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TOXIC NEUROPATHIES

TOXIC NEUROPATHIES: CLINICAL & PATHOLOGICAL FEATURES

Axonal			Demyelinating	Mixed
Sensory	Sensory & Motor	Motor
Almitrine Benznidazole Bortezomib Brentuximab Chloramphenicol Cyclosporine Dioxin Doxorubicin Ethambutol Ethionamide Etoposide (VP-16) Flecanide Gemcitabine Glutethimide Hydralazine Ifosfamide Interferon-α Isoniazid Ixabepilone Lead Leflunomide Lenalidomide Levodopa Linezolid Metronidazole Misonidazole Nitrous oxide Nucleosides   ddC; ddI;   d4T; 3TC Phenytoin Platinum analogs Propafenone Pyridoxine Silver Statins Thalidomide	Acrylamide Alcohol (Ethanol) Allyl chloride Arsenic Cadmium Carbon disulfide Chlorphenoxy Ciguatoxin Cobalt Colchicine Cyanide Dapsone Dichloroacetate Dinitrophenol Disulfiram DMAPN Ethylene oxide Heroin Ipilimumab 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 Porcine brain Procainamide Tellurium TNF-α antagonists Zimeldine	Amiodarone Diethylene glycol Ethylene glycol 1,1'-Ethylidinebis   [tryptophan] Gold Hexacarbons n-Hexane Na+ Cyanate Suramin
		A B C D E F G H I L M N O P S T V Z
		Tubulin-related agents   Brentuximab vedotin   Eribulin   Ixabepilone   Podophyllin   Taxol   Vinca alkaloids     Also see:   Cerebellar toxins   Channel toxins   Muscle toxins   Snake venom toxins   Vitamin disorders

• Toxicity
  • Monomer
  • Sources
    • Industrial settings
    • Cooking: Potato; Coffee; Bakery
  • Route: Skin contact; Occasionally inhalation or GI
  • Prodrome: Dermatitis of hands
  • Mechanisms
    • NSF or SNARE proteins
    • FAK & Pyk2 pathways
• Neuropathy
  • Onset
    • Numbness & Sweating: 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
    • Ataxia
  • Skin
    • Early in course
    • Focal irritation & desquamation
    • Abnormal sweating
• Laboratory
  • Electrodiagnostic: Distal denervation
  • CSF: Normal protein
• Nerve pathology
  • Axon loss: Large fibers
  • Distal
  • Accumulations of 10-nm neurofilaments: Especially paranodal & terminal
  • Fast axon transport: Abnormal

Epidemiology Incidence Frequency: 9% of alcoholics have clinical 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% B1 deficiency Alcohol may inhibit B1 absorption Motor neuropathy: Non-length dependent B6 deficiency Alcohol may alter B6 metabolism Family history: 40% to 50% Age Polyneuropathy: Clinical ~ 40% Asymptomatic Muscles: Thin, Tender Tendon reflexes: Reduced distally Pain & Temperature sensation: ± Reduced distally Pain Dull ache & burning in feet ± legs Hyperesthesia Occasional: Lancinating pains Distribution of signs: Distal; Symmetric Sensory Panmodal loss: Varied involvement Hyperesthesia Weakness: Legs > Hands Tendon reflexes: Reduced at Ankle in 80% Autonomic Hyperhidrosis: Feet & Hands Parasympathetic cardiac responses: Reduced Esophageal dysmotility Cranial nerves: Hoarse voice Disease course Slow progression Reduced alcohol intake: Slow improvement Electrodiagnostic: NCV changes Axonal loss: Distal Sensory & Motor Sensory potentials: Small amplitude Conduction velocities: Mildly slowed 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 External link: EtOH metabolism

Oppenheim 1894

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

• 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

• 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
    • Increased with greater duration of treatment: > 1 year
    • ? Dose related: > 400 mg/day
• 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: Orthostatic hypotension, Rare
  • CNS
    • Tremor (40%)
    • Ataxia (Gait)
    • Encephalopathy: Cognitive impairment
    • 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

Arsenic (inorganic) Toxicity Forms: Toxicity Inorganic >; Organic As3+ > As5+ 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 Drinking water: 6 million people exposed 300,000 people manifest signs of chronic arsenicosis Contaminated opium: Punjab Chinese medicinal herbal preparations Toxic agent: Arsenic sulfide Chronic poisoning Marine organisms May contain: Trimethylated organoarsenic, Arsenobetaine No known toxic effects Well-absorbed Excreted unchanged in urine Chemotherapy: As03 91 Acute promyelocytic leukemia More neurotoxicity with Obesity (High BMI > 35; Weight > 100 kg) Increased dose (> 500 mg; > 10 mg/day) Onset: 2 to 8 weeks after exposure 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 May be slower in Caucasians Excretion: Urine; Along with residual inorganic arsenic Pathophysiology: Uncouples oxidative phosphorylation Trivalent As+++ More toxic than pentavalent form Interaction with: Thiol on lipoic acid in PDH complex ? Inhibits pyruvate → Acetyl CoA reaction: Substitutes for phosphate Possible association: Thiamine deficiency 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 Lower level exposures: Slowly progressive; 3 stages Exposures Chronic environmental absorption > 500-1000 μg/d Chemotherapy Onset (1st stage): Malaise; Anorexia; Vomiting 2nd stage Membrane irritation Skin Hyperkeratosis Feet & Hands Precancerous state Arginine variant of codon 72 of p53 gene Homozygosity associated with: Keratosis Dark (Gray) skin Hypopigmentation ("Raindrop pattern") Nails: White stria (Mees lines), May occur months after 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: Common; Better in mildly affected More common in patients with skin hyperkeratosis Other Myopathy: Arsenic trioxide Arsine gas: Hemolysis Liver Cardiac CNS: Seizures; Encephalopathy Long term: Carcinogen; Lung, Skin, Liver, Kidney, Bladder 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

Oppenheim 1894

• Uses: Chagas disease
• Drug type
  • Nitroimidazole
  • Also see: Metronidazole; Misonidazole
• Toxicity
  • "Polyneuropathy"
    • Dose related: Cumulative; Total dose 12-18 grams
    • Clinical
      • Onset after treatment
        • 5 days to 2 months
        • Most > 3 weeks
      • Sensory
        • Distal
        • Legs &177; Arms
        • Paresthesias
        • Numbness
      • Cold sensitivity
      • Taste: Loss; Bitter sensation
      • Course: Mean resolution after drug discontinued = 31 days
    • Pathology
      • Axon damage: ? Small fiber predominant
  • Other side effects
    • General: More frequent in females
    • Asthenia
    • GI: Nausea & Vomiting; Pain
    • Hypersensitivity dermatitis
    • Bone marrow suppression
    • Arthritis & Arthralgias
    • CNS: Headache & Sleep disorders

Black Widow Spider Venom (Latrotoxin) 53 Insect: Lactrodectus mactans (Female) Red hourglass marking on abdomen US geography Most common in Southeast Present in all US states but Alaska Webs located in dark dry spaces Spider bite location Two small red marks: Not easily found Often on buttocks, genitals or exposed areas Not painful No skin necrosis Local sweating & piloerection: 25% Erythema: Occasional Bites most common in Summer or Early Autumn Related dangerous species L. geometricus; L. bishopi; L. hasselti (Australia); L. variolus; L. hesperus Diagnosis By history Lay identification not reliable Venom Absorbed from site of bite Distributed systemically Does not cross blood-brain or blood-nerve barrier Neurotoxin: α-Latrotoxin 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 General Clinical (Latrodectism) Most patients with only local symptoms (66%) Headache Vomiting Hypertension Rhabdomyolysis: Occasional Course Subside within 12 to 72 hours Symptoms may fluctuate Usually not fatal: More likely serious in young or elderly Treatment Anti-venoms: For severe cases; Intramuscular or Intravenous Horse serum: Require sensitivity testing Usually vs venom of all Latrodectus species Benefit not definitely better than placebo Calcium gluconate for muscle spasms Local: Cleansing; Ice packs Neuropathy: Hyperactivation of motor, sensory & autonomic axons Onset 30 to 60 minutes after bite Severe local pain Spontaneous activity Muscle spasms & Cramping: Generalized; Especially proximal Fasciculations Tremor Sensory Pain Initial: Local; Radiating (Proximal); Regional Some patients: Generalized Subsides within hours Abdominal pain & rigidity: Common Paresthesias & Hyperesthesias Autonomic Salivation: Increased Lacrimation Priapism Hyperhidrosis Tachycardia Tendon reflexes: Hyperactive Pathology: Degeneration of very distal axon terminals

