Between a Rock & a Hard Place: A Review of the Neurological Aspects of Bioterrorism

1. Between a Rock & a Hard Place: A Review of the Neurological Aspects of Bioterrorism Amy Gutman MD Amy.Gutman@uc.edu

2. Overview • Epidemiology of Bioterrorism • Neurological Agents of Bioterrorism & Their Mechanisms of Action • Response to Bioterrorism • Prehospital • Emergency Department • In-Patient Care • Chronic Care

3. “The American military superiority presents a paradox; potential adversaries know they can’t win a conventional challenge to US forces, so they’re likely to try unconventional methods, such as biologic or chemical weapons.” W. Cohen, Defense Secretary Thoughts to Ponder

4. Epidemiology of Bioterrorism

5. 40,000 Metric Ton Russian Chemical Stockpile(2005 United Nations Report )

6. Consider The Bioterrorism Sources In Hamilton County

7. Likelihood of Agent Release • Vapor / Aerosol Inhalation: • Potentially massive morbidity & mortality • Immediately affects those in close proximity • May have large affected area due to weather conditions • Liquid Release: • Rapid onset of symptoms limits potential victims even in a large water source • Either direct contact or via ingestion

8. Exposure vs Contamination* *Credited to Dr Leonard Singer

9. ACh released when impulse reaches presynaptic neuron Ach travels in synaptic cleft to postsynaptic membrane, binding a muscarinic or nicotinic receptor ACh receptor activated generating an action potential ACh detaches from receptor & degraded by AChE regenerating the receptor Neurotoxins inhibit ACh: Bind to the active site rendering it incapable of deactivating ACh Undegraded ACh continues to interact with receptors, resulting in persistent & uncontrolled stimulation until fatigued Same principle as neuromuscular blocker succinylcholine Neurotoxin Mechanisms of Action

10. Pathophysiology • Irreversibly inactivate AChE causing toxic accumulation of ACh at muscarinic, nicotinic, & CNS synapses • Muscarinic: Miosis, bronchoconstriction, N/V/D, bradycardia, glandular hypersecretion, urinary & fecal incontinence • Nicotinic Skin: Sweating • Nicotinic Muscle: Defasciculation then weakness & flaccid paralysis • CNS Cholinergic: Irritability, giddiness, fatigue, lethargy, amnesia, ataxia, seizures, coma, & respiratory depression • CNS Delayed: behavioral changes (anxiety, emotional lability), ataxia, insomnia, nightmares, depression, difficulty concentrating, slow recall, confusion, slurred speech • Adrenal Medulla: Tachycardia & HTN • GABA & NMDA: Neurotransmission antagonized mediating seizures & CNS neuropathology

11. Nerve Agent Pharmacologic Effects“DUMBELS” or “M T W Th F”* • Diarrhea • Urination • Miosis • Bronchorrhea / Bronchoconstriction • Emesis • Lacrimation • Salivation • Alternative is “Days of The Week” • Mydriasis • Tachycardia • Weakness • Hypertension • Fasciculations *Common mnemonic "SLUDGE" does not include bronchorrhea or bronchoconstriction

12. Alphaviruses (viral encephalitis) Arenaviruses (Lassa, Machupo) Bacillus anthracis (anthrax) Clostridium botulinum (botulism) Clostridium perfringens Brucella species Burkholderia mallei (glanders) Burkholderia mallei(meliodosis) Chlamydia psittaci (psittacosis) Coxiella burnetii (Q fever) Escherichia coli 0157:H7 Filoviruses (Ebola, Marburg) G Agents (Sarin, Soman) Francisella tularensis(tularemia) Hantavirus Hydrogen Cyanide Nipah virus (encephalitis) Organophosphates Ricin toxin Rickettsia prowazekii (typhus) Salmonella species (salmonellosis) Salmonella Typhi (typhoid fever) Shigella (shigellosis) Smallpox (variola major) Staphylococcal enterotoxin B V Agents (VX) Variola major (smallpox) Vibrio cholerae (cholera) Yersinia pestis (plague) Bioterrorism Agents* *Chemical Weapons Convention of 1997 banned production, stockpiling & use of chemical weapons, & provides for the monitoring of their destruction

