Neurotoxicology

1. Neurotoxicology By: Laurence Poliquin-Lasnier R4 Neurology

2. Outline • General principles • Terrestrialbiotoxins • Metal intoxications • Organicchemicals intoxications • Marine Neurotoxins

3. General Principles • Peripheralneuropathy of the distal axonopathy type is the mostcommonpresentation of North American neurotoxicdisease • Detailedhistoryis important to establish causative agent • Virtually all neurotoxicdiseaseimproves or stabilizesfollowingwithdrawalfromexposure • Progression of illness for yearsfollowingremovalstronglysuggests the condition is not due to an exogenouschemical • Laboratory data are available for heavymetals and drugs of abuse, but not for mostindustrial or environmentalagents and electrodiagnosticstudies are non-specific • Age and preexistingconditions (eg.: hereditaryneuropathy) canincreasevulnerability to neurotoxicagents • Eg.: a personwith Charcot-Marie-Toothdiseasegivenvincaalkaloidtxmaydevelop an unusuallysevereneuropathy

4. Vulnerability of peripheralnervous system motor unit and subcellularstructures

5. Terrestrialbiotoxins • Bacterial • Clostridial • Envenomation • Botanical

6. 1-Bacterial toxin: Diphteria • Diphtheriais an acute, contagiousdiseasecaused by the gram-positive bacillusCorynebacteriumdiphtheriae • There are twoforms of symptomatic infection (respiratory and cutaneous) and an asymptomatic carrier state • The respiratoryform of diphtheria causes the characteristicpseudomembranouspharyngitis • Othercommon complications of severe infection includemyocarditis, neuritis, and lessoftennephritis • C. diphtheriaesolelylives in the mucous membrane and skin of humansand infects via airbornerespiratorydroplets, direct contact withrespiratorysecretions of symptomaticindividuals, or infected skin lesions • Asymptomaticcarriers are an important mode of transmission • Whatis the mostcommonsevere complication of C. diphteria?

7. Diphteria • Acute demyelinatingpolyneuropathy ->mostcommonsevere complication • Diphtheriticneuropathyis an uncommondisease in Western Europe and the United States due to vaccination • Large epidemicfrom 1990 to 1995 wasreported in the former Soviet Union • Fatality rate 2-3%

8. Diphteria • 15% incidence of neurologic complications wasreported in adults • Correlationbetween the severity of the diphtheriticpolyneuropathy and the severity of the diphtheriainfection • Latency in development of diphtheriticpolyneuropathy varies from 18 to 46 daysfrom the initial infection (mean 30 days) • Approximately 2/3 of patients whodeveloped a diphtheriticpolyneuropathyhad a precedingseriousdiphtheria infection withbothcardiac and renalimpairment • Neurologicmanifestations of diphtheria are biphasic • Earlybulbardisturbance (wks3 to 5) withcranial neuropathies (ocular and lower CN maybeaffected) • Latemotorweakness in the trunk and extremities (wks5 to 8) • Improvementin cranial nerves occurswithongoingmotordisturbance in trunk and extremities

9. Diphteria • Weakness in the limbscanbeboth proximal and distal withassociatedatrophy in severecases • Paralysisof the diaphragm and respiratoryfailurecanoccur • Sensorydisturbances in all modalitieswithparaesthesias of distal extremities and often a sensoryataxia • Hypotonia, hyporeflexia, and downgoingplantarresponses • Significantabnormalities of parasympathetic and sympatheticfunction are oftenpresentand more commonwithsevere cases

10. Diphteria • Pathogenesis: paranodaldemyelination and segmental demyelinationbothat ventral and dorsal spinal roots and peripheral nerve

11. Diphteria • Large DDx • Diagnosis: Isolation of C. diphtheriae on culture withtoxigenictestingwithnasopharyngealswabfrom the patient and his/hercontacts • C. diphtheriaerequiresspecial culture mediancontainingtellurite • Elektest isperformed to determine if the bacillusproducestoxin and is an important test in the diagnostic process • Measurementof serumantibodies to diphtheriatoxinmayalso help assess the probability of diphtheria • PCR available for confirmation • NCS: demyelinating

