- Email: [email protected]
Henipavirus encephalitis
Handbook of Clinical Neurology, Vol. 123 (3rd series) Neurovirology A.C. Tselis and J. Booss, Editors © 2014 Elsevier B.V. All rights reserved
Chapter 32
Henipavirus encephalitis SUHAILAH ABDULLAH AND CHONG TIN TAN* Division of Neurology, Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
INTRODUCTION In 1994, there was an outbreak of respiratory and neurologic infections affecting horses and humans who had been in close contact with the sick horses. To date, there have been seven human cases, with four mortalities. A new zoonotic virus from the paramyxovirus family was discovered and was named Hendra virus (HeV). In 1998–1999, there was an outbreak of fatal encephalitis among the pig-farming community in Malaysia, involving more than 350 patients, with a mortality rate of 40%. Isolation of a new zoonotic paramyxovirus closely related to HeV, in cerebrospinal fluid (CSF) samples of patients in Sungai Nipah village, Malaysia, led to the discovery of Nipah virus (NiV) as the etiologic agent. Although there have been no more outbreaks since May 1999 in Malaysia, there have been two outbreaks in West Bengal, India: the first in Suliguli in 2001, and the second in Nadia district in 2007. There have been outbreaks almost annually in Bangladesh between 2001 and 2012. These outbreaks were associated with more prominent respiratory symptoms and a higher mortality rate of 70%. The natural reservoir host for the henipaviruses was identified as fruit bats of the Pteropus species based on the presence of neutralizing antibodies to the virus, and isolation of virus from their urine and saliva. The wide geographic distribution of Pteropus bats as the disease vector, which expands from Asia and Australasia to West Africa, makes Henipavirus an important emerging cause of fatal encephalitis.
THE HENIPAVIRUS HeV and NiV can be isolated from patients’ CSF, saliva, urine, pharyngeal and nasal secretions. They grow easily in all types of mammalian cells, but not in insect cell lines (Chua et al., 1999, 2000). They are single-stranded RNA paramyxoviruses, in the genus Henipavirus. Hence, they
share many common characteristic features with other members of the Paramyxoviridae family. In tissue culture, they show a typical cytopathic effect pattern of cell fusion and formation of giant syncytial cells. Histologically, they exhibit a pleomorphic lipid bilayer envelope, with the formation of intracytoplasmic inclusions of viral nucleocapsids that gives rise to the typical “herringbone” appearance in infected cells under negative staining (Chow et al., 2000; Goldsmith et al., 2003). Like their other Paramyxoviridae family, the genomic makeup of both HeV and NiV consists of six genes (N-PM-F-G-L) flanked by a 3’ leader and 5’ trailer region. Both viruses have identical leader and trailer sequence lengths and hexamer-phasing positions for all of their genes (Chan et al., 2001). However, they demonstrate longer genomic length of 18 246 nucleotides for the Malaysian strain of NiV, 18 252 nucleotides for the Bangladesh strain, and 18 234 nucleotides for HeV, as compared to the average of 15 500 nucleotides in other paramyxoviruses (Chan et al., 2001; Harcourt et al., 2001). The Bangladesh NiV strain also exhibits the most genetic variability, with a 92% homology to the Malaysian strain (Harcourt et al., 2005), hence the probability of the more virulent nature of the Bangladesh NiV, associated with a higher mortality rate among the population affected.
EPIDEMIOLOGY The first outbreak of HeV infection occurred in September 1994, in Hendra, Brisbane, Australia, involving 18 horses and two humans. This resulted in 14 deaths among the horses and one human fatality (Selvey et al., 1995). Retrospectively, in August 1994, there was a similar case reported in Mackay, North Queensland, where a person caring and assisting in the autopsy of two sick horses developed aseptic meningitis, initially with full
*Correspondence to: Prof. C.T. Tan, c/o Neurology Laboratory, University Malaya Medical Centre, 59100 Kuala Lumpur, Malaysia. Tel: 03-79672967/2585, E-mail: [email protected]
664
S. ABDULLAH AND C.T. TAN
recovery, but then died from severe encephalitis 13 months later (O’Sullivan et al., 1997). To date, there have been seven reported human cases with four deaths (Playford et al., 2010). The natural reservoir host has been tracked down to the Pteropus bats. The mode of transmission of this virus is via direct contact with respiratory secretions, contaminated tissue, or excretion from infected horses. NiV was first discovered in 1999 during a fatal encephalitis outbreak among the pig-farming community in Peninsular Malaysia. The first outbreak occurred in September 1998, in Tambun, Perak, followed by Negeri Sembilan (Sikamat, Bukit Pelanduk and neighboring Sungai Nipah, Sepang), Selangor (Sungai Buloh) from December 1998 to March 1999, and Singapore in March 1999, where 11 abattoir workers were affected, with one fatality (Fig. 32.1). In total, more than 350 patients were affected, with 40% mortality. Fruit bats of the Pteropus species were the natural reservoir host. The pigs were infected by consuming the half-eaten fruits contaminated by the bats’ saliva or urine, and then acted as an intermediate and amplifying host. Transmission to humans was via close contact with infected pigs or fresh pig products. The risk of human-to-human transmission was low in the Malaysian series (Mounts et al., 1999; Tan and Tan, 2001). The fatal encephalitis outbreak was contained by massive culling of over a million pigs and prohibition of importation of pigs into Singapore from Malaysia. The last human fatality was
THAILAND
MALAYSIA
Perak 1
Selangor
5 6
Negeri Sembilan 2
4 3 Name of towns 1. Tambun 2. Sikamat 3. Bukit Pelandok 4. Sepang 5. Sungai Buloh 6. Kuala Lumpur
SINGAPORE
Fig. 32.1. Map of peninsular Malaysia showing spread of Nipah encephalitis outbreak among neighboring states, then to Singapore. (Reproduced with permission from Sim et al., 2002.)
seen on 27 May 1999, and Malaysia was declared free of NiV in the livestock population by the Office International de Epizooties in June 1999 (Chua, 2003). During the NiV encephalitis outbreaks in Bangladesh and West Bengal, India, multiple modes of transmissions were postulated. The most important was thought to be from bats to humans by consumption of contaminated raw date palm sap in the 2005 Tangail outbreak (Luby et al., 2006), and human-to-human transmission in the 2001 Meherpur and Seliguli, 2003 Naogaon, and 2004 Faridpur outbreaks (Chadha et al., 2006; Gurley et al., 2007). Other modes of transmission were from sick cows and herds of pigs to humans in the 2001 Meherpur and 2003 Naogaon outbreaks (Hsu et al., 2004), and direct contact with bat droppings by children climbing trees in the 2004 Goalanda outbreak (Montgomery et al., 2008); again, the natural reservoir host was identified as fruit bats of the Pteropus species.
THE RESERVOIR HOST When HeV was first discovered in 1994, serologic survey of bat colonies along the eastern coast of Queensland showed positive results among Pteropus species (Young et al., 1996). Since then, up to 42% of wild-caught pteropid bats in Australia have shown serologic evidence of HeV infection (Mackenzie, 1999). In view of the close similarity of these viruses, bats were investigated as the reservoir host for NiV during the Nipah encephalitis outbreak in Malaysia. Neutralizing antibodies to NiV were detected primarily in fruit bats of the Pteropus genus. Subsequently, NiV was isolated from bat urine and swabs of contaminated fruits collected in Tioman Island, Malaysia (Chua et al., 2002b). Further studies revealed that reactive and/or neutralizing antibodies to NiV were detected in Pteropus bats from Malaysia, to Cambodia, Thailand, India, Bangladesh, and Papua New Guinea, and also non-pteropid bats in Madagascar, Ghana, and China (Yob et al., 2001; Olson et al., 2002; Reynes et al., 2005; Wacharapluesade et al., 2005, Iehle et al., 2007; Hayman et al., 2008; Li et al., 2008; Epstein et al., 2008). This indicates that the virus was prevalent in both geographic distribution and species of bats affected. The mode of transmission from bats to pigs/horses remains unclear, but it was postulated that virus transfer occurred through contact with contaminated secretions and/or bat excretions via consumption of half-eaten fruits (Chua et al., 2002b). The infected pigs and horses then act as amplifying hosts, resulting in significant pig-to-pig/horse-to-horse transmission, and subsequent human transmission.
