External Eye Manifestations of Biological and Chemical Warfare

Key Concepts

The use of biological and chemical agents as weapons is not a new concept.
Recognition and preparation are essential to limit exposure and treat victims.
Anthrax, botulism, smallpox, vaccinia, tularemia, and the viral hemorrhagic fevers have characteristic ophthalmic signs.
Chemicals such as sarin nerve gas and sulfur mustard have been used as weapons with significant ocular manifestations.

The spectrum of biological and chemical agents that can be used in warfare is frightening. Healthcare providers must be alert to patterns of illness and the constellation of clinical findings associated with an outbreak of biological or chemical warfare. The intentional release of an unusual infectious agent can be difficult to recognize because many of the commonly used organisms are rarely seen in their natural form. When used as weapons, there is potential for an immense number of casualties due to ease of dispersal, rapid onset of effect, and lack of preparation for containment and defense. Timely recognition of symptoms and early treatment are key to victim survival.

Background

The deliberate use of microorganisms and toxins as weapons dates back to the middle ages. During the 14th-century siege of Kaffa (now Feodosiya, Ukraine), the attacking Tatars catapulted plague-infested cadavers into the city in order to initiate an epidemic. South American aboriginals are well known for using curare and amphibian-derived toxins as arrow poisons, and British forces used smallpox against native North Americans during the French and Indian War of the mid-18th century. The advent of modern microbiology and Koch postulates during the 19th century afforded the opportunity to isolate and produce stockpiles of specific pathogens. There is evidence that Germany developed an aggressive biological warfare program during World War I, including operations to infect livestock and contaminate animal feed of the Allied forces using Bacillus anthracis and Burkholderia ( Pseudomonas ) mallei , the etiologic agents of anthrax and glanders.

The first widespread use of chemical weapons occurred during World War I, when more than 1 million casualties resulted from the use of sulfur, mustard, and chlorine gases. These horrors led to the first international diplomatic efforts to limit weapons of mass destruction. The 1925 Geneva Protocol for the Prohibition of the Use in War of Asphyxiating, Poisonous, or Other Gases, and of Bacteriological Methods of Warfare was enacted to prohibit the use of biological weapons. Unfortunately, there were no provisions for inspection, and many countries that ratified the treaty still began research programs to develop biological weapons.

During World War II, Japan conducted experiments in which prisoners were infected with various bacterial pathogens, which led to at least 10,000 deaths. Many Chinese cities were attacked by contaminating water supplies and food items with pure cultures of B. anthracis , Vibrio cholerae , Shigella species, Salmonella species, and Yersinia pestis . International concern heightened during the late 1960s, which led to the signing of the 1972 Biological and Toxin Weapons Convention. The treaty prohibited the development, possession, and stockpiling of pathogens or toxins in “quantities that have no justification for prophylactic, protective, or other peaceful purposes.” Transferring technology or expertise between countries was also prohibited.

In 1979, the ineffectiveness of the convention was demonstrated by an accidental airborne release of anthrax spores by a Soviet military microbiology facility in Sverdlovsk (now Ekaterinburg, Russia), which led to numerous deaths. Non-state-sponsored biological terrorism began to surface in the 1980s, which culminated with the 1995 sarin gas attack of the Tokyo, Japan, subway system by the Aum Shinrikyo cult. Soon after the September 11th, 2001, terrorist attacks on the United States, letters laced with anthrax were sent to several news agencies and two Senators. This led to five deaths and many illnesses and one of the most extensive Federal Bureau investigations in the US history. In 2013, the United Nations confirmed the use of government-sponsored chemical weapons (sarin and chlorine) during the Syrian Civil War.