12. Diphteria • Treatment: • Antibiotictherapy in combinationwithantitoxin administration within 48 hours of diagnosis to decrease the chances of developingdiphtheriticpolyneuropathy • Antitoxindoes not neutralizetoxinthatisalreadybound to tissues-> delayingits administration isassociatedwith an increase in mortalityrisk • Antibiotics to eradicate and avoid transmission

13. Case #1 • 57-year-old farmerwasadmitted to the hospitalwith a 1-week history of right lowerextremitymuscularrigiditythat over a period of a weekstarted to spread to his axial muscles including the neck, back, and abdominal muscles • He reportedstepping on a nail in the barn 2 weeksprior to the onset of symptoms and stillhad an open festeringwoundat the puncturesite • He thendevelopedlaryngospasmsthatled to respiratory compromise requiringintubation • Hissensorium remainedclear • Diagnosis?

14. 2- Bacterialtoxin: Clostridial-> Tetanus • Clostridium tetani • Anaerobic, gram positive rod • Metabolizesin anaerobic conditions and reproduces via spores thatcan survive in aerobicconditions • The spores are the common mode of transmission • The bacterium survives in soil and in the intestines and feces of animals, fromwhich the spore invades the body throughseeminglyinsignificantwounds and subsequentlymultiplies

15. Tetanus • Early manifestations of generalizedtetanusincluderigidity of the masseter muscles (trismusakalockjaw) and of facial muscles with a distinct straightening of the upperlipcausing a grimacing posture to the face (risussardonicus) • Frequentlocalizedstiffnessnear the site of the penetratingwoundfollowed by rigidity of the axial muscles involving the neck, back muscles (opisthotonus), and abdomen • With progression, extremitiesbecomestiffwith relative sparing of the distal muscles • Spasmscanbesignificantenough to break long bones of the extremities • Paroxysmal reflex spasmscanoccur in severe cases, generally in response to voluntarymovements or to external and internalstimuli • In severe cases, muscles of deglutitionmayalso go into trismus, causingdysphagia and dysarthria-> laryngospasmscan lead to respiratory compromise and asphyxia • Over a period of approximately 2 wks, the severity of symptomscanworsen, and by 4 weeksrecoveryusuallybegins • A hypersympathetic state maybe a manifestation of more severecases with fluctuations of BP and HR • Profuse sweating, highfever, and hypersalivation are alsocommonsigns of autonomicinstability

16. Tetanus • Neonataltetanususuallyoccurs in the generalizedform and tends to carry a highmortalityrate • The mostcommonsymptoms of neonataltetanus are a failure to suck and musculartwitching • Neonataltetanusgenerallydevelops in the first 2 wksof life in childrenborn to motherswho have been poorlyimmunized • Theseinfants often have umbilicalstumpinfections • In someunderdeveloped countries, some practices occur in the birthingprocessthat put infants atrisk, including the application of clarified butter withcontaminateddung fuel on umbilicalcords

17. Tetanus • Pathogenesis: • Tetanusistransported to the spinal cordfrom the neuromuscularjunction and thentransported by transcytosis to the inhibitoryRenshawcell and to the uppermotorneurons • Blocks the release of glycine and GABA frominhibitoryneurons, leading to spasticparalysis -> no relaxation of the antagonistic muscle during normal contraction

18. Tetanus • Diagnosis: Clinical • Positive spatula test on physical: reflex spasm of the masseter muscle on touching the posteriorpharyngealwall • Continuous, spontaneousmotor unit discharges on EMG reported but not diagnostic of tetanus • In someserious cases, elevated CSF protein and immunoglobulinlevels have been documented • C. tetanicanbecultured in about 1/3 of confirmed cases fromwounds • PCR assays for neurotoxingenefragments available • The presence of serumantitoxin of 0.01 unit per mL or higherisconsidered protective and makes a diagnosis of tetanusunlikely • Prognosis: relatedto degree of autonomicinstability and type of wound/injury. Burns, infectedumbilicalstumps, and compound fractures are frequentlyrelated to a poorprognosis