13. V Agents: VX • Developed by England in 1952 • Information traded with US for nuclear weapons technology • Oily, odorless, amber liquid which does not readily evaporate • Must be aerosolized into tiny droplets • Degrated products persist on the ground for 2 - 6 days • Continue to have neurotoxic effects • Enters body via skin or inhaled as a vapor • V agents ~10X more poisonous than GB (sarin)

14. G “Deutsche Grun Drei” Agents Other 1st V agent; discovered by Nazis Released on Iranians, Kurds & Japanese 1967 Yom Kippur War

15. Botulism:Clostridium botulinum • Paralytic illness caused by an anaerobic, gram positive, spore-forming rod • Lethal dose: one microgram is lethal to humans • ~110 cases in US annually • 72% are infant botulism • 3% are wound botulism • 25% are food born outbreaks due to home-canning • The heat-labile toxin blocks ACh release at nerve synapses

16. Symptoms & Diagnosis • Symptoms at 12-48 hours: • Dry mouth, double &/or blurred vision, difficulty swallowing, muscle weakness, ptosis, SOB, slurred speech, vomiting, incontinence, diarrhea then constipation (paralytic ileus) • Death secondary to respiratory failure (8% case fatality rate) • Long-term effects include: fatigue & SOB (decades) • DDX: • Guillain-Barré syndrome • CVA • Masthenia gravis • Diagnostic Testing: • CT, MRI • LP with CSF analysis • EMG • Edrophonium Chloride (Tensilon) • Toxin identification via ELISA or tissue culture in serum, blood, GI contents, vomit or feces

17. Botulinum Symptoms40 x 10-12g/mL of type A botulinum toxin in serum • Patient at rest • Bilateral mild ptosis, mydriasis, disconjugate gaze, & symmetric facial muscles • Patient smiling • Absent periorbital smile creases, ptosis, mydriasis, disconjugate gaze, & asymmetric smile

18. Botulism Evaluation

19. Botulism Treatment • Supportive, including mechanical ventilation • If detected early, passive immunity can be induced via a horse-serum derived antitoxin • Botulinum Antitoxins: • Trivalent (A,B,E) derived from equine sources utilizing Fab & Fc antibodies • Heptavalent (A,B,C,D,E,F,G) derived from "despeciated" equine IgG antibodies which have had the Fc portion cleaved off leaving the F(ab') portions

20. Anthrax: Bacillus anthracis • Long-lived endospore (centuries) that when inhaled, ingested, or in direct contact with skin reactivates & rapidly multiplies • Can be grown in vitro • Does not spread directly from one infected animal or person to another, but spores can be transported by clothing, shoes, or a dead body • Pasteur developed the first effective vaccine for anthrax in 1881, followed by a century of animal vaccination programs, sterilization of raw animal waste materials & world-wide anthrax eradication programs • 5 US confirmed fatalities in 2006 • Fact: Thought to be the 6th Biblical Plague (shkhinשְׁחִין) or “boils”

21. Bacillus Anthracis • Rod-shaped bacterium 1 by 9 um in size, discovered by R. Koch in 1877, currently with 89 strains • Once ingested, absorbed or inhaled the bacterium begins multiplying, killing the animal within days to months via an exo-toxin • Most anthrax bacteria inside the body are destroyed by “normal” anaerobic bacteria The greater danger lies in the bodily fluids that spill from the body into the soil where the anthrax bacteria turn into a dormant protective spore form • The virulence of a strain of anthrax primarily dependant upon the poly-D-glutamic acid capsule that protects the bacterium from phagocytosis by host neutrophils & its toxins: “edema” toxin & “lethal” toxin

22. Anthrax Types • Pneumonic / “Woolsorter’s Disease” • Presents with cold or flu-like symptoms for several days, followed by severe & often fatal respiratory collapse (mortality is near 100%) • This mode of infection is used as a bioweapon • Gastroenteric / Foodborn • Hematemesis, gastrointestinal difficulty, severe diarrhea, acute GIT inflammation & anorexia • Spreads through the bloodstream with a fatality rate of 25% to 60% • Cutaneous • Boil-like skin lesion that eventually forms an ulcer with a large, painless central eschar • If untreated, 20% of all cutaneous skin infection cases progress to toxemia & death • 5% fatality rate with treatment

