Main [  Home  |  Novels  |  Bio  |  Photo Gallery  |  FAQ  |  Workshop  |  Author Notes  |  Science  |  Links  ]
FAQ [  Writing  |  Queries  |  Agents  |  Publishers  |  Editors  |  Contracts  |  Authors  |  Books  ]

[  Medical Terms  ][  Return to Notes on Disease  ]

Copyright 2003 Tara K. Harper.  All rights reserved.

TKH Virology Notes:
Rabies -- updated!

•  Description      •  Mechanism      •  Outbreaks
•  Location      •  Incubation Period      •  Vaccine
•  Vector      •  Symptoms      •  Odds 'n' Ends
     •  Diagnosis - updated!      •  Links
     •  Mortality Rates
     •  Treatment

Science and Literary  Links for Writers
Science and Technical  References for Writers


NOTE:  This file is for information only.  It is not intended for diagnosis.


Rabies
     Also known as:  
          •  hydrophobia

          •  lyssa (Old-World term)

Description.   An acute, central nervous system infection, characterized by CNS irritation, followed by paralysis and death.  Rabies, a member of the Rhabdovirus family,  is caused by the virus Neurotropic lyssavirus.  It is a single-stranded, neurotropic, negative-sense RNA virus which encodes 5 proteins:  a glycoprotein, a nucleoprotein, and three others.  The mature virus has a bullet shape, a protein coat, and a lipid envelope.  The outer surface of the virus is covered with thumblike glycoprotein projections 5-10 nm long and 3 nm in diameter.  The virus averages approximately 780 nm in length.

The virus is found in the salivary glands and CNS of infected, warm-blooded animals (including humans).  Worldwide, where approximately 50,000 people die each year from rabies, the highest risk of human infection is from rabid dogs.  In the U.S., where domestic dogs are usually vaccinated, only occasional cases of human rabies usually occur, usually from the bites of wild animals.

The word rabies comes from the Sanskrit rabhas, which means, "to do violence."  Rabies is thought to be the oldest communicable disease of humans.

Next topic  ][  Top of file  ]


Location.   Worldwide.

Next topic  ][  Top of file  ]


Vector.   There are three vectors for rabies:
  1. Usually the bite or scratch of an infected animal, which introduces the virus through the skin or mucous membrane.  Bites (vs. nonbite exposure) cause approximately 99% of rabies cases worldwide.  Wild animals account for 70% of rabies cases in the U.S..  World-wide, rabid dogs cause most cases of the disease.  Rodent rabies is rare.
2. Aerosol transmission from an infected animal, usually a bat.
3. Tissue transplants (such as corneas) from infected humans.  There have been at least 6 recorded cases of humans contracting the disease from transplants of corneas from infected donors.

The chances of contracting the disease:
     •  60% if the bite is on the face.
     •  15% to 40% if the bite is on the upper extremities.
     •  10% if the bite is on the lower extremities.

Next topic  ][  Top of file  ]


Mechanism.   The rabies virus attacks nervous tissue and appears to replicate almost exclusively in neuronal cells.  Once introduced through the skin or mucous membrane, the virus begins replicating in the striated muscles at the wound site.  The virus can replicate in muscle cells for hours or weeks, or it can migrate immediately to the nervous system via unmyelinated sensory nerve endings at the inoculation site.

Migration to the nervous system is via the nearest sensory or motor neuron in the ganglion at the base of the spinal cord or to the spinal cord itself.  Once there, the virus continues to replicate.   (It can then be transported back to the wound site or up to the brain via the central nervous system.)  Axonal transport to the CNS is at a rate of 3 mm per hour.  It is possible however, that the virus also moves across cell-to-cell junctions, and not just among nerve trunks.

In the brain, the virus infects neurons in almost all brain regions, where it continues replication.  Neuronal virus transmission from the periphery of the body to the brain is called "centripetal virus spread."   Possible receptors for the virus are:  acetylcholine receptors, gangliosides, and phospholipids.

In aerosol transmission, the virus enters the body through the nasal epithelium and is subsequently transported to the olfactory bulb.  It is thought that the virus replicates in the neurons of the olfactory bulb before spreading to other neurons in the brain.

After the rabies virus infects the brain, it can continue to spread throughout the body via efferent neural pathways.  At this stage, the virus can be found in salivary glands, taste buds, nasal cavities, tears, skin, the adrenal glands, pancreas, kidney, heart muscle, brown fat, hair follicles, retina, and cornea. (The virus has never been detected in blood or blood cells.)

Additional notes:
 . Neurological research has suggested that death from rabies is not a result of structural damage caused by the virus, but rather a result of functional alteration of neurons.  The rabies RNA most likely competes with host RNA, impairing neural functions.  Neurologic damage is exacerbated by the production of certain cytokines, such as tumor necrosis factor-alpha.  In addition, the body's own immune response to rabies includes the production of nitric oxide, which may act as a toxin to the CNS.  .    .    .
One of the determining factors of rabies virulence is the glycoprotein (GP) which makes up the viral membrane.   In particular, the amino acid site at position 333 seems to be critical to pathogenicity.   Argine or lysine residues at this site seem to confer virulence.  Substituting different amino acids at this position resulted in viruses which were attenuated.  The attenuated viruses spread more slowly in the CNS and do not seem able to infect certain types of nerve fibers.  Reverting to the original amino acid (arginine) at the site restores neurovirulence.  .  .