19. Tetanus • Treatment: elimination of the source of toxin, toxinneutralization, control of muscle rigidity and spasms, and ventilatory support • If no woundisfound, carefulexamination for signs of parenteraldrug abuse, otitis, and careful rectal and vaginal examinations are recommended • A retainedforeign body mayresult in continuoustoxin production • Althoughcontroversial, the use of metronidazole (500 mg IV every 6 hours for 7 to 10 days) is the drug of choice • Penicillin has a central GABA antagonisticeffect and canworsenspasms • Administration of humantetanusimmunoglobulinisrecommendedbeforemanipulating a wound-> recommendeddose is 500 unitsIM • Combinedintrathecal (1000 units) and IM antitetanusimmunoglobulin administration givesbetterclinicaloutcomesthan IM administration alone

20. Bacterialtoxins • Anotherclostridialtoxin -> clostridium botulinum (covered in neuromuscular talk) with the typicaldescendingflaccidparalysis • Anthrax (Bacillus anthracis) -> hemorrhagicmeningoencephalitis

21. 3-Envenomation/Snake • With the exception of the coralsnake, all the venomoussnakes in the United States are pitvipers (rattlesnakes, cottonmouths, and copperheads) • The incidence of venomoussnake bites in the United States isapproximately 7000 to 8000 per year, but only5-6 result in death • Confident diagnosis of a venomoussnakebiterequires a positive identification of the snake and recognition of the clinical manifestations of the envenomation • Rarelya snakewillbebrought in alive or dead for inspection at the clinic • Caution shouldbetakenhandlingdeadsnakesas a bite reflex canoccurevenafter the death • Envenomationdoes not alwaysoccurwithvenomoussnakes(25% of all viper bites are dry)

22. 3-Envenomation/Snake • Toxins • α-Bungarotoxin and cobrotoxin: postsynapticblockadeof acetylcholinereceptors (AChRs) • β-Bungarotoxin and crotoxin: presynaptic inhibition of acetylcholine (ACh) release • Local pain, swelling, and erythemaat site of the bite • Focal weakness or compartment syndrome • Diffuse proximal weaknessresemblingmyastheniagravis • Ptosis, cranial neuropathies, myokimia, dysphagia, areflexia, fasciculations, respiratorydistress • Systemicmanifestations, including hypotension and shock

23. 3-Envenomation/Snake • Withpitviperenvenomations, incision and suctioningat the bite site within minutes canremovevenom • Antivenin, most effective whengivenwithin 4 hrs of bite • Beware of anaphylacticreaction

24. 3- Envenomation/Scorpion • Tityustoxin, produced by Tityusserrulatus, causes presynapticfacilitation of ACh release and postsynapticactivation of voltage-gated sodium channels • Local pain and erythemaat site of the bite • Excesscholinergicactivity: salivation, lacrimation, urinary incontinence, defecation, gastroenteritis, and emesis (SLUDGE) • Local paresthesias, followed by diffuse paresthesias (thalamicinvolvement) , fasciculations, tremors, hyperreflexia, ptosis, nystagmus, blurred vision, dysarthria, and dysphagia • Pandysautonomia: hypertension, hyperthermia, hypersalivation, diaphoresis, urinaryfrequency, fecalurgency

25. 3- Envenomation/Scorpion • Treatment: supportive care • Anti-venin • With the use of Centruroidesantivenin, moderate to severeneurologicsymptomsmay reverse in 15 to 90 minutes

26. 3- Envenomation/Femaleblack widowspider(Latrodectusmactans) • Most important spider to cause potentiallysignificantmorbidity • Poorlylighted area-> oftenstinggenitalia • Toxin: α-latrotoxin, causingpresynaptic facilitation of AChrelease and depletion of Ach • Erythemaat site of the bite, intense pain, and involuntarymuscle spasmsinvolving the limbs, trunk, and diaphragm (latter causingrespiratoryarrest), dysarthria, chest pain • Autonomicsymptoms: hypertension, piloerection, diaphoresis, brochospasm • Acute symptomsincrease in severityduring the first dayafter a bite. Most symptomsgenerallydeclineafter 2 to 3 days, but somemildresiduamay continue for severalwks • Tx: antivenin

