Ophthalmic Features of Nipah Virus

Key Points at a Glance

Key Points at a Glance

• Nipah virus (NiV) is an RNA virus of the Paramyxoviridae family, genus Henipavirus, with a case fatality rate (CFR) of 40–75%.
• Ophthalmic complications include cranial nerve palsies (CN3, CN6), Horner syndrome, nystagmus, and branch retinal artery occlusion (BRAO).
• Delayed ocular complications may appear months to one year after initial infection.
• Abnormal doll’s eye reflex (87% of fatal cases) and pinpoint pupils (97% of fatal cases), indicating brainstem involvement, are poor prognostic indicators.
• Definitive diagnosis is made by RT-PCR. No approved treatment exists; management is primarily supportive.
• Ribavirin was associated with reduced mortality in some studies, but its efficacy has not been established.

1. Ophthalmic Features of Nipah Virus

Nipah virus (NiV) is an enveloped, negative-sense single-stranded RNA virus belonging to the genus Henipavirus in the family Paramyxoviridae. It was first identified in 1998 in Sungai Nipah village, Malaysia. The natural reservoir is flying foxes of the genus Pteropus, which are distributed across Southeast Asia, the South Pacific, and Australia. It is classified as a Biosafety Level 4 (BSL-4) pathogen.

The WHO has recorded 429 cases and 307 deaths across 25 outbreaks. The main epidemic regions and scales are as follows^{1, 2)}.

Epidemic region/year	Number of cases	CFR
Malaysia 1998–1999	265 cases	38.5%
Bangladesh 2001–2015 (17 outbreaks)	261 cases	75.9%
India (4 outbreaks)	92 cases	73.9%
Philippines 2014	17 cases	52.9%

The main clinical features of NiV infection are systemic symptoms such as fever and encephalitis, but it is known to be accompanied by ophthalmic and neuro-ophthalmic complications. This article focuses on these ophthalmic features.

Q In which regions does Nipah virus occur?

A

Recurrent outbreaks have been reported mainly in South and Southeast Asia. Outbreaks have been confirmed in Malaysia, Bangladesh, India, and the Philippines, with many occurrences in areas overlapping the habitat of the natural host, fruit bats (Pteropus) ²⁾.

2. Main symptoms and clinical findings

Subjective symptoms

Systemic symptoms (first 2 weeks after onset)

• Fever: Most common, reported in 80% of cases in a systematic review (68 cases)¹⁾.
• Headache and myalgia: Each reported in 47%¹⁾.
• Dyspnea/ARDS: 44.1%. Altered mental status at similar rate¹⁾.
• Vomiting: 42.6%¹⁾.
• Neurological symptoms: Disorientation, confusion, somnolence, coma, convulsions, myoclonus, cerebellar dysfunction.

Ocular symptoms

• Blurred vision
• Double vision
• Transient vision loss
• Photophobia

Clinical Findings

Neuro-ophthalmologic Findings in the Acute Phase

In an analysis of 94 cases from the Malaysia outbreak, the following findings were confirmed.

• Decreased level of consciousness (GCS <15): observed in 55%.
• Abnormal doll’s eye reflex: an indicator of brainstem dysfunction observed in 87% of fatal cases.
• Pinpoint pupils: an indicator of brainstem dysfunction observed in 97% of fatal cases.

Delayed Ocular Complications

Several delayed ocular complications following NiV infection have been reported.

Cranial Nerve Palsy

Oculomotor nerve palsy (CN3): Observed in 2 of 22 survivors. Appeared several months to 1 year after initial infection. 2 of 4 cases of delayed cranial nerve palsy were CN3 palsy.

Abducens nerve palsy (CN6): Cause of persistent diplopia. Reported in 3 of 92 cases (4.4%) in a systematic review ¹⁾. May persist as a sequela after discharge.

Other Ocular Complications

Horner syndrome: One case reported left-sided Horner syndrome (ptosis, miosis, anhidrosis of forehead) 9 months after infection. Electrophysiological testing showed C8-T1 denervation, and MRI confirmed C7 spinal cord lesion.