Mechanism of Attack

A biological weapon is more than a microorganism or toxin. It is a system composed of four major components: payload (the biological agent), munition (a container that keeps the payload intact and virulent during delivery), delivery system (missile, artillery shell, aircraft, etc.), and dispersal mechanism (an explosive force or spray device to dispense the agent to the target population). Certain agents are attractive because of low visibility, small volume, high potency, and easy delivery. Aerosolization would be the predominant method of dissemination because advanced delivery systems are not required, and small quantities make transportation and concealment quite easy. In 1970, the World Health Organization predicted the effect of an aerosol release of 50 kg of biological weapon over a city of 500,000 people ( Table 97.1 ). ^,

TABLE 97.1

Estimates of Casualties Produced by a Hypothetical Biological Attack ^∗

From Biological warfare and bioterrorism: a historical review. Proc (Bayl Univ Med Cent) 2004; 17 (4):400–6. Table 1 . Based on data from WHO Group of Consultants. Health aspects of chemical and biological weapons . Geneva, Switzerland: World Health Organization; 1970.

Agent	Downwind Reach (km)	Number Killed	Number Incapacitated
Rift Valley fever	1	400	35,000
Tick-borne encephalitis	1	9,500	35,000
Typhus	5	19,000	85,000
Brucellosis	10	500	125,000
Q fever	>20	150	125,000
Tularemia	>20	30,000	125,000
Anthrax	>20	95,000	125,000

∗ Release of 50 kg of agent (aerosolized) by aircraft along a 2-km line upwind of a population center of 500,000 (23).

Highly contagious organisms with delayed onset of symptoms make ideal weapons for a covert attack. In an overt attack, chemical agents are likely to be deployed, causing rapid onset of symptoms and an overwhelming demand for emergency medical services. Both biological and chemical weapons can incapacitate an entire city and impede the mobilization of military personnel.

Warning Signs

In order to recognize a bioterrorism attack, one must be familiar with the various clinical presentations of these agents. The American College of Physicians and the American Society of Internal Medicine have suggested that the following epidemiologic clues be considered :

1.
Unusual temporal or geographic clustering of illness
2.
Unusual age distribution of common disease (i.e., an illness that appears to be chickenpox in adults but is really smallpox)
3.
Large epidemic, with greater caseloads than expected, especially in a discrete population
4.
More severe disease than expected
5.
Unusual route of exposure
6.
A disease that is outside its normal transmission season or is impossible to transmit naturally in the absence of its normal vector
7.
Multiple simultaneous epidemics of different diseases
8.
A disease outbreak with health consequences to humans and animals
9.
Unusual strains or variants of organisms or antimicrobial resistance patterns.

The Centers for Disease Control and Prevention (CDC) of the United States has listed the high-priority biological diseases ( Box 97.1 ) that pose significant risk to national security based on the following: can be easily disseminated and/or transmitted from person to person; result in high mortality rates and have the potential for major public health impact; might cause public panic and social disruption; and require special action for public health preparedness.

BOX 97.1

Biological Diseases

From Centers for Disease Control and Prevention: Biological Diseases/Agents List . https://emergency.cdc.gov/agent/agentlist-category.asp

Anthrax (Bacillus anthracis)
Botulism (Clostridium botulinum toxin )
Plague (Yersinia pestis)
Smallpox (Variola major and minor)
Tularemia (Francisella tularensis)
Viral hemorrhagic fevers
Filoviruses—Ebola, Marburg
Arenaviruses—Lassa, Machupo

Most of these agents have significant ophthalmic manifestations that may aid in diagnosis or complicate management.

Biological Diseases

Anthrax

B. anthracis is the ideal biological weapon because of its stability in spore form, its ease to grow in culture, the lack of natural immunity in many industrialized nations, and the severity of infection.

Microbiology/Epidemiology

B. anthracis is an encapsulated, aerobic, gram-positive, spore-forming, rod-shaped bacterium. Spores form when environmental nutrients are depleted, such as occurs with dry soil, the natural reservoir. Spores can survive for decades in contaminated soils or workplaces and can resist temperatures of over 10°C for prolonged periods. ^, Inhalation (wool-sorter disease) can occur from animal products such as wool fibers or bone meal, leading to outbreaks in slaughterhouses, textile industries, and tanneries. Herbivores such as cattle, goats, and sheep ingest spores and serve as the natural transmitters of infection. Humans become infected through direct contact with contaminated carcasses or from eating infected meat. Animal husbandmen, butchers, and veterinarians are most susceptible.