Next topic  ][  Top of file  ]


Incubation Period:   Generally 20 days to 2 months.  However, the period can be as short as a few days or as long or longer than 6 years.  Anecdotal evidence in the past has suggested that the incubation period could be as long as 21 years.

The incubation period appears to be determined by several factors:
     •  site of the bite wound
     •  proximity to the CNS
     •  severity of the bite
     •  type of virus
     •  quantity of virus injected into the site
     •  age of the patient
     •  immune status of the host

Next topic  ][  Top of file  ]


Symptoms.  Initial symptoms include a general feeling of discomfort or uneasiness, nervousness, anxiety, insomnia, depression, and apathy;  pain at the site of infection, fever, chills, cough, sore throat, headache, nausea and vomiting.  Patients usually present with serious neurologic symptoms within 2 to 10 days after onset of the initial symptoms.

Rabies manifests in two forms:  furious rabies and paralytic (or dumb) rabies.  
 .  Furious rabies is characterized by agitation, thrashing, biting, viciousness, choking, gagging, hyperventilation, cardiac arrhythmias, paralysis and death.  .  .  .
Paralytic or dumb rabies is characterized more by paralytic symptoms, which may include apathy, apparent depression, increased blood pressure, tachycardia, confusion, hallucinations, and disorientation.  These symptoms are followed by increased periods of hyperactivity, stiffness in the back of the neck, and an increase in the number of cells in the cerebrospinal fluid. Dumb or paralytic rabies ends with coma and death by respiratory failure.  Paralytic rabies is most often experienced by patients who have been exposed to the virus via bats.  .  .

Approximately 20% of rabies cases present (usually after aerosol exposure to the virus from bats) with severe progressive encephalitis or ascending paralysis with encephalitis.  One of the differences between encephalitis and rabies is that the rabies patient is conscious during the course of the disease.  

Rabies develops with three main phases:  prodromal period, acute neurological period, and coma.  The onset of symptoms follows these general stages:
 . 1. Prodromal stage.  Prodromal or premontive symptoms are mild and nonspecific.  They include:  a slight fever (100 F to 102 F), chills, malaise, headache, anorexia, nausea, sore throat (the beginnings of hydrophobia), photophobia, musculoskeletal pain, and a persistent loose cough.  This stage usually lasts 2-10 days.  A specific early symptom is local or radiating pain, burning, or itching, a sensation of cold, and/or tingling at the inoculation bite  .  .
2. Acute neurological or excitation phase.  This stage usually lasts 2 to 7 days.   Patients experience nervousness, anxiety, agitation, marked restlessness, apprehension, irritability, hyperesthesia, sensitivity to loud noises, hydrophobia, excessive salivation (1 to 1.5 liters in 24 hours), lacrimation (secretion of tears), and perspiration.  As the virus begins replicating in the brain, impairment of the cranial nerve occurs.  This causes eye conditions:  palsies, lack of parallelism of the visual axes of the eyes, asymmetrical dilation of constriction of the pupils, and an absence of corneal reflexes.  At the same time, there is weakness of facial muscles and hoarseness.  Systemic symptoms are severe, and they include:  tachycardia or bradycardia, cyclic respirations, urinary retention, and a temperature of 103 F.  The patient is often lucid between excitation and hydrophobic episodes.  .  .
3. Coma, or terminal phase.  This phase is characterized by generalized flaccid paralysis.  Eventually, the patient experiences peripheral vascular collapse, coma, and death.  .

Hydrophobia is experienced by 17% to 80% of rabies patients.  In this stage there are forceful, painful muscle spasms of the throat, which expel any liquids administered orally.  It is suspected that this is an exaggerated protective reflex of the respiratory tract.  The patient experiences apnea (interruption or halt of breathing while swallowing).  Cyanosis and death can occur in this phase.  In addition, the patient's difficulty in swallowing results in a frothy saliva which drools from the patient's mouth because of growing muscular weakness.  Eventually, a variety of stimuli (the mention of water, a tactile sense or scent of water, the thought of water, etc.) can cause uncontrollable spasms and drool.  Hydrophobic episodes last 1-5 minutes.

Next topic  ][  Top of file  ]


Diagnosis.   Diagnosis by bite and symptom history is not necessarily accurate, because such history cannot be established in 22% to 40% of the cases.  Diagnosis is confirmed by isolation of the virus from the patient's saliva, throat, corneal impression, facial skin, or skin from the hair-covered occipital part of the neck.  Electron micrographs can confirm Negri bodies (oval or round eosinophilic masses) in the brain, usually in the cornu Ammonis.  However, Negri bodies, which consist almost entirely of viral nucleocapsid, cannot be found in approximately 30% of human rabies cases.