27. Case #2 • 12-year-old girl presentsto the ER withprogressive gaitinstability, ascendingweakness, shortness of breath on exertion, slurred speech, and swallowingdifficulties over 3 days • No GI or pulmonarysymptoms, norfeverpreceding the onset of symptoms • On examination, shewasalertwithsome facial weakness, dysarthria, and diffuse 3-4/5 weaknessworse in the legs than the arms • Reflexes were absent, and shehad no sensoryabnormalities • A neurologistsaw the patient in the ER and thought Guillain-Barré syndrome waslikely • CSF analysis and NCVsincludingrepetitive stimulation were normal, except for low-amplitude CMAPs, making the diagnosis of Guillain-Barré syndrome unlikely • A carefulexamination of the patient with a combrevealed a tickat the nape of her neck. Withinhours of itsremoval, the patient started to getbetter and eventually made an uneventfulrecoverywithin a week • Diagnosis?

28. 3- Tickparalysis • Resultsfrom inoculation of toxincontained in the tick saliva at the time of a bloodmea • Tickparalysisisassociatedwith over 40 species of tickworldwide, including five species in NorthAmerica; yetonly four tickspecies cause humandisease • The tickspeciesresponsible for most cases of humantickparalysis in the United States and Canada are Dermacentorandersoni (the Rocky Mountainwoodtick), and Dermacentorvariabilis (the American dog tick) • Otherareas of the body involvedinclude the nose, earcanals, and genitalarea • The incidence ismostfrequent in spring and summer

29. 3-Tick paralysis • Acute ascendingparalysis over dayswithoutsensorysymptoms • UnlikeLymedisease, symptomsregularlyresolveaftertickisremoved • Symptomsusuallybegin 2 to 6 daysafter the tickbecomesattached • Constitutionalsymptomssuch as feverare lacking, but generalized fatigue is not an uncommon initial symptom • Oftenmistaken for GBS-> Gaitinstability-> falling-> total inability to walkis a commonpresentation over a couple of days and mayquicklyinvolverespiratorymuscles and cranial and bulbarmuscle -> intubation • Weaknessworse in the LE and ass. withhypotonia and hypo/areflexia • Isolatedfacial weakness has been described, although more diffuse involvement of the cranial nerves leading to ophthalmoplegia, dysarthria, and dysphagiais more common • Reports in children of ataxia, mildencephalopathy, minorsensorydisturbances

30. 3- Tickparalysis • Pathogenesis not entirelyunderstood but thoughtto block axonalNa+ channels and to inhibit the release of AChatpresynapticmotor nerve terminals, causing total neuromuscularblockade • EMG/NCVsare welldescribed and suggestaxonalinvolvementwithevidence of denervation • CMAPs are of low amplitude and improvewith the removal of the tick as does the clinicalstatus • Treatment: Remove the tick • Coatingthe tickwithpetroleumjelly to makeit release itsholdishelpful and one shouldattempt to grasp the tick as close to skin as possible and make sure to remove all of the tick'scapitulum (head) • Detectionand removal of the tickusuallyresults in rapidimprovement (hours to 1 or 2 days) in the patient'scondition • Antiserumisgenerallyneitherrecommended, nornecessary

31. 4- Botanicaltoxin:Amanitamushrooms • Afterconsumption, there are initially no signs of toxicity, but a severegastroenteritisensuesafter about 6 to 12 hrswithN/V, abdocramping, and diarrhea • For the next 24 to 48 hrs, the patient mayimproveclinically, givinga sense of false hopeas duringthat time renal and hepaticfunctiondeteriorate • Toxicitybeginsupon active transport intohepatocyteswhereitbinds to and inhibits RNA polymerase II, leading to inhibition of proteinsynthesis and ultimatelyhepatocytedeath • Hepatotoxicityand renalfailuredevelop in the next 3 to 5 days, followed by secondarymetabolicencephalopathy • Neurologiccompromise mayberelated to direct effects of α-amatoxin and indirect effects of brainedemafromliverfailure • The key psychoactive constituents in thesemushrooms are ibotenicacid, muscimol, and muscazone • The GABA receptoragonist, muscimol, issomewhatsedating,Ibotenicacidbinds to glutamate receptors and inducesan agitateddelirium • Tx: supportive

32. Outline • General principles • Terrestrialbiotoxins • Metal intoxications • Organicchemicals intoxications • Marine Neurotoxins

