmium exposure
Neuropathy
- Often subclinical
- Motor
  - Clinical: Normal strength
  - Electrodiagnostic: CMAP amplitude mildly reduced ; Distal denervation on EMG
- Sensory: Subjective complaints
- Correlates with cadmium body burden & older age
Systemic: itai-itai
- Pulmonary: Emphysema
- Anosmia
- Yellow dental necks
- Proteinuria
- Skeletal: Osteomalacia; Fractures
Carcinogen: Leads to mutations by inhibiting DNA mismatch repair³⁰
Diagnosis: Urinary cadmium level (μg/g creatinine)
Experimental PNS
- Acute: Hemorrhage in trigeminal & spinal ganglia; Endothelial damage
- Chronic: Neuropathy; Membrane-bound glycogen deposits in axons; Axon loss ± demyelination

Carbon Disulfide (CS₂)

Toxicity
- Uses
  - Production of viscose rayon fibers & cellophane films
  - Pesticides
- Exposure: Airborne
Acute high dose exposure: Psychosis
Neuropathy
- Chronic low dose exposure; 4 to 6 months
- Onset: Lower extremity numbness & paresthesias
- Motor: Distal weakness
- Pansensory loss: Distal; Stocking-glove
- Pain: Myalgias
- Prognosis after exposure stopped
  - Initial worsening may occur
  - Long term slow improvement
- Pathology
  - Distal axonopathy
  - Neurofilamentous swellings: Fusiform; Terminal axon; PNS & CNS
CNS
- High level exposure
- Encephalopathy; Extrapyramidal Neurasthenia
Ocular: Visual loss (Retinopathy); Optic neuropathy; Corneal reflexes reduced
Monitoring: 2-thiothiazolidine-4 carboxylic acid (ITCA) in urine

Chloramphenicol

Uses: Antibiotic
Risks
- Prolonged high doses: Children with cystic fibrosis
- ? Renal failure
Clinical features
- Neuropathy
  - Onset: Chronic
  - Sensory; Painful
  - Distal
  - Maximum severity: Mild
- Other: Aplastic anemia; Retinopathy; Optic neuropathy

Chloroquine & Hydroxychloroquine (4-aminoquinolones)

Uses: Autoimmune disorders; Malaria
Clinical features
- Neuropathy
  - Onset: 1 to 2 years
  - Sensory-motor
  - Distal
  - Maximum severity: Mild
  - Pathology:
    - Demyelination + Axonal loss
    - Schwann cell (lamellar/crystalline) cytoplasmic inclusions: Similar to amiodarone
- Myopathy: Amphiphilic drugs
  - Mechanisms: Lysosomal storage disorders
    - Chloroquine activates transport of newly synthesized lysosomal enzymes
    - Enzymes move from secretory pathway via the trans-Golgi network (endosomal)
    - Increased autophagosome formation
  - Clinical
    - Weakness: Proximal; Legs > Arms; May progress to face
    - Cardiomyopathy: Some patients
    - Neuropathy: Usually mild
    - Course: Slow improvement after drug discontinued
    - Hydroxycloroquine less severe than chloroquine
  - Pathology
    - Acid phosphatase-positive vacuoles
    - Curvilinear & myeloid bodies
    - Membrane proliferation
- Cardiac
- Other: Encephalopathy; Blood dyscrasias; Retinopathy; Corneal deposits

Colchicine

Carr, Hawaii
Gloriosa superba

Uses: Gout
Natural source
- Tubers of Gloriosa superba
- Distribution: Central Africa & Asia
- External link: NatureServe
Risk
- Renal failure: High serum levels
- Chronic treatment
Neuropathy
- Weakness: Distal
- Sensory loss: All modalities
- Severity: Generally Mild
- Incidence: Low
- Prognosis: Improvement with stopping drug
- Pathology: Axonal loss
Other features
- Myopathy (Vacuolar)
- Systemic: GI; Hepatic; Acute gout

Cyanide

Epidemiology: Ingestion of cyanogenic plants
- Cassava plant (Manihot esculenta esculenta)
  - Consumption of food processed from starchy roots with high cyanide levels
  - Higher risk: Protein-deficient diet with low intake of sulphur amino acids
    - Sulphur substrates needed for conversion (detoxification) of cyanide to thiocyanate
- Disease geography: Southwestern Nigeria, Ijebu speaking¹⁴
Nosology
- Names: Nigerian neuropathy; Tropical ataxic neuropathy
- Also see: Konzo myelopathy
Neuropathy
- Onset
  - Dysesthesias in feet
  - Insidious
  - Age: Often > 40 years
- Sensory loss
  - Ataxia (84%)
  - Large & Small fiber modality loss
  - Distribution: Distal; Symmetric; Feet & Hands
- Motor
  - Distal weakness
  - Distal wasting: Especially upper limbs
- Tendon reflexes
  - Reduced: Ankles (38%)
  - Increased: Biceps & Knees (50%)
- Primitive reflexes (38%)
- Progression: Slow; Persistent symptoms
- Associated with poor health & riboflavin deficiency
CNS
- Myelopathy: Increased DTRs (50%); Spasticity
- Optic atrophy (48%)
- Posterior column signs
- Hearing loss (55%)
External links: Toxicity; Cyanide

Dapsone

Uses: Leprosy; Dermatitis herpetiformis
Actions
- Facilitates conversion of myeloperoxidase to inactive form
- Inhibition of neutrophil adherence to vascular endothelium
Risk
- Dose related; > 300 mg/day
- Slow acetylation
Neuropathy
- Onset: 2 weeks to 10 years after starting treatment; ? Shorter with highest doses
- Motor predominant
  - Arms > Legs
  - Distal
- Course
  - Coasting: Progression after drug stopped
  - Improvement: Later after drug stopped or dose reduced
  - NCV: Small CMAPS; Sensory normal
- Pathology: Axonal loss
Hematologic effects
- Hemolytic anemia: More severe with glucose-6-phosphate dehydrogenase deficiency
- Methemoglobinemia
- Leukopenia: 1st 3 months of treatment; Especially with dermatitis herpetiformis
CNS effects: Insomnia; Headache; Tinnitus; Nausea

Dichloroacetate³⁹

Dichloroacetate

Use: Lactate lowering
Dose: 25 mg/kg/day by mouth
Clinical
- Onset: 3 to 12 months after starting medication
- Frequency: 86%
- Paresthesias: Distal limb
- Pain
- Numbness: Distal
- Gait disturbances & falling
- Course: Partial or complete improvement aver 6 to 18 months after stopping drug
Laboratory: Axonal neuropathy
- NCV: Reduced CMAP & SNAP amplitudes

Diethylene glycol⁴²

Epidemiology: Case reports & Epidemics
Structure
- HO-CH₂-CH₂-O-CH₂-CH₂-OH
- External link: Chemicalland
Uses
- Antifreeze
- Sterno
- Finishing agent for clothing material
- Solvent for dyes & drug synthesis
Exposure
- Suicide attempts
- Substitution for glycerin in medications
  - 1937: Sulfanilamide elixir
  - 3rd world countries: Panama epidemic
Onset: Acute, Days
Clinical
- Peripheral neuropathy
  - Onset
    - Often delayed after renal failure
    - Days to weeks after exposure
  - Weakness: Diffuse; Distal > Proximal + Face; Severe
  - Sensory loss
  - Tendon reflexes: Reduced
  - Course: Recovery over months after elimination of exposure
- CNS: Encephalopathy
- Systemic: Renal & Hepatic failure
Laboratory
- NCV
  - Acute phase: Axon loss; Reduced CMAP amplitudes & Noraml conduction velocity
  - Recovery: ? Demyelinating features; Slow NCV & Prolonged distal latency
- Pathology: Nerve
  - Myelin loss: Severe
  - Axons: Loss; Swelling
- MRI: Cranial nerve enhancement, late
- EEG: Diffuse slowing
- Metabolic acidemia
Treatment: Hemodialysis
See: Ethylene glycol

Dimethylamine Borane³⁷

DMAB

(CH₃)₂NHBH₃
Epidemiology: Case report
Exposure
- Industrial use
  - High-temperature printed circuit boards, thin metal film,
    floppy disks, semiconductors, power transistors.
- Acute
- High dose
- Skin +
Polyneuropathy: Motor predominant
- Onset: Days after exposure
- Distribution: Distal; Arms & Legs
- Weakness: Hands & Feet
- Sensory loss: Pan-Modal; Hands & Feet
- Course: Partial recovery over years
Other clinical
- Encephalopathy: Acute
- Skin & mucosal irritation
Laboratory
- EMG: Denervation, Distal & proximal limbs
- NCV: Small CMAPs
- Skin innervation: Reduced
Pathology: Sural nerve
- Axon loss: Large & small myelinated
- Ultrastructure
  - Axonal degeneration
  - Vacuoles
  - Derangement of microtubules & neurofilaments in some axons

Dioxins & Furans (2,3,7,8-polychlorinated)⁵

2,3,7,8-tetrachlorodibenzo-p-dioxin

Exposure
- Pesticide production
- By-products of 2,4,5-trichlorophenol production
- > 1 year of exposure
Clinical
- Chloracne
- Neuropathy: Mild; Especially with chloracne
  - Distribution: Legs predominantly affected; Symmetric
  - Sensory loss: Vibration; Pain sense
  - Autonomic: Sexual impotence
  - No weakness
  - Electrophysiology: Reduced Common peroneal CMAP; ? Axonal loss
External link: Dioxins

