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Summary Table

Category	Detail
Risk Factors	Exposure to rabies-transmitting animals (dogs account for 99% of human deaths globally); living in or traveling to endemic areas (26 of 38 Indonesian provinces are endemic); children under 15 years (40% of bite victims); occupational exposure (veterinarians, animal handlers, lab technicians)
Etiology	Lyssavirus, family Rhabdoviridae; single-stranded RNA virus; neurotropic, bullet-shaped (130-300 nm length, 70 nm diameter); lipid envelope with glycoprotein G spikes
Patient Presentation	History of animal bite/scratch/lick on broken skin weeks to months prior; prodromal fever and paresthesia at wound site; progressive encephalitis with hydrophobia, aerophobia, photophobia; or ascending paralysis
Classic Physical Exam	Agitation, hyperactivity, hypersalivation, spasms triggered by attempts to drink water (hydrophobia) or air drafts (aerophobia); autonomic instability; alternatively, ascending flaccid paralysis beginning at the bite site
Key Diagnostic Results	Clinical diagnosis in most cases; confirmatory: Fluorescent Antibody Test (FAT) or PCR on saliva, skin biopsy (nuchal), CSF, or corneal impression; Negri bodies on histology (pathognomonic but not always present); virus cannot be detected by routine blood tests
Management	Post-exposure prophylaxis (PEP): immediate wound washing with soap and water for 15 minutes, antiseptic application (povidone-iodine, 70% alcohol), Rabies Vaccine (VAR) per WHO schedule, and Rabies Immunoglobulin (SAR/RIG) for Category III or high-risk wounds; once clinical rabies develops, the disease is nearly 100% fatal and treatment is supportive only
Keywords	Hydrophobia, aerophobia, Negri bodies, furious rabies, paralytic (dumb) rabies, post-exposure prophylaxis, wound washing 15 minutes, neurotropic virus, zoonosis, fatal encephalitis

1. Pathophysiology

Rabies virus enters the body through a bite, scratch, or contact of infected saliva with mucous membranes or non-intact skin. The virus cannot penetrate intact skin. After inoculation, the virus replicates locally in muscle tissue near the wound for approximately 2 weeks before entering peripheral nerves.

The virus then travels via retrograde axonal transport along peripheral nerves toward the central nervous system. This journey occurs without any detectable viremia, which is why routine blood tests cannot detect the virus and why there is currently no technology for early diagnosis before clinical symptoms appear. The absence of hematogenous spread is a critical exam concept: unlike most viral infections, rabies evades the immune system by hiding inside neurons.

Once the virus reaches the brain, it undergoes rapid replication and spreads widely throughout the CNS, preferentially targeting limbic system neurons, the hypothalamus, and the brainstem. Infection of the limbic system explains the behavioral changes, agitation, and emotional lability. Involvement of the brainstem explains the characteristic pharyngeal and respiratory muscle spasms that produce hydrophobia (spasm triggered by swallowing attempts) and aerophobia (spasm triggered by air drafts).

After replicating in the brain, the virus then travels centrifugally (away from the CNS) via efferent nerves, both voluntary and autonomic, to reach virtually every organ including the salivary glands (enabling transmission), cornea, kidneys, and skin. The presence of virus in salivary glands is what makes animal bites infectious.

The incubation period ranges from 2 weeks to 2 years, with a typical duration of 3 to 8 weeks. Factors influencing incubation length include the viral strain and inoculum size, depth and location of the wound (bites closer to the brain, such as the face or neck, shorten incubation), nerve density at the wound site, and the patient's immune status.

Death results from respiratory center dysfunction in the brainstem, respiratory muscle paralysis, or cardiac arrhythmia leading to cardiorespiratory failure. Once clinical symptoms appear, the case fatality rate is effectively 100%.