HENIPAVIRUS ENCEPHALITIS
CLINICAL MANIFESTATIONS Both HeV and NiV encephalitis cause rapid fatal encephalitis with a high mortality rate. During the NiV encephalitis outbreak in Malaysia, the incubation period ranged from 4 days to 2 months; 92% of patients became symptomatic in less than 2 weeks (Chong et al., 2000; Goh et al., 2000). The mean age of patients was 37 years (range, 13–68), with a male to female ratio of 4.5:1, and pig farming was an occupational risk factor (Goh et al., 2000). The clustering of cases among family members, with 33% of members having NeV infection, suggested a disease with high infectivity. The ratio of symptomatic and subclinical infection was estimated to be about 3:1; there were 27% symptomatic versus 8% asymptomatic cases in the household (Tan et al., 1999; Parashar et al., 2000). The main presenting clinical features were acute encephalitis with fever, headache, dizziness, and vomiting, with more than 50% of patients having reduced level of consciousness (Chua et al., 1999; Chong et al., 2000; Goh et al., 2000). Distinctive clinical features were areflexia, hypotonia, prominent autonomic disturbance, and segmental myoclonus, which was reported in 32% of patients (Goh et al., 2000). Respiratory involvement, presented as cough, was reported in 14% of Malaysian patients, with atypical pneumonia reported in 3 out of 11 patients in Singapore (Paton et al., 1999; Chong et al., 2000). The mortality rate during the Malaysia NiV encephalitis outbreak was 40%. The mean time from onset of illness to death was 10.3 days. The indicators of poor prognosis were: ● ● ● ●
● ● ●
Older age (Chong et al., 2000; Goh et al., 2000) Concomitant diabetes mellitus, probably due to immunoparesis (Chong et al., 2001b) Elevated hepatic aminotransferase and thrombocytopenia on admission (Goh et al., 2000) Brainstem involvement, as evidenced by reduced level of consciousness, abnormal doll’s eye reflex, hypertension, tachycardia (Chong et al., 2000; Goh et al., 2000) Presence of seizures, segmental myoclonus, areflexia (Goh et al., 2000) Isolation of NiV in the CSF (Chua et al., 2001) Presence of independent bitemporal periodic complexes on the background of diffuse slow waves on electroencephalogram – associated with 100% mortality (Chew et al., 1999).
Patients with normal conscious level recovered fully. Twenty-two percent of surviving patients had residual neurologic deficits that ranged from mild cerebellar disabilities to significant cognitive impairment and vegetative state (Goh et al., 2000).
665
The NiV encephalitis outbreaks in Bangladesh and India showed a wider age range from 12 to 70 years old (Harith et al., 2006). There was no occupational linkage as the mode of transmission was postulated to be multifactorial. The incubation period was shorter than the Malaysian outbreak, with a range of 6–11 days (Hossain et al., 2008). Although acute encephalitis was the prominent clinical manifestation, there was significant respiratory involvement, which presented as cough and respiratory distress in up to 70% of patients (Chadha et al., 2006; Hossain et al., 2008). Nevertheless, segmental myoclonus, which was one of the poor prognostic indicators in the Malaysian series, was not observed. A higher mortality rate of 70% was observed in the Bangladesh and India outbreaks. The mean time from onset of illness to death was also shorter, ranging from 4 to 6 days (Hsu et al., 2004; Hossain et al., 2008). Though suboptimal medical access may play a role, the probability of a more virulent NiV strain in view of its longer genomic nucleotides needs to be considered and investigated. HeV infection manifests as influenza-like illness with fever, headache, and myalgia that can progress to pneumonia with respiratory distress, or encephalitis with confusion and reduced level of consciousness (O’Sullivan et al., 1997; Playford et al., 2010). The incubation period was estimated at 5–21 days, with a mortality rate of more than 50% (Playford et al., 2010). To date, there have been seven reported human cases, with four mortalities.
PATHOLOGY The pathologic hallmark of acute NiV encephailitis was vasculitis of medium to small-sized blood vessels, causing disseminated microinfarctions, with or without thrombosis, as well as direct neuronal infection by the virus (Wong et al., 2002; Wong and Tan, 2012) (Fig. 32.2). The earliest lesion was the formation of multinucleated syncytium in the endothelium. Inflammatory cells, consisting of neutrophils, lymphocytes, macrophages, and plasma cells, were found within the endothelium. Vasculitis was frequently associated with vascular occlusions and subsequent necrosis and infarcts. Examination of the brain parenchymal inflammation revealed perivascular cuffing and neurophagia. The surviving neurons showed paramyxoviral-type inclusions. Both vessels and neurons showed presence of viral antigen on immunohistochemical staining, indicating the ability of NiV to infect the blood vessel and neurons directly. The brain was the most severely affected organ, hence, it was consistent with acute encephalitis as a prominent clinical presentation. This was followed by the lungs, kidneys, heart, and lymphoid organs. Similar patterns of vasculitis and disseminated microinfarcts were seen
666
S. ABDULLAH AND C.T. TAN
Fig. 32.2. (A) Cerebral cortex with microinfarct associated with vascular thrombosis. (Hematoxylin & eosin stain, magnification 4 objective). (B) Nipah antigen in neurons detected by immunohistochemistry. (Magnification 40 objective.) (Courtesy of Dr. K.T. Wong, University of Malaya.)
in these organs, coupled with detection of viral antigen on immunohistochemical staining. The dual pathogenetic mechanisms of vasculitis-induced microinfarctions and direct neuronal damage in multiple organs appeared to be unique in this virus pathogenesis (Wong and Tan, 2012). There is limited knowledge regarding the pathologic findings in HeV encephalitis as published data are based on a single case. Nevertheless, it is believed that both viruses cause similar pathology.
LABORATORY, RADIOLOGIC, AND DIAGNOSTIC INVESTIGATIONS Basic bloods investigation, such as full blood count, liver function test, and CSF examination, were non-specific. During the Malaysian NiV encephalitis, thrombocytopenia and leukopenia were seen in 30% and 11% respectively. Elevated transaminases were seen in 30–45% of patients upon hospital admission. Though these findings were non-specific for NiV encephalitis, elevated transaminases and thrombocytopenia on admission were associated with poor prognosis (Goh et al., 2000). CSF examination revealed lymphocytic pleocytosis and elevated protein levels in 75% and 77% respectively. Though these findings were non-specific, viral isolation from the CSF was associated with high mortality (Chua et al., 2001). The diagnostic laboratory test for NiV encephalitis consisted of detection of anti-NiV immunoglobulin M (IgM) and IgG antibody in the serum and CSF, with or without viral isolation. The anti-NiV-specific IgM was detected by direct enzyme-linked immunoabsorbent assay (ELISA), while the IgG antibody utilized the indirect IgG ELISA (Chua et al., 1999). The rate of positivity
was 60–71% by day 4 and 100% by day 12 of illness. On the other hand, the IgG was positive in 7–29% by day 1–10, and 100% by day 25–26 of illness (Ramasundrum et al., 2000). The IgG were persistently positive whereas the IgM became negative by 10 years of illness (Siva et al., 2009). Other testing methods include serum neutralizing tests (Bossart et al., 2007) and realtime polymerase chain reaction (RT-PCR) for detection of viral RNA from serum, urine, and CSF (Abu Bakar et al., 2004; Guillaume et al., 2004). Less is known regarding the laboratory changes in HeV encephalitis. However, neutropenia, thrombocytopenia, elevated CSF protein, and pleocytosis have been documented in some patients with HeV encephalitis. The viral RNA can be detected using the quantitative RT-PCR performed at baseline and at 3 and 6 weeks of exposure. ELISA and serum neutralizing test could be used for antibody detection. However, the diagnostic sensitivity of the ELISA was not well established (Isabel et al., 2011). Magnetic resonance imaging (MRI) of the brain was a sensitive diagnostic tools in acute and relapse/late-onset NiV encephalitis. The MRI in Malaysian acute NiV encephalitis showed characteristic discrete and disseminated hyperintense lesions best seen in the fluid attenuated inversion recovery (FLAIR) sequences (Fig. 32.3), which represent widespread microinfarctions on brain autopsy (Ahmad Sarji et al., 2000). However, there was poor correlation between severity of neurologic status and MRI findings. Sixteen percent of asymptomatic patients also showed similar changes on MRI, suggesting subclinical cerebral involvement (Tan et al., 2000). The Malaysian MRI findings in acute NiV encephalitis differed from those of the Bangladesh series, where there was confluent cortical involvement rather than
HENIPAVIRUS ENCEPHALITIS
667
Fig. 32.3. Magnetic resonance imaging. (A) Axial T2W and (B) coronal fluid attenuated inversion recovery of the brain, showing characteristic discrete and disseminated hyperintense lesions in the subcortical and deep white matter of the parietal lobes (white arrows) in Malaysian acute Nipah virus encephalitis. (Adapted from Abdullah et al., 2012 with permission.)
discrete disseminated lesions (Quddus et al., 2004). This could be associated with the variation in the viral genomic sequence. Similar changes were noted in HeV encephalitis (Playford et al., 2010). The most common finding on electroencephalogram (EEG) was diffuse polymorphic slow waves; this was non-specific but correlated well with the severity of illness. The presence of independent bitemporal periodic complexes carried a poor prognosis, with mortality of 100% (Chew et al., 1999). A similar pattern of diffuse slowing was seen in HeV encephalitis that improved with clinical improvement (Playford et al., 2010).