Bretonneau: Named diphtheria

Diphtheria

^8,11

Exotoxin produces cardiomyopathy & neuropathy
- 58.3 kD protein
- Production
  - Encoded by
    - Lysogenic phage beta
    - Phage contains gene for diphtheria toxin
  - Expression controlled by host bacterium
    - Repressor protein, product of the DtxR gene
      - Present in host bacterium
      - Activated by iron
    - Higher expression with reduced iron in environment
- Structure: A/B toxin
  - A portion: Produces toxicity
  - B portion: Binds toxin to receptor
- Receptor: Heparin binding-epidermal growth factor
- Action: Inhibits protein synthesis in affected cells
  - Catalyzes covalent attachment of ADP ribose moiety of NAD to Elongation factor 2
- ? also activates cytotoxic mechanisms
- Disease production
  - Effects are both localized near infection and systemic
  - Lesions most prominent near permeable regions of intraneural vessels
Acute infection
- Corynebacterium diphtheriae
  
  Gram stain
  - Gram positive, aerobic, nonmotile, rods
  - Reservoir: Human carriers
  - Transmission: Respiratory; Person-to-Person
- Incubation period: 2 to 5 days
- Disease location
  - Usually in throat, upper respiratory tract or skin
  - Laryngitis, Nasopharyngitis, Tonsilitis
  - Neck edema ("Bull neck")
- Early symptoms: Aching pains; Anorexia; Headache
- Diagnosis: Culture from throat or skin ulcer
- Treatment: Antitoxin
  - Reduces severity of neuropathy
  - Most effective when given early, within 48 hours of onset
  - Treat before bacterial diagnosis
- Prevention
  - Immunization recommended
    - Children: Age 2, 4, 6, 12-15 months & 4 to 6 years
    - Adults: Booster every 10 years, especially for protection in endemic areas
  - In US 20% to 50% of adults > 20 years now susceptible
  - Reduced Immunity with increasing Age, especially aged 30 to 50 years
  - Natural infection probably confers life-long immunity
Epidemiology
- Most frequent disease
  - 8 to 9 year old children
  - Populations without vaccination
  - Adults with lapsed immunizations (> 10 years previously), 30 to 60 years of age
    - Now frequent in adults in former states of Soviet Union
  - Urban
  - Temperate zones
- Neuropathy in untreated patients
  - Palatal paralysis (local effect) in 15%
  - Polyneuropathy (systemic effect) in 10% to 20%%
  - More frequent in more severe disease

Neuropathy: 2 syndromes; Biphasic course

Local effect of toxin
- Onset
  - Time
    - Range: 2 to 50 days after throat infection
    - Mean: 10 to 20 days
  - Sensory loss
    - Usually pharyngeal-palatal
    - May be in limbs with cutaneous diphtheria
  - ± Weakness: Dysphonia with Dysphagia
- Progression
  - Over 2 to 3 weeks
  - Then rapid improvement
  - Often complete recovery until 2nd phase
- Clinical syndrome
  - Incidence: 15% to 75%
  - Sensory > Motor
  - Weakness: Nasal speech; Poor cough
  - Sensory loss: Pharyngeal
  - Cranial nerve: Paralysis of accommodation with preserved EOM
  - Late weakness: Diaphragm; Face; Oculomotor
  - Recovery: Onset 4 weeks, Range 1 to 14 weeks

Systemic radiculoneuropathy: ? Blood borne toxin

	Diphtheritic neuropathy	Guillain-Barré Syndrome
Time course	Biphasic Slower onset Rapid recovery	Monophasic Rapid onset Slower recovery
Cranial nerve Δ	Palatal Accomodation ê ® Blurry vision ± Facial weak	Facial weak: Common
Autonomic features	Parasympathetic Vagalê Tachycardia Bladder Δ	Sympathetic + Parasympathetic
Systemic features	Myocarditis

Epidemiology
- Male = Female
- Incidence
  - Mild cases: 10%
  - Severe cases (Bull neck & Toxic shock): 75%
  - Increased with: Myocarditis; Nephrosis
Onset
- 8 to 12 weeks after infection
- Sensory loss
Sensory loss
- Usually mild
- Distal; Symmetric
- Modalities
  - Especially vibration & joint position sense
  - Sensory ataxia: Occasional
- Paresthesias & Myalgias: Distal; Face; Tongue
Weakness
- Course
  - Onset: ~20 days
  - Maximum: 50 days
- Bulbar
  - Weakness 90%: Palate; Tongue
  - G-tube needed in 30%
- Respiratory
  - Weakness 30%: Diaphragm paralysis
  - Laryngospasm in severe cases
  - Support needed 20%
- Limb weakness (80%)
  - Onset after Bulbar & Respiratory
  - Distal > Proximal
- Facial weakness: Some patients
- Ophthalmoplegia
Autonomic
- Tachycardia: Nodose ganglion of vagus nerve
- Bladder dysfunction
- Hypotension
Tendon reflexes: Absent in 75%
Optic nerve: Atrophy & Visual disturbance in 6%
Time course
- Progression: Over longer period than
- Peak severity: 7 weeks, Range 2 to 12 weeks
- Recovery: Usually complete; Begins after days to weeks; More rapid than GBS

Laboratory
- Electrophysiology
  - Minimal changes in 1st 2 weeks
  - Late: Slow NCV; Long distal motor latencies
- CSF
  - Protein moderately elevated
  - ± Pleocytosis
  - Pressure: Increased
Pathology
- Non-inflammatory demyelination
  - Begins in paranodal zones
- Lesions
  - Dorsal root & nodose ganglia
  - Neighboring dorsal & ventral roots
- Axons spared

Systemic involvement
- Cardiac
  - Cardiomyopathy
    - 3rd week of illness
    - Myocarditis 10% to 25%
  - Tachycardias & arrhythmias: 8 to 12 weeks with autonomic neuropathy
- Skin
  - Population infected: Homeless; Tropics
  - Infection of disruption in skin
  - No early involvement of bulbar function
- Renal failure: Acute
Prognosis
- Mortality 15%
  - Cardiac arrhythmias after exertion
  - Sepsis: Pneumonia
  - More common with severe diphtheria
- Disability at 1 year
  - 13% unable to walk
  - 40% unable to return to manual work
External links: eMedicine

Disulfiram

Uses: Alcoholism
Risks: Dose related; > 500 mg/day; > 2 weeks
Neuropathy
- Distal
- Sensory: Pain & Paresthesias; Pansensory loss
- Motor: Legs > Arms
- Improvement with stopping drug
Other: Drowsiness; Headache; Sexual dysfunction; Optic neuritis
Pathology
- Neurofilamentous axonal swelling
- Axonopathy: Loss of large > small axons

Doxorubicin

Uses: Chemotherapy
Neuropathy
- No clinical cases in humans
- Experimental animals: Sensory ganglionopathy; Myelin swelling
- Autopsy: Ganglion cell loss
Cardiotoxicity: Arrhythmia; Myopathy
Other: Myelosuppression; Nephrotoxicity

Ethambutol

Uses: Tuberculosis
Neuropathy: Mild
- Sensory; Distal
- Axonal
- Recovery: Following drug withdrawal
Optic neuropathy

Ethionamide

Uses: Tuberculosis
Neuropathy
- Sensory: Paresthesias; Large fiber modalities
- Distal
- ? Axonal
- Recovery: Following drug withdrawal
Gastrointestinal; Skin; CNS

Ethylene Glycol

Uses: Solvent for paint, detergents & anti-freeze
Exposure
- Oral: Accidental ingestion or suicide
- Alcoholics
- Doses
  - Lethal level: 200 mg/dL
  - Toxicity: 25 mg/dL; Dose 100 mL ethylene glycol
Metabolism
- Rapid absorption from GI tract
- Ethylene glycol is non-toxic
- Degradation & Excretion
  - Urine: 20% excreted in 1st 2 hours
  - Liver
    - Slow metabolism via Alcohol dehydrogenase to glycoaldehyde
    - Rapid further conversion to glycolic acid, glyoxylic acid & oxalic acid
Clinical
- Phases
  - I. CNS depression: 30 minutes to 12 hours
  - II. Cardiopulmonary toxicity: 12-72 hours
  - III. Renal Toxicity: 24-72 hours
- Onset
  - 12 to 24 hours after ingestion
  - Early features
    - Nausea & Vomiting
    - Abdominal pain
    - Myalgia
    - Patient appears "inebriated", but no alcohol on breath
- Cranial nerve disorders
  - Onset: 5 to 20 day after ingestion
  - Facial weakness: Bilateral
  - Optic neuropathy: Edema; Atrophy
  - Hearing loss
  - Dysphagia
  - Tongue weakness
  - Pathophysiology: ? Nerve root disorder
- CNS: Onset 1 to 24 hours; Coma; Seizures
- PNS¹⁶: Radiculopathy or Neuropathy
  - Weakness (1 patient)
    - Onset: Acute
    - Distribution: Diffuse; Asymmetric¹⁶
  - Sensory loss: Distal; Panmodal
  - Tendon reflexes: Reduced
- Systemic: Renal failure after 24 to 72 hours
Laboratory
- Diagnosis: Gas chromatography
- CSF: High protein (Albuminocytologic dissociation)
- NCV: Proximal root involvement
- Serum: Acidosis with high anion gap; Low Ca⁺⁺
- Urine: Crystaluria
- Deposition of oxalate crystals in meninges
Treatment
- Correction of acidosis
- Hemodialysis
- Alcohol dehydrogenase inhibitor: Antizol (formepizole)
See: Diethylene glycol

