History

Fact Explanation
Neuropathic pain, itching and paresthesia at the site of wound or injection. Due to viral replication in non neural tissue following inoculation and local inflammation [1]
Irritability and agitation Due to encephalitis [1]
Vomiting, diarrhoea During the initial prodromal period
Cranial nerve involvement - facial asymmetry, trismus, drooping lower jaw etc Due to neuritis/ encephalitis involving cranial nerve nucleus
Diaphoresis Due to autonomic system excitation
Excessive salivation Autonomic neuritis, with anterograde flow of the virus it enters the no neural tissues such as the salivary gland, adrenal etc. [2]
Fear of swallowing/ hydrophobia (laryngeal muscle spasm and inspiratory muscle spasm pathognomonic but can also have spasm of all mucle which can progress to a convulsion or cardio respiratory arrest. Hyper excitability of nerve endings is the key feature seen in furious rabies. stimuli such as water excites the nerve endings of laryngeal muscles and other muscles causing sudden spasm of these muscles. Because of the association with the stimuli they get phobia for swallowing. [1]
Aerophobia Hydrophobia can progress to occur for subtle stimuli leading to aerophobia. They progress to death within days to weeks.[1]
flaccid paralysis usually starting from the bitten limb and ascends[3] This is the other type of presentation - paralytic/dumb rabies. 20 -30% present this way [3]. Due to prominent myelitis. Usually seen after bat bites or following post exposure prophylaxis.[1]
Sphincter disturbance Flaccid paralysis progress to involve the sphincter muscles[1]
Difficulty breathing and swallowing Flaccid paralysis progress to involve respiratory muscles and deglutition muscles. Death follows [1]
Cardiac arrhythmias, hypotension. Most likely due to the neuritis of the autonomic nerves which gets involved in anterograde transmission of the virus after multiplying in the CNS [2]
Death Established disease is invariably fatal. Only few (4) case reports of survival.[1] But they were left with neurological deficits[4]
References
  1. MCKAY N, WALLIS L. Rabies: A review of UK management. Emergency Medicine Journal [online]. 2005, 22(5), 316-321. [viewed 23 March 2014]. Available from: doi: 10.1136/emj.2003.013805
  2. SMITH J S. New aspects of rabies with emphasis on epidemiology, diagnosis and prevention of the disease in the United States. Clinical microbiology reviews. [online]. NCBI. April 1996, vol 9(2), 166- 176. [viewed 23 March 2014]. Available from: PMCID: PMC172889
  3. GHOSH J B, ROY M et al. Acute flaccid paralysis due to rabies. Journal of paediatric neurosciences. [online]. 2009, vol 4(1), 33-35. [viewed 23 March 2014]. Available from: doi: 10.4103/1817-1745.49106
  4. JACKSON C Alan, WARRELL J Marry et al. Management of Rabies in Humans. Clinical Infectious Diseases [Online]. Oxford University press. 2003, vol 36(1), 60 - 63. [viewed 23 March 2014]. Available from: 10.1086/344905.

Examination

Fact Explanation
Hyperaesthesia of the site wound Stimulation of the sensory ganglia of the bite site.
Hyperthermia Initial inflammation
Upper motor neuron lesions[1](spasticity, hyper reflexia, reduced muscle power) Occurs due to encephalitis, there is hyper excitability of the nerves causing spasms. In between the spasms tone remains normal.
Fluctuating Blood pressure [2] Due to encephalitis and autonomic neuritis.
flaccid paralysis (fasciculation, flaccid tone, absent reflexes, reduced muscle power) [3] Seen in paralytic/dumb rabies.
Cranial nerve lesions [1] Due to neuritis/ encephalitis involving cranial nerve nucleus.
References
  1. MCKAY N, WALLIS L. Rabies: A review of UK management. Emergency Medicine Journal [online]. 2005, 22(5), 316-321. [viewed 23 March 2014]. Available from: doi: 10.1136/emj.2003.013805
  2. SMITH J S. New aspects of rabies with emphasis on epidemiology, diagnosis and prevention of the disease in the United States. Clinical microbiology reviews. [online]. NCBI. April 1996, vol 9(2), 166- 176. [viewed 23 March 2014]. Available from: PMCID: PMC172889
  3. GHOSH J B, ROY M et al. Acute flaccid paralysis due to rabies. Journal of paediatric neurosciences. [online]. 2009, vol 4(1), 33-35. [viewed 23 March 2014]. Available from: doi: 10.4103/1817-1745.49106