Clinical Manifestations

Three principal forms of anthrax occur in humans: cutaneous, inhalational, and gastrointestinal. The majority of naturally occurring disease is cutaneous, comprising more than 95% of cases. Spores sent in mailed letters or packages can lead to either cutaneous or inhalational anthrax. The differential diagnosis of cutaneous anthrax includes cowpox, spider bite, ecthyma gangrenosum, ulceroglandular tularemia, plague, scrub typhus, rickettsial spotted fever, rat bite fever, staphylococcal or streptococcal cellulitis, and herpes simplex virus.

Cutaneous Anthrax

Cutaneous disease begins as a small, painless, pruritic, red macule that progresses to a papule. The papule then vesiculates, ruptures, and ulcerates. It then forms a classic 1–5-cm, brown or coal-black eschar surrounded by significant nonpitting edema. The term anthrax is derived from the Greek anthrakos meaning “coal.” It appears at the site of inoculation (spores or bacilli) within 3–10 days. The edema can spread, and translucent epidermal bullae vesicles often surround the lesion—the so-called “pearly wreath.” After 2–4 weeks, the eschar sloughs away, leaving an exposed area of granulation tissue. Although fatalities due to cutaneous disease are rare, 10%–20% of untreated patients develop malignant edema, septicemia, shock, renal failure, and death.

Ophthalmic manifestations

Ocular findings in cutaneous anthrax relate to eyelid involvement. ^, The main complication is cicatricial ectropion due to late eyelid scarring ( Fig. 97.1 ). Lid malposition causes exposure keratopathy, which can lead to epithelial breakdown and secondary infectious keratitis. Corneal scarring is more likely to occur in patients who present late without treatment during the acute stage. It appears that upper eyelid involvement is more likely to result in ectropion. Severely affected patients have undergone release of contractures and full-thickness postauricular skin grafts with satisfactory resolution of ectropion. Temporal artery inflammation has been reported as a complication of overlying cutaneous anthrax.

Diagnosis

Anthrax bacilli can be visualized by Wright or Gram stain of peripheral blood or isolated by blood culture. Diagnostic testing for cutaneous disease includes Gram stain and culture of vesicular fluid, tissue biopsy, specific enzyme-linked immunosorbent assays (ELISAs) to measure antibody titers, immunomagnetic electrochemiluminescence (ECL) assays for antigen detection, and polymerase chain reaction (PCR) for nucleic acid detection. Spores have a diameter of 2–6 mm, which is ideal for entrapment in the lower respiratory tract. The time for infection is variable because spores must germinate into bacilli after phagocytosis by tissue macrophages. The dose of anthrax in an exposure is inversely correlated with incubation time. Cases in the accidental release in Sverdlovsk developed 2–43 days after exposure. Thus it may be hard to trace the onset of an attack, making response and containment more difficult.

Treatment

Treatment of inhalational and gastrointestinal anthrax should begin with intravenous ciprofloxacin 400 mg every 12 hours ( Table 97.2 ). Doxycycline 100 mg every 12 hours can be used but has poorer central nervous system penetration. One or two of the following additional antibiotics should be added until susceptibility testing is performed: rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin. Cutaneous disease can be treated with either oral ciprofloxacin or doxycycline alone. Treatment should be continued for 60 days because of the possibility of delayed germination of spores. Direct contact with wound or wound drainage should be avoided when caring for a patient with cutaneous anthrax.

TABLE 97.2

Centers for Disease Control and Prevention Recommendations for Antimicrobial Therapy Against Anthrax

Adapted from Centers for Disease Control and Prevention Update. Investigation of Anthrax Associated with Intentional Exposure and Interim Public Health Guidelines, October, 2001. MMWR 2001; 50 :889–97 and Centers for Disease Control and Prevention Update. Investigation of Bioterrorism-Related Anthrax and Interim Guidelines for Exposure Management and Antimicrobial Therapy, October 2001. MMWR 2001; 50 :909–19.