From Crew Black widow spider

• Drug type
  • Boronic acid dipeptide
  • Proteasome inhibitor (Reversible)
  • Similar drug: Carfilzomib
• Uses: Anti-neoplastic (Multiple myeloma; POEMS; Mantle cell lymphoma)
• Actions
  • Proteasome (26S) inhibitor, reversible
  • Schwann cells: May induce lysosomal dysfunction (LC3 ↑)
  • 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
  • Frequency
    • Pain: 30% to 46%
    • Severe neuropathy: 15%
  • Risk
    • Dosing
      • Cumulative dose related
      • May be less frequent with subcutaneous, weekly dosing
    • 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
    • Genetic ⁶⁴
      • PKNOX1 (rs2839629) & CBS-related (rs915854) polymorphisms
        • 1.8x to 2.0x increased risk of severe neuropathy
        • Variants located in non-coding regions: 3’UTR of PKNOX1; Intergenic region between PKNOX1 & CBS
        • Variants alter PKNOX1 & CBS expression
        • PKNOX1 & CBS proteins may be involved in neuropathic & inflammatory pain
      • Drug metabolism (ABC transporters): ABCC1, ABCC6
      • Nervous system: POGZ , NFATC1 , NFATC4 , EDN1
      • Immune: IL17RD , IL10RA
      • NF-κB signaling pathway: PSMB4 , BTRC , F2
  • Clinical
    • Time to occurrence
      • Mean 69 days of treatment
      • Range 21 to 184 days
    • Sensory loss
      • Subjective numbness
      • Modalities: Often pan-modal
        • Small fiber (C & Aδ): Pain, Sharpness & Temperature
        • Aβ fiber: Touch
        • Vibration
      • Distal
      • Legs > Arms
    • Pain ⁴¹
      • 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
        • Distal > Proximal
        • Legs > Arms
    • Tendon reflexes: Reduced or absent at ankles
    • Course
      • Severe neuropathy: 12% to 15%
      • Compression neuropathy: ? Increased susceptibility
      • May be difficult to treat with analgesics
      • Improvement: After treatment stopped; Often (71%) to baseline
      • Persistent: 10%
  • Electrophysiology
    • Sensory: Axon loss
      • SNAP amplitudes: Reduced
      • NCV: ≥ 32 M/s
    • May be normal
    • Demyelination: Few patients
  • Dose modification with polyneuropathy ³¹
    • Paresthesias, or Loss of reflexes, Without pain or loss of function: Continued treatment
    • Pain ± Interference with function: Reduce dose to 1.0 mg/m2
    • Pain + Interference 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

• Drug type
  • Anti-CD30 monoclonal antibody + Monomethyl auristatin E (Anti-Tubulin agent)
  • Disease treated: Hodgkin's lymphoma
• Neurotoxicity: Sensory neuropathy
  • Frequency
    • Neuropathy (69%)
    • Symptomatic Neuropathy (50%)
    • Dose related
      • Each 100 mg increase in BV total dose: 23% increase in likelihood of symptomatic neuropathy
    • More common & severe: T-cell cutaneous lymphomas
  • Clinical
    • Numbness: Distal; Hands & Feet
    • Sensory loss: Vibration reduced
    • Motor (5%): Usually normal; Distal leg weakness may occur
    • Course
      • Time to symptom onset: Mean 15 weeks; Range 3 days to 48 weeks
      • May continue to worsen after last BV dose
      • Time to improvement after drug stopped: Mean 30 weeks; 74% by 2 years
  • Laboratory
    • Electodiagnostic: Axon loss, Length dependent
    • Nerve biopsy: Axon loss
• Other side effects
  • Fatigue
  • Pyrexia
  • Diarrhea
  • Nausea
  • Neutropenia

• 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

• Sources
  • Occupational
    • Inhalation of dust
    • Often associated with lead or zinc exposure
  • Cigarette smoke
  • Exposure is cumulative with long half-life (> 15 years)
• Neuropathy
  • Onset: Late; After cadmium exposure
  • 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 repair ³⁰
• 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

• Toxicity
  • Uses
    • Production of viscose rayon fibers & cellophane films
    • Pesticides
  • Exposure: Airborne
• Clinical
  • 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
  • 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
• Pathology
  • Distal axonopathy
  • Neurofilamentous swellings: Fusiform; Terminal axon; PNS & CNS

• 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

• Uses: Autoimmune disorders; Malaria
• Mechanisms
  • Abnormal lysosomal function
  • Inhibits autophagy
• Clinical features
  • Neuropathy
    • Epidemiology: Few reported cases
    • Clinical
      • Onset: 1 to 2 years
      • Sensory-motor
      • Distal
      • Maximum severity: Mild
    • Nerve Pathology
      • Demyelination
      • Schwann cells
        • Inclusions: Lamellar/Crystalline; Cytoplasmic
        • Similar to: Amiodarone
      • Axon loss
      • Perineurium: Calcification
  • Myopathy: Amphiphilic drugs
    • Epidemiology: Prevalence 6%
    • 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
      • Increase pH in lysosomes → Reduced function of lysosomal hydrolases
      • May be potentiated by
        • Denervation
        • Drugs: Statins; Corticosteroids
        • Renal failure
    • Clinical
      • Onset: Usually after prolonged exposure (0.5 years to Decades)
      • Weakness: Proximal; Legs > Arms; May progress to face
      • Cardiomyopathy: Some patients
      • Neuropathy: Usually mild
      • Course
        • Onset: Slow progression
        • After drug discontinued: Slow improvement
      • Hydroxychloroquine less severe than Chloroquine
    • Laboratory
      • EMG: Irritable myopathy; Some with myotonia
      • Serum CK: Mildly high or Normal
    • Pathology
      • Acid phosphatase-positive: Vacuoles & Granules
      • Ultrastructure
        • Curvilinear bodies
        • Myeloid bodies
        • Membranous whorls
        • Autophagic structures
  • Cardiac
    • Atrial flutter
    • Cardiomyopathy
    • Conduction block
    • Cardiac enzymes: High
  • Other
    • Encephalopathy
    • Blood dyscrasias
    • Retinopathy
    • Corneal deposits
    • Skin: Hyperpigmentation

• General
  • Biologically active cobalt compound: Vitamin B₁₂
  • N₂O toxicity: Oxidation of Cobalt atom in Vitamin B₁₂
  • Actions
    • Increases lipid peroxidation & malondialdehyde levels
    • Reduces antioxidant defense mechanisms of nerve cells
  • Toxic effects: Co ions dissolved from particulate aggregates
• Uses & Sources
  • Hip replacement: Metallic debris from total hip arthroplasty using metal-on-polyethylene or -on metal components (DePuy Orthopedics)
  • Occupational exposure: Fabrication of tungsten carbide
  • Uremia
  • Skin whitening creams
  • Ingestion
    • Multivitamin preparations
    • Beer: 1960's; Cardiomyopathy
• Clinical
  • Onset time: 4 to 36 months
  • Neurologic: CNS
    • Headache
    • Seizures
    • Encephalopathy
    • Tremor
  • Polyneuropathy: Predominantly sensory
    • Paresthesias & Dysesthesias
    • Sensory loss: Pan-modal
    • Distal predominant: Arms & Legs
    • Tendon reflexes: Reduced at ankles
    • Weakness: Minor
  • Eye
    • Optic atrophy
    • Retinopathy
    • Color vision: Reduced
    • Ceco-Central scotoma
  • Ear: Hearing loss, Sensorineural; tinnitus
  • Thyroid: Hypotrhyroid
  • Cardiac: Hypertrophic cardiomyopathy; Tachycardia; Congestive failure
  • Course: Improvement after removal of cobalt source
• Laboratory
  • Cobalt: High levels in blood & CSF
  • NCV: SNAP amplitudes reduced or absent
  • Nerve pathology: Axonal loss

Colchicine 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

Carr, Hawaii Gloriosa superba

• 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 speaking ¹⁴
  • Some patients: Genetic or Mitochondrial variants ⁹³
• 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

• Uses
  • Leprosy
  • Dermatitis herpetiformis & Dermatoses with neutrophil infiltration
  • Pneumocystis jiroveci pneumonia
• Actions
  • Facilitates conversion of myeloperoxidase to inactive form
  • Anti-inflammatory: Inhibition of neutrophil adherence to vascular endothelium
• Risk
  • Dose related; > 300 mg/day
  • ? Slow acetylation
  • Cumulative dosages: Usually 25g to 600g; Few patients 4g
  • ? Reduced with cimetidine
• Neuropathy
  • Onset after treatment
    • 2 weeks to 10 years
    • ? Shorter latency with highest doses
  • Motor predominant
    • Arms & Legs
    • Distal
  • Sensory loss: Stocking-Glove; Mild
    • Arms & Legs
    • Distal
  • Course
    • Coasting: Progression after drug stopped
    • Improvement: Later after drug stopped or dose reduced
    • Most improvement after drug cessation: 1 to 3 years
  • NCV
    • Motor
      • CMAP amplitudes: Small
      • Conduction velocities & Distal latencies: Mildly slow
    • Sensory: Often 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; Optic neuropathy

Dichloroacetate 39 Use: Lactate lowering Dose: 25 mg/kg/day by mouth Clinical Onset: 3 to 12 months after starting medication Frequency: 86% Paresthesias: Distal limbs 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