33. Metal intoxication • Arsenic • Lead • Manganese • Mercury

34. Industrial/environmentaltoxins A few caveats…

35. General principles of industrial and environmentaltoxins

36. Case #3 • A 62-year-old womanwasevaluated for a 3-year history of slowly progressive, ascending, distal lowerlimbparesthesias. Shewas on no medications and did not give a history of potentialtoxicexposure. Herexaminationwasremarkable for decreased perception of vibration and position at the toes and a gradeddecreased perception of pinprick and touch distal to the mid-shinlevel. Herankle jerks were absent. No otherabnormalitieswerenoted on hergeneral and systemicexamination. Nerve conductions studiesrevealed an axonal, symmetric, length-dependent, predominantlysensory PN. Extensive investigations examiningvarious causes of neuropathywereunrewarding. A urine heavymetalscreenwas, however, remarkable for a 24-hour arsenic excretion of 862 μg (normal: lessthan 120 μg/24 h) • What’syourdiagnosis?

37. Case #3 • Elevation in urinaryarsenic excretionissometimes due to the organic, nontoxicformresultingfrompriorseafoodingestion • Withinhours of seafood ingestion total urinary arsenic concentration maybe in the range of 100 μg/L to 10,000 μg/L • Seafoodshouldbeavoided for 3 to 4 daysprior to a urine arsenic determination • This patient admitted to seafood ingestion during and prior to the urine collection and a repeat collection was normal

38. Arsenic • May be due to poisoning or man-made sources (eg.: metalsmelting, mining, abrasive blasting, pesticide manufacturing, combustion of coal, and burning of agricultural wastes,burningof chromatedcopperarsenate-treatedwood in fireplaces or woodstoves), found in tap water in Bangladesh • Arsenic isalsousedin the ceramicindustry and manufacture of semiconductors, light-emitting diodes, transistors, lasers, computer microchips, and microwave circuits • Shortlyafter ingestion, arsenic isstored in reticuloendothelialsystem, kidney and intestines and isslowlyreleased • Slow excretion via kidney and feces • Deposited in hairwithin 2 wks and remains in hair for years

39. Arsenic • Clinicalfeatures • Acute or subacuteexposure: abdo pain, nausea, vomiting, hyperthermia, headaches, anxiety, vertigo, possiblyseizure, encephalopathy • Fatal acute poisoning: precipitousdevelopment of lethargyand coma followed by death in few days, maybe due to diffuse edema and/or hemorrhagicencephalopathy • Low-dose chronicexposure: similarclinicalfeatures but muchlesssevere (abdo pain, vertigo, longstanding cognitive disturbance, persistent headaches and development of peripheralneuropathy • Opticneuropathy: possible delayed manifestation • Metallic taste • Mee’slines: white lines in nails, usuallyappear 2-3 wksafterexposure • Peripheralneuropathy • Painful, distal, axonal, maymimic GBS in severe cases • Glove-stocking distribution withinvolvement of small and large fibersleading to pseudoathetosis and allodynia • Distal weakness • Hypo/areflexia • Associatedwithexfolliativedermatitis

40. Arsenic Diagnosis: • 24h urine heavymetal arsenic level (maybefalselyelevated by shellfish ingestion), serumlevelsunreliable • Increased arsenic levels in nailclippings or pubichair (preferable to scalp as less chance of environmental contamination) Treatment • Acute: supportive (hydration, pain control, gastric lavage) • Chelationtherapywithdimercaprol or its water soluble derivativedimercaptosuccinicacid (DMSA); or penicillamine (best if startedearly)

41. Inorganic lead • Childrenabsorb lead more effectivelythanadults • Lead reachesbones, teeth, and soft tissue, and long-termstorageoccurs in the skeletalsystem • Boneresorption causes reentry of lead into the bloodstreamwith the potential of causingdelayeddeleteriouseffects • Pregnancy, lactation, menopause, osteoporosis, and othereventsthat lead to increasedboneresorptionmay lead to increasedbloodlevel in individualswithsubstantialamount of lead stored in bone • Found in oldpaints, drinkingwater through dissolution of lead in oldplumbing, manufacture of lead-acid batteries, batteryrecycling plants, crushing and smelting of lead and othermetal ores, radiation shielding, blasting and sanding of lead-coated surfaces, and soilcontaminatedfromvehicleexhaust and industrialemissions, ammunition, cosmetics