Ethylene oxide¹

Uses: Sterilization of heat sensitive material
Exposure: Airborne; Skin contact
Neuropathy
- Chronic low dose exposure
- May be worst in regions near skin contact
- Pansensory
  - Distal; Stocking-glove
  - Paresthesias
- Motor: Mild
- Recovery: Gradual after withdrawal of exposure; Often incomplete
- Nerve conduction studies: Often unremarkable
- Pathology: Distal axonopathy
Encephalopathy
Headache
Skin rash at sites of contact

Etoposide (VP-16)

Uses: Lymphoma; Leukemia; Small cell lung cancer; Testicular Ca
Neuropathy (4% - 10%)
- Distal
- Sensory predominant
- Axonal
Rare: Autonomic neuropathy
Also see: Podophyllin

FK506 (Tacrolimus)

Uses: Solid organ transplant; Immunosuppression (T-cell)
Frequency: 3 of 1,000
Onset: 2 to 10 weeks after onset of therapy
Clinical
- Peripheral nerve: Sensory & Motor involvement
  - Distal > Proximal
  - Asymmetric
- CNS: Mutism; Seizures; Encephalopathy; Headache; Tremor
Nerve conduction: Multifocal demyelinating
Treatment: Some benefit from IV Ig or Plasma exchange

Gemcitabine

Uses: Anti-Neoplastic
Drug type: Nucleoside analogue
Neuropathy
- Paresthesias (10%)
- Recovery: Following drug withdrawal
Myalgias
- Flu-like syndrome: Fever; Asthenia

Glutethimide

Uses: Sedative
Neuropathy: Rare
- Pansensory; Paresthesias; Pain
- Distal
- ? Axonal
- Recovery: Months; Following drug withdrawal
Gastrointestinal; Skin; CNS

Gold (Aurothioglucose)

Uses: Rheumatoid arthritis
Risk: Dose related; Cumulative > 1 gm
Neuropathy: Rare
- Onset: Slow or sudden; Pain; Sensory loss
- Motor predominant: Weakness often asymmetric
- Sensory: Distal loss; Hyperesthesia
- Tendon reflexes: Lost
- Myokymia
- Cranial nerve: EOM; V; VII
- CSF: High protein
- Recovery: Weeks to months after stopping drug
- Pathology
  - Axonal loss
  - ± Segmental demyelination
Muscle: Myalgias; Myokymia
CNS: Encephalopathy; Seizures; Headache
Other: Skin; GI; Liver; Hematologic; Renal

Hexacarbons

Toxic compounds
- n-Hexane
- n-butyl ketone
- 2,5-hexanedione
Metabolism
- n-Hexane & n-butyl ketone metabolized to active agent: 2,5-hexanedione
- 2,5-HD half-life: 13--14 hours; Accumulation may occur during workweek
- Detection: Acid-hydrolyzed urinary levels of 2,5-HD
  - Sampled at the end of a shift
  - Correlate with workplace concentrations of n-hexane
Uses
- n-Hexane: Glues & Lacquers: Solvents
  - Exposure: Glue sniffing; Gasoline sniffing; Occupational
- n-butyl ketone: Solvent
Exposure routes
- Common: Airborne
- Occasional: Dermal; Latex gloves not effective protection
- Exposure limit: 50 ppm
Epidemiology
- Young males: Glue sniffing; Gasoline sniffing
- Occupational: Auto mechanics; Printing plants; Sandal shops; Furniture factories
- Geography: Asia; Europe; US
- Neurotoxic effects of n-hexane may be intensified
  - Use with other chemicals: Acetone, MEK, Isopropanol
Chronic low dose exposure: Neuropathy syndrome
- Exposure: Gasoline sniffing²³
- Onset
  - Subacute or Slowly progressive: 2 months
  - Sensory loss: Distal
  - Paresthesias
- Weakness
  - Distal > Proximal
  - Legs > Arms
  - Distribution
    - Symmetric: Most common
    - Mononeuritis multiplex: Rare; ? Due to nerve compressions
- Sensory
  - Loss
    - Distal; May progress to proximal involvement
    - Hands & Feet
    - Large & Small fiber modalities
  - Paresthesias
    - Distal
    - Hands & Feet
- Tendon reflexes: Absent or Preserved except at ankles
- Recovery: With delay after removal of toxin
  - Progression ("coasting") for 1 to 4 months
  - Improvement: Months to years
  - Residual deficits in more severe cases
    - Distal sensory loss & weakness
    - ± Spasticity
- CNS
  - Encephalopathy: Hallucinations
  - Myelopathy: Occasional; Delayed onset; Spasticity
- Systemic disorders: Weight loss; Malaise; Anorexia; Abdominal pain
Glue sniffer syndrome: n-Hexane exposure by inhalation
- Weakness
  - Phrenic nerve
  - Bulbar
  - Course: May be subacute with quadriplegia after 2 months
- Autonomic
  - Hands & feet especially involved
    - Hyperhidrosis
    - Blue discoloration
    - Mees's lines
    - Reduced temperature
  - Vascular: Hypotension; Instability
  - Impotence
- NCV: More features of demyelination
Laboratory
- CSF: Normal
- Electrophysiology: Axonal loss + Features of demyelination
  - Axonal loss: Small CMAPs
  - Conduction block
    - Partial; Non-focal (Graded); Distal (Forearm & Leg)
    - Especially rapid onset cases exposed to high doses
      - Glue sniffing more than chronic industrial exposure
    - In progressive phase of disease
  - Late: Disproportionate distal slowing of NCV
  - CNS: Abnormal visual & auditory evoked potentials
- Pathology
  - Distal axonopathy
  - Giant neurofilamentous swellings
    - In PNS & CNS
    - At proximal sides of nodes of Ranvier
    - Distal, non-terminal regions of axons ® Progress proximally
    - Consist of 10 nm neurofilaments
    - May produce 2° demyelination: Thin myelin sheaths
  - Axoplasmic transport may be impaired
  - Nerve biopsies may be normal with mild disease
Treatment: Removal from n-hexane exposure
External links

Hexachlorophene

Toxicity
- Source: Soaps, Anti-microbial agent
- Absorption: Skin; Gut; Mucous membranes
- Tissue targets: Myelin (Vacuolar myelinopathy); Retinal photoreceptors
- Toxic mechanisms
  - Dose related
  - Binds to myelin
  - Intramyelinic edema
  - May uncouple oxidative phosphorylation
Clinical
- Rash: Ulcerative
- Hyperthermia
- Diarrhea
- Encephalopathy: Increased Intracranial pressure; Seizures; Paresis
- Neuropathy: Demyelinating; Mainly documented in experimental animals

Hydralazine

Uses: Hypertension
Neuropathy
- Sensory: Paresthesias
- Distal
- Mechanism: Pyridoxine depletion
- Pathology: ? Axonal
- Recovery: Following drug withdrawal

Ifosfamide²²

Uses: Oncology; Recurrent sarcomas
Neuropathy
- Epidemiology
  - Frequency: ? 8%
  - ? Exacerbates subclinical neuropathies
  - Especially associated with high drug doses
- Onset: Acute; Paresthesias in feet
- Distribution: Distal
- Sensory
  - Pain & Paresthesias: May be severe
  - Loss: Panmodal; Especially Pain & Temperature
- Weakness
  - Early: None
  - Late: Present; Poorly described distribution
- Tendon reflexes: Reduced
- Recovery: Following drug withdrawal, over years; Incomplete
- Electrophysiology
  - Axonal loss: Small CMAPs & SNAPs
  - Conduction velocities: Normal
  - Some improvement over time
- Treatment
  - Discontinue drug
  - Pain management
Other side effects: May be heralded by neuropathy
- Ranal failure
- Bladder: Irritation; Hematuria
- Encephalopathy
- Cardiomyopathy

Interferon-α¹³

Uses: Anti-viral (Hepatitis C); Anti-neoplastic (Leukemia & Lymphoma)
Neuropathy
- Clinical
  - Frequency: Uncommon; ? Dose related
  - Distribution: Distal
  - Sensory
    - Pain & Paresthesias
    - Loss: Especially pain & Temperature
  - Weakness: Mild; Distal legs
  - Recovery: Following drug withdrawal
- Laboratory
  - Electrophysiology: Axonal loss
  - Pathology
    - Axonal loss
    - Increased HLA-DR molecules on non-myelinating Schwann cells
  - CSF: Normal
Precipitation or exacerbation of immune disease
- Vasculitis: Exacerbation of Mononeuritis multiplex in Hepatitis C ²⁶
- CIDP
- Cryoglobulinemia
Muscle
- Myalgias: Associated with fever & chills
- Inflammation: May precipitate myositis
CNS effects
- Encephalopathy: Frequently reversible
- Optic neuropathy