Differential Diagnoses

Fact Explanation
Delirium tremens Patients with furious rabies have irritability , agiation and confudsion due to encephalitis form encephalopathy which can mimic delirium tremens. but history of an animal bite and no history of longstanding alcohol use suggest rabies.
Botulism It also have a progressing flaccid paralysis. But cranial nerve symptoms are more prominent and it is a descending paralysis[1]
Diphtheria Causes difficulty of swallowing and breathing. but this is due to the development of a thick pseudo membrane in the larynx and throat [2]
Drugs like phenothiazines, amphetamines Usage of stimulant drugs may mimic symptoms of rabies such as hyperesthesia, mood change etc.
Datura fastuosa poisoning Datura contains chemicals that can cause Para sympatholytic activities in the central nervous system to produce delirium.[3]
Tetanus Can also follow an animal bite. Hydrophobic tetanus (tetanus involving pharyngeal muscle) mimics rabies but have a short incubation period, sustained spasticity and the CSF findings are normal [4]
Guillain-Barre syndrome Mimics dumb rabies. [5]
References
  1. SOBEL Jeremy. Botulism. Clinical Infectious Disease [online]. Oxford University press. 2005, vol 41(8), 1167-1173 [viewed 21 March 2014]. Available from: doi:10.1086/444507
  2. Diphtheria: Centers for Disease Control and Prevention. 13 May 2013 [viewed 21 March 2014]. Available from: http://www.cdc.gov/diphtheria/about/symptoms.html
  3. BASU A, BASU S K. Datura: A deadly deliriant. Guyana Journal [online]. June 2012 [viewed 21 March 2014]
  4. WARRELL M J, WARRELL D A. Rhabdoviruses: rabies and rabies related viruses. In: WARRELL D A, COX M Timothy, FIRTH D John. Oxford Text Book of Medicine. Edition 4, Vol . United States. Oxford university press. 2005, 372
  5. GHOSH J B, ROY M et al. Acute flaccid paralysis due to rabies. Journal of paediatric neurosciences. [online]. 2009, vol 4(1), 33-35. [viewed 23 March 2014]. Available from: doi: 10.4103/1817-1745.49106

Investigations - for Diagnosis

Fact Explanation
WBC/DC- Peripheral neutrophil leukocytosis [1] It is seen in early stage of the disease. But non specific.
Brain biopsy from the offending animal Antigen detection by direct immunofluorescence or RNA by polymerase chain reaction(PCR). histopathology findings of the biopsy will show Negri bodies which are cytoplasmic inclusion bodies seen in infected nerve cells, Babes nodules consisting of glial cells and features of inflammation such as mononuclear infiltration, polymorph nuclear cells and lymphocytes surrounding perivascular space. [2]
Neck skin biopsy from patient - antigen detection by direct immunofluorescence or RNA by RT-PCR More sensitive than corneal biopsy. skin biopsy immunofluorescence sensitivity 0.86 [1]
Corneal scrapings Antigen/ RNA detection
Antibody detection in Serum/ CSF Not evident until late (usually seen after 8 days from the onset of symptoms - patient might die before that) [3]
Salivary RT-PCR Sensitivity is less than skin biopsy (0.30) [1]
References
  1. MCKAY N, WALLIS L. Rabies: A review of UK management. Emergency Medicine Journal [online]. 2005, 22(5), 316-321. [viewed 23 March 2014]. Available from: doi: 10.1136/emj.2003.013805
  2. Rabies - Histologic Examination: Centers for Disease control and prevention. 22 April 2011 [viewed 27 March 2014]. Available from: http://www.cdc.gov/rabies/diagnosis/histologic.html
  3. SMITH J S. New aspects of rabies with emphasis on epidemiology, diagnosis and prevention of the disease in the United States. Clinical microbiology reviews. [online]. NCBI. April 1996, vol 9(2), 166- 176. [viewed 23 March 2014]. Available from: PMCID: PMC172889

Management - General Measures

Fact Explanation
Supportive care This is the mainstay of management after established disease.[1] Usually patients will require ICU care. The WHO recommends that medical and nursing staff must wear mask, gloves, and goggles.Since it is theoretically possible for human-to-human transmission to occur.
Sedation To control pain and spasms. Ketamine is appropriate for this purpose.( see specific management for details)
ventilation Needed when the respiratory muscles are paralyzed.
Nutritional support Spasm of muscles of deglutition and hydrophobia can cause difficulty in swallowing. So they will need nutrition by other means nasogastric feeding/ total parenteral nutrition.
References
  1. MCKAY N, WALLIS L. Rabies: A review of UK management. Emergency Medicine Journal [online]. 2005, 22(5), 316-321. [viewed 23 March 2014]. Available from: doi: 10.1136/emj.2003.013805