Dichloroacetate

• Epidemiology
  • Case reports & Epidemics
  • Exposure
    • Suicide attempts
    • Substitution for glycerin in medications
      • USA 1937: Sulfanilamide elixir
      • Bangladesh epidemic: 67 cases; 51 deaths
      • Haiti epidemic 1995: 109 patients; 85 deaths
      • Panama epidemic 2006
        • "expectorante sin azucar" ("sugarless cough syrup")
        • 119 patients: 78 deaths
• Structure
  • HO-CH₂-CH₂-O-CH₂-CH₂-OH
• Uses
  • Antifreeze
  • Sterno
  • Finishing agent for clothing material
  • Solvent or diluent for dyes & drug synthesis
• Metabolism
  • Excretion: Kidney
  • Metabolized to: Hydroxyethoxyacetic acid & Diglycolic acid
  • Diglycolic acid: Reabsorbed into proximal tubules of kidney; Nephrotoxic
• Clinical
  • Onset
    • Time: Acute, Days
    • Renal failure
  • Peripheral neuropathy
    • Onset
      • Often delayed after renal failure
      • Days to weeks after exposure: Mean 3 days
    • Weakness (67%)
      • Diffuse: Distal > Proximal + Face (60%)
      • Severe: Flaccid quadriplegia (20%)
    • Sensory loss
    • Tendon reflexes: Reduced or absent (65%)
    • Autonomic dysfunction (63%): Later in course
    • Unilateral or Asymmetric (10%)
  • CNS: Encephalopathy (33%); Seizures (33%); Ataxia (10%)
  • Systemic: Onset 5 days after symptom onset
    • Renal failure: > 2 fold rise in creatinine
    • Hepatic failure
  • Treatment: Hemodialysis
  • Prognosis
    • Mortality: 50% to 90%
    • Course: Recovery over months after elimination of exposure
    • Sequellae: Face & Limb weakness
• Laboratory
  • NCV
    • Sensory-Motor axonopathy (90%)
    • Acute phase
      • Axon loss: Reduced CMAP & SNAP amplitudes; Normal 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
  • Serum
    • Metabolic acidemia
    • Creatinine high
  • CSF: Protein high (39 to 517); Cells normal
• See: Ethylene glycol

Dimethylamine Borane 37 (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

DMAB

• Epidemiology of polyneuropathy: 1 patient
• Exposure
  • Used for weight loss
  • Uses: Explosive manufacture; Dyes & Wood preservatives; Pesticides
  • Dose: Up to 1 gram daily x 6 months
• Polyneuropathy
  • Sensory loss
    • Distal
    • Symmetric
    • Hands & Feet
    • Panmodal, including proprioception
  • Discomfort: Pain; Allodynia
  • Course: Partial improvement of symptoms after discontinuation
  • Electrodiagnostic
    • Axon loss: Motor & Sensory
    • EMG: Normal
• Other features with chronic use
  • Body temperature: Increased
  • Cataracts
  • Agranulocytosis,
  • Renal failure
  • Blood pressure fluctuations
  • Rash

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

Diphtheria 8, 11 Clinical   Acute infection   Epidemiology   Peripheral neuropathy   Systemic Toxin

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

Gram stain Bretonneau: Named Diphtheria

• 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 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
    
    • 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

• Names
  • Tetraethylthiuram disulfide
  • Antabuse
• Uses: Alcoholism
• Mechanisms
  • Inhibits: Aldehyde dehydrogenase
  • ? Neuropathy related to CS₂ accumulation
  • Half-life: 60 to 120 hours
• Risks
  • Dose related
    • Often: ≥ 500 mg/day; > 2 weeks
    • May be 250 mg/day
    • May follow disulfiram-alcohol interaction
• Clinical
  • Onset latency: 10 days to Months; Mean 5.5 months
  • Neuropathy
    • Distribution
      • Distal
      • Symmetric
    • Motor
      • Weakness
        • Legs > Arms
        • Symmetric
      • May be motor predominant
    • Sensory
      • Pain & Paresthesias
      • Pansensory loss: Distal
      • Sensory ataxia in some
    • Tendon reflexes: Reduced or Normal
    • Course
      • Progression: Rapid
      • Improvement after stopping drug: May be complete
  • Other
    • CNS: Drowsiness; Headache; Optic neuritis; Extrapyramidal
    • Sexual dysfunction
    • Hepatitis
• NCV
  • Motor: Axon loss; Mild slowing
  • Sensory: May be preserved
• EMG: Distal denervation
• Nerve Pathology
  • Axon swellings: Neurofilamentous
  • Axon loss
    • Chronic: Large > Small myelinated
    • Ongoing: Wallerian degeneration

• Uses: Chemotherapy
• Drug type: Amphiphilic
• Neuropathy
  • No clinical cases in humans
  • Experimental animals: Sensory ganglionopathy; Myelin swelling
  • Autopsy: Ganglion cell loss
• Cardiotoxicity
  • Mechanisms of toxicity
    • Amphiphilic
    • Mitochondrial: Increased production of reactive oxygen species
    • Calpain activation
  • Clinical: Arrhythmia; Myopathy
• Other: Myelosuppression; Nephrotoxicity

• Uses: Tuberculosis treatment
• Mechanisms
  • Chelates metal ions involved in prokaryotic ribosomes
  • Inhibits arabinosyl transferase: Enzyme in mycobacterial cell wall synthesis.
  • Similarity of mammalian mitochondrial DNA & ribosomes to bacteria: Mitochondrial protein synthesis may be inhibited
• Neuropathy: Mild
  • Sensory; Distal
  • Axonal
  • Recovery: Following drug withdrawal
  • May exacerbate neuropathy in CMT2A2 ⁵⁰
    • Epidemiology: 1 case report
    • Clinical: Increased weakness, hoarseness, sensory loss & visual loss
• Optic neuropathy
  • Risk factors
    • Frequency: 1-5% of patients
    • Other risk factors
      • Age
      • Ethambutol: Duration, Dose
      • Renal function
      • OPA1
      • LHON: May precipitate visual loss in patients with mitochondrial DNA mutations
  • Clinical
    • Onset: Dyschromatopsia
    • Visual acuity loss: Slowly progressive
    • Field defects
      • Central or Ceco-central scotomas: Common
      • Other: Bitemporal defects; Peripheral field constriction
    • Loss of high spatial frequency contrast sensitivity
    • Treatment
      • 25 mg/kg/day dose for 2 months reduced to 15 mg/kg/day maintenance
  • Pathology
    • Axon loss: Lesions in optic chiasm & nerves
    • Selective damage: Papillomacular bundle

• Uses: Tuberculosis treatment
• Clinical
  • Neuropathy
    • Frequency: Uncommon
    • Sensory: Paresthesias; Large fiber modalities
    • Distal
    • ? Axonal
    • Recovery: Following drug withdrawal
  • Gastrointestinal; Skin; CNS

• 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
  • Toxins are breakdown products
  • Glycolate, Glyoxylate, & Oxalate
  • Toxicity related to acidosis & deposition of oxalate crystals
  • 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
  • PNS ¹⁶: Radiculopathy or Neuropathy
    • Weakness (1 patient)
      • Onset: Acute
      • Distribution: Diffuse; Asymmetric ¹⁶
    • 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

• 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

• Uses: Lymphoma; Leukemia; Small cell lung cancer; Testicular Ca
• Mechanisms
  • Disrupt mitotic spindle formation
  • Inhibit Topoisomerase II
• Peripheral Neuropathy
  • Frequency: 4% to 10%; Incomplete data
  • Distal
  • Sensory predominant
  • Axonal
• Other
  • Autonomic neuropathy
  • Encephalopathy, Acute & Seizures: With high doses
• Also see: Podophyllin

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

• Uses
  • Cardiac arrhythmias
  • Inhibitor of voltage-gated K_v2.1 potassium channels
• Frequency: Rare
• Onset: Years after treatment onset
• Clinical
  • Sensory loss: Distal legs; Pain & Vibration
  • Paresthesias
  • Strength: Normal
  • Autonomic: Normal
  • Course: Improvement after drug discontinuation
• Laboratory
  • Nerve conduction studies: Normal or Axon loss
  • Skin biopsy: Reduced axons, Distal > Proximal

• Uses: Anti-Neoplastic
• Drug type: Nucleoside analogue
• Neuropathy
  • Sensory
    • Paresthesias (10%)
    • Recovery: Following drug withdrawal
  • Autonomic
• Myalgias
  • Flu-like syndrome: Fever; Asthenia
• Focal myositis ("Radiation recall")
  • After radiation therapy
  • Pain: Gluteal; Abdominal; Upper chest
  • MRI: "Edema"
• Multifocal myositis
  • Some patients previously radiated
  • Clinical
    • Weakness: Proximal; Legs > Arms; Mild
    • Pain: Legs
    • Fasciculations
    • Treatment: Corticosteroids may reduce pain
    • Neoplasm type: Commonly Non-small cell lung cancer or Pancreas
    • Course: Improvement in pain; Gemcitabine may be restarted
  • Laboratory
    • CK: Normal to 1,800
    • Aldolase may be high
    • EMG: Irritative myopathy
    • MRI: Focal T2 hyperintensity of thigh muscles; Subcutaneous edema
    • Muscle biopsy
      • Perimysium: Wide; Increased intermediate sized vessels
      • Vessels: Occlusion; Inflammation

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

• 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

• 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 sniffing ²³, Shoemakers
  • 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
  • Electrodiagnostic
    • SNAPs: Subclinical exposure to 2,5-hexanedione can reduce amplitudes
• 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
  • MMWR report, n-hexane intoxication