Isoniazid

Uses: Tuberculosis
Risks
- When slowly metabolized (slow acetylators)
- High doses
Neuropathy: 1 to 2% of patients
- Onset: Paresthesias; Acute or chronic
- Sensory predominant: Especially large fiber
- Motor: Mild
- Distal; Symmetric
- Mechanism: Pyridoxine depletion
- Prophylaxis: Pyridoxine 10 to 50 mg/day
- Pathology: Axonal loss; Myelinated > Unmyelinated
- Recovery: Slow & incomplete unless early treatment
CNS
- Ataxia
- Encephalopathy: Seizures; Mental status change
- Cranial nerves: Optic neuritis; Tinnitus
Rhabdomyolysis: Associated with isoniazid overdose (> 2.4 g)¹⁷
- 3% of patients have clinical syndrome
- 50% of patients have clinical syndrome
General: Fever; Nausea
Other: Hematologic; Hepatitis; Skin eruptions

Lead⁴⁰

Epidemiology of lead toxicity
- Common in children: Especially black non-hispanic children (22%)
- Most common in homes built from 1920 to 1950
- Identical twins often have concordant lead levels
- Lead neuropathy: Especially from industrial exposure
- Exposure: Most common with ingestion & inhalation
- Sources
  - Ingestion: Paint; Moonshine whiskey; Rum processed in lead pipes; Asian folk medicines⁹
  - Occupational: Smelting; Battery manufacture; Demolition; Auto radiator
Toxicity
- Absorption
  - Ingestion: Children absorb ~ 50% of lead ingested; Adults absorb 10% to 20%
  - Inhalation
  - Skin: Organic lead
- Body storage
  - Rapid turnover pool: Blood (95% in RBCs) & organs; 1/2 life of 1 to 20 days
  - Slow turnover pool: Bones; 1/2 life of 7 to 20 years; 95% of body lead burden
  - Renal excretion
- Toxic levels
  - Children: > 10 μg/dL
  - Adults: > 30 μg/dL (1.5 μmol/L) mean level over years
- Possible Mechanisms of toxicity
  - ? Related to affinity for cell membranes and mitochondria
  - Reduced Activity of mitochondrial oxidative phosphorylation & Na, K, and Ca ATPases
  - Reduced Activity of C-dependent intracellular messengers & Brain protein kinase C
  - Stimulates formation of inclusion bodies
  - Susceptibility: ? Genetic polymorphisms of aminolevulinic acid dehydratase gene
  - Reduces heme formation
Neuropathy: Motor
- Exposure: Subacute to high environmental lead concentrations
- Patterns of weakness: Variable
  - Childhood: Lower extremity
  - Adults
    - Arms (Wrist & Finger extensors) > Legs
    - Distal > Proximal
    - Asymmetric
    - Recovery: Good with elimination of exposure, unless severe weakness
  - Variants
    - Severe exposure: May produce quadriplegia
    - Chronic low level exposure: No weakness
    - Older literature: Focal weakness
      - Wrist & finger extensors
      - Proximal shoulder
      - Hand intrinsic muscles
      - Peroneal muscles
      - Laryngeal paralysis
- Associated disorders
  - Pain: Abdominal; Headache; Joint
  - General: Fatigue; Irritability
  - Anemia
  - Sickle cell disease
- Electrophysiology
  - Motor
    - Axon loss
    - Mild cases: Prolonged distal latencies or Normal
  - Sensory
    - Vibratory thresholds: Increased
    - Mild slowing of NCV
- Pathology
  - Humans: Axonal degeneration
  - Experimental animals
    - Segmental demyelination
    - Endoneurial edema
- Recovery: Slow improvement
Neuropathy: Sensory¹⁵
- Chronic low level lead exposure: Often decades
- Distal; Legs > Arms; Symmetric
- Subclinical changes common
CNS
- Encephalopathy in children: Lethargy; Ataxia; Dysarthria
- Severe: Cerebral edema; Seizures
- Chronic
  - Intellect impaired in dose dependent fashion
  - More severe: Exposure at 2 years; Long duration of exposure
Systemic features
- GI: Constipation; Abdominal pain
- Renal failure
- Hypertension
- Gums: Blue discoloration
Lab
- Hematologic: Mild anemia
  - Hypochromic & Microcytic
  - Basophilic stippling of erythrocytes
  - Always present with neuropathy
    
    Basophilic
    stippling
- Uric acid: Low
- CSF: Usually normal
- Urine
  - Coproporphyrin: High
  - Lead: High (> 0.2 mg/L); Related to intake
- Blood lead levels
  - Usual test for lead exposure
  - Symptoms usually with levels > 80 μg/dL
  - Not accurate indicator of degree of symptomatology or body burden
- Radiology
  - Bones: Lead lines
  - GI: Paint chips in GI tract with acute ingestion
Treatment
- Elimination of exposure
- Chelation: Children > 25 μg/dL; Adults > 70 μg/dL
  - Penicillamine: Mild intoxication < 70 μg/dL
  - Succimer (DMSA)
  - Ca-Na₂ EDTA: Lead level > 70 μg/dL
  - BAL: Added with severe toxicity
  - Dimerval (DMPS)
External link: e-Medicine

Leflunomide³²

Uses
- Rheumatoid arthritis
Metabolism
- Metabolized to active metabolite
- Metabolite highly bound to albumin
- Unbound drug concentrations 2x higher in renal failure
- Active metabolite half life: > 14 days
- Inhibitor of cytochrome P450 (CYP) 2C9
Neuropathy
- Possible risk factors
  - Increased age
  - Diabetes
  - Other nerve-toxic drug
  - No relationship between age, sex or dose: Time to onset of neuropathy or Degree of reversibility
- Onset
  - Age: Mean = 63 years
  - Drug dose: Mean = 19 mg per day
  - Time: Mean = 6 months after starting drug; Range = 3 days to 3 years
  - During period of improved RA symptoms
  - Concomitant medications metabolized by CYP2C9: Uncommon (20%); NSAIDS
  - Symptoms: Numbness; Paresthesias; Pain; Occasional weakness
- Clinical
  - Sensory loss
    - Frequency: 95%
    - Distribution: Distal > Proximal; Legs ± Arms; Symmetric or Asymmetric
    - Panmodal
  - Weakness: 35%; Distal; Symmetric
  - Course
    - Improvement
      - Best when stopping drug with 30 days of onset
      - Begins: Months after onset
    - Little improvement with continued drug administration
- Electrophysiology
  - Axonal loss: Sensory ± Motor
  - Occasional demyelination
- Nerve pathology: Axon loss

Lithium

Uses: Psychiatric disorders
Neuropathy
- Onset: With acute intoxication
- Sensory & Motor
- Course: Recovery with drug withdrawal
- Pathology: Axonal loss
Fasciculations
Myopathy
Myasthenia gravis: Drug induced
Neuroleptic malignant syndrome
Ataxia: Associated with acute toxicity

Mercury - inorganic

Toxicity
- Elemental metal
  - Usually airborne exposure
  - Often produces neural disease without systemic disorders
- Salts: GI absorption
  - Produce systemic & neural effects
- Organic mercurials: Methyl mercury
  - Little peripheral nerve toxic toxicity
  - Early paresthesias & ataxia related to CNS effects
  - Converted from inorganic mercury by microorganisms
  - Then enters food chain
  - Outbreaks of toxicity
    - Minimata Bay: Spillage of HgCl into sea
    - Iraq: Ethyl Hg fungicide in grain used for baking bread
Subacute: Metallic mercury vapor
- Neuropathy
  - Motor
  - Axonal
  - Myokymia
- Encephalopathy
- Other: Mouth inflammation; GI; Fetid breath
Chronic
- CNS: Encephalopathy; Psychosis; Extrapyramidal; Ataxia
- Neuropathy: Sensory & Motor; Pain & paresthesias
Children: Acrodynia
- Encephalopathy
- Autonomic: Tachycardia; Hypertension; Sweating on trunk
- Insomnia; Weight loss; Constipation
Diagnosis: 24 hour urinary excretion
- Inorganic toxicity only
Treatment: ?Chelation; Spironolactone
External links
- NIEHS: Toxicity data; Exposures
- Toxicity

Methyl bromide (CH₃Br)

Uses: Fumigant; Fire extinguisher; Refrigerators
Characteristics: High volatility; Odorless
Acute intoxication
- Interval of hours until symptoms appear
- Encephalopathy
Neuropathy
- Exposure
  - Chronic high level: Onset after months
  - Occasionally acute: Dermal exposure
  - Route: Inhalation (Repetitive); Occasionally transdermal
- Clinical
  - Sensory: Numbness; Paresthesias; Distal
  - Motor: Distal weakness
  - Distribution: Distal; Symmetric
  - Calf muscle tenderness
  - Recovery: Over year after exposure eliminated
- Laboratory
  - NCV: Axonal loss; Motor > Sensory
  - Pathology: Axonopathy, especially large myelinated axons
  - CSF: Unremarkable
CNS (Occasional)
- Visual: Optic atrophy; Loss of color vision (Early)
- Upper motor neuron signs: Brisk tendon reflexes
- Ataxia
- Neuropsychiatric disorders
External links
- NIEHS
- Mednet

