Journal of Neuroinfectious Diseases
Open Access

Human rabies; List of survivors; Indian study; Rare case report; Milwaukee protocol; Largest comparative study

Derived from a Sanskrit synonym “Rabhas”, meaning “violence”, Rabies, is a violent outrageous infection of the brain1 recognised in Vedic Indian scriptures dating to a period as back as 1500 B.C. Very deadly, rabies has been described as ‘the dog accompanying The God of Death’ [1].

Rabies is a fatal zoonotic viral disease transmitted from mammals to humans, that’s characterised by an acute excitogenic encephalitis and generalised paresis [2].

With about 99% of cases being dog bite mediated, almost any mammal (domesticated or wild) is capable of incubating and transmitting the virus. The Rhabdovirus (RABV), of Family Lyssavirus is responsible for around 59,000 deaths worldwide annually, accounting to more than 60% of the deaths within India, owing to its lesser surveillance because of not being categorized a notifiable disease [3].

With only 24 documented cases of survival worldwide, till date, post development of symptoms, we are hereby reporting another classical case of rabies, which underwent gradual recovery, with minimal neurological sequalae.

Case Report

Our case, hereby, is a young female, aged 33 years, who was brought to the Emergency Room, by her husband and relatives, at around midnight of 28th September 2017 [4].

Giving a prompt history of a wild animal (Indian Civet, Viverricula indica) bite on her right leg 18 days back, the patient was now brought to our hospital, with complaints of altered sensorium for past 5-6 hours, with gradual deterioration to generalized immobility and nonresponsiveness for past 2-3 hours [5]. The patient was brought from NICD (National Institute of Communicable diseases), New Delhi, where the clinical diagnosis of “Acute Rabies Viral Encephalitis” was made. The attendants were counselled there for an isolation room for the patient, with a fatal prognosis succeeding it [6]. Thus, well-aware of the outcome, the patient was brought by her husband, for the terminal hospice care and palliation.

Admitted with us under Intensive Care Unit, the patient was examined, elaborately. The patient was in an unconscious state, responding by wincing (but with no withdrawal) to deep painful stimulus [7]. Her blood pressure was 130/90 mmHg, heart rate was 126 bpm, pulse rate 124 bpm, with no irregularities. Her respiratory rate was 24/min and, she was afebrile with an axillary temperature of 98.4 degree Fahrenheit [8]. Her saturation, on a pulse oximeter, displayed 94% at room air, and there were no signs of any respiratory distress. Upon further examination, both her plantar reflexes (Babinski’s) were flexors, both her pupils were normal sized, sluggishly reactive [9]. There was no neck rigidity, but, all other deep and superficial reflexes were diminished. Tone of her muscles were intact, and power was not elicitable. There was no history or any finding suggestive or urinary or bowel incontinence.

Her chest was clear, with normal vesicular conducted sounds, and the heart sounds were normal. Her right leg’s lateral aspect had a wound, which was dressed antiseptically [10]. The wound, upon exposure, had multiple lacerations, imprinting the bite marks of the animal (mentioned above), each 2-3 cm deep, with localised surrounding rubor. Patient was catheterized for urine, keeping her sensorium in view. There was no history of any abnormal body movements, any frothing from mouth, tongue bite [11].

Upon retrograde history, her husband, who witnessed the incident had explained of an unprovoked bite by the animal, in the wake of light (around 5am IST) [12], which ferociously kept held on to the patient’s leg, until it was killed. Immediately, the patient was taken to a local physician, the wound was washed and antiseptically dressed [13]. The wound was bleeding actively. The patient was started on Anti-Rabies Vaccine (Rabipur/Verorab), within 4 hours of bite, along with a stat dose of Tetanus toxoid, and was immunised regularly, as per the WHO guidelines, on Days 0-3-7-14 thereafter [14]. No local immunoglobulins were given. The patient was brought home immediately, prescribed on symptomatic medications.

But, 3 Days post-Bite, the local (bite-site) residual pain , started aggravating , and the over next 4-5 days, the patient used to vividly explain , the radiation of pain, beginning from the leg extending to the chest, and then progressed to the head, manifesting as a severe headache by Day-9 post-bite and patient was admitted for the same in a local hospital [15]. The patient started developing anxiousness, restlessness, and could not sleep, until was sedated, 10th day onwards (post-bite). On Day 15 post-bite, patient developed fever (high grade), along with multiple episodes of vomiting, incompletely responsive to medications [16]. It was when the patient started refusing water, with inability to swallow (Hydrophobia: Pathognomonic of Rabies), that the patient was referred to NICD, New Delhi, suspecting Rabies Encephalitis [17].