RELAPSED AND LATE-ONSET ENCEPHALITIS Relapsed encephalitis is defined as patients presenting with another neurologic manifestation after recovery from acute encephalitis. Late-onset encephalitis, on the other hand, is defined as the appearance of neurologic presentation for the first time 10 weeks after initial exposure (Tan et al., 2002). The prevalence of relapsed NiV encephalitis and late-onset encephalitis in Malaysia was approximately 9% and 5% respectively (Tan et al., 2002; Chong and Tan, 2003). The longest interval for late-onset encephalitis was 11 years after the initial exposure (average 8.4 months), with a relapse occurring 1 year later (Abdullah et al., 2012). The clinical manifestations were as for acute encephalitis. However, fewer patients had fever, and a higher proportion had seizures and focal cortical signs (Chong et al., 2000). This was supported by MRI findings of confluent cortical involvement (Fig. 32.4), as opposed to discrete and disseminated lesions in acute NiV encephalitis (Ahmad Sarji et al., 2000).
Fig. 32.4. Magnetic resonance imaging axial fluid attenuated inversion recovery image in Malaysian relapsed and late-onset Nipah encephalitis showing confluent hyperintense lesions located at anterior temporal lobes bilaterally, affecting the white matter and cortex (arrows), as opposed to discrete and disseminated lesions in acute Nipah virus encephalitis. (Adapted from Abdullah et al., 2012 with permission.)
The pathologic findings revealed confluent inflammation of the brain parenchyma with demonstration of neuronal viral antigen, corresponding to the MRI findings. However, there was no vasculitis or perivenous demyelination, suggesting that relapse and late-onset
668
S. ABDULLAH AND C.T. TAN
NiV encephalitis were the result of recurrent infection rather than postinfectious demyelination following other paramyxovirus infection (Tan et al., 2002). In contrast to acute NiV encephalitis, no NiV was isolated from patients’ secretion, excretion, and CSF, though viral antigen could be demonstrated by positive immunolocalization. This suggests that NiV, like the measles virus in subacute sclerosing panencephalitis, could have undergone mutations, resulting in the failure of viral morphogenesis at the cell membrane (Tan et al., 2002). The mortality rate was 18%. However, patients have worse neurologic outcomes, with 61% having residual neurologic deficits, compared to 22% after acute NiV encephalitis (Goh et al., 2000; Tan et al., 2002). Among the 22 survivors in Bangladesh, 18% developed relapsed encephalitis manifesting as ophthalmoplegia and cervical dystonia (Sejvar et al., 2007). The pathologic hallmark of relapsed encephalitis is neuronal inflammation, with more prominent and abundant viral inclusion, and extensive confluent parenchymal necrosis, giving rise to focal encephalitis (Tan et al., 2002; Wong, 2010). Hence, focal neurologic signs are the prominent clinical manifestation in relapsed Henipavirus encephalitis. To date, there has been one reported case of relapse in HeV encephalitis that occurred 13 months after a complete recovery from the initial event (O’Sullivan et al., 1997). The MRI showed similar confluent lesions as per relapsed NiV encephalitis. Despite evidence of encephalitis on tissue necropsy with positive staining for HeV viral antigen, no virus was isolated.
TREATMENT The most important mode of treatment in acute Nipah encephalitis remains supportive, with mechanical ventilation, anticonvulsants for patients with seizures, prevention of deep venous thrombosis, and broad-spectrum antibiotic for nosocomial infection (Goh et al., 2000). A broad-spectrum virustatic antiviral agent, ribavirin, was used in the treatment of both acute HeV and NiV encephalitis. This was associated with a 36% reduction of mortality during the Malaysian outbreak (Chong et al., 2001a). Potential therapeutic treatments include soluble versions of G glycoprotein and Ephrin B2, that have been shown to inhibit NeV envelope-mediated infection. Asprin and pentoxifillyne may be used as prophylaxis against vasculitis-induced thrombosis, on the basis of pathologic changes of disseminated microinfarctions from vasculitis on autopsy (Goh et al., 2000).
PREVENTION Henipavirus is a recognized source of zoonotic infection, with bats of the Pteropus species identified as the
reservoir host. A complex interplay of multiple factors was postulated to be the reason for the spillage of this virus into the domestic animal population and subsequent transmission to humans. This includes substantial deforestation and severe haze from anthropogenic forest fires that have resulted in the reduction of wildlife habitats, hence encroachment of these fruit bats into the fruit orchards and subsequent contact with domestic animals and humans. As for the Malaysian NiV encephalitis outbreak, the mixed agro–pig farming practices and poor design of pigsties were important means for disease transmissibility (Chua et al., 2002a). The wide geographic distribution of Henipavirus and its reservoir host, and the ease of virus transmissibility make HeV and NiV important causes of zoonotic infection. Table 32.1 lists the clinical features that may indicate possible Henipavirus infection in areas where the infection is not known to be endemic. Although there was an early response to developing livestock vaccines to prevent viral re-emergence, good surveillance and culling of infected domestic animals were key to rapid control of disease propagation. In Bangladesh, the use of bamboo skirts to prevent access of bats to date palm sap and avoidance of consumption of raw date palm juice are important measures to prevent food-borne transmission. A good practice of general hygiene, such as hand washing, and barrier nursing within the hospital setting can prevent human-to-human transmission. Education on proper handling of sick animals and good general hygiene among horse handlers and pig farmers is essential to prevent spread of infection. Overall, a deeper understanding of the environmental and epidemiologic factors that favor spillover of this virus into the domestic animal population is crucial to prevent re-emergence of this fatal zoonotic encephalitis.
Table 32.1 Clinical features that may indicate possible Henipavirus infection in areas where the infection is not known to be endemic 1. History of illness in animals, such as pigs or horses, that may be exposed to Pteropus or other fruit bats 2. Clustering of cases in the same household or geographic area that may suggest an outbreak 3. Clustering of cases that may suggest zoonosis or human-tohuman spread of infection; e.g., illness involving animal workers, healthcare workers, or family members 4. Acute febrile illness involving neurologic or respiratory systems Patients to be screened by Henipavirus serology or polymerase chain reaction and magnetic resonance imaging
HENIPAVIRUS ENCEPHALITIS
REFERENCES Abdullah S, Chang LY, Rahmat K et al. (2012). Late-onset Nipah virus encephalitis 11 years after the initial outbreak: a case report. Neurol Asia 17: 71–74. Abu Bakar S, Chang LY, Ali AR et al. (2004). Isolation and molecular identification of Nipah virus from pigs. Emerg Infect Dis 10: 2228–2230. Ahmad Sarji A, Abdullah BJ, Tan CT et al. (2000). MR imaging features of Nipah encephalitis. Am J Roentgenol 175: 437–442. Bossart KN, McEachern JA, Hickey AC et al. (2007). Neutralization assays for differential henipavirus serology using Bio-Plex protein array system. J Virol Methods 142: 29–40. Chadha MS, Comer JE, Lowe L et al. (2006). Nipah virus associated encephalitis outbreak, Siliguri, India. Emerg Infect Dis 12: 235–240. Chan YP, Chua KB, Koh CL et al. (2001). Complete nucleotide sequences of Nipah virus isolates from Malaysia. J Gen Virol 82: 2151–2155. Chew NK, Goh KJ, Tan CT et al. (1999). Electroencephalography in acute Nipah encephalitis. Neurol J Southeast Asia 4: 45–51. Chong HT, Tan CT (2003). Relapsed and late-onset encephalitis, a report of 3 cases. Neurol J Southeast Asia 8: 109–112. Chong HT, Kunjapan SR, Thayaparan T et al. (2000). Nipah encephalitis outbreak in Malaysia, clinical features in patients from Seremban. Neurol J Southeast Asia 5: 61–67. Chong HT, Kamarulzaman A, Tan CT et al. (2001a). Treatment of acute Nipah encephalitis with Ribavirin. Ann Neurol 49: 810–813. Chong HT, Tan CT, Goh KJ et al. (2001b). Occupational exposure, age, diabetes mellitus and outcome of acute Nipah encephalitis. Neurol J Southeast Asia 6: 7–11. Chow VTK, Tambyan PA, Yeo WM et al. (2000). Diagnosis of Nipah virus encephalitis by electron microscopy of cerebrospinal fluid. J Clin Virol 143–147. Chua KB (2003). Nipah virus outbreak in Malaysia. J Clin Virol 26: 265–275. Chua KB, Wong KT, Tan CT et al. (1999). Fatal encephalitis due to Nipah virus among pig-farmers in Malaysia. Lancet 354: 1257–1260. Chua KB, Bellini WJ, Rota WJ et al. (2000). Nipah virus: a recently emergent deadly paramyxovirus. Science 288: 1432–1435. Chua KB, Lam SK, Tan CT et al. (2001). High mortality in Nipah encephalitis is associated with presence of virus in cerebrospinal fluid. Ann Neurol 48: 802–805. Chua KB, Chua BH, Wang CW (2002a). Anthropogenic deforestation, El Nino and the emergence of Nipah virus in Malaysia. Malaysian J Pathol 24: 15–21. Chua KB, Koh CL, Hooi PS et al. (2002b). Isolation of Nipah virus from Malaysian flying-foxes. Microbes Infect 4: 145–151. Epstein JH, Prakash V, Smith CS et al. (2008). Henipavirus infection in fruit bats (Pteropus gigenteus), India. Emerg Infect Dis 14: 1309–1311.