Metronidazole³⁸

Use: Antibiotic & Antiprotozoal; Inflammatory bowel disease
Neuropathy
- Onset
  - Chronic drug usage (Months - Years, e.g. Crohn's)
    - Especially total dose > 30 grams
    - Sensory neuropathy may occur in 85% after 1 year of treatment
  - Neuropathy onset: May be chronic or subacute
- Clinical: Neuropathy
  - Distribution: Distal; Symmetric
  - Sensory loss: Pan-modal
  - Pain: Distal; Burning; May rarely be severe
  - Skin: Vasomotor changes may occur
  - Recovery
    - Complete or partial: 6 to 12 months after stopping drug
    - Neuropathy may progress after stopping drug
- Laboratory
  - NCV: Small CMAPs & SNAPs; Velocity nearly normal
  - Sympathetic skin response: May be reduced or absent
  - CSF protein: May be high
- Pathology
  - Axonal loss
    - Especially large myelinated
    - Relative sparing of unmyelinated axons
Clinical: Other
- Ataxia: Reversible & Chronic
- Cardiomyopathy
- Oral: Mucosal; Taste
- Neutropenia & thrombocytopenia

Misonidazole

Uses: Adjunct to radiation therapy
Neuropathy
- Distribution: Distal; Symmetric
- Pansensory; Pain
- Incidence
  - High (35%)
  - Dose related
    - Cumulative > 16 to 18 g
    - Increased frequency (> 2x/week)
- Time course
  - Onset: Several weeks after completion of therapy
  - Stopping drug: Limits severity
  - Recovery: Slow; Only partial with severe involvement
Other clinical features: Nausea; Dizziness; Seizures; Encephalopathy
Pathology: Axonal loss, especially large myelinated axons

Nitrofurantoin

Use: Urinary tract infections
Risk factor: Renal failure
Neuropathy
- Onset
  - With renal dysfunction
  - Acute
- Motor predominant
- Sensory: Paresthesias
- Distribution: Distal > proximal; Symmetric
- Recovery
  - Stop drug at 1st sign of neuropathy
  - Often only partial
- Pathology: Axonal loss; Especially large myelinated axons
Other: Hematologic; Hepatitis; Erythema multiforme; Lupus syndrome; Pulmonary

Myelopathy after N₂O: Spinal cord
T1 MRI	T2 MRI
from T Schwartz & J Wippold

Nitrous oxide (N₂O)

Uses: Dental anesthetic
Neuropathy
- Pansensory
- Motor: Related to neuropathy or myelopathy
- Distal
- Pathology: Axonal loss
Myelopathy
- Source: Gas used in general anesthesia & Dental analgesia
- Some patients with associated cobalamin deficiency
- Syndromes: Myelopathy or Polyneuropathy
- Onset: Delayed; 3 months to 5 years after exposure
- Prognosis: Slow, often incomplete recovery
Optic neuropathy
Megaloblastic anemia
Mechanisms: ? Toxicity related to
- Inhibition of methionine synthetase in vitamin B₁₂ related pathways
Association: Sickle cell disease

Nucleosides

Specific drugs
- 2',3'-dideoxycytidine (ddC)²; Zalcitabine
- dideoxyinosine (ddI)
- Stavudine (d4T)
- Lamivudine (3TC)
Uses
- Acquired immunodeficiency syndrome (AIDS)
- Other viral infections
Mechanism: ? Deplete mitochondrial DNA
- Inhibit POLG
- Stavudine: Especially potent
Neuropathy: Moderate to severe
- Onset
  - Abrupt (vs. insidious HIV neuropathy)
  - Paresthesias
- Dose related
  - Most severe > 0.18 mg/kg/day (ddC)
  - Some neuropathy develops at lower doses
  - Similar risk for monotherapy with ddI & d4T
- Sensory: Pain
- Distal: Feet then hands
- Weakness
  - Mild
  - Only in severe toxicity
  - Severe weakness reported with lamivudine
- Risk factors
  - Diabetes
  - Weight loss
  - Neuropathy from other causes
  - Combined treatment
    - ddI + d4T + Hydroxyurea: 7 to 8 times higher risk than monotherapy
    - d4T + ddI & ddI + HU: 2 to 4 times higher
  - Reduced risk (by 70%) in Hemochromatosis gene (HFE ) \ mutation (Cys282Tyr) heterozygotes³⁶
- Recovery: Following drug withdrawal
  - Coasting for up to 6 weeks
  - Then partial ± complete resolution
- Serum lactate²⁹
  - High (> 2.2 mmol/l) in patients with nucleoside neuropathy (90%)
  - Normal in patients with HIV-related distal sensory polyneuropathy
  - Lactate level distinguishes between HIV & nucleoside neuropathy: 90% sensitivity; 90% specificity
- Nerve: Axonal loss
- Muscle
  - mtDNA depletion
Other systemic syndromes
- Pancreatitis
- Lipoatrophy, Peripheral
Also see: Nucleoside-related myopathy

Organophosphate compounds

Organophosphorous Esters

Uses
- Insecticides
- Petroleum additives
- Flame retardants
- War gases: Nerve agent manual CDC (pdf)*
- Suicide: Especially common in Sri Lanka¹⁹
Exposure: Absorbed through skin, respiratory, GI tract
Toxic mechanisms
- Possible associated processes
  - Phosphorylation of nervous system esterases
    - Especially neurotoxic esterase (NTE)
  - "Aging" of phosphoryl-esterase complex: Cleavage of neurotoxic esterase
    - Molecular chain cleaved from bound phosphorous atom
    - Produces negatively charged monosubstituted phosphoryl residue at active site
- Evidence regarding involvement of "aged" neurotoxic esterase in organophosphate toxicity
  - For: Delayed neuropathy more common with organophosphate agents having "aging" properties
  - Against: Neurotoxic esterase knockout mice (heterozygotes) more susceptible to organophosphate toxicity²⁸
- Toxicity limited by activity of paraoxonases
Toxins

Parathion
- chlorpyrifos: Sensory neuropathy; Memory loss
- leptophos
- methamidophos: Non-aging NTE inhibitor
- metrifonate
- mipafox
- parathion
- Saran: CDC external link
- Soman: CDC external link
- Tabun: CDC external link
- trichlorphonate
- Triorthocresyl phosphate (TOCP)
- VX: CDC external link
Clinical syndromes
- Acute Toxicity: Cholinesterase inhibition ("Cholinergic crisis")
  - Clinical
    - Onset
      - Water soluble agents: Few hours
      - Lipid soluble agents: 24 to 96 hours
    - Miosis
    - Muscle activity: Fasciculations & Cramps
    - Secretions: Diarrhea; Lacrimation; Salivation; Urination; Emesis
    - Pulmonary: Bronchospasm; Edema
    - Muscarinic (Most common): Hypotension, Bradycardia & Increased secretions
    - Nicotinic: Hypertension, Tachycardia, Muscle cramps & Fasciculations
    - CNS: Altered mental status
  - Laboratory
    - Low serum cholinesterase
  - Treatment
    - Decontamination
    - Atropine & Anticholinergic agents
    - Pralidoxime (2PAM): 1-2 g IV over 15 min; Then 500 mg/h IV
    - Avoid: Opiates; Phenothiazines; Antihistimines; Succinylcholine
- Intermediate syndrome: ? Excitotoxicity at neuromuscular junctions
  - Onset: 1 to 3 days
  - Clinical
    - Weakness: Proximal; Respiratory
    - Cranial neuropathy
  - Duration: 2 to 3 weeks
  - Depends on
    - Severity & duration of poisoning
    - Type of organophosphate compound
- Neuropathy
  - Onset
    - Paresthesias & Muscle cramps
    - Delayed 7 to 12 days following single exposure
  - Clinical
    - Motor: Distal weakness
    - Sensory: Distal loss & paresthesias
  - Pathology
    - Axonal loss: Wallerian degeneration
      - Distal regions of long axons
      - PNS & CNS
    - Underlying cause: Phosphorylation of nervous system proteins
  - Historical exposures
    - Phosphocreosote treatment of tuberculosis
    - Ginger Jake: TOCP adulterated alcohol extract of Jamaican ginger in 1930's in US
    - Adulterated cooking oil in 1950's in Morocco
- Myelopathy: Spastic paraparasis
- Prognosis
  - Neuropathy: Slow improvement over time
  - Myelopathy: Little or no improvament
Lab marker: Reduced erythrocyte acetylcholinesterase activity

Triorthocresyl phosphate (TOCP)

Uses: Plastic softener; High temperature lubricant
Toxicity
- Substance type: Organophosphorous ester
- Routes of exposure: Ingestion; Also skin contact, inhalation
  - Jamaica ginger extract (jake leg paralysis)
  - Morocco: Contaminated cooking oil
  - Sri Lanka: Adulterated gingli oil
Onset: Single large exposure
- Transient (1 day) cholinergic response
  - Diarrhea; Perspiration; Fasciculations
- Other organophosphate esters
  - May be rapidly fatal with more potent anti-cholinesterase properties
- Chronic exposure: No cholinergic symptoms
Neuropathy
- Onset
  - 7 to 12 days after exposure
  - Cramping pain in calves
  - Tingling & burning in feet ± hands
- Motor > Sensory
- Weakness: Distal; Feet then hands then proximal
- Course: Maximum severity after 2 weeks
- Recovery: Residual distal weakness & spasticity
- Incidence: Variable
- Electrophysiology: Axonal; Distal
- CSF: Unremarkable
- Pathology: Distal axonopathy in PNS & CNS
CNS
- Myelopathy
  - Spasticity: Legs > arms
  - Becomes apparent when neuropathy recovers
- Ataxia