2. Classification and Clinical Manifestation

Stage	Duration	Features
Incubation	2 weeks to 2 years (typically 3-8 weeks)	Asymptomatic; virus replicating locally and traveling along nerves
Prodrome	1-2 days	Non-specific: fever, malaise, paresthesia/pain/burning at the healed bite site (pathognomonic prodromal clue)
Acute Neurologic Phase	See subtypes below	Either furious or paralytic form
Coma and Death	Days after neurologic onset	Cardiorespiratory failure

Two Clinical Subtypes of Acute Neurologic Rabies

Feature	Furious Rabies	Paralytic Rabies
Frequency	~80% of cases	~20% of cases
Hallmark	Hyperactivity, agitation, aggression	Ascending flaccid paralysis
Hydrophobia	Present (classic)	Usually absent
Aerophobia	Present	Usually absent
Photophobia	Present	Usually absent
Motor findings	Intermittent spasms, hyperexcitability	Weakness starting at bite site, ascending; fasciculations
Duration	1-4 days before coma	Longer course, often misdiagnosed
Common mimic	Psychiatric illness, tetanus, drug intoxication	Guillain-Barre syndrome
Cause of death	Sudden cardiorespiratory arrest	Respiratory muscle paralysis

Clinical Stages in Dogs

Stage	Duration	Features
Prodromal	2-3 days	Behavioral change: does not recognize owner, avoids commands, easily startled, pupil dilation, decreased corneal reflex, fever
Excitative	3-7 days	Photophobia (hides under furniture), hallucinated snapping ("fly-biting"), pica (chews rocks, wire, sticks), progressive aggression, attacks all moving objects, laryngeal/pharyngeal paralysis causing voice change and hypersalivation with foamy/bloody drool
Paralytic	Very brief	Jaw drop (masseter paralysis), choking sounds, hind limb paralysis with dragging gait, death

Dogs may present as the "furious" type (dominated by the excitative phase) or the "dumb/quiet" type (prodrome progresses directly to paralysis without obvious aggression). The dumb type is diagnostically treacherous because the animal does not display the classic aggressive behavior people associate with rabies.

3. Diagnostic Workup

Test	Specimen	What It Detects	Role
Fluorescent Antibody Test (FAT)	Brain tissue (post-mortem in animals); skin biopsy of nuchal area, corneal impression (ante-mortem in humans)	Viral antigen	Gold standard for animal diagnosis; rapid, highly sensitive and reliable
RT-PCR	Saliva, CSF, skin biopsy, brain tissue	Viral RNA (nucleic acid)	Most sensitive ante-mortem test in humans; confirmatory
Sellers staining	Brain tissue	Negri bodies (eosinophilic intracytoplasmic inclusions)	Classic histologic finding; pathognomonic but sensitivity is only ~70-80%
Virus isolation	Saliva, brain tissue, CSF	Live virus	Research and reference labs; slow
Serology (antibody detection)	Serum, CSF	Anti-rabies antibodies	Limited utility; antibodies appear late and often the patient dies within 3-5 days of symptom onset before seroconversion; useful mainly in vaccinated individuals

There is no reliable ante-mortem diagnostic test that can confirm rabies before symptoms appear. This is the single most important diagnostic concept for the exam. The virus travels inside neurons, not in blood, so standard blood work is unremarkable.

The best initial diagnostic approach in a living patient with suspected clinical rabies is RT-PCR on saliva combined with direct fluorescent antibody (DFA) testing on a nuchal skin biopsy (the nape of the neck is chosen because of its high density of nerve endings innervating hair follicles). Multiple specimens should be collected because viral shedding is intermittent.

The gold standard for definitive confirmation remains FAT on brain tissue, but this is obviously a post-mortem test in humans. In animals, FAT on brain tissue is the standard.

For the animal that inflicted the bite, the Kemenkes guideline specifies a 14-day observation period by veterinary authorities. If the animal remains healthy for 14 days, it was not shedding rabies virus at the time of the bite, and vaccination can be discontinued. If the animal dies, develops symptoms, or the brain specimen tests positive, the full vaccine course must be completed.

Key exam point: rabies diagnosis is primarily clinical in endemic settings. The combination of a bite history plus hydrophobia or aerophobia in a patient from an endemic area is essentially diagnostic. Do not delay post-exposure prophylaxis while waiting for laboratory confirmation.

