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Clinical Assessment of NeurotoxicityChris Martin, MD, MSc, FRCPCcmartin@hsc.wvu.eduDirector, Institute of Occupational and Environmental HealthOccupational and Environmental Medical Association of Canada29th Annual Scientific Conference

These are among the most challenging cases in Occupational MedicineMany complain of their Memory, few of their Judgment. - Benjamin FranklinTout le monde se plaint de sa mmoire, et personne ne se plaint de son jugement.

- Franois de la Rochefoucauld

OverviewReview neuroanatomy VulnerabilityTargets of neurotoxicityClinical approachCase discussion

1. Review of NeuroanatomyWhat makes the nervous system LESS vulnerable?Blood brain barrier for CNS

What makes the nervous system LESS vulnerable?Excess neuronal capacity

What makes the Nervous System MORE vulnerable?High aerobic energy requirementsMost sensitive tissue to loss of oxygen supplyPresence of long, complex cell structuresAxons are most sensitive to damageStructure of the Neuron

Targets of NeurotoxicityDamage to:Cell bodyneuronopathyAxonaxonopathyMyelinmyelinopathySynapse or neuromuscular junctiontransmissionopathy

Neuronopathy Damage is irreversible Neuronopathy Damage is irreversible Examples: methyl mercury MPTP

Axonopathy Damage isreversible in PNSirreversible in CNS Sensorimotor neuropathies Stocking and glove distributionAxonopathy Damage isreversible in PNSirreversible in CNS Sensorimotor neuropathies Stocking and glove distributionExamples:carbon disulfiden-hexaneacrylamide monomerarsenictrichloroethylene

Myelinopathy leadTransmissionopathyOrganophosphate pesticides

2. Clinical ApproachWhat is the typical case before you?CNS: Chronic encephalopathyPNS: Sensorimotor peripheral neuropathy

HistoryTake a detailed exposure historyStrong dose-response relationship

HistoryTake a detailed exposure historyAsk about symptoms of acute intoxication for any body system when actively exposedHistoryTake a detailed exposure historyAsk about symptoms of acute intoxication for any body system when actively exposedExample: For solvents, dermatitis? Headache? Nausea? Felt drunk? Syncope?

HistoryObtain detailed information about symptomsAsk for examples of symptom manifestationsFunctional status, activities of daily living

HistoryObtain detailed information about symptomsDetermine chronology of symptoms in relation to exposureSymptoms occur at the time of or shortly after exposureCourse of symptoms after cessation of exposure important

HistoryObtain detailed information about symptomsDetermine chronology of symptoms in relation to exposureComplete medical history to ascertain other possible causesAlcohol, cardiovascular disease, psychiatric disease, family history

Physical ExaminationFolstein Mini-Mental Status Exam

Physical ExaminationFolstein Mini-Mental Status ExamDetailed neurological examinationParticular attention to nature and distribution of any abnormalitiesInvestigationsPeripheral Nervous System:

Nerve conduction studies / electromyographyQuantitative sensory testingNerve biopsy if n-hexane peripheral neuropathyPeripheral Nervous SystemKey points in formulating diagnosis:Most toxic neuropathies are symmetric with greater distal involvementRecovery following cessation of exposureIn general, for about 25-40% of peripheral neuropathies, diagnosis is unknown

InvestigationsCentral Nervous System:Imaging studies usually normal unless very advanced diseaseOther investigations (lumbar puncture, EEG, labs) to rule out other causesMost sensitive investigation is neuropsychiatric testingTesting is user dependentReport should provide numerical scores on testRead the entire reportInclude investigations for effects of exposure on other systems (Example LFTs for solvents)

Central Nervous SystemKey points in formulating diagnosis:Most toxic CNS disorders are diffuse without focal pathologyOnset when exposedStable following cessation of exposure for chronic solvent encephalopathy1Must rule out other causesMay need longitudinal informationConsider the impact of a diagnosis of brain damage from chemical poisoning

1. van Valen E, Wekking E, van der Laan G, Sprangers M, van Dijk F. The course of chronic solvent induced encephalopathy: A systematic review. Neurotoxicology. 2009 Nov;30(6):1172-86.323. Case DiscussionCase Discussion39-year old female clerk at prison facilityExposed to sewer gases as well as agents applied to unclog commodesAt 1:30 PM upper airway irritation, headache, nausea with vomitingLeft work at 2:50 PM

Case Discussion3 days later:difficulty with concentration, poor memory, photophobia, difficulty speaking, reduced smell and taste, difficulty writingVery poor level of functioning since exposurePresents to ER one week after exposure

Case DiscussionPhysical exam:Mental status - poor recall, serial 7s, good judgement, general knowledgePerforms tasks after approximately 3 second delayReduced olfaction, otherwise cranial nerves intactPhotophobia

Case DiscussionPhysical exam:Difficulty with alternating movements, finger-nose, tandem gaitRombergs sign negativePower, tone, reflexes, sensation intactAphasia: rhythmic quality, selective omission of articles

Case DiscussionDo you think her presentation is due to the exposure?

Case DiscussionDo you think her presentation is due to the exposure?Not a high level exposure, not likely to have been exposed to compatible neurotoxic agent

Case DiscussionDo you think her presentation is due to the exposure?Not a high level exposure, not likely to have been exposed to compatible neurotoxic agentDelay in symptoms