Upon leading with questions further, the husband also gave a vague history of the patient exhibiting intolerance to light (Photophobia) while driving from hospital to hospital in his car, resistance to air on switching on the ceiling fan or opened windows while moving the car (Aerophobia) and inability to produce proper phonation (aphonia) preceding the current comatose state of patient’s presentation, all presenting since 11th day post-bite [18]. The restlessness, irritability progressed immediately, with the patient not slept at all for past 3-4 days before her presentation to our hospital.

Post her admission in our hospital, the patient was duly investigated. All her blood and serum investigations were non-significant except Renal function test, CSF examination and Magnetic resonance imaging of Brain [19]. Her renal function test was deranged with Urea = 88.0, Creatinine = 2.2 with reduced and dark coloured urine output (about 300-400ml per 24 hours), but with no alteration in Kidney echotexture / morphology (as examined on ultrasonography) [20]. The CSF fluid was clear, colourless with RBS = 74mg/dl, Proteins = 130mg/dl, TLC = 120 cells with 90% lymphocyte predominance in cellularity. The MRI Brain showed features of encephalitis, probably of viral aetiology [21].

The patient was then palliatively managed conservatively with antimicrobial agents (Acyclovir, Ceftriaxone) with an emphasis on hydration [22]. Keeping the most probable diagnosis as-‘Acute Rabies Viral Encephalitis’, palliative approach to manage the patient’s vitals and preventing her condition from further deterioration was primarily aimed, since most viral illnesses are self-limiting within 1-2 weeks [23].

Falling blood pressure was managed by adequate hydration, with monitoring of urine output, and regular blood sampling for renal function follow-up [24]. Any bradycardia was improved by Atropine on SOS basis. Regular suctioning using laryngoscope, nebulization and chest physiotherapy was done to maintain any respiratory inadequacy, with a mechanical ventilator kept on stand-by [25]. Limb physiotherapy, TPN (Total Parenteral Nutrition) was added for a generalised appreciable response. Maintained mostly in propped -up position, regular visits by her husband, brother , relatives were encouraged to boost her morale, as patient’s positive will was also primarily paid heed to once her sensorium started improving [26].

Miraculously , by Day 7 post-admission (Day 23 post-bite) , the patient responded positively with eye opening on touch ,followed by gradual improvement to spontaneous eye opening, with interspersed periods of varying conscious levels (lucid intervals) ,over the next 6 days [27]. On Day 13, the patient started showing signs of further improvement by accepting oral sips, and on day 20 (post-admission), the patient was shifted to ward. She was now able to interpret verbal commands and respond by speech, but in bi-syllables. Nasogastric tube feeds were initiated, along with TPN (Total Parenteral Nutrition) [28]. The patient was typically aimed at being managed, by stabilizing through the periods of vital impairments and agitation, using sedatives and other counter drugs [29].

The patient underwent physiotherapy and speech therapy, until Day 33 (post admission) / Day 51 (post bite), when the patient showed the ability of independent voluntary movements, and was discharged with prominent dysarthria, quadriparesis of improving prognosis.12 months post-discharge, the patient was followed up on out-patient basis, persistent with a mild neurological sequelae of wide stepped gait and myalgia, but was independent enough to perform her household chores [30].

Hence, we confirm that the patient had outlived the acute phase of neurological system inflammation, with a mild physical residua [31].

Most of the present day knowledge about rabies has evolved from in vitro studies using fixed (attenuated) laboratory strains, and thus cannot be accurately matched with highly non-specific features, in clinical settings [24].

How to diagnose rabies?

For a laboratory disease confirmation, WHO recommends brain tissue biopsy demonstrating virus antigen as 100% sensitive gold standard technique, but this technique is preferred in post mortem diagnosis. The antemortem diagnostic tests, are limited, and highly influenced by intermittent virus shedding, timing of sample collection, type of sample, and the type of rabies, reflecting the peculiar pathogenesis of the virus lacking a viraemic phase and evading exposure to the systemic immune responses [24], with the standard being the Fluorescent antibody test demonstrating the presence of viral antigen.

Is rabies treatable?

Though no aggressive management was required in this case, the non-specific spectrum of the classic rabies survival cases, had no patterned management technique, other than conservatively treating the patient until the proposed theory of hyperactive immune response (natural or artificial) with high antibody levels in CSF and serum, successfully led to viral clearance [24]. Table 1 provides a brief detailed list of rare documented rabies survivors worldwide, till date.