Branch retinal artery occlusion (BRAO): BRAO was confirmed in one case with unilateral blurred vision 1 month after discharge (by fluorescein angiography).

The frequency of ocular findings in a systematic review (92 cases) is as follows¹⁾.

• Nystagmus: 3 cases (4.4%)
• Sixth cranial nerve palsy: 3 cases (4.4%)
• Diplopia: 2 cases (2.9%)
• Transient vision loss, Horner syndrome, blurred vision, bilateral ptosis: Each reported in 1 or more cases

Q When do ocular symptoms typically appear?

A

Ocular symptoms include acute-phase symptoms and delayed-onset symptoms. Delayed cranial nerve palsy may appear several months to one year after the initial infection. BRAO has been reported to occur one month after hospital discharge, and long-term ophthalmological follow-up is important even after recovery.

3. Causes and Risk Factors

Pathogen: NiV belongs to the family Paramyxoviridae, genus Henipavirus, and has two main strains: NiV-M (Malaysia) and NiV-B (Bangladesh). The genomes of the two strains are 91.8% homologous, but NiV-B causes more respiratory symptoms, more human-to-human transmission, and has a higher CFR (approximately 75% vs 40%) ²⁾.

Transmission routes: A systematic review found that human-to-human direct contact accounted for 59.76%, zoonotic transmission 37.8%, and contaminated food 2.44% ¹⁾.

• Bat → Human: Ingestion of contaminated date palm sap or fruit is the main route.
• Animal → Human: Contact with infected pigs (main cause of the initial Malaysian outbreak), slaughter of horses and consumption of horse meat (Philippines 2014) ²⁾.
• Human-to-human: Droplets, respiratory secretions, and contact with body fluids. This has been the main route of transmission since the outbreak in Bangladesh^{1, 2)}.

Risk factors:

• Close contact with pigs and horses: Pig farmers, slaughterhouse workers²⁾.
• Consumption of raw date palm sap²⁾.
• Nurses and healthcare workers caring for infected patients: Risk of nosocomial infection¹⁾.

Prevention and daily care

• Cover the collection site of date palm sap and boil it before consumption.
• Wash fruits thoroughly and peel them before eating. Discard fruits with bat bite marks.
• Wear gloves and protective clothing when handling sick animals.
• Avoid unprotected contact with infected individuals and practice strict hand hygiene.

Q How can infection via date palm sap be prevented?

A

Covering the sap collection site to prevent bat contact is effective. Additionally, boiling raw sap before consumption can inactivate the virus. It is also recommended to discard fruits with bat bite marks.

4. Diagnosis and Testing Methods

Definitive Diagnosis

• RT-PCR (Gold Standard): Collect specimens from throat/nasal swabs, cerebrospinal fluid (CSF), urine, and blood. A systematic review reported its use in 81.8% of cases¹⁾.
• Specimen Collection and Transport: Safe collection and triple-container packaging, transport at 2–8°C. For storage exceeding 48 hours, keep at -20°C¹⁾.
• Virus Isolation: Performed in BSL-4 facilities using Vero cell lines. Cytopathic effect (CPE) can be observed within 3 days¹⁾.

Serological Tests (ELISA)

Test method	Detectable period	Duration
IgM ELISA	1 week after symptom onset	Approximately 3 months
IgG ELISA	2 weeks after onset	8 months or more

In a systematic review, IgM ELISA was used in 35% of cases and IgG ELISA in 22.07% of cases¹⁾.

Laboratory Tests

• CBC: Thrombocytopenia and leukopenia are common.
• Liver function tests: Elevated liver enzymes.
• CSF examination: Increased white blood cell count and protein.

Imaging Studies

• Brain MRI: Multiple small (2–7 mm) hyperintense lesions on T2-weighted images, predominantly in subcortical and deep white matter, periventricular regions, and corpus callosum.
• Evaluation of Horner syndrome: Brain MRI and head/neck MRA (with or without contrast) are recommended (ACR Appropriateness Criteria).