4. Management and Treatment

WHO Category	Type of Exposure	Wound Care	VAR	SAR (RIG)
Category I	Touching or feeding the animal; licking on intact skin	Wash with soap and running water for 15 minutes	Not indicated	Not indicated
Category II	Minor scratches or abrasions without bleeding; nibbling on uncovered skin	Wash with soap and running water for 15 minutes + antiseptic	Yes (may be deferred if animal is owned, healthy, vaccinated, observable for 14 days)	Not indicated
Category III	Single or multiple transdermal bites or scratches; contamination of mucous membrane or broken skin with saliva; direct bat exposure	Wash with soap and running water for 15 minutes + antiseptic	Yes (immediate, no deferral)	Yes, for high-risk and non-immune patients

Step 1: Immediate Wound Care (Most Critical First Step)

Wash the wound with soap and running water for 15 minutes as soon as possible after exposure. This alone can reduce rabies risk by up to 90% when combined with PEP. The rationale is that the rabies virus has a lipid envelope that is dissolved by soap (detergent action). Do not use instruments or scrub aggressively, as this may deepen the wound and push virus further into tissue. After washing, apply antiseptic: povidone-iodine, 70% alcohol, or equivalent. This step can be performed by the patient or family at home before reaching a health facility.

Step 2: Assess Immune Status

Determine whether the patient is "immune" or "non-immune."

Status	Definition
Immune	Previously completed PrEP or PEP, or received at least 2 doses of VAR
Non-immune	No prior rabies vaccination history

Step 3: Rabies Vaccine (VAR) Administration

VAR is a cell-culture or purified vaccine (2.5 IU per vial). Two routes are available:

Route	Non-Immune PEP Schedule	Immune Booster Schedule	Notes
Intramuscular (IM)	2-0-1-0-1 (Day 0: 2 doses, Day 7: 1 dose, Day 21-28: 1 dose)	1-1-0-0-0 (Day 0: 1 dose, Day 3: 1 dose)	Inject at 90 degrees into deltoid (adults) or anterolateral thigh (children under 1 year); never inject into gluteal area
Intradermal (ID)	2-2-2-0-0 (Day 0: 2 sites, Day 3: 2 sites, Day 7: 2 sites)	1-1-0-0-0 or 4-0-0-0-0	Each ID injection is 0.1 mL; requires trained personnel; contraindicated if patient is taking chloroquine (use IM instead)

The notation "2-0-1-0-1" means: Day 0 = 2 vials, Day 3 = 0, Day 7 = 1 vial, Day 14 = 0, Day 21-28 = 1 vial.

Booster VAR is given only if the new exposure occurs more than 3 months after the last completed PrEP or PEP. If the new bite occurs within 3 months of completed vaccination, no additional VAR is needed.

Step 4: Rabies Immunoglobulin (SAR/RIG) for Category III or High-Risk Wounds

Type	Source	Dose	Administration
HRIG (Human Rabies Immunoglobulin)	Human serum	20 IU/kg body weight	Infiltrate as much as anatomically possible into and around the wound; inject any remainder IM at a site distant from the VAR injection site
ERIG (Equine Rabies Immunoglobulin)	Equine (horse) serum	40 IU/kg body weight	Same as HRIG; perform skin testing first due to serum sickness risk

SAR is given only once, on Day 0, simultaneously with the first dose of VAR but at a different anatomic site. Its purpose is to provide passive immunity during the first 7 days before the vaccine induces an active antibody response. SAR is never given to immune patients (those with prior vaccination history).

High-risk criteria for SAR administration (per Kemenkes guideline): multiple bite wounds, deep wounds, bites in highly innervated areas (head, neck, face, genitals, hands), severely immunocompromised patients, bites from animals confirmed or strongly suspected to be rabid (clinically or by laboratory), and any bat exposure.

Step 5: Animal Observation

Report the biting animal to veterinary authorities (Dinas Peternakan) for a 14-day observation or brain specimen testing. If the animal remains healthy for 14 days or the brain specimen is negative, VAR can be discontinued. If the animal develops rabies signs, dies, or the specimen is positive, complete the full VAR course.

Step 6: Additional Considerations

Immunosuppressed patients (on corticosteroids or immunosuppressive drugs) may have vaccine failure. Serologic testing for rabies antibodies is recommended in these patients. All contraindications to VAR are considered secondary when there is true rabies exposure, meaning there is no absolute contraindication to post-exposure rabies vaccination when exposure has occurred. Always prepare medications for anaphylaxis management when administering VAR or SAR.