Perhexiline

Uses: Coronary vasodilatation
General: Neuropathy
- Incidence: High
- Risk factor: Chronic higher doses (>300 mg/day for > 4 months)
Neuropathy
- Onset: After weeks to months; Pedal paresthesias
- Motor: Weakness distal then proximal
- Sensory loss: Pansensory
- Autonomic: Occasional orthostatic hypotension
- Maximum disability: Severe 2° to weakness
- Time course
  - "Coasting": Progression after drug is stopped
  - Resolution over months after drug stopped
Other clinical
- Myopathy: Proximal weakness described
- CNS: Papilledema
- Systemic: Weight loss; Liver function changes
Laboratory
- CSF: Very high protein
- Electrophysiology: Demyelinating; Slow NCV
- Pathology
  - Demyelination
  - Lipid intracytoplasmic inclusions, similar to amiodarone & chloroquine

Phenytoin

Uses: Anti-epileptic
Toxicity: Pharmacologic
- Blocks voltage-gated Na⁺ channels
- Usage dependent
- Requires open Na⁺ channels
Neuropathy
- Sensory: Mild; Symmetric; Distal legs
- Maximum disability: Minor
- Incidence: High with chronic usage
- Electrophysiology: Axonal loss
- Pathology: Axonal loss
Other
- Ataxia
- Stevens-Johnson
- Gingival hyperplasia
- Hypertrichosis

Platinum analogs²⁴

General
Carboplatin
Cisplatinum
Oxaliplatin

Platinum analogs: General

General anti-tumor mechanisms

Reacts with DNA
DNA is damaged by intra- and interstrand crosslinks
Induces apoptotic cell death in rapidly dividing cell lines & cancer cells

Metabolism
- Bind to plasma proteins
- Little crosses blood brain barrier
- Enter PNS: Levels detected in dorsal root ganglia & sensory nerves
PNS toxicity
- Induce shrinking of nuclear & cytoplasmic compartments
- ? Disturb cellular metabolism & axonal transport

cis-platinum (Platinol)

from PDR

cis-platinum

Uses: Chemotherapy - Epithelial, testicular neoplasms
Clinical features
- Neuropathy
  - Risk
    - Dose related: Limit to < 400 mg/M²
  - Onset
    - ~ 1 month after starting treatment
    - Discomfort: Paresthesias; Lhermitte's sign
  - Sensory
    - Loss: Large fiber modalities
    - Paresthesias: Hands & Feet
    - Lhermitte sign
  - Motor
    - Weakness: Little or none
    - Muscle cramps
  - Autonomic: Rare; Orthostatic hypotension; Ileus
  - Maximum disability: Severe; 2° to sensory loss
  - Time course
    - Latency: Months
    - May progress even after cessation of drug: Coasting
    - Resolution better with lower drug doses
  - Electrodiagnostic
    - Sensory NCV: Slowing; Reduced SNAP amplitude; Abnormal H-reflex
    - Motor NCV: Normal
  - Incidence: High
  - Weakness: Generalized; Symmetric
  - Associated with hypomagnesemia
- Cranial neuropathy²⁰
  - Exposure
    - Injection of cis-platinum into internal carotid artery
    - Onset: 48 hours after injection
  - Nerves: III, V & VI
- CNS: Reversible posterior leukoencephalopathy (RPLE)
- Ototoxicity
- Renal failure
- Hypokalemia ³³
Pathology: Probably neuronopathy
- Axonal loss: Large myelinated; Small axons preserved
- Dorsal root ganglia: Neuronal necrosis; Proliferation of satellite cells; Small neuronal soma
- Myelin
  - Osmiophilic inclusions in Schwann cells
  - Myelin thickness: Reduced
- Spinal cord: Dorsal column axonal loss
- Platinum levels: Highest in liver; Elevated in DRG & nerve

Carboplatin

Uses: Chemotherapy
Toxic dose: > 400 mg/m² cumulative
Clinical
- Sensory: Some patients
  - Paresthesias: Hands & Feet
  - Loss: Large fiber modalities; Ataxia
- Motor: Normal
- Tendon reflexes: Reduced
NCV
- Changes after high doses
- SNAPs: Small amplitude; Mild Slowing
Pathology
- Loss of large myelinated sensory axons
- Loss of dorsal root ganglion cells

Oxaliplatin

Uses: Chemotherapy; Colo-Rectal cancer
Mechanisms
- Anti-Tumor: Cross-binding of DNA; Blocking DNA-synthesis
- Nerve
  - Interferes with axonal ion conductance;
  - Alters neural excitability
  - Chronic neurotoxicity mediated through effects on nodal voltage gated transient Na⁺ channels
Clinical: Acute neuromuscular hyperexcitability²⁵
- Frequency: Occurs in most patients
- Paresthesias
  - Distribution: Perioral, Pharynx & Larynx, Hands & Feet
  - Cold triggered
  - Begin 30 to 60 min after infusion
  - Disappear within days to weeks
  - Recur with each dose: May increase in severity
  - No benefit from carbamazepine treatment
- Pain: Jaw; Arm; Arm used for infusion
- Cranial nerve
  - Ptosis
  - Throat tightness: Subjective
  - Numbness: Peri-oral
  - Jaw stiffness: Increased during chewing
  - Slurred speech
  - Visual field disturbances
- Motor
  - Cramps: Legs; Jaw
  - Fasciculations
  - Strength: Normal
- Electrodiagnostic
  - NCV
    - Repetitive CMAPs with single nerve stimulation
    - Normal SNAPs
  - EMG
    - Spontaneous high-frequency discharges of motor unit multiplets
    - Bursts of muscle fiber action potentials
Clinical: Chronic neuropathy³⁵
- May occur in absence of acute syndrome
- Dose relation
  - Associated with larger cumulative doses
  - Frequency at 100 mg/M²: 50%
  - Most with > 540 mg/M² develop neuropathy
- Sensory loss
  - Large fiber modalities
  - Ataxia
  - Persists for months to years after treatment stopped
- Discomfort
  - Paresthesias
  - Reduced with time after treatment stopped
- Motor: Normal
- Tendon reflexes: Reduced
- Course
  - Partly reversible in 80% of patients
  - Complete resolution over months in 40%
- NCV
  - SNAPs: Small amplitude; Mild Slowing
  - Low threshold of axonal simulation: Occasional repetitive firing
  - Motor: Normal

Podophyllin

Sources
- Podophyllum peltatum (Mayapple) or P. emodi: Located in rhizomes
- Chinese herb gui jiu
Uses
- Oral purgative
- Topical ointment for genital warts
- Anti-neoplastic derivatives (glucopyranosides): Etoposide; Etopophos; Teniposide
Toxicity
- Routes: Topical & Ingestion
- Active compound: Podophyllotoxin
- Tubulin binding agent: Depolarizes mitotic spindles; Disrupts axonal architecture
- Inhibits topoisomerase II (Enzyme that uncoils DNA): Inhibits synthesis of nucleic acids
Neuropathy
- Onset: May follow encephalopathy
- Sensory: Ataxia
- Weakness: Variable; May be severe
- Pathology: Distal loss of large myelinated axons
CNS
- Encephalopathy
- Optic atrophy
External link: NCSU

Polychlorinated biphenyls (PCBs)

Uses: Plasticizers; Electrical insulation
Outbreaks: Contamination of cooking oil by tetrachlorobiphenyl
Neuropathy
- Sensory: Distal numbness (pin)
- Electrophysiology: Slow NCV
Other: Acne; Brown nails; Meibomian gland discharge
Biphenyl alone: Sensory-motor demyelinating neuropathy; Psychosis

Procainamide

Uses: Antiarrhythmic
Neuropathy
- Onset
  - After 1 to 4 years on drug
  - Paresthesias
- Weakness: Symmetrical; Proximal + Distal
- Sensory loss: Panmodal
- Tendon reflexes: Absent
Lab
- Nerve conductions: Prolonged distal latency; Reduced velocity
- Biopsy: Perivascular inflammation; Demyelination; Onion bulbs
- CSF: Protein increased
Other neuromuscular: Myasthenia Gravis; Inflammatory myopathy
Systemic effects: Lupus erythematosis; + ANA vs nuclear histones
Prognosis: Recovery, ? after stopping drug

Propafenone

Uses: Anti-arrhythmic
Mechanism: Inhibits fast Na⁺ channels in myocardium
Frequency: Few case reports
Neuropathy
- Predominantly sensory
- Pain
- Distribution: Distal
- Autonomic: Hypotension
- Prognosis: Improvement when drug stopped
- Pathology: Loss of small axons
CNS: Encephalopathy; Seizures; Vertigo
Cardiac: Failure; Conduction defects