Ophthalmic Evaluation

• Evaluation of CN3 palsy: Ocular motility testing in H-pattern, penlight pupil examination.
• Evaluation of CN6 palsy: Check abduction in each eye.
• Evaluation of Horner syndrome: 1% apraclonidine eye drops (miosis → mydriasis indicates positive). After confirming Horner syndrome with cocaine (4–10%) eye drops, use tyramine (1–2%) or hydroxyamphetamine (1%) eye drops to differentiate preganglionic from postganglionic lesions.
• Doll’s eye reflex: Assess conjugate eye movements during passive head rotation. Indicates brainstem function.
• BRAO: Fundus examination shows segmental retinal whitening and arterial narrowing. Confirmed by OCT and fluorescein angiography (FA).

Differential diagnosis of cranial nerve palsy

In the differential diagnosis of abducens nerve (CN6) palsy, Miller Fisher syndrome (triad of ophthalmoplegia, ataxia, and areflexia) should also be considered. In oculomotor nerve (CN3) palsy, the presence or absence of pupillary dilation is an important distinguishing point, and pupillary sparing is common in vascular palsy.

5. Standard Treatment

There is no approved treatment for NiV infection. Symptomatic treatment (rest, hydration, organ support) is the mainstay of therapy. No specific treatment for ocular complications has been established.

Ribavirin

It is the most studied antiviral drug for NiV infection.

• Malaysia 1999: An open-label trial of 140 cases correlated with a 36% reduction in mortality²⁾.
• The second study of the same outbreak (78% of 94 cases used ribavirin) did not show a significant reduction in mortality²⁾.
• Kerala 2018: Oral ribavirin in 6 cases was reported to reduce mortality by 20% compared to the untreated group (100% mortality)¹⁾.
• Animal experiments: Does not prevent death but may delay it by up to 5 days.
• Indian National Centre for Disease Control recommends ribavirin for NiV infection (not recommended for post-exposure prophylaxis)²⁾.
• Dosage (based on WHO Lassa fever criteria): Pediatric loading dose 30 mg/kg, adult 2000 mg/kg, followed by 10 days of treatment¹⁾.

Acyclovir

In 1999, it was used in 9 slaughterhouse workers in Singapore, and 8 survived. However, the causal relationship is unknown ²⁾. It is considered when encephalitis is suspected ¹⁾.

Post-exposure prophylaxis

In Kerala, 8 healthcare workers received prophylactic ribavirin, and none developed NiV infection ²⁾.

Precautions in treatment

• No antiviral drugs are formally approved for NiV.
• Data on the efficacy of ribavirin are inconsistent, and there is no established evidence.
• There is also no specific treatment for ophthalmic complications (cranial nerve palsy, Horner syndrome, BRAO).

Q Are there currently any effective treatments for Nipah virus infection?

A

Currently, there are no approved treatments for NiV infection. Ribavirin has been correlated with reduced mortality in some studies, but its efficacy is not established. Symptomatic treatment is the mainstay of therapy^{1, 2)}.

6. Pathophysiology and Detailed Pathogenesis

Viral Entry Mechanism

NiV enters cells through a two-step process: binding to host receptors and membrane fusion.

• NiV-G protein: Binds to host receptors ephrin-B2 and ephrin-B3. Ephrin-B2 is highly expressed on endothelial cells, smooth muscle-associated vasculature, airway epithelium, and neurons, while ephrin-B3 is abundant in the CNS²⁾.
• NiV-F protein: Mediates pH-independent membrane fusion. Binding of G protein to ephrin triggers F protein activation, enabling membrane fusion²⁾.

Routes of Transmission Within the Body

After entry via the oral-nasal route, initial replication occurs in the airway epithelium (lymphoid tissue, bronchiolar epithelium). After breaching the epithelial barrier, circulating leukocytes carry the virus via heparan sulfate (without infecting the cells themselves)¹⁾.

There are two mechanisms for CNS invasion²⁾.