With the references taken from the study of 25 (including current case) survivors, in an otherwise 100% fatal rabies encephalitis in humans, the maximum number of cases have been reported from the Indian continent, which directly corresponds to the endemicity in the region. Most of the survivors observed to be of the younger age group, and also the survivors noted to be presenting with high titres of antirabies virus antibody, it showcases the potential of a healthy immune competent body, with a pressing importance of passive immunization, to counteract the disease. With 16 out of 25 survivors presenting in the non-furious type, a trend of survival has thus been seen in the nonaggressive form of rabies, thus also stating the role of virulence and strain of the virus, in prognosis. Clinical manifestation of the disease was faster with the bite closer to head and neck, though no significant variation in the recovery process. As in diagnosing, confirmatory antemortem tests from the laboratory need to be readily upgraded with recent most techniques and availability for prompt intervention and treatment, with RT-PCR climbing up the charts in reliability.

The 2009 case of Texas, USA, is the first case reported of Abortive type, where recovery from rabies without any conservative or intensive care was noted 19. 6 out of 25 survivors have been tried management using Milwaukee protocol, and though not much of a beneficial track record for the same has been reported earlier, it seems to have a marginal incidental benefit in survival of the patient, and proposed to be promoted in its usage as an additional support therapy to conservative management.

With most cases , recovering within the span of 2-3 months of conservative intensive management, 3-4 cases have extended for up to 6 months and only one case took 13 months of hospital stay, before discharge, suggesting the time span of aggressive approach required to wade through to survive, for a symptomatic case. As most of the cases, have had remnants of neurological disability, 7 out of 22 cases have ended with Complete neurological recovery with no or mild neurological sequalae. Hence, it is not only important to clear the virus from CNS but also to ameliorate the neuronal injury caused by the viral infection. Therefore, a combination of antiviral therapy, immunotherapy and neuro-protective therapy, should be an important area of research in animal models, to contribute in establishing an effective treatment and therapy of human rabies.

1. Mahadevan A, Suja MS, Mani RS, Shankar SK (2016) Perspectives in Diagnosis and Treatment of Rabies Viral Encephalitis: Insights from Pathogenesis. Neurotherapeutics 13: 477-492.

Indexed at,  Google Scholar,  Crossref

2. Menezes R (2008) Rabies in India. CMAJ 178(5): 564-566.

Indexed at,  Google Scholar,  Crossref

3. WHO, The Global Strategic Plan to End Human Deaths from Dog-Mediated Rabies By 2030.
4. WHO, Expert Consultation on Rabies, third report WHO Technical Report Series 1012, Geneva, 2018.

Google Scholar

5. Salomão C, Nacima A, Cuamba L, Gujral L, Amiel O, et al. (2017) Epidemiology, clinical features and risk factors for human rabies and animal bites during an outbreak of rabies in Maputo and Matola cities, Mozambique, 2014: Implications for public health interventions for rabies control. PLoS Negl Trop Dis 11(7):e0005787.

Indexed at,  Google Scholar,  Crossref

6. Hemachudha T, Laothamatas J, Rupprecht CE (2002) Human rabies: A disease of complex neuropathogenetic mechanisms and diagnostic challenges. Lancet Neurol 1(2):101-109.

Indexed at,  Google Scholar,  Crossref

7. Chacko K, Parakadavathu RT, Al-Maslamani M, Nair AP, Chekura AP, et al. (2017) Diagnostic difficulties in human rabies: A case report and review of the literature. Qatar Med J 2016(2):15.

Indexed at,  Google Scholar,  Crossref

8. Susilawathi NM, Darwinata AE, Dwija IBNP,  Budayanti NS, Wirasandhi GAK, et al. (2012) Epidemiological and clinical features of human rabies cases in Bali 2008-2010. BMC Infect Dis 12:81.

Indexed at,  Google Scholar,  Crossref

9. World Health Organization (2018) Rabies vaccines: WHO position paper, April 2018 – Recommendations. Vaccine 36(37): 5500-5503.

Indexed at,  Google Scholar,  Crossref

10. Hattwick MAW, Weiss TT, Stechschulte CJ (1972) Recovery from rabies. Annals Internal Med 76(6):931-942.

Indexed at,  Google Scholar,  Crossref

11. Porras C, Barboza JJ, Fuenzalida E, Adaros HL, Oviedo AM, et al. (1976) Recovery from rabies in man. Ann Intern Med 85(1):44-48.

Indexed at,  Google Scholar,  Crossref

12. Tillotson JR, Axelrod D, Lyman DO (1977) Rabies in a laboratory worker - New York. Morbidity Mortality Weekly Rep 26:1830-1834.