Sodium cyanate

Uses: Sickle cell anemia
Neuropathy: Severe
- Onset
  - With chronic therapy
  - Gradual progression
- Motor-sensory
- Distal
- Axonal ± demyelination
- Recovery: Following drug withdrawal

Spanish Toxic Oil³⁴

Outbreak epidemiology
- Spain 1981
- Ingestion of adulterated rapeseed oil
Toxin
- Not clearly identified
- ? Related to oils containing fatty acid esters of 3-(N-phenylamino)-1,2-propanediol (PAP)
Acute event: Clinical features
- Myalgias
  - Onset: 3rd & 4th weeks of illness
  - Severe; Diffuse
  - Duration: Last for months
- Neuropathy
  - Sensory: Patchy or mononeuritic
  - Weakness: Diffuse
  - Incidence: Common
- Other clinical
  - Respiratory insufficiency: Pulmonary infiltrates
  - Headache
  - Malaise
Long term features
- Mortality
  - Higher among women aged < 40 years
  - No late excess
- Long term disability: 1% to 2%
- Neuromuscular
  - Motor neuropathy: 10%
  - Cramps: 70�80%
  - Paresthesias: 60�70%
  - Musculoskeletal pain: 30% and 80%
- Systemic
  - Chronic liver disorders: 1-7%
  - Skin: Sclerodermia in 9�13%
  - Contractures
  - Cachexia
  - Pulmonary hypertension: 1�3%
  - Obesity (body mass index > 30): 40%
- Laboratory
  - Hyperlipidemia (total cholesterol> 240 mg/dL): 44%
  - Hypothyroidism: 7%
  - Diabetes mellitus: 7�9%; 2-fold risk
Laboratory
- Eosinophilia
  - ? Degranulation with release of eosinophil granule major basic protein (MBP)
- Cytokines
  - Soluble interleukin-2 receptor: High in serum
  - IL-4 & IL-5 release
- HLA-DR2 may be aggravating factor
Pathology
- Inflammation
  - Nerve: Epi- & perineurium
  - Muscle: Perimysium; Vasculitic, involving intima of small arteries & veins
- Late: Perineurial fibrosis

Statins⁶

Drugs
- Lovastatin; Pravastatin; Simvastatin
- Dose: ~ 10 to 40 mg per day
Uses: Lipid lowering agents
Mechanism of action: Inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-A) reductase
Clinical syndromes
- Neuropathy
  - Epidemiology
    - After long term use: 1 to 7 years
    - Age: 41 to 68 years
    - Frequency
      - Occasional: 26-fold increased risk after 2 years of use
      - One excess case of peripheral neuropathy for every 2,200 person-years of statin use
    - Strength of association: Strong
  - Sensory loss
    - Feet > Hands
    - Distal
    - By examination: 55%
    - Quantitative testing: 80%
  - Paresthesias
  - Weakness: Distal (20%)
  - Gait instability: Occasiional
  - Tendon reflexes: Reduced (50%)
  - Course: Improvement or No change after drug stopped
  - Nerve conduction testing
    - Small sural SNAP (100%)
    - Axonal loss
- Myopathy
- Rhabdomyolysis

Suramin

Uses
- Trypanosomiasis
- Chemotherapy: Solid tumors; Lymphoma, Prostate, Ovarian
Mechanism of action: Uncertain
- ? Inhibition of growth factors
- ? Blockade of P2 purinergic receptors
Neuropathy
- Incidence
  - High (10% to 15%)
  - Dose related
    - > 17 to 18 g over 4 to 6 weeks
    - Plasma levels > 350μg/ml
    - No relation to total dose or duration of therapy
- Clinical
  - Early
    - Rapid onset
    - Paresthesias, Distal limb & Face
  - Weakness: Proximal & Distal; May become severe
  - ± Sensory loss
  - Severe forms: Acute, Demyelinating
  - Time course
    - Onset: Acute or Progressive
    - Variable recovery: Some rapid, others poor
  - Treatment
    - Prevention: Monitor drug levels
    - Stop drug treatment
- Laboratory
  - Electrophysiology: Predominantly demyelinating
  - CSF: Moderately high protein
Systemic toxicity
- Adrenal cortical
- Marrow suppression
- Renal
- Hepatic
- Hyperglycemia
- Hypophosphatemia
Animal model: Axonal neuropathy²¹
- Drug dosing effects: Length, Time & Dose dependent
- Clinical: Sensory & Motor loss
- Pathology: Axonal loss; Glycolipid lysosomal inclusions

Taxol (Paclitaxel)
(Also other taxanes: Docetaxel¹⁰)

Uses: Chemotherapy - Refractory breast & ovarian neoplasms
Actions
- Causes excessive stability of polymerized microtubules
  - Inhibits: Mitosis; Axonal transport
  - Causes: Apoptosis
- Cell effects: Schwann cell; Axons
- Rapid effect: Membrane depolarization
Neuropathy
- Toxic dose
  - Typical: > 175�200 mg/m²
  - Cumulative
  - Neuropathy may develop after single dose
  - Site of action (Animal models): Distal axons or Ganglion cells
- Incidence
  - High
  - Risk factors
    - Concurrent cis-platinum or Ethanol abuse
    - Genetic predisposition (Docetaxel & Paclitaxel)⁴⁴
      - ABCB1 genetic variation: 2677GG genotype longer time to neuropathy
- Clinical
  - Onset: Paresthesias
  - Sensory loss
    - Distal
    - Feet & Hands
    - Symmetric
  - Discomfort
    - Paresthesias: Distal; Symmetrical
    - Pain
    - Myalgias: Proximal
  - Weakness
    - Distal: With neuropathy
    - Proximal: Early; With myalgias; Occasional patients
  - Tendon reflexes: Reduced
  - Autonomic: Rare; Hypotension; Ileus; Arrhythmia
  - CNS: Rare; Optic neuropathy
  - Maximum disability: 2° Sensory ataxia & Distal weakness
  - Time course
    - Recovery after stopping drug: Coasting may occur
    - Increased risk of severe neuropathy if drug started again
- Laboratory
  - Electrophysiology
    - Axonal loss: Rarely demyelinating features
    - Sensory > Motor
    - EMG
      - Distal denervation in some patients
      - Proximal myopathic changes with myalgias
  - Blood: Neutropenia
- Nerve Pathology
  - Neuronopathy
  - Axonal loss: Large > Small; Distal > Proximal
  - Axonal atrophy: Secondary demyelination
  - Little axonal regeneration
Proximal weakness syndrome
- Onset: Variable; 1st to 25th Rx cycle
- Idiosyncratic: 17% of treated patients
- Course
  - Often improves 2 to 8 weeks after Rx stopped
  - Independent of sensory neuropathy
- Serum CK: Normal
- ? Motor neuropathy vs. myopathy
Myalgia/Arthralgia syndrome: Paclitaxel
- Frequency: Up to 60%; Severe in 3% to 14%
- Not clearly dose related
- Onset: 2 to 3 days after drug treatment
- Duration: Several days
- Less common with: Docetaxel
Other
- Myelosuppression
- Hypersensitivity
- Mucositis
- Alopecia
- Cardiac Arrhythmias

Tellurium

Uses: Manufacture of alloys, rubber thermoelectric devices; Coloring glass, ceramics & metalware
Exposure: Inhalation of volatile tellurium
Clinical
- General: Headache & Drowsiness
- Metallic taste
- Hypohidrosis
- Skin
  - Rash
  - Discoloration (Blue-Black): Face, neck & hands
  - Hair loss
- Breath odor: Garlic-like
- Recovery: Generally spontaneous
Produces demyelinating neuropathy in neonatal rats

Thalidomide¹⁸

α-[n-phthalimido]glutarimide
Uses
- Sedative
- Dermatological disorders (leprosy)
- Autoimmune disorders
- Inhibition of angiogenesis
- Usual doses: 25 to 100 mg per day
Pharmacologic actions
- Tumor necrosis factor-α: Inhibition
- FGF-2 mediated angiogenesis: Inhibition
- CNS: Sedation by ? mechanism
Neuropathy
- Incidence
  - Common: ~10% to 20%; Up to 100% at 9 months
  - Increased with
    - Age (> 70)
    - Higher cumulative dose: Frequency
      - 70% at 20 grams
      - Most at 50 grams
  - Dose limiting side effect of long term treatment
- Clinical
  - Onset
    - Time: 1 to 9 months after starting drug
    - Paresthesias: Feet & Hands
    - Numbness
    - Leg cramps
  - Sensory changes: Predominant feature
    - Modalities: Pansensory
    - Distribution
      - Distal ± Proximal or Face
      - Legs ± Arms
      - Symmetric
    - Paresthesias: Hands & Feet
  - Weakness
    - Occasional: Usually mild; Toe extensors
    - Proximal
  - Fatigue
  - Tendon reflexes: Reduced distally at ankles
  - Course: Progressive until drug is withdrawn
  - Recovery: Partial; Persistent pain
- Laboratory
  - Electrophysiology
    - NCV: Sensory; Axonal loss
      - Small SNAPs: Legs more abnormal than arms
      - CMAPs: Occasional mild reduction in legs
    - EMG: Distal denervation
    - Most abnormalities begin at same time as symptoms
  - Nerve pathology
    - Axonal loss: Large myelinated fibers
    - Wallerian degeneration
    - Regeneration: Few clusters
Other
- Brittle finger nails
- Red palms
- Sedation