669
Goh KJ, Tan CT, Chew NK et al. (2000). Clinical features of Nipah virus encephalitis among pig farmers in Malaysia. N Engl J Med 342: 1229–1235. Goldsmith CS, Whistler T, Rollin PE et al. (2003). Elucidation of Nipah virus morphogenesis and replication using ultrastructural and molecular approaches. Virus Res 92: 89–98. Guillaume V, Lefeuvre A, Faure C et al. (2004). Specific detection of Nipah virus using RT-PCR (Taqman). J Virol Methods 120: 229–237. Gurley ES, Montgomery JM, Hossain MJ et al. (2007). Person to person transmission of Nipah virus in Bangladeshi community. Emerg Infect Dis 13: 1031–1037. Harcourt BH, Tamin A, Ksiazek TG et al. (2001). Molecular characterization of Nipah virus, a newly emergent paramyxovirus. Virology 287: 192–201. Harcourt BH, Lowe T, Tamin A et al. (2005). Genetic characterization of Nipah virus, Bangladesh, 2004. Emerg Infect Dis 1594–1597. Harith AK, Ichhpujani RL, Gupta S et al. (2006). Nipah/ Hendra virus outbreak in Siliguri, West Bengal, India in 2001. Indian J Med Res 123: 553–560. Hayman DTS, Suu-Ire R, Breed AC et al. (2008). Evidence of Henipavirus infection in West African fruit bats. PLoS One 3: e2739. Hossain MJ, Gurley ES, Montgomery JM et al. (2008). Clinical presentation of Nipah virus infection in Bangladesh. Clin Infect Dis 46: 977–984. Hsu VP, Hossain MJ, Parashar UD et al. (2004). Nipah virus encephalitis re-emergence, Bangladesh. Emerg Infect Dis 109: 2082–2087. Iehle, Razafitrimo G, Razainirina J et al. (2007). Henipavirus and Tioman virus antibodies in pteropid bads, Madagascar. Emerg Infect Dis 13: 159–161. Isabel MRH, Massey PD, Walker B et al. (2011). Hendra virus: what do we know? NSW Publ Hlth Bull 22: 118–122. Li Y, Wang J, Hickey AC et al. (2008). Antibody to Nipah and Nipah-like viruses in bats, China. Emerg Infect Dis 14: 1974–1976. Luby SP, Rahman M, Jahangir Hossain M et al. (2006). Foodborne transmission of Nipah virus, Bangladesh. Emerg Infect Dis 12: 1888–1894. Mackenzie JS (1999). Emerging virus disease: an Australian perspective. Emerg Infect Dis 5: 1–8. Montgomery JM, Hossain MJ, Gurley E et al. (2008). Risk factors for Nipah virus encephalitis in Bangladesh. Emerg Infect Dis 14: 1526–1532. Mounts AW, Kaur H, Parashar UD et al. (1999). A cohort study of health care workers to assess nosocomial transmissibility of Nipah virus, Malaysia. J Infect Dis 183: 810–813. Olson JG, Rupprecht C, Rollin PE et al. (2002). Antibody to Nipah-like virus in bats (Pteropus lylei), Cambodia. Emerg Infect Dis 8: 987–988. O’Sullivan JD, Allworth AM, Paterson DL et al. (1997). Fatal encephalitis due to novel paramyxovirus transmitted from horses. Lancet 349: 93–95. Parashar UD, Lye MS, Ong F et al. (2000). Case-control study of risk factors for human infection with the new zoonotic paramyxovirus, Nipah virus, during a 1998–1999 outbreak
670
S. ABDULLAH AND C.T. TAN
of severe encephalitis in Malaysia. J Infect Dis 181: 1755–1759. Paton NI, Leo YS, Zaki SR et al. (1999). Outbreak of Nipah virus infection among abattoir workers in Singapore. Lancet 354: 1253–1256. Playford EG, Mc Call B, Smith G et al. (2010). Human Hendra virus encephalitis associated with equine outbreak, Australia, 2008. Emerg Infect Dis 16: 219–223. Quddus R, Alam S, Majumdar MA et al. (2004). A report of 4 patients with Nipah encephalitis from Rajbari district, Bangladesh in the January 2004 outbreak. Neurol J Southeast Asia 9: 33–37. Ramasundrum V, Tan CT, Chua KB et al. (2000). Kinetics of IgM and IgG seroconversions in Nipah infection. Neurol J Southeast Asia 5: 23–28. Reynes JM, Counor D, Ong S et al. (2005). Nipah virus in Lyle’s flying foxes, Cambodia. Emerg Infect Dis 11: 1042–1047. Sejvar JJ, Hossain J, Saha SK et al. (2007). Long term neurological and functional outcome in Nipah virus infection. Ann Neurol 62: 235–242. Selvey LA, Wells RM, McCormack JG et al. (1995). Infection of humans and horses by a newly described morbillivirus. Med J Aust 162: 642–645. Sim BF, Jusoh MR, Chang CC et al. (2002). Nipah encephalitis: A report of 18 patients from Kuala Lumpur Hospital. Neurol J Southeast Asia 7: 13–18. Siva SR, Chong HT, Tan CT (2009). Ten years clinical and serological outcome of Nipah virus infection. Neurol Asia 14: 53–58.
Tan CT, Tan KS (2001). Nosocomial transmissibility of Nipah virus. J Infect Dis 184: 1367. Tan KS, Tan CT, Goh KJ (1999). Epidemiological aspects of Nipah virus infection. Neurol J Southeast Asia 4: 77–81. Tan KS, Ahmad Sarji S, Tan CT et al. (2000). Patients with asymptomatic Nipah virus infection may have abnormal cerebral MR imaging. Neurol J Southeast Asia 5: 69–73. Tan CT, Goh KJ, Wong KT et al. (2002). Relapsed and lateonset Nipah encephalitis. Ann Neurol 51: 703–708. Wacharapluesade S, Lumlertdacha B, Boongird K et al. (2005). Bat Nipah virus, Thailand. Emerg Infect Dis 11: 1949–1951. Wong KT (2010). Nipah and Hendra viruses: recent advances in pathogenesis. Future Virol 5: 129–131. Wong KT, Tan CT (2012). Clinical and pathological manifestations of human Henipavirus infection. Curr Topics Microbiol Immunol 359: 95–104. Wong KT, Shieh WJ, Kumar S et al. (2002). Nipah virus infection : pathology and pathogenesis of an emerging paramyxoviral zoonosis. Am J Pathol 161: 2153–2167. Yob JM, Field H, Rashdi AM et al. (2001). Nipah virus infection in bats in Peninsular Malaysia. Emerg Infect Dis 7: 439–441. Young PL, Halpin K, Selleck PW et al. (1996). Serologic evidence for the presence in Pteropus bats of a paramyxovirus related to equine morbillivirus. Emerg Infect Dis 2: 239–240.