Lab results may indicate:
     •  Elevated white blood count
     •  Increased number of polymorphonuclear cells
     •  Increased number of monoculear cells
     •  Elevated levels of urinary glucose, acetone, and protein.
     •  Abnormal number of cells in the cerebrospinal fluid

Diagnosis is also confirmed in skin biopsies and post-mortem tissue samples by the fluorescent antibody test or by the avidin-biotin technique.  Postmortem examinations will show that vessel engorgement occurred in the meninges and brain, resulting in inflammatory lesions or point hemorrhages.  In addition, lymphocytes may have collected in the tissues surrounding the blood or lymph vessels, but nerve cells will have shown little damage.

Next topic  ][  Top of file  ]


Mortality Rates.  Rabies is usually 100% fatal if untreated.  If symptoms have appeared, the victim usually dies in spite of subsequent immunization and treatment with rabies immunoglobulin.  There are only three documented cases of patients recovering from rabies infection.

Next topic  ][  Top of file  ]


Treatment.   Standard wound treatment and postexposure rabies immunization as soon as possible after exposure to rabies.  If the wound requires sutures, make sure the suturing techniques allow for adequate drainage.  For patients who have already demonstrated symptoms, aggressive supportive care can make the dying process less agonizing, even after coma sets in.

If the person who has been bitten has not had the HDCV shot before, he should receive multiple shots of the passive immunization with rabies immune globulin (RIG), either human or equine type;  followed by the active, HDCV shot.  The adsorbed rabies vaccine (RVA) can be given in place of the HDCV shot.  The shots should be given at different sites.  The combination of passive, followed by active immunization provides the best postexposure prophylactic treatment.

If the person who has been bitten has previously received the HDCV shot and has an adequate rabies antibody titer, he should be given only an HDCV booster shot.  

Specific recommendations of vaccines and doses are provided through the World Health Organization (WHO).

Next topic  ][  Top of file  ]


Outbreaks and History of Infection.   Uncontrolled outbreaks of rabies occur in both Asia and Africa.  Worldwide, rabies kills approximately 50,000 people every year.  Approximately 98% of all human rabies deaths occur in developing countries.  In the U.S., on average, 1-2 cases of human rabies are reported annually, but over 8000 cases of animal rabies can be reported in a single year.  One exception was 1994, in which 6 cases of human rabies occurred:  all 6 patients died;  4 of the cases were contracted from bats, 1 from a dog, 1 from a coyote.

Next topic  ][  Top of file  ]


Vaccine.  A live human diploid cell vaccine (HDCV) is available, but it is expensive, and is usually given only to veterinarians and other at-risk populations, such as animal researchers, cavers, and lab workers.  It is more effective and has fewer adverse reactions than other rabies vaccines.  An adsorbed (RVA) rabies is also available, but should not be administered intradermally.

Recent research has shown that DNA vaccines work well against rabies.  The vaccine DNA encodes a glycoprotein found on the rabies virus, is stable, and does not become denatured by heat.  Such a DNA vaccine could cost as little as 5 -10 cents per shot.  If so, this could provide an inexpensive method of prophylactically vaccinating poorer populations in developing countries.

Vaccination does not eliminate the need for postexposure treatment.  Vaccination merely gives greater protection from the virus and reduces the treatment required after exposure.

Next topic  ][  Top of file  ]


Odds 'n' Ends.  
  The earliest known text which specifically describes rabies is from the pre-Mosaic Eshmuna Code of Babylon, 23rd century B.C..  The first record of the true nature of rabies was written in 1584 by an Italian, Girolamo Fracastoro. 
Because of  fear of rabies, suspected victims have been shot, poisoned, suffocated, or otherwise killed or condemned to die.  In France in 1810, a law was finally passed to deal with this problem:  "It is forbidden under pain of death to strangle, suffocate, bleed to death or in any other way to murder individuals suffering from rabies, hydrophobia or any disease causing fits, convulsions, furious and dangerous madness."
Each year in the U.S., over 7,000 animals, both domestic and wild, are diagnosed with rabies.
Chloroquine, a prophylactic treatment for malaria, is apparently iatrogenic for rabies.  In other words, prophylactic treatment with chloroquine for malaria, while protecting against malaria, reduces the body's ability to create antibodies for rabies and other diseases.  For example, three months after vaccination against rabies, chloroquine users have approximately half the antibody response to rabies that non-chloroquine users have.  Patients who have been vaccinated against rabies can die from rabies if they are also chloroquine users.
Rabies viruses collected from different animal species and from different parts of the world are distinct.

Next topic  ][  Top of file  ]


Links:
     •  coming soon!


Copyright 2004 Tara K. Harper

All rights reserved.  It is illegal to reproduce or transmit in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, any part of this copyrighted file without permission in writing from Tara K. Harper.  Permission to download this file for personal use only is hereby granted by Tara K. Harper.


Main [  Home  |  Novels  |  Bio  |  Photo Gallery  |  FAQ  |  Workshop  |  Author Notes  |  Science  |  Links  ]
FAQ [  Writing  |  Queries  |  Agents  |  Publishers  |  Editors  |  Contracts  |  Authors  |  Books  ]

_______________

[ Top of  File ]