A 21-year-old male college student goes on a spelunking expedition with his roommate and several other friends. While exploring a cave in southern New Mexico, the man is bitten on his left index finger by a bat who apparently resented the invasion of his home by humans. The man is urged by his friends to seek medical treatment for the bite, but he refuses to do so. About three months later, the man happens to sustain a puncture wound (from a dirty piece of glass) on his left hand. After a few days, he develops fever, which is accompanied by occasional headaches, malaise, fatigue, nausea, and an itching sensation on his left hand. He also experiences weakness in that hand and goes to the ER for help. When asked about injuries to his hand, the man mentions the recent puncture wound, but does not recall the earlier bat bite. As a result, he is treated with an antibiotic and given a tetanus shot.

Several days after his visit to the ER, the man starts to experience episodes of rigidity, hallucinations, breath holding, and difficulty in swallowing. His roommate brings him back to the ER, where his previous visit is noted and a preliminary diagnosis of tetanus or encephalitis is made. The man is intubated because he has uncontrollable oral secretions. Because of the seriousness of the situation, the physicians question his roommate the next day (when he returns to visit his friend) and finally hear about the caving incident and the bat bite.

Question 3.1: What is your diagnosis?

When viewed in the context of the earlier symptoms and the history of a bat bite, the man's neurological symptoms clearly point to a symptomatic case of rabies. The timing of the progression of symptoms also fits this diagnosis.

Question 3.2: What is the differential?

The differential diagnosis for rabies includes delirium tremens, tetanus, hysteria, psychiatric disorders, other forms of viral encephalitis, Guillain-Barré syndrome, and poliomyelitis.

Question 3.3: What tests can you do?

You could have the laboratory test serum, CSF, and skin samples for the presence of rabies antigens. The skin biopsy is usually taken from the hair-covered portion of the neck.

Test Results and Continued History:

In this case, all of the tests were negative for rabies antigens. However, the man's condition continued to deteriorate, despite supportive therapy. He died four days later, after the severity of his symptoms increased, eventually leading to coma and respiratory failure. Postmortem samples of brain tissue were positive for rabies by the fluorescent antibody test. Negri bodies (cytoplasmic inclusions consisting of viral nucleocapsids) were visible in stained preparations of neurons.

Question 3.4: What is the pathogenic process?

The virus initially infects tissue near the site of entry (the bite) and probably remains in that area (exact location unknown) during much of the incubation period. The incubation period may last for up to 12 months or longer. The length of the incubation period depends on the size of the viral inoculum and the length of the neural path from the wound to the brain. (So, bites on the face or head tend to have the shortest incubation periods.) Eventually, the virus enters the peripheral nervous system and then quickly advances to the spinal ganglia, spinal cord, and brain. This migration is via passive movement within the axoplasm of peripheral nerves to the CNS. From the brain, the virus often returns to the periphery at various locations, especially the salivary glands, which are highly innervated. Continued replication of the virus leads to cell death and damage to neural tissues, thereby causing the symptoms that are characteristic of the disease.

Question 3.5: How is this disease transmitted?

Rabies is transmitted to humans during a bite by an infected animal. (The virus is present in the saliva of an infected host.) The rabies virus is known to infect dozens of mammalian species, including humans. The most important animal carriers vary from one location to another. In countries where domestic animals are vaccinated, most cases stem from exposure to wild animals. In the U.S., for example, skunks, raccoons, foxes, and bats are the most important hosts. Believe it or not, the mongoose is the primary carrier in India and some other parts of Asia! Human-to-human transmission is also possible, either through corneal transplantation or through exposure to contaminated saliva (e.g., in airborne respiratory droplets). For this reason, prophylaxis is recommended for anyone who has been in close contact with a symptomatic rabies victim.

Question 3.6: What is the prevalence of this disease in the U.S.?

Symptomatic cases, which invariably lead to death, are rare in the U.S. Only 14 deaths were reported between 1990 and 1994. Approximately 20,000 people are vaccinated as a preventative measure each year in the U.S., but there is no way to know how many of these individually really were exposed to the virus. A zone of raccoon rabies centered in northern Virginia has expanded to cover much of the Northeastern U.S. over the past two decades. This development could lead to an increase in rabies cases among hunters and other who spend time outdoors in the woods.

Question 3.7: What if the man had sought treatment right after the bite?

His prognosis would have been excellent. Treatment probably would have included three steps: (1) local wound treatment (washing with antiviral substances), (2) passive administration of antibody (human rabies immune globulin; HRIG), and (3) vaccination. The current vaccine is based on tissue culture techniques and requires five IM injections in the deltoid area. Several vaccines have been produced over the years since Louis Pasteur developed the first successful one during the 1800s and used it to treat a young boy named Joseph Meister.

Historical Perspective:

"The death of this child appearing to be inevitable, I decided, not without lively and sore anxiety, as may well be believed, to try upon Joseph Meister, the method which I had found constantly successful with dogs. Consequently, 60 hours after the bites, and in the presence of Drs. Vulpian and Grancher, young Meister was inoculated under a fold of skin with half a syringeful of the spinal cord of a rabbit, which had died of rabies. It had been preserved (for) fifteen days in a flask of dry air. In the following days, fresh inoculations were made. I thus made thirteen inoculations. On the last days, I inoculated Joseph Meister with the most virulent virus of rabies."

The boy survived and Pasteur knew that he had found a vaccine for rabies. Three months later, when he examined Meister again, Pasteur reported that the boy was in good health.

Pasteur was not held in high regard publicly. However, he continued his work and started to devise tests to prove that he was right. He was able to prove that:

* Air contained living organisms

* That these microbes can produce putrefaction

* That these microbes could be killed by the heating of the liquidthey were in

* That these microbes were not uniformly distributed in the air.

In April 1864, Pasteur explained his beliefs in front of a gathering of famous scientists at the University of Paris. He proved his case beyond doubt even if some of those present refused to believe him including Dr. Charlton Bastian who maintained his belief that putrefaction was a result of spontaneous generation and not from the growth of micro-organisms.

Not all of Pasteur's ideas were readily adopted. He recommended that surgical instruments be boiled before an operation to sterilize them, but surgeons generally ignored this advice. Aseptic surgery was developed primarily in the 20th century.