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TOXIC NEUROPATHIES


TOXIC NEUROPATHIES: CLINICAL & PATHOLOGICAL FEATURES

Axonal Demyelinating Mixed
Sensory Sensory & Motor Motor  
Almitrine
Benznidazole
Bortezomib
Brentuximab
Chloramphenicol
Dioxin
Doxorubicin
Ethambutol
Ethionamide
Etoposide (VP-16)
Flecanide
Gemcitabine
Glutethimide
Hydralazine
Ifosfamide
Interferon-α
Isoniazid
Ixabepilone
Lead
Leflunomide
Lenalidomide
Levodopa
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


Acrylamide

Alcoholic (Ethanol) polyneuropathy 7
  • Epidemiology
    • Incidence
      • 9% of alcoholics with 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%
        • ? Specific involvement of B1 deficiency
      • Family history: 40% to 50%
      • Age
  • Polyneuropathy: Clinical
    • ~ 40% Asymptomatic
      • Muscles: Thin, Tender
      • Distal tendon reflexes: Reduced
      • Distal pain & temperature sensation: ± Reduced
    • Pain
      • Dull ache & burning in feet ± legs
      • Occasional: Lancinating pains
    • Distribution of signs: Distal; Symmetric
    • Sensory
      • Panmodal loss: Varied involvement among individuals
      • Hyperesthesia
    • Weakness: Legs > Hands
    • Tendon reflexes: Reduced at Ankle in 80%
    • Autonomic
      • Hyperhidrosis: Feet & Hands
      • Reduced Parasympathetic cardiac responses
      • Esophageal dysmotility
    • Cranial nerves: Hoarse voice
    • Disease course
      • Slow improvement with reduced alcohol intake
    • Electrodiagnostic: NCV changes
      • Axonal loss: Distal
      • Sensory & Motor
        • 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

Allyl chloride

Almitrine
Amiodarone

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



Oppenheim 1894

Benznidazole
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

Bortezomib (Velcade) 31

Brentuximab vedotin (SGN-35; BV) 68
Buckthorn fruit

Cadmium 4

Carbon Disulfide (CS2)

Chloramphenicol

Chloroquine & Hydroxychloroquine (4-aminoquinolones)

Cobalt 58

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

Cyanide

Dapsone

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

Diethylene glycol 42

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

Dinitrophenol 59

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

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

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

Disulfiram

Doxorubicin

Ethambutol

Ethionamide

Ethylene Glycol
Ethylene oxide 1

Etoposide (VP-16)

FK506 (Tacrolimus)

Flecanide 57

Gemcitabine

Glutethimide

Gold (Aurothioglucose)

Hexacarbons

Hexachlorophene

Hydralazine

Ifosfamide 22

Interferon-α 13

Immune Checkpoint Inhibitors (ICPIs) 61

Drugs
  Anti-PD ligand 1 (PD-L1)
    Avelumab
    Durvalumab
    Atezolizumab
  Anti-Cytotoxic lymphocyte associated protein 4 (CTLA-4)
    Ipilimumab
  Anti-Programmed cell death 1 (PD-1)
    Nivolumab
    Pembrolizumab
    Cemiplimab

General
Myasthenia
Myopathy
Polyradiculoneuropathy
Syndromes


Isoniazid

Ixabepilone 62

Lead 40
  • 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
      • 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
    • 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

Leflunomide 32

Lenalidomide 65

Levodopa/Carbidopa Intestinal Gel (LCIG) 66

Lithium

Mercury - Inorganic 67

Methyl bromide (CH3Br)

Metronidazole 38

Misonidazole

Nitrofurantoin

Myelopathy after N2O: Spinal cord

T1 MRI

T2 MRI
from T Schwartz & J Wippold
Nitrous oxide (N2O)

Nucleosides

Organophosphate compounds

Organophosphorous Esters
Triorthocresyl phosphate (TOCP)

Perhexiline

Phenytoin

Platinum analogs 24

General
Carboplatin
Cisplatinum
Oxaliplatin
<i>cis</i>-platinum
from PDR
cis-platinum

Platinum analogs: General cis-platinum (Platinol)
Carboplatin Oxaliplatin 81
Podophyllin

Polychlorinated biphenyls (PCBs)

Porcine aerosolized brain-associated polyradiculopathy 45

Procainamide

Propafenone

Silver 77

Sodium cyanate

Spanish Toxic Oil 34
Statins 6

Suramin

Taxol (Paclitaxel)
  (Other taxanes: Docetaxel 10; Cabaliztaxel)
Tellurium

Thalidomide 18
Thallium

Tick Paralysis 3,12

Trichloroethylene (TCE)

Tumor Necrosis Factor-α (TNF-α) Antagonists 55
Vacor (N-3-pyridylmethyl-N-p-nitrophenyl urea; PNU; Pyriminil)

Vinca alkaloids (Vincristine, Vinblastine, Vinorelbine & Vindesine) 78
  • 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
        • 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
        • 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
        • Hepatic impairment: L-asparaginase
        • Childhood: Older patients
        • 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%)
      • Tendon reflexes: Reduced early (Common)
      • Cranial neuropathies
        • 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

Zimeldine

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References
1. Neurology 1996;46:992-996
2. Neurology 1996;46:999-1003
3. Brain 1997;120:1975-1987
4. NeuroToxicology 1999;20:7-16, Nature Genetics 2003;34:326-329
5. Acta Neurol Scand 1999;100:1-5
6. Eur J Clin Pharmacol 1999;54:835-838, Neurology 2002;58:1333–1337
7. Clinical Neurology, eds Joynt & Griggs, 1986;61:48-55, Alcohol & Alcoholism 2001;36:271-275
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