42. Inorganic lead Children • Acute intoxicatio(90 μg/dL): acute GI illness, confusion, lethargy, seizures, coma, and respiratoryarrestwithhighlevels of exposure • Chronic, low-levelexposure (10 μg/dL): gradualonset of listlessness, behavioral changes, psychomotorslowing, sleepdisturbance, seizures, gaitdisordercharacterized by clumsiness or frankataxia

43. Inorganic lead • Adults • Polyneuropathy: predominantlymotorneuropathy, withdistal weakness, atrophy, and fasciculations (pain uncommon) • Motormanifestation maybe more prominent in upperextremities: maypresentwithbilateralwristdrop, with or without distal lowerlimbweakness, oftenasymmetric • Motorneuropathycommonlyinvolvesradial nerve (wristdropismostcommon) • There may or may not besensorysymptoms, predominantlyparesthesias (allodynia and dysesthesiasare uncommon)

44. Inorganic lead • Laboratorydiagnosis • Microcytic, hypochromicanemia • Basophilicstippling of redbloodcells on bloodsmear • Renalinsufficiency, azotemia • Elevatedbloodlevelsof lead • Lead interfereswithhemoglobinsynthesis by inhibiting the enzymes δ-aminolevulinicaciddehydratase and ferrochelatase and results in elevated free erythrocyteprotoporphyrin (FEP) whichis more accuratethanserum lead levels for chronictoxicity but because of poorsensitivity, serum lead levelisstill the preferred screening method • Treatment: chelationwith DMSA, intravenous calcium disodium-EDTA, or penicillamine

45. Manganese • Exposure • Primarysource of exposure (occupational): miners, ferromanganesesmelting plant workers, workers in manganese ore-crushing plants, welders, and thoseinvolved in the manufacture of dry batteries • Patients receiving total parenteral nutrition containingmanganese • Pathology: neuronal loss and gliosisaffecting the globuspallidus and subthalamic nucleus; uncommoninvolvementof substantianigra • Main source of disposalisbiliaryexcretion: patients withbiliaryatresia or chronicliverdisease are prone to developmanganesetoxicity (mayexplainhigh T1 signal in pallidum observed in chronicliverdisease) • Mechanism: oxidativestress generatedthrough mitochondrial perturbation, NMDA-mediatedexcitotoxicity, and disruption in ironmetabolism

46. Manganese • Clinicalfeatures • Onsetof symptomsmayoccurearly (1-2 monthsafterexposure) or maybedelayed (about 20 yearsafterexposure) • Headaches, neuropsychiatric manifestations (memorydisturbance, hallucinations, aggressivebehavior, apathy, irritability, social withdrawal, personality changes, and psychosis, referred to as “manganesemadness”) • Extrapyramidal symptoms: parkinsonism • Hypophonicand monotonous speech • Absence of typicalparkinsonianresttremor, but theremaybe a fine, low-amplitude, high-frequencytremor • Gait: retropulsion, propulsion, oftentendency to walk on toeswithelbowsflexed and erect posture

47. Manganese Symmetricabnormallyincreased signal in the globuspallidus (A) and substantianigra (B) (maybetransient) The typicalfindingisreally the increasedpallidal signal

48. Manganese • Diagnosis: • Manganesecanbedetected in blood for days to weeksafterexposureceases • Manganeselevels in urine and fecesmaybeused as a marker for exposurewithin the previous few hours • BrainMRI: high T1 signal in the globuspallidus (also striatum and midbrain) bilaterallybecause of manganese accumulation • Treatment: • Levodopa: partial to no benefit • Chelationwith EDTA: improvement in some patients

49. Mercury

50. InorganicMercury • Acute intoxication: acute colitis, vomiting, renalfailure, stomatitis, little cognitive impairmentexcept for irritabilityand delirium withacute poisoning • Chronic, low-grade toxicity: tremor, peripheralneuropathy • Personalitychanges, anxiety, but little cognitive impairment • Peripheralneuropathy: sensorimotoraxonopathy, associatedwithsensoryloss, sensoryataxia, pain, paresthesias, distal weakness, atrophy