Chapter 32
Henipavirus encephalitis SUHAILAH ABDULLAH AND CHONG TIN TAN* Division of Neurology, Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
INTRODUCTION In 1994, there was an outbreak of respiratory and neurologic infections affecting horses and humans who had been in close contact with the sick horses. To date, there have been seven human cases, with four mortalities. A new zoonotic virus from the paramyxovirus family was discovered and was named Hendra virus (HeV). In 1998–1999, there was an outbreak of fatal encephalitis among the pig-farming community in Malaysia, involving more than 350 patients, with a mortality rate of 40%. Isolation of a new zoonotic paramyxovirus closely related to HeV, in cerebrospinal fluid (CSF) samples of patients in Sungai Nipah village, Malaysia, led to the discovery of Nipah virus (NiV) as the etiologic agent. Although there have been no more outbreaks since May 1999 in Malaysia, there have been two outbreaks in West Bengal, India: the first in Suliguli in 2001, and the second in Nadia district in 2007. There have been outbreaks almost annually in Bangladesh between 2001 and 2012. These outbreaks were associated with more prominent respiratory symptoms and a higher mortality rate of 70%. The natural reservoir host for the henipaviruses was identified as fruit bats of the Pteropus species based on the presence of neutralizing antibodies to the virus, and isolation of virus from their urine and saliva. The wide geographic distribution of Pteropus bats as the disease vector, which expands from Asia and Australasia to West Africa, makes Henipavirus an important emerging cause of fatal encephalitis.
THE HENIPAVIRUS HeV and NiV can be isolated from patients’ CSF, saliva, urine, pharyngeal and nasal secretions. They grow easily in all types of mammalian cells, but not in insect cell lines (Chua et al., 1999, 2000). They are single-stranded RNA paramyxoviruses, in the genus Henipavirus. Hence, they
share many common characteristic features with other members of the Paramyxoviridae family. In tissue culture, they show a typical cytopathic effect pattern of cell fusion and formation of giant syncytial cells. Histologically, they exhibit a pleomorphic lipid bilayer envelope, with the formation of intracytoplasmic inclusions of viral nucleocapsids that gives rise to the typical “herringbone” appearance in infected cells under negative staining (Chow et al., 2000; Goldsmith et al., 2003). Like their other Paramyxoviridae family, the genomic makeup of both HeV and NiV consists of six genes (N-PM-F-G-L) flanked by a 3’ leader and 5’ trailer region. Both viruses have identical leader and trailer sequence lengths and hexamer-phasing positions for all of their genes (Chan et al., 2001). However, they demonstrate longer genomic length of 18 246 nucleotides for the Malaysian strain of NiV, 18 252 nucleotides for the Bangladesh strain, and 18 234 nucleotides for HeV, as compared to the average of 15 500 nucleotides in other paramyxoviruses (Chan et al., 2001; Harcourt et al., 2001). The Bangladesh NiV strain also exhibits the most genetic variability, with a 92% homology to the Malaysian strain (Harcourt et al., 2005), hence the probability of the more virulent nature of the Bangladesh NiV, associated with a higher mortality rate among the population affected.
EPIDEMIOLOGY The first outbreak of HeV infection occurred in September 1994, in Hendra, Brisbane, Australia, involving 18 horses and two humans. This resulted in 14 deaths among the horses and one human fatality (Selvey et al., 1995). Retrospectively, in August 1994, there was a similar case reported in Mackay, North Queensland, where a person caring and assisting in the autopsy of two sick horses developed aseptic meningitis, initially with full
*Correspondence to: Prof. C.T. Tan, c/o Neurology Laboratory, University Malaya Medical Centre, 59100 Kuala Lumpur, Malaysia. Tel: 03-79672967/2585, E-mail: [email protected]
664
S. ABDULLAH AND C.T. TAN
recovery, but then died from severe encephalitis 13 months later (O’Sullivan et al., 1997). To date, there have been seven reported human cases with four deaths (Playford et al., 2010). The natural reservoir host has been tracked down to the Pteropus bats. The mode of transmission of this virus is via direct contact with respiratory secretions, contaminated tissue, or excretion from infected horses. NiV was first discovered in 1999 during a fatal encephalitis outbreak among the pig-farming community in Peninsular Malaysia. The first outbreak occurred in September 1998, in Tambun, Perak, followed by Negeri Sembilan (Sikamat, Bukit Pelanduk and neighboring Sungai Nipah, Sepang), Selangor (Sungai Buloh) from December 1998 to March 1999, and Singapore in March 1999, where 11 abattoir workers were affected, with one fatality (Fig. 32.1). In total, more than 350 patients were affected, with 40% mortality. Fruit bats of the Pteropus species were the natural reservoir host. The pigs were infected by consuming the half-eaten fruits contaminated by the bats’ saliva or urine, and then acted as an intermediate and amplifying host. Transmission to humans was via close contact with infected pigs or fresh pig products. The risk of human-to-human transmission was low in the Malaysian series (Mounts et al., 1999; Tan and Tan, 2001). The fatal encephalitis outbreak was contained by massive culling of over a million pigs and prohibition of importation of pigs into Singapore from Malaysia. The last human fatality was
THAILAND
MALAYSIA
Perak 1
Selangor
5 6
Negeri Sembilan 2
4 3 Name of towns 1. Tambun 2. Sikamat 3. Bukit Pelandok 4. Sepang 5. Sungai Buloh 6. Kuala Lumpur
SINGAPORE
Fig. 32.1. Map of peninsular Malaysia showing spread of Nipah encephalitis outbreak among neighboring states, then to Singapore. (Reproduced with permission from Sim et al., 2002.)
seen on 27 May 1999, and Malaysia was declared free of NiV in the livestock population by the Office International de Epizooties in June 1999 (Chua, 2003). During the NiV encephalitis outbreaks in Bangladesh and West Bengal, India, multiple modes of transmissions were postulated. The most important was thought to be from bats to humans by consumption of contaminated raw date palm sap in the 2005 Tangail outbreak (Luby et al., 2006), and human-to-human transmission in the 2001 Meherpur and Seliguli, 2003 Naogaon, and 2004 Faridpur outbreaks (Chadha et al., 2006; Gurley et al., 2007). Other modes of transmission were from sick cows and herds of pigs to humans in the 2001 Meherpur and 2003 Naogaon outbreaks (Hsu et al., 2004), and direct contact with bat droppings by children climbing trees in the 2004 Goalanda outbreak (Montgomery et al., 2008); again, the natural reservoir host was identified as fruit bats of the Pteropus species.
THE RESERVOIR HOST When HeV was first discovered in 1994, serologic survey of bat colonies along the eastern coast of Queensland showed positive results among Pteropus species (Young et al., 1996). Since then, up to 42% of wild-caught pteropid bats in Australia have shown serologic evidence of HeV infection (Mackenzie, 1999). In view of the close similarity of these viruses, bats were investigated as the reservoir host for NiV during the Nipah encephalitis outbreak in Malaysia. Neutralizing antibodies to NiV were detected primarily in fruit bats of the Pteropus genus. Subsequently, NiV was isolated from bat urine and swabs of contaminated fruits collected in Tioman Island, Malaysia (Chua et al., 2002b). Further studies revealed that reactive and/or neutralizing antibodies to NiV were detected in Pteropus bats from Malaysia, to Cambodia, Thailand, India, Bangladesh, and Papua New Guinea, and also non-pteropid bats in Madagascar, Ghana, and China (Yob et al., 2001; Olson et al., 2002; Reynes et al., 2005; Wacharapluesade et al., 2005, Iehle et al., 2007; Hayman et al., 2008; Li et al., 2008; Epstein et al., 2008). This indicates that the virus was prevalent in both geographic distribution and species of bats affected. The mode of transmission from bats to pigs/horses remains unclear, but it was postulated that virus transfer occurred through contact with contaminated secretions and/or bat excretions via consumption of half-eaten fruits (Chua et al., 2002b). The infected pigs and horses then act as amplifying hosts, resulting in significant pig-to-pig/horse-to-horse transmission, and subsequent human transmission.