Indication	Adults	Children
Postexposure prophylaxis	Ciprofloxacin 500 mg by mouth twice a day OR Doxycycline 100 mg by mouth twice a day	Ciprofloxacin 10–15 mg/kg by mouth every 12 h ∗ OR Doxycycline: >8 years and >45 kg 100 mg by mouth every 12 h >8 years and ≤45 kg 2.2 mg/kg by mouth every 12 h ≤8 years: 2.2 mg/kg by mouth every 12 h
Cutaneous anthrax	Ciprofloxacin 500 mg by mouth twice a day OR Doxycycline 100 mg by mouth twice a day	Ciprofloxacin 10–15 mg/kg by mouth every 12 h ∗ OR Doxycycline: >8 years and >45 kg: 100 mg by mouth every 12 h >8 years and ≤45 kg: 2.2 mg/kg by mouth every 12 h ≤8 years: 2.2 mg/kg by mouth every 12 h
Inhalational anthrax	Ciprofloxacin 400 mg intravenously every 12 h OR Doxycycline 100 mg intravenously every 12 h PLUS (for either drug) One or two additional antibiotics (e.g., rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin)	Ciprofloxacin 10–15 mg/kg intravenously every 12 h ∗ OR Doxycycline: >8 years and >45 kg: 100 mg intravenously every 12 h >8 years and ≤45 kg: 2.2 mg/kg intravenously every 12 h ≤8 years: 2.2 mg/kg intravenously every 12 h PLUS (for either drug) One or two additional antibiotics

∗ Ciprofloxacin dose in children not to exceed 1 g/day.

Despite aggressive supportive therapy and antibiotics, fatality is very high. In the 20th-century series of 18 patients in the United States, the mortality rate of occupationally acquired inhalational anthrax was 89%, but the majority of these cases occurred before the development of critical care units and antibiotics.

Prevention

Antitoxin therapies have been developed but are still experimental. There is one anthrax vaccine (BioThrax, Anthrax Vaccine Adsorbed, Emergent BioDefense Operations Lansing LLC) licensed for use in the United States by the Food and Drug Administration. It protects about 90% vaccinated prior to exposure. Should an attack occur, those exposed must be vaccinated and receive chemoprophylaxis with either oral ciprofloxacin or doxycycline.

Botulism

Botulism is a serious paralytic illness caused by a nerve toxin produced by the bacterium Clostridium botulinum . Three forms of naturally occurring botulism exist: foodborne, wound, and intestinal. The oldest and the most common form observed on a worldwide basis is foodborne, which typically occurs after ingestion of improperly prepared home-canned food that contains preformed neurotoxin. It poses a major bioweapons threat because of its extreme potency and lethality, its ease of production, transportation, and misuse, and the need for prolonged intensive care among affected persons.

Microbiology

C. botulinum is a rod-shaped, spore-forming, obligate anaerobe commonly found in soil. There are seven types of toxin designated A through G, which are defined by their absence of cross-neutralization (i.e., anti-A antitoxin does not neutralize toxin types B–G). Types A, B, and E account for greater than 99% of human botulism. Type A toxin is the most potent poison known to humans, 100,000 times more toxic than sarin nerve gas. Once absorbed, the toxin is carried via the blood to peripheral cholinergic synapses. It irreversibly binds to the presynaptic neuromuscular junction, where it is internalized and blocks acetylcholine release, causing paralysis.

Clinical Manifestations

During an attack, botulinum toxin would likely be used as an inhalational agent or to contaminate food deliberately because it does not penetrate intact skin and is not transmitted from person to person. Symptoms generally begin 12–72 hours after ingestion. The time of onset after an inhalational exposure is not known but experimentally is similar to foodborne exposure. Botulism classically presents as an acute, afebrile, symmetric, descending flaccid paralysis that always begins in the bulbar musculature ( Box 97.2 ). ^, Patients have a clear sensorium because the toxin does not penetrate the brain tissue. The prominent bulbar palsies (the 4Ds) include diplopia, dysarthria, dysphonia, and dysphagia. If the origin is foodborne, the neurologic signs may be preceded by abdominal cramps, nausea, vomiting, or diarrhea. Sensory changes are not present. As the disease progresses, weakness extends below the neck with loss of deep tendon reflexes, constipation, and unsteady gait. Severe cases lead to respiratory collapse from diaphragm and intercostal muscle involvement and airway obstruction from pharyngeal muscle paralysis. Autonomic nervous system involvement can lead to cardiovascular lability.