Thallium

Uses: Rodenticides; Insecticides
Toxicity: Homicides; Accidental ingestion (children)
Neuropathy
- Acute
  - Day 1: GI - Vomiting; Diarrhea; Abdominal pain
  - Day 2 to 5: Burning paresthesias in legs; Joint pain
  - Sensory: All modalities; Distal
  - Tendon reflexes: Retained
  - Weakness: Mild
  - Hair loss: After 2 to 6 weeks
  - CNS: Coma; Lethargy
  - Systemic: Cardiac & respiratory failure
  - Treatment: ? Prussian blue; KCl
- Subacute
  - Onset: > 1 week after exposure
  - Sensory
    - Pain & paresthesias in legs
    - Large > Small fiber loss
  - Weakness: Mild; Distal
  - Tendon reflexes: Normal or mildly reduced
  - Autonomic: Tachycardia & hypertension
  - Skin: Scalp alopecia; Hyperkeratosis
  - Prognosis: Recovery over 6 months
  - Pathology
    - Distal axonopathy: Large myelinated sensory axons
    - Swollen mitochondria
Chronic exposure: Extrapyramidal; ? Neuropathy
Lab
- CSF: Normal
- Diagnosis: Urine or tissue thallium
Treatment: ? KCl or Prussian blue

Tick Paralysis^3,12

Toxicity
- Neurotoxin in saliva of female ticks
  - Few tick species cause human weakness
    - Dermacentor
      - variabilis: Common dog tick
      - andersoni: North American wood tick
      - Dermacentor ticks can also harbor rickettsiae & cause Rocky Mountain spotted fever
    - Ixodidae holocyclus: Australian marsupial tick; Hard tick
    - Argasidae: Soft tick
  - Toxin
    - Specific toxins not identified
    - ? Ixodidae toxin acts on presynaptic motor nerve terminal: Release of acetylcholine reduced
    - ? Dermacentor toxin blocks axonal sodium channels
- Outbreaks also occur in animals
  - Llamas; One-humped camels; Dogs
  - May be caused by 60 species of tick
  - Only 3 or 4 tick species cause weakness in humans
Neuropathy
- Epidemiology
  - Most frequent: Spring & Summer
  - Age range: Children 1 to 6 years
  - ? Female > Male children; Adult males (Occasional)
  - North America: Rural; Most common in East & Southeast (Georgia) US; Northwest
- Tick
  - Location: Usually in scalp, often behind the ear; Also axilla & perineum
  - Often detected by passing fine-toothed comb through hair
- Onset: Acute
  - ~5 days after attachment of female tick to skin
    - Tick engorgement limited until mating with male
    - Mating produces: Engorgement; Fertilization of eggs & Production of neurotoxin
    - Continued feeding accelerates toxin production
  - General symptoms: Fatigue; Irritability
  - Paresthesias: Distal
  - Weakness: Legs
  - Ataxia
  - More rapid & severe with Ixodidae holocyclus
- Clinical
  - Weakness Pattern
    - Distal & Proximal; Respiratory
    - Symmetric
    - Ascending
    - Cranial nerves
      - Ophthalmoplegia
        
        Internal & External: Especially Australian
        
        Ptosis
      - Bulbar: Speech & Swallowing; Face
  - Sensory: Unremarkable
  - Tendon reflexes: Reduced or Absent
  - Autonomic: Occasioinal; Tachycardia; Hypertension
  - CNS: Ataxia; Lethargy
- Course
  - Peak weakness: Hours to a few days
  - May progress to quadriplegia & respiratory failure
  - Recovery
    - Begins 8 to 48 hours after removal of engorged tick
    - May progress for 1/2 to 2 days after Ixodidae holocyclus tick removal
    - Improvement: Slow over weeks; Slower with Ixodidae holocyclus
    - Full recovery is common with removal of tick
  - Untreated mortality ~ 11%
- Treatment
  - Locate & Remove tick
  - ? Antitoxin for Ixodidae holocyclus
- Laboratory
  - Electrodiagnostic²⁷
    - Reduced CMAP amplitudes
    - Dermacentor: Motor & Sensory NCV reduced; Distal latency prolonged
    - Normal
      - Repetitive nerve stimulation
      - Sensory: SNAP amplitudes may increase with recovery
  - CSF: Normal

Trichloroethylene (TCE)

Exposure
- Uses: Dry cleaning; Rubber production; Degreasing agent; General anesthetic
- Other: Contaminant of hazardous waste sites, groundwater & drinking water
Toxicity
- Exposure: 6 weeks to Chronic
- ? Dichloracetylene from TCE interaction with alkaline materials
- Mitochondrial disorder: Complex I activity reduced
- Toxic to dopaminergic neurons
- May be linked to HLA susceptibility locus (HLA-B*1301)
Neuropathy
- Epidemiology: Case reports
- Trigeminal: Sensory & Motor
  - Sensation: Reduced on face; Pan-modal; Asymmetric
  - Taste: Reduced on anterior 2/3 of tongue
- Eye: Increased blind spot size
- ? Brachial plexus involvement in occasional patient
- No clear effect on peripheral nerves
- Electrodiagnostic: May cause prolonged blink reflex latency
- Recovery: Partial or None; Residual face numbness & pupil reflex loss
Other
- Myelopathy, transverse: Case report
- Parkinson's syndrome⁴³
- Orofacial herpes simplex
- Hypersensitivity dermatitis
- Possibly a carcinogen
Measurement of exposure
- Urine: Trichloroacetic acid; Trichloroethanol
External link: ATSDR A, B

Vacor (N-3-pyridylmethyl-N-p-nitrophenyl urea; PNU; Pyriminil)

Uses: Rodent poison
Toxicity
- Usually related to suicidal ingestions
- Incidence: High with large doses
- Experimental prevention: Nicotinamide - High doses
Neuropathy
- Onset: Rapid (large doses < 1 hour) weakness
- Weakness
  - Limbs: Distal > Proxmal; May be severe (Quadriplegia)
  - Cranial nerves: With higher doses
- Sensory loss: Milder than motor changes
- Autonomic dysfunction: Urinary retention; Orthostatic hypotension
- Maximum disability: 2° quadriplegia
- Pathology: Axonal degeneration; Distal > Proximal
Other: Diabetes mellitus (necrosis of pancreatic β-cells); Encephalopathy; Cardiac arrhythmias
Treatment: ? Nicotinamide
Recovery
- Slow
- Persistent disorders: Autonomic dysfunction; Diabetes

Catharanthus
roseus

Vinca alkaloids (vincristine, vinblastine, vinorelbine & vindesine)

Uses: Chemotherapy
Natural source
- Catharanthus roseus: Periwinkle
- Used for tea in Caribbean
- External link: Ohio State
Mechanism
- Binds to tubulin
- Prevents polymerization & formation of microtubules
Neuropathy: Clinical features
- General
  - Toxic dose: Cumulative; 30 mg to 50 mg
  - Incidence: High
  - Increased risk of neuropathy
    - Neuropathy especially common & severe in HMSN I
    - Concomitant treatment with other chemotherapeutic drugs associated with neuropathy
    - Childhood
- Onset
  - Within 2 months of starting drug
  - Paresthesias: Hands involved early
- Weakness
  - Distal
  - Wrist extensors
  - May become severe
- Sensory loss
  - Distal; Symmetric
  - Hands & Feet
- Pain & Paresthesias
  - Distal
  - Early incourse of disease
  - Resolve within 2 weeks of stopping therapy
- Autonomic (40%)
  - Urinary retention
  - Orthostatic hypotension
  - Bowel dysmotility: Constipation; Ileus
- Tendon reflexes: Reduced early
- Cranial neuropathies: Extraocular; VIII; IX
- Course
  - Maximum disability: 2° Sensory ataxia & Distal weakness
  - Recovery
    - Slow up to 2 years
    - Persistent distal sensory loss and reduced ankle DTRs
Other clinical features
- Dyspnea
- Alopecia: 20%
- Rash
- CNS
  - Encephalopathy
  - Bilateral white matter changes: Focal Findings
  - VI nerve palsy
Laboratory features
- Electrophysiology: Axonal loss
  - Motor & Sensory involvement
  - CMAP amplitudes reduced
  - Conduction velocities relatively preserved
  - EMG: Distal denervation
- Hematologic: With overdoses; Anemia, Leukocytopenia, Thrombocytopenia
- Hyperuricemia
- Inappropriate ADH: Hyponatremia; Seizures with overhydration
Pathology
- Axonal loss: Large & small myelinated axons
- Microtubular pathology: Disorganization & loss

Zimeldine

Uses: Anti-depressant
Neuropathy
- Onset: Acute; Distal paresthesias; Asymmetric
- Weakness: Distal > Proximal; ± Cranial nerves
- Maximum disability: 2° weakness
- Electrophysiology: GBS-like, demyelinating
- CSF: High protein
- Pathology: Wallerian degeneration; cytoplasmic inclusions
- Recovery: With drug withdrawal
- Incidence: Low; 23-fold increase in GBS syndrome incidence
Other: Hypersensitivity flu-like syndrome; Myalgia

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11/28/2008