Pre-Exposure Prophylaxis (PrEP)

Indicated for individuals at occupational risk: healthcare workers handling rabies cases, veterinarians, animal control officers, and laboratory workers.

Route	Schedule	Details
IM	1-0-1-0-0 (Day 0 and Day 7)	1 dose per visit; 2 visits total
ID	2-0-2-0-0 (Day 0 and Day 7)	0.1 mL at 2 sites (right and left deltoid); 2 visits total

For immunocompromised individuals receiving PrEP, an additional dose is given on Day 21-28 (schedule becomes IM 1-0-1-0-1), and the IM route is mandatory.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Tetanus	Both follow animal bites/wounds; both produce muscle spasms; both are fatal if untreated	Tetanus causes sustained tonic contraction (trismus, opisthotonus, risus sardonicus) with a clear sensorium; rabies causes intermittent phobic spasms (triggered by water/air) with progressive encephalopathy and behavioral changes. Tetanus has no hydrophobia.
Guillain-Barre Syndrome (GBS)	Paralytic rabies mimics GBS closely: ascending flaccid paralysis, areflexia	GBS has no bite history, no fever at onset, no paresthesia at a wound site, and CSF shows albuminocytologic dissociation (high protein, normal cells). Paralytic rabies has bite history, wound-site paresthesia, and CSF may show mild pleocytosis.
Viral encephalitis (HSV, Japanese encephalitis)	Altered mental status, seizures, fever, CSF pleocytosis	HSV encephalitis shows temporal lobe involvement on MRI; Japanese encephalitis has thalamic involvement. Rabies shows no focal brain lesion on imaging and has the pathognomonic bite history plus hydrophobia.
Psychiatric illness / Acute psychosis	Furious rabies can present with agitation, hallucinations, bizarre behavior	Psychiatric patients have no autonomic instability, no hydrophobia on examination (the pharyngeal spasm is involuntary and reproducible on exam), and no bite history. The combination of autonomic dysfunction + phobic spasms is not psychiatric.
Delirium tremens	Agitation, autonomic instability, hallucinations, tremors	History of alcohol use/withdrawal; no bite history; no hydrophobia; visual hallucinations predominate; responds to benzodiazepines
Acute transverse myelitis	Paralytic form could mimic this with limb weakness and sensory level	Usually has a clear sensory level; bladder dysfunction is early and prominent; no bite history; MRI shows spinal cord lesion

6. Traps and High-Yield Pearls

The most common way students lose points on rabies questions is by failing to prioritize wound washing as the first and most important step in post-exposure management. When a vignette describes a bite by a suspected rabid animal and asks for the "next best step," the answer is always immediate wound care with soap and water for 15 minutes, not rushing to give vaccine or immunoglobulin. The soap mechanically removes and inactivates the lipid-enveloped virus. This is the highest-yield management pearl.

A second frequent trap involves paralytic rabies. Students are trained to associate rabies with hydrophobia and aggression, so when a vignette presents ascending paralysis after a remote animal bite, they default to GBS. The discriminator is the bite history combined with paresthesia at the wound site during the prodrome. Always scan the vignette for a history of animal contact in any case of unexplained ascending paralysis, especially in endemic regions.

Third, students often confuse who gets immunoglobulin. SAR/RIG is indicated only for non-immune patients with Category III or high-risk exposures. Previously vaccinated (immune) patients receive only a booster of VAR, never RIG, because they already have an anamnestic antibody response that can be rapidly recruited.

Fourth, remember that rabies virus is undetectable in blood. If a question asks which test to order in a patient with suspected clinical rabies, do not select serum antibody titers as the initial test. Antibodies appear too late (and many patients die before seroconversion). The best ante-mortem test combination is saliva RT-PCR and nuchal skin biopsy DFA.

Finally, the concept that once clinical symptoms of rabies appear, the disease is almost universally fatal is itself a high-yield testing point. The exam may present a patient with established clinical rabies and ask about prognosis or appropriate goals of care. There is no proven curative treatment. The entire emphasis of rabies medicine is on prevention through PEP, not treatment of established disease. This is the core competency being tested: recognizing that rabies is a preventable but incurable disease, and that the window for intervention is entirely in the pre-symptomatic period.

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