• 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

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

• 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

• 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

• Uses: Anti-neoplastic treatment, Melanoma, Renal, Lung, Hodgkin
• Mechanisms
  • Monoclonal antibody
  • Target: Cytotoxic T-lymphocyte antigen 4 (CTLA-4)
  • Act on immune checkpoints
    • Normally inhibit T-cell activation to maintain self-tolerance
    • Prevent autoimmunity in context of chronic antigen stimulation
  • Prevent interactions between cell membrane receptors that mediate negative regulation of T-cell activation
    • Enhance & Sustain antitumor immune responses
    • Receptors targeted
      • Programmed cell death protein 1 (PD-1)
      • PD1 ligand (PD-L1)
      • Cytotoxic T-lymphocyte associated protein 4 (CTLA-4)
• Clinical: General
  • Side effect mechanism: Often immune syndromes
  • Contra-indication: Ongoing autoimmune disorder
  • Prescreening
    • General: For subclinical autoimmune disorders
    • Neuromuscular: Serum AChR antibodies, CK & Aldolase; NCV for Slowing or Conduction block
    • B-cell levels
  • Disease frequency: 1% to 3%
  • Onset time
    • Range = 4 to 10 weeks after treatment onset
    • May occur up to 1 year, especially if drug is changed
    • Times to onset: Median 3 to 16 weeks
      • Meningitis: 3 weeks
      • Myasthenia gravis: 4 weeks
      • Immune myopathy: 4 weeks
      • Encephalitis/Myelitis: 5 weeks
      • Polyradiculoneuropathy: 6 weeks
      • Hypophysitis: 13 weeks
      • Hypopitutuiarism: 16 weeks
  • Types of associated disorders
    • Neuropathy
      • Polyradiculoneuropathy: Odds ratio = 1.7
      • Cranial neuropathy
      • Demyelinating: GBS-like disorder; CIDP
      • Small fiber
    • Myositis/Myasthenia/Myocarditis ⁸⁵
      • Immune myopathy: Odds ratio = 10.6
      • Myasthenia gravis: Odds ratio = 45; Higher rate of poor outcome
      • MG & IIM: Often present together
      • Associated antibodies
        • Striational (50%)
        • AChR (40%)
        • Myositis specific (25%)
    • Eye (0.5%) ⁹⁴
      • Most common drug: Pembrolizumab
      • Optic neuritis
      • Neuroretinitis
      • Giant cell arteritis
      • Myasthenia gravis
      • Thyroid-like eye disease: May be euthyroid
      • Orbital myositis
      • General myositis + Ptosis
      • Internuclear ophthalmoplegia
      • Opsoclonus-myoclonus-ataxia
      • Oculomotor nerve palsy
    • CNS
      • Hypophysitis or Hypopituitarism: Odds ratio = 234
      • Meningitis: Odds ratio = 1.8
      • Encephalitis/Myelitis: Odds ratio = 11.4
    • Any neurologic AE: 7.7%; Odds ratio = 2.3
    • Systemic
      • Myocarditis
      • Endocrine: TPO & Thyroglobulin antibodies
      • Skin: BP180 antibodies
      • Rheumatologic
      • GI: Hepatitis; Colitis
      • Pulmonary/Pneumonitis
  • Pretreatment
    • Associated neoplasms: Melanoma, Non-small cell lung; Often stage IV
    • Immune disorders: Uncommon
  • Agent related disorders: Increased frequency
    • Anti-PD-L1: Encephalitis/Myelitis; Meningitis
    • Ipilimumab: Hypophysitis or Hypopituitarism, Meningitis; Less neuropathy
• Polyradiculoneuropathy
  • Epidemiology: > 10 patients described
  • Clinical
    • Onset: Often acute or subacute
    • Weakness: Motor predominant neuropathy
      • May be severe
      • Distribution
        • Limbs: Arms & Legs
        • Respiratory
          • Phrenic neuropathy: May be bilateral ⁸⁷
        • Cranial nerves: Ptosis; EOM; VII
        • Asymmetric
        • Often non-length dependent
      • More common than in cytotoxic chemotherapy PN
    • Sensory loss
      • Pan-modal
      • Distal
      • Legs only
      • None in some patients
    • Tendon reflexes: Reduced
    • Course
      • Monophasic
      • Onset: After 3 to 4 drug doses
      • Improvement: After drug discontinuation
  • Laboratory
    • EMG/NCS
      • Axon loss: Motor + Sensory
      • Polyradiculoneuropathy
      • Motor conduction blocks: Multifocal; Early in disease course
    • CSF
      • Protein: Very high (749 mg/dl)
      • Cells: 130, most CD3+ lymphocytes
      • IgG index & synthesis rate: High
    • Nerve pathology
      • Inflammation: Around endoneurial microvessels
      • Subperineurial edema & inflammation
      • Axon loss: Patchy
    • Serum antibody: TS-HDS
    • Spine MRI
      • Leptomeninges & Anterior + Posterior roots: Enhancement
• anti-PD-1 antibody treatment: Associated immune disorders
  • Myasthenia gravis ⁷¹
    • Classification: Drug induced MG
    • Epidemiology
      • Frequency: 0.12% to 0.24%
      • Exacerbation of Pre-existing MG
        • 17% to 25% of ICI-associated MG
    • Clinical Features
      • Onset
        • Often acute
        • Mean age: 70 to 73 years
        • Early in treatment course: Mean 4 to 6 weeks
      • Weakness
        • Ptosis: Common
        • Bulbar
        • Limbs
        • Respiratory
      • Severity & Course
        • General: Mild or Severe
        • May, on average, be more severe than idiopathic MG: Higher mortality
        • Drug (ICI) rechallenge: MG often does not reappear
      • Associated disorders
        • Inflammatory myopathy
        • Cardiomyopathy/Myocarditis
        • Ocular Myositis
        • Prognosis: Worse with MG + Associated disorders
        • No thymoma
      • Treatments
        • Most common: Corticosteroids
          • Response: 60% to 70% of patients
        • Other immunomodulation: With more severe disease
    • Laboratory
      • Antibodies
        • AChR binding: 50% to 83%; Lower titer & frequency than idiopathic MG
        • K_v1.4
        • Titin
        • Ryanodine receptor
      • Serum CK: High, 60% to 80%; Range 50 to 12,000
  • Neuropathies
    • Meningo-(radiculitis)
    • Polyradiculitis
    • Cranial neuropathies
      • VII: May be unilateral or bilateral
      • Other: EOM; V; IX
      • Treatment: Prednisone
    • Polyradiculopathy
      • Sensory-Motor
      • Motor ⁶⁹
    • CIDP, acute onset
    • Acute immune neuropathy: CSF pleocytosis in 50%
    • Enteric neuropathy, Inflammatory
  • ICI Myopathy, Immune ⁸²
    • Common drugs
      • Nivolumab; Pembrolizumab
      • More common with
        • Combination ICI treatment: 3-fold
        • PD-/PD-L1 inhibitors > CTLA-4 inhibitors
    • Epidemiology
      • Onset Age: 3rd to 9th decade
      • ? Male > Female
      • ? ↑ with Thymoma
    • Clinical
      • Onset after treatment: Mean 4 weeks; Range 5 days to 3 months
      • Weakness
        • Limbs: Proximal; Symmetric
        • Axial: Posterior neck; Respiratory (42%)
        • Extraocular muscles (37%)
        • Bulbar (25%): Dysphagia
        • Oculobulbar involvement may occur
          • Without systemic weakness
          • With normal serum CK
      • Myalgias (40% to 55%): Often acute onset
      • Associated disorders: May occur as triad
        • Myocarditis (15% to 30%)
          • Ventricular arrhythmia
          • Conduction delay
          • High mortality
          • Screen with: Troponin I; B-type natriuretic peptide (BNP)
        • Myasthenia gravis
        • Orbital myositis
      • Course: High mortality (40% to 50%)
        • Causes: Respiratory; Cardiac; Neoplasm
        • Increased with intubation
        • Higher with: Myositis, Myocarditis, MG triad
      • Treatments
        • Corticosteroids
        • Stop ICI
        • Severe disease: Other immunomodulation; IVIg; PlEx
    • Laboratory
      • Serum CK
        • 68% high (Median 686; 45% > 1,000; Up to 17,000)
        • May be high before weakness begins
        • Higher mean in AChR Ab- patients
        • May be normal
      • Serum aldolase (64% high)
      • Serum AChR Ab (binding): 20%
      • Lymphopenia: 75%
      • Muscle pathology: Varied patterns
        • Necrosis: Clustered > Scattered
          • May be similar pathology to RIIM
        • Inflammation (Some patients): CD8 lymphocytes; Histiocytes
        • Mitochondrial changes: SDH+ & COX- fibers
        • MHC1 on muscle fibers: May be increased
        • Immune cells
          • Perimysium: Histiocytes
          • CD68+ cells express PD-L1
          • CD8+ lymphocytes express PD-1
        • Dermatomyositis-like patterns: Some patients
      • Serum antibodies
        • Myositis-specific antibodies: Uncommon
        • Striational antibodies (45%)
        • Tropomyosin autoantibodies (IgA): 1 patient
        • ANA: Low or Normal
      • Muscle MRI
        • T2 hyperintensity (50%)
        • May be regional: Paraspinous, cervical muscles; EOM in oculobulbar subtype
      • EMG
        • Myopathic ± Spontaneous activity
        • May be selectively abnormal in: Paraspinous or Masticatory muscles
      • Troponin T: Often high
  • CNS
    • Frequency: 0.5%
    • General: Fatality rate 6% to 13%
    • Meningo-encephalitis
    • Limbic encephalitis
    • Meningitis
    • Myelitis
  • Systemic: Colitis, Skin rash, Uveitis, Hepatitis, Hypophysitis, Cardiac
• Treatments
  • Stop checkpoint inhibitor
  • Corticosteroids
  • Retreatment with checkpoint inhibitor: Often causes recurrence of immune syndrome