HENIPAVIRUS ENCEPHALITIS
CLINICAL MANIFESTATIONS Both HeV and NiV encephalitis cause rapid fatal encephalitis with a high mortality rate. During the NiV encephalitis outbreak in Malaysia, the incubation period ranged from 4 days to 2 months; 92% of patients became symptomatic in less than 2 weeks (Chong et al., 2000; Goh et al., 2000). The mean age of patients was 37 years (range, 13–68), with a male to female ratio of 4.5:1, and pig farming was an occupational risk factor (Goh et al., 2000). The clustering of cases among family members, with 33% of members having NeV infection, suggested a disease with high infectivity. The ratio of symptomatic and subclinical infection was estimated to be about 3:1; there were 27% symptomatic versus 8% asymptomatic cases in the household (Tan et al., 1999; Parashar et al., 2000). The main presenting clinical features were acute encephalitis with fever, headache, dizziness, and vomiting, with more than 50% of patients having reduced level of consciousness (Chua et al., 1999; Chong et al., 2000; Goh et al., 2000). Distinctive clinical features were areflexia, hypotonia, prominent autonomic disturbance, and segmental myoclonus, which was reported in 32% of patients (Goh et al., 2000). Respiratory involvement, presented as cough, was reported in 14% of Malaysian patients, with atypical pneumonia reported in 3 out of 11 patients in Singapore (Paton et al., 1999; Chong et al., 2000). The mortality rate during the Malaysia NiV encephalitis outbreak was 40%. The mean time from onset of illness to death was 10.3 days. The indicators of poor prognosis were: ● ● ● ●
● ● ●
Older age (Chong et al., 2000; Goh et al., 2000) Concomitant diabetes mellitus, probably due to immunoparesis (Chong et al., 2001b) Elevated hepatic aminotransferase and thrombocytopenia on admission (Goh et al., 2000) Brainstem involvement, as evidenced by reduced level of consciousness, abnormal doll’s eye reflex, hypertension, tachycardia (Chong et al., 2000; Goh et al., 2000) Presence of seizures, segmental myoclonus, areflexia (Goh et al., 2000) Isolation of NiV in the CSF (Chua et al., 2001) Presence of independent bitemporal periodic complexes on the background of diffuse slow waves on electroencephalogram – associated with 100% mortality (Chew et al., 1999).
Patients with normal conscious level recovered fully. Twenty-two percent of surviving patients had residual neurologic deficits that ranged from mild cerebellar disabilities to significant cognitive impairment and vegetative state (Goh et al., 2000).
665
The NiV encephalitis outbreaks in Bangladesh and India showed a wider age range from 12 to 70 years old (Harith et al., 2006). There was no occupational linkage as the mode of transmission was postulated to be multifactorial. The incubation period was shorter than the Malaysian outbreak, with a range of 6–11 days (Hossain et al., 2008). Although acute encephalitis was the prominent clinical manifestation, there was significant respiratory involvement, which presented as cough and respiratory distress in up to 70% of patients (Chadha et al., 2006; Hossain et al., 2008). Nevertheless, segmental myoclonus, which was one of the poor prognostic indicators in the Malaysian series, was not observed. A higher mortality rate of 70% was observed in the Bangladesh and India outbreaks. The mean time from onset of illness to death was also shorter, ranging from 4 to 6 days (Hsu et al., 2004; Hossain et al., 2008). Though suboptimal medical access may play a role, the probability of a more virulent NiV strain in view of its longer genomic nucleotides needs to be considered and investigated. HeV infection manifests as influenza-like illness with fever, headache, and myalgia that can progress to pneumonia with respiratory distress, or encephalitis with confusion and reduced level of consciousness (O’Sullivan et al., 1997; Playford et al., 2010). The incubation period was estimated at 5–21 days, with a mortality rate of more than 50% (Playford et al., 2010). To date, there have been seven reported human cases, with four mortalities.
PATHOLOGY The pathologic hallmark of acute NiV encephailitis was vasculitis of medium to small-sized blood vessels, causing disseminated microinfarctions, with or without thrombosis, as well as direct neuronal infection by the virus (Wong et al., 2002; Wong and Tan, 2012) (Fig. 32.2). The earliest lesion was the formation of multinucleated syncytium in the endothelium. Inflammatory cells, consisting of neutrophils, lymphocytes, macrophages, and plasma cells, were found within the endothelium. Vasculitis was frequently associated with vascular occlusions and subsequent necrosis and infarcts. Examination of the brain parenchymal inflammation revealed perivascular cuffing and neurophagia. The surviving neurons showed paramyxoviral-type inclusions. Both vessels and neurons showed presence of viral antigen on immunohistochemical staining, indicating the ability of NiV to infect the blood vessel and neurons directly. The brain was the most severely affected organ, hence, it was consistent with acute encephalitis as a prominent clinical presentation. This was followed by the lungs, kidneys, heart, and lymphoid organs. Similar patterns of vasculitis and disseminated microinfarcts were seen
666
S. ABDULLAH AND C.T. TAN
Fig. 32.2. (A) Cerebral cortex with microinfarct associated with vascular thrombosis. (Hematoxylin & eosin stain, magnification 4 objective). (B) Nipah antigen in neurons detected by immunohistochemistry. (Magnification 40 objective.) (Courtesy of Dr. K.T. Wong, University of Malaya.)
in these organs, coupled with detection of viral antigen on immunohistochemical staining. The dual pathogenetic mechanisms of vasculitis-induced microinfarctions and direct neuronal damage in multiple organs appeared to be unique in this virus pathogenesis (Wong and Tan, 2012). There is limited knowledge regarding the pathologic findings in HeV encephalitis as published data are based on a single case. Nevertheless, it is believed that both viruses cause similar pathology.
LABORATORY, RADIOLOGIC, AND DIAGNOSTIC INVESTIGATIONS Basic bloods investigation, such as full blood count, liver function test, and CSF examination, were non-specific. During the Malaysian NiV encephalitis, thrombocytopenia and leukopenia were seen in 30% and 11% respectively. Elevated transaminases were seen in 30–45% of patients upon hospital admission. Though these findings were non-specific for NiV encephalitis, elevated transaminases and thrombocytopenia on admission were associated with poor prognosis (Goh et al., 2000). CSF examination revealed lymphocytic pleocytosis and elevated protein levels in 75% and 77% respectively. Though these findings were non-specific, viral isolation from the CSF was associated with high mortality (Chua et al., 2001). The diagnostic laboratory test for NiV encephalitis consisted of detection of anti-NiV immunoglobulin M (IgM) and IgG antibody in the serum and CSF, with or without viral isolation. The anti-NiV-specific IgM was detected by direct enzyme-linked immunoabsorbent assay (ELISA), while the IgG antibody utilized the indirect IgG ELISA (Chua et al., 1999). The rate of positivity
was 60–71% by day 4 and 100% by day 12 of illness. On the other hand, the IgG was positive in 7–29% by day 1–10, and 100% by day 25–26 of illness (Ramasundrum et al., 2000). The IgG were persistently positive whereas the IgM became negative by 10 years of illness (Siva et al., 2009). Other testing methods include serum neutralizing tests (Bossart et al., 2007) and realtime polymerase chain reaction (RT-PCR) for detection of viral RNA from serum, urine, and CSF (Abu Bakar et al., 2004; Guillaume et al., 2004). Less is known regarding the laboratory changes in HeV encephalitis. However, neutropenia, thrombocytopenia, elevated CSF protein, and pleocytosis have been documented in some patients with HeV encephalitis. The viral RNA can be detected using the quantitative RT-PCR performed at baseline and at 3 and 6 weeks of exposure. ELISA and serum neutralizing test could be used for antibody detection. However, the diagnostic sensitivity of the ELISA was not well established (Isabel et al., 2011). Magnetic resonance imaging (MRI) of the brain was a sensitive diagnostic tools in acute and relapse/late-onset NiV encephalitis. The MRI in Malaysian acute NiV encephalitis showed characteristic discrete and disseminated hyperintense lesions best seen in the fluid attenuated inversion recovery (FLAIR) sequences (Fig. 32.3), which represent widespread microinfarctions on brain autopsy (Ahmad Sarji et al., 2000). However, there was poor correlation between severity of neurologic status and MRI findings. Sixteen percent of asymptomatic patients also showed similar changes on MRI, suggesting subclinical cerebral involvement (Tan et al., 2000). The Malaysian MRI findings in acute NiV encephalitis differed from those of the Bangladesh series, where there was confluent cortical involvement rather than
HENIPAVIRUS ENCEPHALITIS
667
Fig. 32.3. Magnetic resonance imaging. (A) Axial T2W and (B) coronal fluid attenuated inversion recovery of the brain, showing characteristic discrete and disseminated hyperintense lesions in the subcortical and deep white matter of the parietal lobes (white arrows) in Malaysian acute Nipah virus encephalitis. (Adapted from Abdullah et al., 2012 with permission.)
discrete disseminated lesions (Quddus et al., 2004). This could be associated with the variation in the viral genomic sequence. Similar changes were noted in HeV encephalitis (Playford et al., 2010). The most common finding on electroencephalogram (EEG) was diffuse polymorphic slow waves; this was non-specific but correlated well with the severity of illness. The presence of independent bitemporal periodic complexes carried a poor prognosis, with mortality of 100% (Chew et al., 1999). A similar pattern of diffuse slowing was seen in HeV encephalitis that improved with clinical improvement (Playford et al., 2010).