BOX 97.2

Signs and Symptoms of Foodborne and Wound Botulism

Adapted from Caya JG. Clostridium botulinum and the ophthalmologist: a review of botulism, including biological warfare ramifications of botulinum toxin. Surv Ophthalmol 2001; 46 :25–34.

Signs

Ventilatory (respiratory) problems
Extraocular muscle paresis or paralysis (including eyelids)
Muscle paresis or paralysis
Dry mucous membranes in mouth, throat
Dilated, fixed pupils
Ataxia
Somnolence
Hypotension (including postural)
Nystagmus
Decreased to absent deep tendon reflexes
Fever (more common for wound botulism)
Sensory deficits (very rare)

Symptoms

Visual disturbances (blurred vision, diplopia, photophobia)
Dysphagia
Dry mouth
Generalized weakness (usually bilateral)
Nausea or vomiting
Dizziness or vertigo
Abdominal pain, cramps, discomfort
Diarrhea
Urinary retention or incontinence
Sore throat
Constipation
Paresthesias

Ophthalmic manifestations

Visual symptoms of diplopia, photophobia, and blurred vision are present early ( Table 97.3 ). Accommodative paresis and mydriasis account for the blurred vision and photophobia, respectively. Blepharoptosis, gaze paralysis, pupillary dilation, and nystagmus are common ophthalmic signs. Dry eye and dry mouth from parasympathetic cholinergic blockade can also be prominent. Uncommon neuro-ophthalmic manifestations include complete bilateral internal ophthalmoplegia, which can include both permanent and transient tonic pupils. A dilated and poorly reactive pupil with loss of accommodation is a typical finding. Light-near dissociation, sectoral iris contractions, and supersensitivity of the iris sphincter muscle to weak miotics (pilocarpine 0.1%) are also hallmark findings of a tonic pupil.

TABLE 97.3

Ophthalmic Signs and Symptoms of Botulism

Adapted from Caya JG. Clostridium botulinum and the ophthalmologist: a review of botulism, including biological warfare ramifications of botulinum toxin. Surv Ophthalmol 2001; 46 :25–34.

Signs and Symptoms	Frequency (%)
Blurred vision	89
Ptosis	80
Diplopia	59
Abnormal pupil reaction to light	59
Impaired accommodation	59
Nystagmus	56
Mydriasis	52
Extraocular muscle dysfunction on examination	36

Diagnosis

Early diagnosis of botulism is made considering the history and a physical examination. The differential diagnosis includes Guillain-Barré and the Miller Fisher variant, myasthenia gravis, Lambert-Eaton syndrome, tick paralysis, stroke, and various central nervous system disorders. ^, Botulism differs from other causes of flaccid paralyses in that there is the presence of symmetry, absence of sensory nerve damage, and disproportionate involvement of cranial nerves compared with muscles below the neck. An electromyogram can be diagnostic. Demonstration of toxin by mouse bioassay is diagnostic in samples of serum, stool, gastric aspirate, and suspect food. Studies suggest that aerosolized toxin is usually not identifiable in serum or stool but may be present on nasal mucous membranes and detected by ELISA for up to 24 hours after exposure. Fecal, wound, and gastric specimens can be cultured anaerobically if a foodborne or wound source of C. botulinum is suspected.

Treatment

Management is primarily supportive, with ventilatory assistance essential in advanced cases. Early administration with equine-derived trivalent (types A, B, and E) antitoxin can minimize subsequent nerve damage and severity of disease but will not reverse existing paralysis, which can last from weeks to months. In a large outbreak of botulism, the need for mechanical ventilators, critical care beds, and skilled personnel might quickly exceed capacity. Research directed at recombinant vaccines and human antibody may eventually minimize the threat of botulinum toxin as a weapon of mass destruction.

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