1. Hematogenous dissemination: Infected endothelial cells and leukocytes cross the blood-brain barrier (BBB).
2. Olfactory nerve pathway: Anterograde movement from olfactory mucosa → olfactory nerve → olfactory bulb.

Vascular pathology and mechanisms of ocular complications

The central pathology in NiV infection is small vessel vasculitis²⁾.

• Endothelial necrosis and inflammatory infiltration: The virus directly infects endothelial cells, causing cytopathic effects.
• Syncytia formation: Multinucleated giant cells are formed. Characteristic expression of viral glycoproteins on the surface of infected cells¹⁾.
• Necrotic plaques: Observed in almost all cases of brain parenchyma²⁾.

The pathophysiology of ocular complications is as follows.

• Endothelial injury due to small vessel vasculitis → thrombosis, ischemia, and microinfarction occur in the eye and visual pathway.
• CN3 palsy, CN6 palsy, Horner syndrome, and BRAO are thought to result from this vasculitis.

Immune evasion and high lethality

NiV evades the innate immune response by inhibiting interferon activity, contributing to its high mortality rate¹⁾.

In the initial Malaysian outbreak, the disease progressed rapidly, with an average of 3.3 days from fever onset to hospitalization and 9.5 days from fever onset to death²⁾.

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7. Latest Research and Future Prospects (Research-stage Reports)

For Patients: Please Read Carefully

The following information is currently at the research stage or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Antiviral Drug Candidates

Monoclonal Antibodies

m102.4 (anti-NiV-G antibody): Targets the ephrin-B2/B3 binding site of the NiV-G protein. Complete protection was achieved in ferrets when administered intravenously 10 hours after exposure, and efficacy was also confirmed in African green monkeys. Phase 1 clinical trials have been completed²⁾.

h5B3.1 (anti-NiV-F antibody): A NiV-F protein-specific antibody that has shown efficacy in a ferret model²⁾.

Nucleoside Analogs

Remdesivir (GS-5734): An adenosine nucleoside analog prodrug. It shows activity against NiV in vitro, and post-exposure administration in African green monkeys improved survival. While the control group died of severe respiratory failure, the treated group had only mild respiratory symptoms for 3 months²⁾.

Favipiravir (T-705): A purine analog RNA-dependent RNA polymerase inhibitor. Efficacy has been confirmed in vitro and in a Syrian hamster model²⁾.

Vaccine Candidates

HeV-sG-V (recombinant soluble Hendra virus G glycoprotein vaccine) is the most advanced candidate. Based on the Hendra virus G protein, it has 83% amino acid identity with NiV-G. It has shown protection for over 12 months in ferrets, and Phase 1 trials have confirmed good safety and strong immunogenicity. It is used in horses in Australia as “Equivac HeV” ²⁾.

Other major vaccine candidates are listed below ²⁾.

• ChAdOx1 NiV-B: Chimpanzee adenovirus vector. Complete protection in hamsters against both NiV-B and NiV-M.
• rVSV-based vaccine: rVSV vaccine expressing NiV-G protein provided complete protection in 3 out of 3 monkeys.
• rMV-NiV-G: Recombinant measles vaccine, efficacy confirmed in monkeys.
• mRNA vaccine (sHeVG): Hendra virus G protein mRNA, partial protection in hamsters.
• VLP vaccine: NiV G/F/M protein virus-like particles (VLP) confirmed to induce protection and neutralizing antibody production in hamsters.

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8. References

1. Alla D, Shah DJ, Adityaraj N, et al. A systematic review of case reports on mortality, modes of infection, diagnostic tests, and treatments for Nipah virus infection. Medicine. 2024;103(40):e39989.
2. Hauser N, Gushiken AC, Narayanan S, et al. Evolution of Nipah Virus Infection: Past, Present, and Future Considerations. Trop Med Infect Dis. 2021;6(1):24.
3. Liu L, Pan C, Chen Z, Zhang F, Guan W, Zeng A, et al. Mechanistic insights into Nipah virus 5’ UTR functionality reveal an antiviral target. J Gen Virol. 2025;106(8). PMID: 40880179.