RELAPSED AND LATE-ONSET ENCEPHALITIS Relapsed encephalitis is defined as patients presenting with another neurologic manifestation after recovery from acute encephalitis. Late-onset encephalitis, on the other hand, is defined as the appearance of neurologic presentation for the first time 10 weeks after initial exposure (Tan et al., 2002). The prevalence of relapsed NiV encephalitis and late-onset encephalitis in Malaysia was approximately 9% and 5% respectively (Tan et al., 2002; Chong and Tan, 2003). The longest interval for late-onset encephalitis was 11 years after the initial exposure (average 8.4 months), with a relapse occurring 1 year later (Abdullah et al., 2012). The clinical manifestations were as for acute encephalitis. However, fewer patients had fever, and a higher proportion had seizures and focal cortical signs (Chong et al., 2000). This was supported by MRI findings of confluent cortical involvement (Fig. 32.4), as opposed to discrete and disseminated lesions in acute NiV encephalitis (Ahmad Sarji et al., 2000).
Fig. 32.4. Magnetic resonance imaging axial fluid attenuated inversion recovery image in Malaysian relapsed and late-onset Nipah encephalitis showing confluent hyperintense lesions located at anterior temporal lobes bilaterally, affecting the white matter and cortex (arrows), as opposed to discrete and disseminated lesions in acute Nipah virus encephalitis. (Adapted from Abdullah et al., 2012 with permission.)
The pathologic findings revealed confluent inflammation of the brain parenchyma with demonstration of neuronal viral antigen, corresponding to the MRI findings. However, there was no vasculitis or perivenous demyelination, suggesting that relapse and late-onset
668
S. ABDULLAH AND C.T. TAN
NiV encephalitis were the result of recurrent infection rather than postinfectious demyelination following other paramyxovirus infection (Tan et al., 2002). In contrast to acute NiV encephalitis, no NiV was isolated from patients’ secretion, excretion, and CSF, though viral antigen could be demonstrated by positive immunolocalization. This suggests that NiV, like the measles virus in subacute sclerosing panencephalitis, could have undergone mutations, resulting in the failure of viral morphogenesis at the cell membrane (Tan et al., 2002). The mortality rate was 18%. However, patients have worse neurologic outcomes, with 61% having residual neurologic deficits, compared to 22% after acute NiV encephalitis (Goh et al., 2000; Tan et al., 2002). Among the 22 survivors in Bangladesh, 18% developed relapsed encephalitis manifesting as ophthalmoplegia and cervical dystonia (Sejvar et al., 2007). The pathologic hallmark of relapsed encephalitis is neuronal inflammation, with more prominent and abundant viral inclusion, and extensive confluent parenchymal necrosis, giving rise to focal encephalitis (Tan et al., 2002; Wong, 2010). Hence, focal neurologic signs are the prominent clinical manifestation in relapsed Henipavirus encephalitis. To date, there has been one reported case of relapse in HeV encephalitis that occurred 13 months after a complete recovery from the initial event (O’Sullivan et al., 1997). The MRI showed similar confluent lesions as per relapsed NiV encephalitis. Despite evidence of encephalitis on tissue necropsy with positive staining for HeV viral antigen, no virus was isolated.
TREATMENT The most important mode of treatment in acute Nipah encephalitis remains supportive, with mechanical ventilation, anticonvulsants for patients with seizures, prevention of deep venous thrombosis, and broad-spectrum antibiotic for nosocomial infection (Goh et al., 2000). A broad-spectrum virustatic antiviral agent, ribavirin, was used in the treatment of both acute HeV and NiV encephalitis. This was associated with a 36% reduction of mortality during the Malaysian outbreak (Chong et al., 2001a). Potential therapeutic treatments include soluble versions of G glycoprotein and Ephrin B2, that have been shown to inhibit NeV envelope-mediated infection. Asprin and pentoxifillyne may be used as prophylaxis against vasculitis-induced thrombosis, on the basis of pathologic changes of disseminated microinfarctions from vasculitis on autopsy (Goh et al., 2000).
PREVENTION Henipavirus is a recognized source of zoonotic infection, with bats of the Pteropus species identified as the
reservoir host. A complex interplay of multiple factors was postulated to be the reason for the spillage of this virus into the domestic animal population and subsequent transmission to humans. This includes substantial deforestation and severe haze from anthropogenic forest fires that have resulted in the reduction of wildlife habitats, hence encroachment of these fruit bats into the fruit orchards and subsequent contact with domestic animals and humans. As for the Malaysian NiV encephalitis outbreak, the mixed agro–pig farming practices and poor design of pigsties were important means for disease transmissibility (Chua et al., 2002a). The wide geographic distribution of Henipavirus and its reservoir host, and the ease of virus transmissibility make HeV and NiV important causes of zoonotic infection. Table 32.1 lists the clinical features that may indicate possible Henipavirus infection in areas where the infection is not known to be endemic. Although there was an early response to developing livestock vaccines to prevent viral re-emergence, good surveillance and culling of infected domestic animals were key to rapid control of disease propagation. In Bangladesh, the use of bamboo skirts to prevent access of bats to date palm sap and avoidance of consumption of raw date palm juice are important measures to prevent food-borne transmission. A good practice of general hygiene, such as hand washing, and barrier nursing within the hospital setting can prevent human-to-human transmission. Education on proper handling of sick animals and good general hygiene among horse handlers and pig farmers is essential to prevent spread of infection. Overall, a deeper understanding of the environmental and epidemiologic factors that favor spillover of this virus into the domestic animal population is crucial to prevent re-emergence of this fatal zoonotic encephalitis.
Table 32.1 Clinical features that may indicate possible Henipavirus infection in areas where the infection is not known to be endemic 1. History of illness in animals, such as pigs or horses, that may be exposed to Pteropus or other fruit bats 2. Clustering of cases in the same household or geographic area that may suggest an outbreak 3. Clustering of cases that may suggest zoonosis or human-tohuman spread of infection; e.g., illness involving animal workers, healthcare workers, or family members 4. Acute febrile illness involving neurologic or respiratory systems Patients to be screened by Henipavirus serology or polymerase chain reaction and magnetic resonance imaging
HENIPAVIRUS ENCEPHALITIS
REFERENCES Abdullah S, Chang LY, Rahmat K et al. (2012). Late-onset Nipah virus encephalitis 11 years after the initial outbreak: a case report. Neurol Asia 17: 71–74. Abu Bakar S, Chang LY, Ali AR et al. (2004). Isolation and molecular identification of Nipah virus from pigs. Emerg Infect Dis 10: 2228–2230. Ahmad Sarji A, Abdullah BJ, Tan CT et al. (2000). MR imaging features of Nipah encephalitis. Am J Roentgenol 175: 437–442. Bossart KN, McEachern JA, Hickey AC et al. (2007). Neutralization assays for differential henipavirus serology using Bio-Plex protein array system. J Virol Methods 142: 29–40. Chadha MS, Comer JE, Lowe L et al. (2006). Nipah virus associated encephalitis outbreak, Siliguri, India. Emerg Infect Dis 12: 235–240. Chan YP, Chua KB, Koh CL et al. (2001). Complete nucleotide sequences of Nipah virus isolates from Malaysia. J Gen Virol 82: 2151–2155. Chew NK, Goh KJ, Tan CT et al. (1999). Electroencephalography in acute Nipah encephalitis. Neurol J Southeast Asia 4: 45–51. Chong HT, Tan CT (2003). Relapsed and late-onset encephalitis, a report of 3 cases. Neurol J Southeast Asia 8: 109–112. Chong HT, Kunjapan SR, Thayaparan T et al. (2000). Nipah encephalitis outbreak in Malaysia, clinical features in patients from Seremban. Neurol J Southeast Asia 5: 61–67. Chong HT, Kamarulzaman A, Tan CT et al. (2001a). Treatment of acute Nipah encephalitis with Ribavirin. Ann Neurol 49: 810–813. Chong HT, Tan CT, Goh KJ et al. (2001b). Occupational exposure, age, diabetes mellitus and outcome of acute Nipah encephalitis. Neurol J Southeast Asia 6: 7–11. Chow VTK, Tambyan PA, Yeo WM et al. (2000). Diagnosis of Nipah virus encephalitis by electron microscopy of cerebrospinal fluid. J Clin Virol 143–147. Chua KB (2003). Nipah virus outbreak in Malaysia. J Clin Virol 26: 265–275. Chua KB, Wong KT, Tan CT et al. (1999). Fatal encephalitis due to Nipah virus among pig-farmers in Malaysia. Lancet 354: 1257–1260. Chua KB, Bellini WJ, Rota WJ et al. (2000). Nipah virus: a recently emergent deadly paramyxovirus. Science 288: 1432–1435. Chua KB, Lam SK, Tan CT et al. (2001). High mortality in Nipah encephalitis is associated with presence of virus in cerebrospinal fluid. Ann Neurol 48: 802–805. Chua KB, Chua BH, Wang CW (2002a). Anthropogenic deforestation, El Nino and the emergence of Nipah virus in Malaysia. Malaysian J Pathol 24: 15–21. Chua KB, Koh CL, Hooi PS et al. (2002b). Isolation of Nipah virus from Malaysian flying-foxes. Microbes Infect 4: 145–151. Epstein JH, Prakash V, Smith CS et al. (2008). Henipavirus infection in fruit bats (Pteropus gigenteus), India. Emerg Infect Dis 14: 1309–1311.