Google Scholar,       Cross ref

13. Alvarez L, Fajardo R, Lopez E, Pedroza R, Hemachudha T, et al. (1994) Partial recovery from rabies in a nine-year-old boy. Pediatric Infect Dis J 13(12):1154-1155.

Indexed at,  Google Scholar,  Crossref

14. Madhusudana SN, Nagaraj D, Uday M, Ratnavalli E, Verendra Kumar M (2002) Partial recovery from rabies in a six-year old girl. Int J Infect Dis 6(1): 85-86.

Indexed at,  Google Scholar,  Crossref

15. Willoughby RE, Tieves KS, Hoffman GM, Ghanayem NS, Amlie-Lefond CM, et al. (2005) Survival after treatment of rabies with induction of coma. N Engl J Med 352(24): 2508-2514.

Indexed at,  Google Scholar,  Crossref

16. Rubin J, David D, Willoughby RE, Rupprecht CE, Garcia C, et al. (2009) Applying the Milwaukee protocol to treat canine rabies in Equatorial Guinea. Scand J Infect Dis 41(5): 372-375

  Google Scholar,  Crossref

17. Weyer J, Msimang-Dermaux V, Paweska JT, Roux KL, Govender P, et al. (2016) A case of human survival of rabies, South Africa. S Afr J Infect Dis 31(2): 66-68.

Google Scholar,  Crossref

18. Karahocagil MS, Akdeniz H, Aylan O, Sünnetçioğlu M, Hikmet U, et al. (2013) Complete Recovery from Clinical Rabies: Case Report. Turk Klin J Med Sci 33(2): 547-552.

Indexed at,  Google Scholar,  Crossref

19. Holzmann-Pazgal G, Wanger A, Degaffe G, Rose C, Heresi G, et al. (2010) Presumptive abortive human rabies – Texas, 2009. MMWR 59(7): 185-190.

Indexed at,  Google Scholar

20. Wiedeman J, Plant J, Glaser C, DVM, Messenger S, et al. (2012) Recovery of patient from clinical rabies – California, 2011. MMWR 61(4):61-65.

Indexed at,  Google Scholar

21. Rawat AK, Rao SK (2010) Survival of rabies patient. Indian Pediatr 25:305-309.
22. de Souza A, Madhusudana SN (2014) Survival from rabies encephalitis. J Neurol Sci 339: 8-14.

Indexed at,  Google Scholar,  Crossref

23. Weyer J, Msimang-Dermaux, V, Paweska TJ, Roux KL, Govender P, et al. (2016) A case of human survival of rabies, South Africa. S Afr J Infect Dis 31(2): 66-68.

Indexed at,      Google Scholar,  Crossref

24. Galvez S, Basque M, Contreras L, et al. Survivor of rabies encephalitis in Chile. Platform presentation at the XXIVth International Meeting on Research Advances and Rabies Control in the Americas in Toronto, Ontario, Canada on October 27, 2013.
25. Kumar KV, Ahmad FMH, Dutta V (2015) Pituitary cachexia after rabies encephalitis. Neurol India 63(2):255-256.

Indexed at,  Google Scholar,  Crossref

26. Manoj S, Mukherjee A, Johri S, Kumar KV (2016) Recovery from rabies, a universally fatal disease. Mil Med Res 3:21.

Indexed at,  Google Scholar,  Crossref

27. Apanga PA, Awoonor-Williams JK, Acheampong M, Adam MA (2016) A Presumptive Case of Human Rabies: A Rare Survived Case in Rural Ghana. Front Public Health 4: 245.

Indexed at,  Google Scholar,  Crossref

28. Secretaria de Estado de Saúde do Amazonas (2018) Amazonas registra o segundo caso de sobrevivência por raiva humana no Brasil.
29. Bokade CM, Gajimwar VS, Meshram RM, Wathore SB (2019) Survival of atypical rabies encephalitis. Ann Indian Acad Neurol 22(3): 319-321.

Indexed at,  Google Scholar,  Crossref

30. Goyal K, Bhagwat C, Suthar R, Saini AG, Ravikumar N, et al. (2020) Enigma of rabies: prolonged survival in a boy with rabies brachial plexitis and encephalomyelitis. Neurol India 68(3): 673-676.

Indexed at,  Google Scholar,  Crossref

31. John B, Kumar S, Kumar S, Dalal SS, Mohimen A (2020) Child survivor of rabies in India: a case report. Paediatr Int Child Health 40(4): 255-260.

Indexed at,  Google Scholar,  Crossref