1. Chris Martin, MD, MSc, FRCPC cmartin@hsc.wvu.edu Director, Institute of Occupational and Environmental Health Occupational and Environmental Medical Association of Canada 29th Annual Scientific Conference

2. These are among the most challenging cases in Occupational Medicine

3. “Many complain of their Memory, few of their Judgment”. - Benjamin Franklin “Tout le monde se plaint de sa mémoire, et personne ne se plaint de son jugement”. - François de la Rochefoucauld

5. Overview 1. Review neuroanatomy Vulnerability Targets of neurotoxicity 2. Clinical approach 3. Case discussion

7. What makes the nervous system LESS vulnerable? 1. Blood brain barrier for CNS

8. What makes the nervous system LESS vulnerable? 2. Excess neuronal capacity

9. What makes the Nervous System MORE vulnerable? 1. High aerobic energy requirements Most sensitive tissue to loss of oxygen supply 2. Presence of long, complex cell structures Axons are most sensitive to damage

10. Structure of the Neuron

11. Targets of Neurotoxicity Damage to: 1. Cell body neuronopathy 2. Axon axonopathy 3. Myelin myelinopathy 4. Synapse or neuromuscular junction “transmissionopathy”

12. Neuronopathy Damage is irreversible

13. Neuronopathy Damage is irreversible Examples: methyl mercury MPTP

14. Axonopathy Damage isreversible in PNS irreversible in CNS Sensorimotor neuropathies “Stocking and glove” distribution

15. Axonopathy Damage isreversible in PNS irreversible in CNS Sensorimotor neuropathies “Stocking and glove” distribution Examples: carbon disulfide n-hexane acrylamide monomer arsenic trichloroethylene

16. Myelinopathy lead

17. “Transmissionopathy” Organophosphate pesticides

19. What is the typical case before you? CNS: Chronic encephalopathy PNS: Sensorimotor peripheral neuropathy

20. History Take a detailed exposure history Strong dose-response relationship

21. History Take a detailed exposure history Ask about symptoms of acute intoxication for any body system when actively exposed

22. History Take a detailed exposure history Ask about symptoms of acute intoxication for any body system when actively exposed Example: For solvents, dermatitis? Headache? Nausea? Felt drunk? Syncope?

23. History Obtain detailed information about symptoms Ask for examples of symptom manifestations Functional status, activities of daily living

24. History Obtain detailed information about symptoms Determine chronology of symptoms in relation to exposure Symptoms occur at the time of or shortly after exposure Course of symptoms after cessation of exposure important

25. History Obtain detailed information about symptoms Determine chronology of symptoms in relation to exposure Complete medical history to ascertain other possible causes Alcohol, cardiovascular disease, psychiatric disease, family history

26. Physical Examination Folstein Mini-Mental Status Exam

28. Physical Examination Folstein Mini-Mental Status Exam Detailed neurological examination Particular attention to nature and distribution of any abnormalities

29. Investigations Peripheral Nervous System: Nerve conduction studies / electromyography Quantitative sensory testing Nerve biopsy if n-hexane peripheral neuropathy

30. Peripheral Nervous System Key points in formulating diagnosis: Most toxic neuropathies are symmetric with greater distal involvement Recovery following cessation of exposure In general, for about 25-40% of peripheral neuropathies, diagnosis is unknown

31. Investigations Central Nervous System: Imaging studies usually normal unless very advanced disease Other investigations (lumbar puncture, EEG, labs) to rule out other causes Most sensitive investigation is neuropsychiatric testing Testing is user dependent Report should provide numerical scores on test Read the entire report Include investigations for effects of exposure on other systems (Example LFT’s for solvents)

32. Central Nervous System Key points in formulating diagnosis: Most toxic CNS disorders are diffuse without focal pathology Onset when exposed Stable following cessation of exposure for chronic solvent encephalopathy 1 Must rule out other causes May need longitudinal information Consider 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.

34. Case Discussion 39-year old female clerk at prison facility Exposed to sewer gases as well as agents applied to unclog commodes At 1:30 PM upper airway irritation, headache, nausea with vomiting Left work at 2:50 PM

35. Case Discussion 3 days later: difficulty with concentration, poor memory, photophobia, difficulty speaking, reduced smell and taste, difficulty writing Very poor level of functioning since exposure Presents to ER one week after exposure

36. Case Discussion Physical exam: Mental status - poor recall, serial 7’s, good judgement, general knowledge Performs tasks after approximately 3 second delay Reduced olfaction, otherwise cranial nerves intact Photophobia

37. Case Discussion Physical exam: Difficulty with alternating movements, finger-nose, tandem gait Romberg’s sign negative Power, tone, reflexes, sensation intact Aphasia: rhythmic quality, selective omission of articles

38. Case Discussion Do you think her presentation is due to the exposure?

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

40. Case Discussion Do you think her presentation is due to the exposure? Not a high level exposure, not likely to have been exposed to compatible neurotoxic agent Delay in symptoms