669
Goh KJ, Tan CT, Chew NK et al. (2000). Clinical features of Nipah virus encephalitis among pig farmers in Malaysia. N Engl J Med 342: 1229–1235. Goldsmith CS, Whistler T, Rollin PE et al. (2003). Elucidation of Nipah virus morphogenesis and replication using ultrastructural and molecular approaches. Virus Res 92: 89–98. Guillaume V, Lefeuvre A, Faure C et al. (2004). Specific detection of Nipah virus using RT-PCR (Taqman). J Virol Methods 120: 229–237. Gurley ES, Montgomery JM, Hossain MJ et al. (2007). Person to person transmission of Nipah virus in Bangladeshi community. Emerg Infect Dis 13: 1031–1037. Harcourt BH, Tamin A, Ksiazek TG et al. (2001). Molecular characterization of Nipah virus, a newly emergent paramyxovirus. Virology 287: 192–201. Harcourt BH, Lowe T, Tamin A et al. (2005). Genetic characterization of Nipah virus, Bangladesh, 2004. Emerg Infect Dis 1594–1597. Harith AK, Ichhpujani RL, Gupta S et al. (2006). Nipah/ Hendra virus outbreak in Siliguri, West Bengal, India in 2001. Indian J Med Res 123: 553–560. Hayman DTS, Suu-Ire R, Breed AC et al. (2008). Evidence of Henipavirus infection in West African fruit bats. PLoS One 3: e2739. Hossain MJ, Gurley ES, Montgomery JM et al. (2008). Clinical presentation of Nipah virus infection in Bangladesh. Clin Infect Dis 46: 977–984. Hsu VP, Hossain MJ, Parashar UD et al. (2004). Nipah virus encephalitis re-emergence, Bangladesh. Emerg Infect Dis 109: 2082–2087. Iehle, Razafitrimo G, Razainirina J et al. (2007). Henipavirus and Tioman virus antibodies in pteropid bads, Madagascar. Emerg Infect Dis 13: 159–161. Isabel MRH, Massey PD, Walker B et al. (2011). Hendra virus: what do we know? NSW Publ Hlth Bull 22: 118–122. Li Y, Wang J, Hickey AC et al. (2008). Antibody to Nipah and Nipah-like viruses in bats, China. Emerg Infect Dis 14: 1974–1976. Luby SP, Rahman M, Jahangir Hossain M et al. (2006). Foodborne transmission of Nipah virus, Bangladesh. Emerg Infect Dis 12: 1888–1894. Mackenzie JS (1999). Emerging virus disease: an Australian perspective. Emerg Infect Dis 5: 1–8. Montgomery JM, Hossain MJ, Gurley E et al. (2008). Risk factors for Nipah virus encephalitis in Bangladesh. Emerg Infect Dis 14: 1526–1532. Mounts AW, Kaur H, Parashar UD et al. (1999). A cohort study of health care workers to assess nosocomial transmissibility of Nipah virus, Malaysia. J Infect Dis 183: 810–813. Olson JG, Rupprecht C, Rollin PE et al. (2002). Antibody to Nipah-like virus in bats (Pteropus lylei), Cambodia. Emerg Infect Dis 8: 987–988. O’Sullivan JD, Allworth AM, Paterson DL et al. (1997). Fatal encephalitis due to novel paramyxovirus transmitted from horses. Lancet 349: 93–95. Parashar UD, Lye MS, Ong F et al. (2000). Case-control study of risk factors for human infection with the new zoonotic paramyxovirus, Nipah virus, during a 1998–1999 outbreak
670
S. ABDULLAH AND C.T. TAN
of severe encephalitis in Malaysia. J Infect Dis 181: 1755–1759. Paton NI, Leo YS, Zaki SR et al. (1999). Outbreak of Nipah virus infection among abattoir workers in Singapore. Lancet 354: 1253–1256. Playford EG, Mc Call B, Smith G et al. (2010). Human Hendra virus encephalitis associated with equine outbreak, Australia, 2008. Emerg Infect Dis 16: 219–223. Quddus R, Alam S, Majumdar MA et al. (2004). A report of 4 patients with Nipah encephalitis from Rajbari district, Bangladesh in the January 2004 outbreak. Neurol J Southeast Asia 9: 33–37. Ramasundrum V, Tan CT, Chua KB et al. (2000). Kinetics of IgM and IgG seroconversions in Nipah infection. Neurol J Southeast Asia 5: 23–28. Reynes JM, Counor D, Ong S et al. (2005). Nipah virus in Lyle’s flying foxes, Cambodia. Emerg Infect Dis 11: 1042–1047. Sejvar JJ, Hossain J, Saha SK et al. (2007). Long term neurological and functional outcome in Nipah virus infection. Ann Neurol 62: 235–242. Selvey LA, Wells RM, McCormack JG et al. (1995). Infection of humans and horses by a newly described morbillivirus. Med J Aust 162: 642–645. Sim BF, Jusoh MR, Chang CC et al. (2002). Nipah encephalitis: A report of 18 patients from Kuala Lumpur Hospital. Neurol J Southeast Asia 7: 13–18. Siva SR, Chong HT, Tan CT (2009). Ten years clinical and serological outcome of Nipah virus infection. Neurol Asia 14: 53–58.
Tan CT, Tan KS (2001). Nosocomial transmissibility of Nipah virus. J Infect Dis 184: 1367. Tan KS, Tan CT, Goh KJ (1999). Epidemiological aspects of Nipah virus infection. Neurol J Southeast Asia 4: 77–81. Tan KS, Ahmad Sarji S, Tan CT et al. (2000). Patients with asymptomatic Nipah virus infection may have abnormal cerebral MR imaging. Neurol J Southeast Asia 5: 69–73. Tan CT, Goh KJ, Wong KT et al. (2002). Relapsed and lateonset Nipah encephalitis. Ann Neurol 51: 703–708. Wacharapluesade S, Lumlertdacha B, Boongird K et al. (2005). Bat Nipah virus, Thailand. Emerg Infect Dis 11: 1949–1951. Wong KT (2010). Nipah and Hendra viruses: recent advances in pathogenesis. Future Virol 5: 129–131. Wong KT, Tan CT (2012). Clinical and pathological manifestations of human Henipavirus infection. Curr Topics Microbiol Immunol 359: 95–104. Wong KT, Shieh WJ, Kumar S et al. (2002). Nipah virus infection : pathology and pathogenesis of an emerging paramyxoviral zoonosis. Am J Pathol 161: 2153–2167. Yob JM, Field H, Rashdi AM et al. (2001). Nipah virus infection in bats in Peninsular Malaysia. Emerg Infect Dis 7: 439–441. Young PL, Halpin K, Selleck PW et al. (1996). Serologic evidence for the presence in Pteropus bats of a paramyxovirus related to equine morbillivirus. Emerg Infect Dis 2: 239–240.