23. Anthrax: Widened Mediastinum

24. Anthrax Treatment & Prevention • Direct person-to-person spread unlikely, but patient’s clothing & body may be contaminated with anthrax spores • Effective decontamination with simple soap & water • Waste water should be treated with bleach • Boil contaminated articles with disinfectants, chlorine or simply burn in a contained area • Early antibiotic treatment of anthrax essential with fluoroquinolones (cipro), doxycycline, erythromycin, vancomycin or penicillin • Anyone working with anthrax in a suspected or confirmed victim should wear a HEPA or P100 filter mask

25. Treatment & Prevention • If death occurs from anthrax the body should be quarantined • Burial does not kill anthrax spores • The most effective form of prevention is vaccination against infection but this must be done well in advance of exposure to the bacillus, and does not protect indefinitely • Components of black tea, such as polyphenols, have the ability to inhibit the activity of anthrax considerably • The addition of whole milk to a standard cup of tea completely inhibits its antibacterial activity against anthrax

26. BioThrax • FDA-licensed vaccine, produced from a non-virulent strain of the bacterium, is called “BioThrax” or “Anthrax Vaccine Adsorbed” (AVA) • Administered in a six-dose series at 0,2,4 weeks & 6,12,18 months • Annual boosters required to maintain immunity • Painful, & causes significant swelling • Soviets developed a live spore vaccine, known as STI, whose serious side effects restrict use to healthy adults Anthrax Hemorrhagic Meningitis

27. Outbreak Features • Rapid increase in incidence of a rare disease • Or endemic disease rapidly & uncharacteristically emerging • Rapid increase in those seeking care for URI / GI illnesses • Systemic symptoms delayed >18 hours if limited dermal exposure • Single location (building, city, stadium) • Large number of rapidly fatal cases • Respiratory Exposure: death in <15 minutes • Skin bbsorption: death in 1 to 2 minutes • Uncommon illness with bioterrorism potential • “Sentinel Patients”, i.e. inhalational anthrax

28. HPI • Often the first history is the only history available if patients rapidly decompensate • History of exposure to a nerve agent may be absent • Always suspect the diagnosis when multiple patients present with symptoms of cholinergic excess • Occupational history can aid in making the diagnosis in cases of accidental releases • Farmers, military personnel, chemical demilitarization laborers, & laboratory workers

29. Physical Exam & DDX • Clinical signs and symptoms related to unopposed stimulation at cholinergic, GABA & NMDA receptors as discussed previously • Diagnosis is easier in the severely symptomatic patient • Pathognomonic: • Miosis, copious secretions, & generalized muscular fasciculations in a gasping, cyanotic, seizing patient • DDX: • Epilepsy • Gastroenteritis • Upper Respiratory Infection • Heat-Related Illness • Stroke / Head Trauma • Drug overdose

30. Laboratory Studies: RBC Cholinesterase Levels • Labs do not aid in acute treatment; treat on clinical suspicion • Never withhold treatment while awaiting results • RBC & plasma cholinesterase (“pseudocholinesterase”) activity can be assayed in blood • Tissue cholinesterase activity cannot be directly measured • RBC cholinesterase is a sensitive indicator of nerve agent toxicity • Clinical symptoms correlate with 20-25% reduction enzyme activity • Rising enzyme levels indicate no further absorption occurring • RBC cholinesterase replaced fully every 120 days

31. Other Studies • ABG: Decreased PaO2, increased PCO2 • Lactate & CPK: Elevated in seizures (hypoxia, fasciculations) • Electrolytes: Hypokalemia (G series agents) • Special Tests: M256A1 or CAM assay, M8, M9 papers • ECG: Bradycardia, AV blocks (muscarinic) Tachycardia, PVC, VT, VF, (hypoxia) PR interval & QT prolongation, torsades • EEG: Monitoring for paralyzed patients Nicotinic effects of agents masks seizures