• Uses: Tuberculosis
  • Usual dose: 3 to 5 mg/kg/day as 2 to 3 divided doses
  • Tuberculous meningitis: 25 to 30 mg/kg/day
• Risks
  • Slow metabolism (slow acetylators)
    • Inuit (Eskimos): 100%
    • Japanese: 90%
    • Europeans: 50%
  • High doses
• Neuropathy
  • Risks
    • Dose related
      • Chronic
      • Frequency: 0.2% to 2% of patients
      • 17% of patients receiving 6 mg/kg/day
    • Malnourishment
    • Drugs: B6 antagonists; Hydralazine, Cycloserine, Penicillamine, Antiretroviral
    • May exacerbate: CMT 2A
  • Mechanism: Pyridoxine depletion
  • Clinical
    • General patterns
      • Sensory predominant
      • Few patients: Motor neuropathy
    • Onset
      • Acute or Chronic: 3 to 5 weeks with high doses
      • Paresthesias
    • Sensory predominant
      • Loss: Especially large fiber modalities
    • Weakness: Mild
    • Distribution: Distal; Symmetric
    • Recovery: Slow & incomplete unless mild signs or early treatment
    • Prophylaxis & Treatment: Pyridoxine (10 to 50 mg/day)
  • Pathology
    • PNS Axon loss: Distal; Myelinated > Unmyelinated axons
    • Intraneural edema
    • CNS: Distal dorsal columns
• CNS
  • Frequency: Rare; Higher INH doses
  • Ataxia
  • Encephalopathy
    • Seizures
    • Mental status change
  • Cranial nerves
    • Optic neuropathy
      • Optic disc: Swelling
      • Visual fields: Bitemporal hemianopic scotomas
      • Treatment: Pyridoxine 25-100 mg/day
    • VIII: Tinnitus
  • Animal pathology: Astrocytes
• Rhabdomyolysis ¹⁷
  • Associated with isoniazid overdose (> 2.4 g)
    • 3% of overdose patients have: Clinical syndrome
  • 50% of patients have: High serum CK
• Systemic
  • General: Fever
  • GI: Nausea & Abdominal pain; With acute toxicity
  • Hematologic
  • Hepatitis
  • Skin eruptions
  • Drug-induced lupus with ANA
• Isoniazid variant: Motor prominent neuropathy
  • Epidemiology: Rare; 4 patients
  • Clinical
    • Onset: Months after treatment onset
    • Weakness: Legs > Arms; distal > Proximal
    • Sensory loss: Large fiber modalities (Vibration & Proprioception)
    • Tendon reflexes: Reduced in legs
    • Treatment: Pyridoxine, oral, 100 mg/day
  • NCV: Polyneuropathy, Axonal, Sensorimotor

• Uses
  • Microtubule-stabilizing agent
    • Also see: Taxanes
  • Chemotherapy: Breast & solid tumors
• Neuropathy
  • Frequency
    • Early untreated breast cancer: 1%
    • Pretreated metastatic breast cancer: 24%
    • Risk factor: Pre-existing neuropathy
    • Dose relation: More with higher doses (32 to 50 mg/m²)
  • Clinical
    • Sensory
      • Loss: Numbness
      • Positive symptoms: Paresthesias, Dysesthesias & Pain (Some patients)
    • Motor: None or Mild
    • Course: Resolution
      • With dose reduction
      • Mean time: 5 to 6 weeks
  • Laboratory
    • Skin biopsy
      • Loss of small axons: Dose dependent
      • Mitochondria: Reduced, or abnormal morphology, in axons & Schwann cells

History Lead induced "palsy": First described by Pliny in 1st century AD 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 9 Paint Moonshine whiskey Rum processed in lead pipes Asian folk medicines Occupational Smelting Battery manufacture; Demolition Auto radiator Silver refining 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: 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 Mitochondrial oxidative phosphorylation Na+, K+ & Ca++ ATPases C-dependent intracellular messengers Brain protein kinase C Stimulates formation of inclusion bodies Susceptibility ? Gene polymorphisms: Aminolevulinic acid dehydratase 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 Improved: Elimination of exposure Poor: 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: Sensory 15 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 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

Metallic Poisoning "I was told that it seemed to be a case of ‘simple neurasthenia’. I looked casually at the bed-card and at once my eye was caught by the record of his occupation ‘Painter’. I looked from the bedcard to his gums, and there I saw written in equally distinct characters the record of the effect of his occupation—in a conspicuous lead-line."   Gowers, 1903. Barker

• 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

• Uses
  • Immunomodulation
  • Multiple myeloma, relapsed or refractory
• Mechanism
  • E3 ligase ligand
• Polyneuropathy: Subclinical, Sensory
  • Epidemiology
    • Frequency: 50% of myeloma patients on long-term lenalidomide therapy
    • No relation between drug dose & neuropathy
  • Clinical: No change in clinical sensory scores
  • Electrodiagnostic: SNAP amplitude reduced (Dorsal sural)
• Also see: Thalidomide

• Uses
  • Parkinson disease, advanced
• Polyneuropathy
  • Epidemiology: Common; 10 patients described
  • Pain: Burning
  • Thermal threshold: Increased
  • Skin biopsy: Small fiber neuropathy
    • Loss of small axons
    • Axon swellings
    • Onset: By 3 months of treatment

• Uses
  • Tuberculosis (Drug resistant) & Gram positive cocci treatment
• Drug mechanisms
  • Oxazolidinone
  • Autophagy: Inhibition
  • Schwann cell proliferation: Inhibited
• Clinical
  • Sensory neuropathy
    • Frequency
      • 30% to 90%
      • More with: Increased duration of drug use
      • May occur with doses ≤ 600 mg/day
      • May be more with serum trough levels > 2 mg/L
    • Onset: 28 days to > 6 months
    • Distal
    • Legs > Arms
    • Pain
    • Loss: Pansensory; Numbness
    • Course: After drug stopped or reduced
      • Pain reduced
      • Incomplete recovery
    • NCV: SNAP amplitudes small
  • Other
    • Optic neuritis
      • Central scotoma
      • Disk edema
    • Myelosuppression
    • Myoglobinuria
    • Hemochromatosis

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

• History
  • Mercurialism at Almaden & Idria mines: Observed by Agricola & Paracelsus
  • Jean Fernel (1557)
    • Gingival pigmentation
    • Tremor & Behavioral changes linked to occupational mercury poisoning
  • Lewis Carroll’s Mad Hatter in Alice in Wonderland
    • Mercuric nitrate: Manufacture of felt hats
  • China: Cinnabar (HgS)
• Toxicity
  • Elemental metal (Quicksilver)
    • Sources
      • Exposure: Usually airborne exposure; Pass through alveolar cells
      • GI: Little absorption; Dental amalgiums, Syringes
      • Injections
    • Metabolism after entry into blood stream
      • Oxidation to mercuric & mercurous ions
      • Bind to serum proteins
      • Metal, but not ions, cross blood brain barrier
    • Clinical
      • Often produces neural disease without systemic disorders
      • Pain; Anorexia; Weight loss
      • Acute, high level: Cough; Fever; Gingivitis
      • CNS: Erethism; Encephalopathy; Visual loss; Tremor
      • Local effects: Erythema; Granulomas, foreign body
  • Hg Salts, Inorganic
    • Sources: Traditional medicines
    • GI absorption: Irritation & Gastroenteritis
    • Toxicity
      • Binds to sulfur molecules
      • Inactivates enzymes & transport molecules: S-adenosylmethionine
      • Inhibits astrocyte uptake of cysteine (Rate-limiting step in production of glutathione)
      • Hypersensitivity reactions
    • Clinical
      • Produce: Systemic & Neural effects
      • Renal: Deposition & Excretion; Proximal convoluted tubules
      • Skin: Acrodynia (Pink disease)
  • Organic mercurials: Methyl mercury (MeHg)
    • Epidemiology
      • Source
        • Fish: Concentrate methyl-& dimethyl mercury
        • Absorbed from: Mucosal surfaces; Skin; GI tract
      • General metabolism
        • Converted from inorganic mercury
          • By microorganisms: Then enters food chain
          • Chemistry: Lipophilic
        • Converted back to inorganic mercury
          • Ions released from unstable carbon-Hg bonds
          • ? In CNS: After crossing blood-brain barrier
      • Outbreaks of toxicity
        • Minimata Bay: Spillage of HgCl into sea
          