Management - Specific Treatments

Fact Explanation
Post exposure prophylaxis Post exposure prophylaxis has been shown to be the only effective way to prevent the disease once there is a bite. once disease is established it is almost always fatal. Only few survived the acute illness but mostly with neurological sequelae[1]
Cleaning the wound. Primary closure of a bite wound is controversial. In some experimental animals when proper wound care was given within 3 hours of exposure rabies transmission was prevented [2]. Though it had been practiced not to close a bite wound primarily due to the risk of infection, a recent study have shown no significant difference in the rate of infection among those who had and not had primary closure [3]
Risk assessment of the exposure depends on- circumstance of the bite (provoked or unprovoked), biting animals behavior, type of contact, extent of contact.[4] Risk determines the treatment which varies according to the countries/ institution's protocol.
Anti rabies vaccination 2 types of vaccines are available. Purified chick embryo cell vaccine and Vero cell tissue culture vaccine. Can be given via 2 routes, either intramuscular or intradermal. Intradermal in multiple sites is better than intramuscular because intramuscular takes at least one week to produce the immune response [1]. Survival from rabies encephalitis in animal is associated with immune response. So its also given in combination therapy after established disease[1]
Human rabies immunoglobulin (HRIG) HRIG neutralizes the virus by binding to it before it enters into the nervous system. since the immunoglobulins doesn't enter through the blood brain barrier [5] it has little impact when it is given once the disease is established.[1] Most of the dose should be infiltrated in to the wound and the rest given intradermally.
In established disease combination therapy is used - Anti rabies vaccine, HRIG, ribavirin, IFN-alpha, Ketamine Combination of multiple specific therapies is better than single therapy.[4]
Ribavirin It has anti viral and immune modulatory effects.[6] Though anti viral activity is shown in vitro[7] it has not proven in vivo in animal models.[8]
Interferon alpha Immune regulatory protein. generates an intra cellular environment which is not suitable for viral replication. High dose treatment IV and intrathecally at the early stage of disease showed no benefit [9]
Ketamine It is a noncompetitive antagonist of the N-methyl-aspartate (NMDA) receptor. It ha sedative and analgesic properties. [1]. It is considered a therapeutic agent as well because in rats it has shown to reduce infection in multiple brain regions.[1].
Corticosteroids Not considered an option to reduce edema in encephalitis because has proven to increase mortality in mouse models. [1]
Prevention - pre exposure anti rabies vaccination It does not give full protection against rabies but since the immunity is developed it gives the patient time to seek medical care. It is given to those at risk due to their occupation (veterinarians, rabies laboratory staff) and to those who travel to rabies endemic areas for long periods.[4]
References
  1. JACKSON C Alan, WARRELL J Marry et al. Management of Rabies in Humans. Clinical Infectious Diseases [Online]. Oxford University press. 2003, vol 36(1), 60 - 63. [viewed 23 March 2014]. Available from: 10.1086/344905.
  2. DEAN D J, BAER G M, THOMPSON W R. Studies on the local treatment of rabies infected wounds. Bull world Health Organ [online]. NCBI 1963, vol 28(4), 477 - 486. [viewed 23 March 2014]. Available from: PMCID: PMC2554747
  3. PASCHOS N K, MAKRIS E A, et al. Primary closure versus non- closure of dog bite wounds, a randomized controlled trials. Injury [online]. NCBI. January 2014, vol 45(1), 237- 240. [viewed 26 March 2014]. Available from: doi: 10.1016/j.injury.2013.07.010. Epub 2013 Aug 2.
  4. MCKAY N, WALLIS L. Rabies: A review of UK management. Emergency Medicine Journal [online]. 2005, 22(5), 316-321. [viewed 23 March 2014]. Available from: doi: 10.1136/emj.2003.013805
  5. MILLER D W. Immunobiology of the blood brain barrier. Journal of Neurovirology [online]. Vol 5(6), 570-578 [viewed 23 March 2014]. Available from: doi: 10.3109/13550289909021286.
  6. TAM R C, LAU J Y, HONG Z. Mechanisms of action of Ribavirin in Antiviral therapies. Antivir chem chemother [online]. NCBI. 2001 September, vol 2(5), 261-272. [viewed 23 March 2014]
  7. BUSSEREAU F, CHERMANN J C, et al. Search for compounds which have an inhibitory effect on Rhabdovirus mulitiplication invitro. Annales de I'Institute Pasteur/ Virologie. [online]. Elsevier. 1983,vol134(1), 127-134. [viewed 23 March 2014]
  8. BUSSEREAU F, PICARD M, et al. Treatment of Rabies in Mice and foxes with antiviral compounds. Acta virol 1988 Jan, 32(1), 33-49. [viewed 23 March 2014]
  9. WARRELL M J, WHITE N J, et al. Failure of interferon alpha and tribavirin in rabies encephalitis. British Medical Journal [online]. 30 September 1989, 299. [viewed 23 March 2014] Available from: doi: 10.1136/bmj.299.6703.830