32. EEG Findings • Greater-than-normal variations in potential • Increased frequency with increased beta waves • Irregularities in rhythm & intermittent appearance of abnormal high-voltage, slow waves most prominent in the frontal leads • EEG abnormalities often decreased or reversed by atropine       • EEG abnormalities of a subject poisoned with sarin showed slow activity with bursts of high-voltage, 5-Hz waves in temporo-frontal leads for 8 days on continuous atropine & benzodiazepine infusion

33. Any respiratory distress, dyspnea, or post intubation to evaluate for non-cardiogenic pulmonary edema Imaging: CXR ARDS Post Neurotoxin Inhalation

34. Initial Management • Goals: rapid termination of exposure, treating life-threatening emergencies, & administration of antidotes • Safety of patients, EMS, rescuers & hospital workers depends on early exposure recognition to avoid creating more victims • Highest level of PPE required: • Fully encapsulated, chemical-resistant, vapor-protective suit via SCBA & full face shielding, & butyl rubber gloves • ABCs • Supplemental O2, oximetry & cardiac monitoring, IV access • Early intubation & ventilatory support if severe toxicity • Respiratory failure is leading cause of death • Medications • Mark I auto-injectors (atropine, pralidoxime chloride 2PAM)

35. Effective Decontamination • In a “normal” MCI, priorities are: stabilize patient then decontaminate; In a neurotoxin release priorities are: decontaminate then stabilize patients • Goal is to prevent further absorption of nerve agents & prevent the spread of nerve agents to others • Remove all clothing & jewelry • Cleanse eyes, mucus membranes, wounds & entire skin surface skin with soap & water or 0.5% hypochloride (1:9 ratio of bleach:water) • Breaks neurotoxin ionic bonds • Clothing & used solution are “contaminated” evidence • Requires double bagging & disposal in a closed container

36. Basic Decontamination Plan Shower & Rinse Drying Area Clean Clothing Cut & Strip Holding Area

37. Although prior to EMS transport from a scene, patients undergo initial decontamination, hospital staff must be trained in self-protection, triage, treatment, & decontamination In an MCI, patients often self-transport without EMS treatment In the Tokyo subway sarin attack, 85% of patients arrived via private car This emphasizes the importance of hospital decontamination facilities & training as many victims likely to require initial triage & decontamination at the ED Hospital Decontamination

38. ED & Hospital Treatment: ABCs • All personnel must wear PPE until adequate decontamination is assured or the need for decontamination is eliminated • Any symptomatic patient: O2, pulse ox, cardiac monitor, & IV • Early ETI & ventilatory support is paramount if severe toxicity • Avoid succinylcholine: metabolized by plasma cholinesterase leading to markedly prolonged paralysis • Suction is an important adjunct, as secretions may be profuse • Early consultation with neurology, toxicology, internal medicine, psychiatry, surgery & critical care is essential • In an MCI, activate the hospital emergency plan (DisasterNet) • DisasterNet automatically starts EOC notifications • Regional poison center (1-800-222-1222)

39. Rapid delivery of critical medical assets to the site of an emergency Coordinates agencies in the event of a terrorist attack or natural disaster SNS anaged by the CDC as a national repository of: Antibiotics, antidotes, antitoxins, life-support meds, IV / airway supplies, & other med-surg items “12-hour Push Package” arrives <12 hours after the federal decision to deploy 2nd phase arrives 24–36 hrs NIMS, EOP, SNS Federal, State & Local Responses

40. Initial Patient Care • Detailed health histories must be obtained as many patients & families may not be aware of initial exposure • The key to recognizing neurotoxin exposure is the appearance of multiple patients with similar signs and symptoms • The route of exposure & the dose of the nerve agent determine the onset & severity of signs & symptoms • Inhaled agents produce a rapid onset of symptoms, potentially misinterpreted as a URI or allergy symptoms • Patients with only ocular findings following vapor exposure can be discharged home safely with rapid opthmology referral • Admit patients with suspected liquid exposures for observation after decontamination • Onset of symptoms may be delayed 18 hours