        • Iraq: Ethyl Hg fungicide in grain used for baking bread
    • Clinical
      • Onset: After months of exposure
      • Encephalopathy
      • Visual loss
      • Hearing loss
      • Early: Paresthesias & Ataxia; Related to CNS effects
      • Little peripheral nerve toxic toxicity
• Subacute Neurologic syndrome: Metallic mercury vapor
  • Neuropathy
    • Motor
    • Axon loss
    • Myokymia
  • Encephalopathy
    • Increased excitability
    • Tremor, Postural
  • Other
    • Mouth inflammation
    • GI
    • Fetid breath
    • Lung: Erosive bronchitis, Interstitial pneumonitis with pulmonary edema
    • Renal insufficiency
• Chronic Neurologic Syndrome
  • CNS
    • Encephalopathy
    • Psychosis
    • Extrapyramidal
    • Ataxia
    • Postural tremor: Most sensitive measure of toxicity
  • Neuropathy
    • Clinical
      • Sensory > Motor
      • Sensory loss: Distal; Legs > Arms; Pan modal; Romberg sign
      • Discomfort: Pain & Paresthesias
      • Tendon reflexes: Absent at ankles
      • Weakness: Distal feet or None
      • Prognosis: Improvement after removal of Hg exposure
    • Laboratory
      • NCV: Small amplitude SNAPs
      • EMG: Chronic denervation in feet
• Children: Acrodynia
  • Nosology: Swift-Feer disease; Pink disease
  • Historic source: Calomel (Mercurous chloride) in teething powder
  • Clinical
    • CNS
      • Encephalopathy: Mood swings; Irritability
      • Insomnia
    • PNS
      • Itch
      • Burning
    • Autonomic
      • Tachycardia
      • Hypertension
      • Sweating: Trunk; Hands & Feet
      • Constipation
    • Weight loss
    • Skin: Peeling; Nail loss; Pink color; Edema
    • Mouth: Stomatitis; Tooth loss
• Diagnosis: 24 hour urinary excretion
  • Inorganic toxicity only
• Treatments
  • Chelation: Thiol groups; DMPS, DMSA
  • Spironolactone
  • Surgical excision of local sources
  • ? Glucocorticoids

• 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

• Use: Antibiotic & Antiprotozoal; Inflammatory bowel disease
• Neuropathy
  • Onset
    • Chronic drug usage (Months - Years, e.g. Crohn's)
      • More common with dosing: Total > 30 to 42 grams; Duration > 4 weeks
      • 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; Distal; Legs > Arms
    • Pain: Distal; Burning; May rarely be severe
    • Tendon reflexes: May be reduced
    • Skin: Vasomotor changes may occur
    • Recovery
      • Neuropathy may initally progress after stopping drug
      • Complete or partial: 6 to 12 months 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

• 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

• 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

Uses & Associations Anesthetic: Dental or General Combustion engines Aerosol propellant Recreational use Sources: Balloons; Whipped cream canisters Recently common in China Age: 2nd & 3rd decade Greenhouse gas Mechanisms: ? Toxicity related to Methionine synthetase Oxidizes cobalt ions in vitamin B12 Inhibits vitamin B12 pathways Direct neuronal toxicity Inhibits synthesis & release of Xanthine,   Dopamine, Norepinephrine, Serotonin Affects cytokine balance Clinical syndromes Neuropathy Motor Predominant in some patients Related to neuropathy or myelopathy Weakness: Distal; Legs > Arms More common with N2O abuse, Chronic Sensory Loss Pansensory Distal Legs > Arms Paresthesias Ataxia Symmetric Tendon reflexes: Absent at ankles Myelopathy Syndromes: Myelopathy or Polyneuropathy Onset Delayed 3 months to 5 years after exposure Acute or Chronic Gait disorder Lhermitte sign GU Erectile dysfunction Urinary incontinence Prognosis: Slow, often incomplete recovery Optic neuropathy Megaloblastic anemia Psychosis Association: Sickle cell disease Pregnancy: Abortion; Fetal teratogenesis Treatment: B12 supplementation Laboratory Homocysteine: High (> 90%) Cobalamin: Normal or Reduced NCV: Motor axon loss; Hyperexcitability EMG: Denervation, Length dependent MRI: Spinal cord lesions in many Longitudinal High T2 signal Dorsal spinal cord Cervical Pathology: Axon loss

Doctor and Mrs Syntax, with other elderly people, taking Laughing gas in the house of a tooth-drawer in Paris. (1820) Aquatint. Wellcome Library Myelopathy after N2O: Spinal cord T1 MRI T2 MRI from T Schwartz & J Wippold

• 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) heterozygotes ³⁶
  • Recovery: Following drug withdrawal
    • Coasting for up to 6 weeks
    • Then partial ± complete resolution
  • Serum lactate ²⁹
    • 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

• Uses
  • Insecticides
  • Petroleum additives
  • Flame retardants
  • War gases: Nerve agent manual CDC (pdf)*
  • Suicide: Especially common in Sri Lanka ¹⁹
• 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 toxicity ²⁸
  • 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

• 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

• 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

• 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
  • Inflammatory myopathy + Eosinophilia

General Carboplatin Cisplatinum Oxaliplatin

from PDR cis-platinum

• General anti-tumor mechanisms
• DNA
  • React with DNA
  • DNA damage: Intra- & interstrand crosslinks
• 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
  • Mechanisms
    • Damage site
      • Neuronopathy: Especially dorsal root ganglia
      • Mitochondria: Platins bind to mtDNA
    • Induce shrinking of nuclear & cytoplasmic compartments
    • ? Disturb cellular metabolism & axonal transport
  • Dose dependent toxicity: Cumulative
    • Cisplatin: 250-500 mg/m² for neuropathy with 10% disabled
    • Oxaliplatin: 750-850 mg/m² for neuropathy in 80% with 20% moderate to severe
  • Clinical: Polyneuropathy features
    • General
      • Distribution
        • Symmetric
        • Upper extremity symptoms: Common
      • Sensory > Motor
      • Sensory: Positive features
        • Paresthesias: Common
        • Pain: Less common
        • Lhermitte sign: With more severe neuropathy
      • Sensory: Loss
        • Modalities: Large & Small fiber
        • Gait disorder: Fall risk increased
    • Coasting
      • Neuropathy continues to worsen after discontinuation of treatment
    • Progression: Distal to Proximal
    • Differential features
      • Carboplatin: Less toxic than Cisplatinum
      • Oxaliplatin: Additional early ("acute") neuropathy; Cold sensitivity
      • Paclitaxel: No coasting; Fewer arm symptoms

• Uses: Chemotherapy - Epithelial, Testicular, Colorectal neoplasms
• Clinical features
  • Neuropathy
    • Risk
      • Dose related
        • Common with doses ≥ 300 mg/M²
        • Limit dose to < 400 mg/M²
      • Incidence: High
      • Severity less with: Sodium thiosulfate use
      • Glutathione S-transferase polymorphisms ⁴⁸
        • GSTM1-null
        • GSTM3 intron 6 AGG/AGG
        • Clinical: Thrombocytopenia, Anemia & Neuropathy less frequent
    • Onset
      • ~ 1 month after starting treatment
      • Discomfort: Paresthesias; Lhermitte's sign
    • Sensory
      • Loss: Large fiber modalities
      • Paresthesias: Hands & Feet
      • Lhermitte sign
      • Orofacial symptoms: Uncommon
      • Abnormal balance
    • Motor
      • Weakness
        • Usual: Little or none
        • When present: Generalized; Symmetric
      • 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; Up to 6 months
      • Resolution ⁴⁹
        • Better with lower drug doses
        • More in hands than feet
        • Slow: Months to Years
        • Often incomplete
    • Electrodiagnostic
      • Sensory NCV: Slowing; Reduced SNAP amplitude; Abnormal H-reflex
      • Motor NCV: Normal
    • Laboratory: Associated with hypomagnesemia
    • Treatment: Vitamin E (α-tocopherol 400 mg/day) may be protective ⁴⁶
  • Cranial neuropathy ²⁰
    • Exposure
      • Injection of cis-platinum into internal carotid artery
      • Onset: 48 hours after injection
    • Nerves: III, V & VI
  • CNS: Reversible posterior leukoencephalopathy (RPLE)
  • Systemic
    • Ototoxicity
      • Tinnitus (40%)
      • Hearing loss (20%)
    • Renal failure
    • Hypokalemia ³³
• PNS Pathology: Probably neuronopathy
  • Axonal loss: Large myelinated; Small axons preserved
  • Dorsal root ganglia
    • Neuronal necrosis
    • Proliferation of satellite cells
    • Small neuronal soma
    • Retained platinum
  • Myelin
    • Osmiophilic inclusions in Schwann cells
    • Myelin thickness: Reduced
  • Spinal cord: Dorsal column axonal loss
  • Platinum levels: Highest in liver; Elevated in DRG & nerve
• Overdose features ⁴⁷
  • Nausea & Vomiting
  • Renal insufficiency
  • Electrolyte abnormalities
  • Myelosuppression
  • Ototoxicity
  • Peripheral neuropathy
  • Hepatotoxicity
  • Retinopathy
  • Other: Diarrhea, Pancreatitis, Seizures, Respiratory failure

• 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

• Uses: Chemotherapy; Colo-Rectal & other Solid tumorrs
• 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 Oxaliplatin PN: Acute neuromuscular hyperexcitability ²⁵
  • Frequency
    • Occurs in most patients (85% to 95%)
    • Polymorphism associations ⁶⁰
      • SCN4A-rs2302237: Also related to syndrome severity
      • SCN10A-rs1263292
  • Mechanisms
    • Altered functional properties of voltage-gated Na⁺ channels
    • Prolonged Na⁺ channel open state
    • Hyper-excitability of dorsal root ganglion (DRG) sensory neurons
  • Clinical features
    • Paresthesias
      • Distribution
        • Perioral
        • Bulbar: 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
      • Treatment
        • ? Lacosamide: 200 mg bid ⁷⁹
        • No benefit from carbamazepine
    • Pain
      • Jaw
      • Arms: More in 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 & Spasms: Legs; Jaw
      • Spontaneous activity: Fasciculations; Myokymia
      • Strength: Normal
    • Other symptoms
      • Shortness of breath
      • Dysphagia
  • 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 neuropathy ³⁵
  • Epidemiology
    • Frequency
      • Incidence
        • General: 64% to 97%
        • Severe neuropathy: 12%
        • After 1 year: 26% to 47%
      • > 60% of patients reduce dose, or discontinue, oxaliplatin due to PN
      • Dose relation
        • Associated with larger cumulative doses (600–700 mg, 540–850 mg/M²)
        • 100 mg/M²: 50%
        • General: 80%
        • Most with > 540 mg/M² develop neuropathy
    • Male > Female
    • More common with
      • More acute neuropathy symptoms
      • Early SNAP amplitude reduction (> 30%): Dorsal sural most sensitive
    • May occur in absence of acute syndrome
  • Clinical
    • 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
      • Coasting: Neuropathic symptoms may progress after drug termination
      • Partly reversible in 80% of patients
      • Complete resolution over months in 40%
  • Laboratory
    • NCV
      • SNAPs: Small amplitude; Mild Slowing
      • Low threshold of axonal simulation: Occasional repetitive firing
      • Motor: Normal
    • Ultrasound: Nerve size
      • Generally normal
      • May be increased at entrapment sites (60%)
• Experimental treatment
  • Metformin: Reduces oxaliplatin-induced loss of small axons in skin (Rats) ⁸⁰

• 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

• 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

• Epidemiology: Swine abattoir workers exposed to aerosolised porcine brain
• Clinical
  • Onset: > 4 weeks after initial exposure
  • Polyradiculoneuropathy
    • Sensory predominant: Loss in 80%
    • Painful (96%)
    • Tendon reflexes: Reduced (70%)
    • Weakness: Distal (76%); Mild (75%); Symmetric (75%)
    • Hypohidrosis: Distal or Patchy
  • CNS: Some patients
    • Transverse myelitis
    • Meningoencephalitis
      • Headache
      • Meningeal stretch signs
  • Course
    • Improvement over months after exposure ceases
    • Exacerbation after repeat exposure
• Laboratory
  • CSF: Protein high; Cells usually normal
  • Serum
    • IgG binding to nervous system & myelin basic protein
    • ANA or ENA positive
  • EMG: Denervation
  • NCV
    • F-wave latencies: Prolonged
    • Trigeminal blink reflexes: Prolonged
    • Distal motor latencies: Prolonged
    • Distal sensory potentials: Reduced amplitude
    • Nerve conduction velocities: Normal motor & sensory
    • Quantitative sensory testing: Abnormal
  • Peripheral nerve pathology
    • Epineurial perivascular inflammation
    • Myelinated axons
      • Demyelination: Scattered
      • Onion bulbs: Few; Small
    • Axon loss
  • MRI
    • Ganglionic enlargement
    • Dorsal roots & cauda equina: T2 hyperintensity, or enhancement
    • Brain abnormal

• 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

• 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

• Uses
  • Art
  • Bactericidal: Silver nanoparticles
  • Prosthesis cement
• Toxic mechanisms
  • Immune cell damage
  • Endothelial cell injury: May disrupt blood-brain barrier
• Neuropathy: 1 patient
  • Drug: NutraSilver (19 mg po/day)
  • Clinical
    • Onset
      • Age: 40 years
      • Numbness & Burning
    • Sensory loss: Distal; Arms, Legs & Trunk (Sensory level)
    • Gait: Unsteady
    • Tendon reflexes: Reduced (Arms) or Absent (Legs)
  • Laboratory
    • Silver level, serum
      • 162 ng/mL (Normal < 15)
      • High levels persist for years after stopping silver intake
    • NCV: Axon loss
      • Length-dependent
      • Sensory predominant
    • Nerve biopsy
      • Loss of myelinated axons
      • Dense microparticles (100–120 μm): In endoneurial fluid & Between perineurial cell layers
    • Skin biopsy: Gray–brown microparticles in sweat glands, epidermis & subepidermal dermis
• Systemic features
  • Skin: Argyria (Silover-blue discoloration of skin
  • CNS: Seizures, Cortical basal degeneration, Psychosis

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

• 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)
  • 1,2-di-oleyl ester (OO-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

• 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

• 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 neuropathy ²¹
  • Drug dosing effects: Length, Time & Dose dependent
  • Clinical: Sensory & Motor loss
  • Pathology: Axonal loss; Glycolipid lysosomal inclusions

• Taxanes: General
  • Uses: Chemotherapy - Refractory breast & ovarian neoplasms
  • Neuropathy: General
    • Dose-dependent
    • Painful
    • Length dependent
    • Sensory loss > Motor involvement
    • Partially reversible after treatment discontinued
  • Cabaliztaxel
    • Less cumulative toxicity
    • Dysgeusia
  • Actions
    • Cause excessive stability of polymerized microtubules
      • Inhibits
        • Mitosis
        • Axon transport: Has effects on KIF5A
      • Causes: Apoptosis
    • Cell effects: Schwann cell; Axons
    • Rapid effect: Membrane depolarization
• Paclitaxel: Clinical syndromes
  • Neuropathy
  • Proximal weakness
  • Myalgia: Musculoskeletal pain, Acute, Transient
• Paclitaxel/Taxane: Neuropathy
  • Epidemiology
    • Prevalence
      • General: 30% to 87%
      • 60% develop peripheral neuropathy in 1st 3 months
    • Risk factors
      • Concurrent cis-platinum or Ethanol abuse
      • Higher neuropathy frequency
        • Paclitaxel: Acute pain
        • Paclitaxel: In albumin-bound (nab-paclitaxel), rather than solvent-based, form
      • Genetic predisposition (Docetaxel & Paclitaxel) ⁴⁴
        • ABCB1 polymorphisms
          • 2677GG: Longer time to neuropathy
          • G1236AA: Grade ≥ 2 neuropathy
        • ARHGEF10 variants: rs9657362, rs2294039, and rs17683288
        • CYP2C8*3 K399R (rs10509681) variant: 2x increased risk of neuropathy
        • Periaxin (PRX): Heterozygous mutations
        • SBF2
      • Systemic
        • Diabetes
        • Triglycerides: High ⁹⁰
      • More severe neuropathies ⁷²
        • Age > 70
        • Serum albumin: Lower, but often in normal range (? Malnutrition)
        • Drug dose: Higher
        • Obesity (Increased body surface area or BMI)
  • Mechanisms (Animal models)
    • Site of action: Distal axons or Ganglion cells
    • Neuropathy & pain in models reduced by: KCNQ/Kv7 channel opening; Retigabine ⁷⁴
    • Neuropathy development associated with mitochondrial abnormalities
    • Matrix Metalloproteinase 9 : Inhibition reduces neuropathy & pain ⁷⁵
    • Mechanical allodynia & Enhanced responses to capsaicin: Mediated by PI3K ⁷⁶
  • Clinical
    • Toxic dose
      • Typical: > 175–200 mg/m²
      • Cumulative
      • Neuropathy may develop after single dose
    • Onset
      • Paresthesias
      • Numbness: Feet
      • Myalgias
    • Sensory loss
      • Distal
      • Feet & Hands
      • Symmetric
      • Modalities: Small & Large fiber
      • Gait: Loss of balance
    • Discomfort
      • Paresthesias: Distal; Symmetrical
      • Pain: Often worse at night; Aching
      • Myalgias
      • Cold sensitivity
        • Proximal
        • Acute onset
        • Onset: Often during treatment course
    • 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
    • Quality of life: Reduced
    • Comparison to Platin neuropathies
      • Coasting: Less
      • Upper extremity symptoms: Fewer
      • Serum NfL: Higher levels ⁹²
  • 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
    • Axon loss: Large > Small; Distal > Proximal
    • Axon atrophy: Secondary demyelination
    • Little axonal regeneration
    • Animal models: Abnormal mitochondria
• Proximal weakness syndrome: Paclitaxel or Docetaxel ⁵⁶
  • ? Motor neuropathy vs. Myopathy
  • Epidemiology
    • Idiosyncratic
    • 17% of treated patients
    • Drugs: Docetaxel or Pacletaxel; Total doses 300 to 6250 mg
    • Associated neoplasm: Most often breast
    • Associated disorders: Diabetes; Hypertension
  • Clinical
    • Onset: Variable; 1st to 25th Rx cycle; Most common ≤ 5 treatments
    • Weakness: Predominantly proximal; Symmetric
    • Sensory neuropathy: 100%; Panmodal loss; Pain
    • Myalgias: 55%
    • Tendon reflexes: Absent
    • Course
      • Often improves 2 to 8 weeks after Rx stopped
      • Independent of sensory neuropathy course
  • Laboratory
    • Serum CK: Normal or High
    • Electrodiagnostic
      • Distal: Axonopathy
      • Proximal: Denervation in some patients; Occasional myopathic features
    • CSF protein: High in 2 patients
    • Muscle biopsy: Acid phosphatase positive granules in 1 patient
    • Muscle MRI: T2 signal with enhancement
• 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: More frequent joint pain
• Other
  • Myelosuppression
  • Hypersensitivity
  • Mucositis
  • Alopecia
  • Cardiac Arrhythmias
  • Neutropeniuc enterocolitis