41. Treatment if Completely Asymptomatic • For those patients that may have been exposed but are not exhibiting any symptoms • This may include malingerers or opportunists • Legally prudent to observe • Reassurance of the rarity of significant health effects • Place under medical observation in a floor bed: • Vapors: 1 hour • Liquids: 18-24 hours

42. Inpatient Care • Patients in respiratory distress may need ventilatory assistance despite aggressive antidotal therapy • If critically ill with complications such as anoxic brain injury (prolonged seizures or respiratory arrest) may require prolonged intensive care • Follow RBC cholinesterase and electrolyte levels • Acute management of & secondary medical or surgical emergencies • Cardiac Arrests • COPD Exacerbations • Blast Injuries

43. Chronic Neurological & Neuropsychological Effects • May persist for months if severe cholinergic effects • If discharged without complications or a significant exposure from the hospital generally no further acute care required • Subtle behavioral & cognitive changes may persist for weeks • Permanent neurological sequelae if anoxic brain injury present • Educate patients on potential long-term complications (>3 years), including: • Behavioral & cognitive changes difficult to distinguish from PTSD • Impaired memory, difficulty concentrating, anxiety, irritability, depression • Symmetric sensorimotor peripheral neuropathy • Night-time miosis • Postural imbalance • Fatigue • Nausea • Joint stiffness

44. Medical Errors - Initial • Failure of EMS to secure scene, turning themselves into victims • Failure to decontaminate victims of liquid nerve agent exposure leads to contamination of rescuers & hospital personnel • Failure to recognize symptoms of cholinergic excess as being caused by nerve agent toxicity leading to delays in care • Failure to recognize succinylcholine causes prolonged paralysis • Disposing of evidence collected during triage or treatment • Poor documentation leading to confusion at hospital

45. Medical Errors - Delayed • Failure to recognize symptoms of cholinergic excess may not appear for 18 hours in low-level exposures • Solely using presence or absence of miosis to guide atropine therapy • Over-reliance on pseudocholinesterase levels to guide treatment • Failure to suspect occult seizures in paralyzed patients & order EEG to prevent hypoxic brain injury

46. Antidotes Atropine Pralidoxime Chloride (2 PAM)

47. Antidotes • Even with rapid administration respiratory failure may occur due to bronchoconstriction, increased airway secretions, & increased airway resistance • Prepare to provide intubation & mechanical ventilation • Supplemental oxygen, suctioning, & careful monitoring of vital signs, electrolyte levels, & cardiac rhythm are essential • Symptoms often improve after antidote administration, though the duration of the symptoms depends on the route & degree of exposure to the nerve agent

48. Antidotes Two-Tiered Mechanisms of Action • Atropine (Anticholinergic): • Counteracts muscarinic effects resulting from excess ACh in the absence of functional AChE • Dries respiratory secretions; does not relieve diaphragm paralysis • Continue dosing until symptoms improve (“atropinization”) • Adverse effects include: flushing, warmth, tachycardia, urinary hesitancy, blurred vision, & drowsiness • 2-PAM (Oxime / Cholinesterase Reactivator) • Removes organophosphate from AChE which then deactivates ACh • Restores normal skeletal muscle function (including diaphragm) • Adverse effects include malignant HTN, tachycardia, diplopia, N/V & dizziness

49. Mark I Auto-Injectors • 2mg atropine auto-injector contains glycerin, phenol, citrate buffer, & water • 600mg 2-PAM auto-injector contains benzyl alcohol, glycine, & water • Do not administer to patient with hypersensitivity to any component solution

50. Pyridostigmine (Mestinon, Regonol) Chemoprophylaxis • Temporarily binds to AChE theoretically blocking binding of nerve agents to AChE • Effective: GA, GD, GF • Ineffective: GB, VX • Orally available cholinesterase inhibitor • Only effective in preventing peripheral effects • Ionized form does not pass into CNS • 50% of the Gulf War military taking chemoprophylaxis experienced flatus, diarrhea, & abdominal cramping • 5-30% had urinary frequency & urgency, headaches, rhinorrhea, diaphoresis, & / or paresthesias