• 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

• α-[n-phthalimido]glutarimide
• Uses
  • Sedative
  • Dermatological disorders (leprosy)
  • Autoimmune disorders: Inflammatory bowel disease
  • Inhibition of angiogenesis
  • Multiple myeloma
  • Usual doses: 25 to 100 mg per day
• Pharmacologic actions
  • Tumor necrosis factor-α & NF-KB: Inhibition
  • FGF-2 mediated angiogenesis: Inhibition
  • May cause reactive oxidative species damage to DNA
  • E3 ligase ligand
  • CNS: Sedation by ? mechanism
• Neuropathy
  • Incidence
    • Common
      • Symptomatic: ~10% to 40%
      • Asymptomatic: 25%
      • 70% to 100% at 9 months
    • Increased with
      • Age (> 70)
      • Higher cumulative dose: Frequency
        • 70% at 20 grams
        • Most at 50 grams
        • Less correlation in children
      • Higher mean daily dose
    • Dose limiting side effect of long term treatment (40%)
    • Protective polymorphisms: ICAM1 ; SERPINB2
  • Clinical
    • Onset
      • Time: 1 to 9 months after starting drug
      • Paresthesias: Feet & Hands
      • Numbness
      • Cramps: Legs
    • Sensory changes: Predominant feature
      • Loss
        • Modalities: Pansensory
        • Distal
      • Distribution
        • Distal ± Proximal or Face
        • Legs ± Arms
        • Symmetric
      • Paresthesias
        • Hands & Feet
        • Pain
        • Burning
      • Numbness
      • Fatigue
    • Weakness
      • Occasional: Usually mild; Toe extensors
      • Proximal
    • Motor, Other
      • Cramps
      • Tremor
    • Tendon reflexes: Reduced distally at ankles
    • Course
      • Progressive until drug is withdrawn
      • Severity: Often mild, without disability
      • Resolution of symptoms after drug is withdrawn: 89%
      • Remaining electrodiagnostic abnormalities: 50%
    • 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
• Also see: Lenalidomide

• Uses: Rodenticides & Insecticides; Electrical industry; Glasses
• Toxicity
  • Exposure types: Homicides; Accidental ingestion (children)
  • Lethal dose: 10 to 15 mg/kg
• Neuropathy
  • Acute
    • Day 1: GI - Vomiting; Diarrhea; Abdominal pain
    • Day 2 to 5: Burning paresthesias in legs; Joint pain
    • Hair loss: After 2 to 6 weeks
    • Neuropathy
      • Sensory: All modalities; Distal
      • Tendon reflexes: Retained
      • Weakness: Mild
    • CNS
      • Encephalopathy: Coma; Lethargy, Memory impairment
      • Seizures
      • Choreiform movements
      • Brain MRI: T2 hyperintense lesions in temporal lobes & corpus striatum
    • Systemic: Cardiac & Respiratory failure
    • Treatment: ? Prussian blue; KCl
  • Subacute
    • Clinical
      • Onset: > 1 week after exposure
      • Sensory
        • Pain & paresthesias in legs
          
        • Large > Small fiber loss
      • Weakness: Mild; Distal; Legs > Arms
      • Tendon reflexes: Normal or mildly reduced
      • Autonomic: Tachycardia & hypertension
      • Skin: Scalp alopecia; Hyperkeratosis
      • Gastrointestinal symptoms
      • Prognosis: Recovery over 6 months to 2 years, may be partial
    • 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

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 Holocyclotoxin ? Ixodidae toxin acts on presynaptic motor nerve terminal Acetylcholine release: 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 Washington State: April Age range: Children 1 to 8 years ? Female > Male children; Adult males (Occasional) Geography US: Rural East & Southeast (Georgia; Louisiana) Northwest (Washington) Australia: East Tick Location: Usually in scalp, often behind the ear; Also axilla & perineum Often detected by passing fine-toothed comb through hair Incubation period: ~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 Longer in Australia Clinical Onset: Acute General symptoms: Fatigue; Irritability Paresthesias: Distal Weakness: Legs Ataxia More rapid & severe with Ixodidae holocyclus (Australian) Weakness Pattern Distal & Proximal; Respiratory Symmetric Ascending Cranial nerves: Earlier in Australia Ophthalmoplegia Internal & External: Especially Australian Ptosis Bulbar: Speech & Swallowing; Face Sensory Paresthesias (50%) Loss: Uncommon Tendon reflexes: Reduced or Absent Autonomic: Occasional; Tachycardia; Hypertension CNS: Ataxia; Lethargy Course Prodrome: 2 to 3 days; Lethargy & Weakness 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: Days to Weeks; Slower with Ixodidae holocyclus Full recovery is common with removal of tick Untreated mortality ~ 11% Treatment Locate & Remove tick Coat tick with petroleum jelly to make it release hold Use forceps Grasp tick as close to skin as possible: Pull up with steady, even pressure Remove all of the tick's capitulum ("head") ? Antitoxin for Ixodidae holocyclus Laboratory Electrodiagnostic 27 NCV: Reduced CMAP amplitudes Dermacentor: Motor & Sensory NCV reduced; Distal latency prolonged Normal Repetitive nerve stimulation Sensory: SNAP amplitudes may increase with recovery CSF: Normal

From Rhode Island Dermacentor variabilis (female)

• 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 syndrome ⁴³
  • Orofacial herpes simplex
  • Hypersensitivity dermatitis
  • Possibly a carcinogen
• Measurement of exposure
  • Urine: Trichloroacetic acid; Trichloroethanol
• External link: ATSDR A, B

Tumor Necrosis Factor-α (TNF-α) Antagonists

• See: TNF-α
• Drugs: Etanercept; Infliximab; Adalimumab
• Drug uses: Immunomodulation
• Neuropathy associations: Anecdotal reports
  • Acute immune neuropathies: Guillain-Barré; Miller Fisher
  • Chronic Immune Demyelinating Polyneuropathy (CIDP)
  • Multifocal Motor Neuropathy (MMN)
• Disease course
  • Onset time: Weeks to Years after drug initiation
  • Disease onset: Sub-acute or Chronic
  • Long-term course
    • Remit after drug withdrawal: Some patients
    • Need for long term treatment: Some patients

• 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

Uses: Chemotherapy, Especially hematologic malignancy Natural source Catharanthus roseus: Periwinkle Used for tea in Caribbean Mechanism Binds to tubulin Prevents polymerization & formation of microtubules Disrupts axon transport Axon degeneration: Dependent on SARM1 Neuropathy 70 General & Epidemiology Toxic dose Cumulative Exception: Early in vocal cord paralysis Adults: 30 mg to 50 mg Children: 3 to 16 mg/M2 (2 to 11 doses) Incidence: High Sensory: 20% to 74% Motor: 32 to 69% Lower in studies of Kenyan children Increased risk of neuropathy Genetic Polymophisms CEP72 polymorphism 63 CEP72: Provides centrosomal microtubule-nucleation activity on γ-tubulin ring complexes TT at rs924607 vs CC or CT: 2.4x to 2.7x increased risk + greater neuropathy severity Reduced CEP72 expression in neurons: Increased sensitivity to vincristine ABCC1 : Also risk association with bortezomib ABCC2 CYP3A5 : Low expression SLC5A7 ACTG1 mir4481 Hereditary neuropathy HMSN IA: Toxicity common & severe EGR2 mutations: Patients may be asymptomatic before treatment PRX mutation heterozygosity: Severe neuropathy in 1 patient 73 MORC2: Acute worsening Systemic Respiratory: Asthma Hepatic impairment: L-asparaginase Childhood: Older patients Concomitant treatment with Other chemotherapeutic drugs associated with more neuropathy Azole anti-fungal agents: Neuropathy risk Most prominent with: Itraconazole Not associated with: Fluconazole Intermediate: Voriconazole Other: Erythromycin, Isoniazid, Phenytoin, Mitomycin c ? Piperacillin-Tazobactam Caucasian Decreased risk of severe neuropathy 52 African-American: Possibly related to CYP3A5 expression CYP3A5*1 allele (At least one) Less motor & autonomic toxicity More rapid recovery miR-3117 Clinical 84 Onset Within 2 months of starting drug: 11 days to 12 weeks Paresthesias: Hands involved early Ankle reflexes: Reduced Taste impairment Sensory Pain & Paresthesias Distal Early in course of disease Resolve within 2 weeks of stopping therapy Loss Distal Symmetric Hands & Feet Vibration Weakness Distal Wrist extensors Onset: Later in course Gait disorder May become severe Autonomic (40% to 56%) General: May be most frequent neuropathy type Urinary retention Orthostatic hypotension Tachyhcardia Bowel dysmotility: Constipation (common); Ileus; Abdominal pain Impotence Tendon reflexes: Reduced early (Common) Cranial neuropathies General: More frequent in children Optic Extraocular VII: Face weakness VIII: Hearing loss IX Vocal cord paralysis 51 Uncommon Often clinically isolated involvement Onset: Often during 1st month of treatment Clinical Voice: Hoarse Stridor Labored respiration Bilateral: Often May require: Ventilatory support; Tracheostomy Resolution: Common; 1 to 38 weeks Treatment: Reduce or Stop vincristine Associations Axonal neuropathy, Subclinical Onset in children XII Course Maximum disability: 2° Sensory ataxia & Distal weakness Recovery Slow up to 2 years Persistent: Distal sensory loss; Reduced ankle DTRs Other clinical features Raynaud syndrome 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 Nerve Pathology Axon loss: Myelinated axons, Large & Small Microtubules: Disorganization & loss Mouse model 83 Produces: Allodynia, Mechanical Pathophysiology May alter Nav1.6 channels Associated with: NLRP3 activation & IL-1β release Pathology: No axon loss or morphologic abnormalities

Catharanthus roseus

• 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