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Acute Viral Infections of the Human Central Nervous System: Pathophysiological Mechanisms, Diagnostic Paradigms, and Therapeutic Interventions

Acute viral infections of the central nervous system (CNS) represent severe neurological emergencies that require rapid clinical recognition, precise diagnostic evaluation, and immediate therapeutic intervention. The clinical spectrum of viral CNS involvement ranges from self-limiting aseptic meningitis to life-threatening necrotizing encephalitis, myelitis, and post-infectious cerebral vasculopathies. Although a wide array of neurotropic viruses can infect the human nervous system, individual viral families demonstrate distinct tropisms for specific anatomical structures, cellular populations, and host demographics. Advances in molecular diagnostics, particularly real-time polymerase chain reaction (PCR) assay of cerebrospinal fluid (CSF) and high-resolution magnetic resonance imaging (MRI), have advanced the diagnostic approach to these complex conditions. However, significant diagnostic challenges persist due to the overlap of clinical manifestations between viral etiologies and nonviral neuroinflammatory mimics, as well as atypical presentations observed in immunocompromised hosts.

Clinical Taxonomy and Epidemiological Dynamics

The clinical classification of acute viral CNS diseases is anchored in the primary anatomical site of inflammation. Aseptic meningitis is defined by inflammation confined to the meninges, manifesting clinically as headache, fever, and stiff neck, frequently accompanied by photophobia, irritability, nausea, vomiting, and meningeal irritation signs such as the Kernig and Brudzinski signs. In contrast, acute encephalitis implies direct parenchymal brain involvement, characterized by lethargy, altered consciousness, mental status changes, behavioral abnormalities, focal neurological deficits, aphasia, hemiplegia, and seizures. When meningeal and parenchymal inflammation co-occur, the condition is termed meningoencephalitis. Viral myelitis refers to inflammation of the spinal cord, often presenting as acute flaccid paralysis, sensory loss, and bowel or bladder dysfunction.

The epidemiology of viral CNS infections exhibits pronounced seasonality and geographical dynamics, dictated by pathogen biology, vector ecology, and human exposure patterns. Enteroviruses represent the leading cause of aseptic meningitis worldwide, peaking characteristically during the summer months in temperate climates. Arthropod-borne viruses (arboviruses)—including Togaviridae, Flaviviridae (such as St. Louis encephalitis virus and West Nile virus), Bunyaviridae (California encephalitis virus group), and Orbiviridae—predominate in the late summer and autumn, coinciding with peak mosquito and tick vector populations. Conversely, respiratory viral infections with neurotropic potential, such as influenza and parainfluenza viruses (especially mumps virus), peak during winter and spring. Infection with lymphocytic choriomeningitis (LCM) virus typically increases in early winter when rodent hosts move indoors. Varicella-zoster virus (VZV) chickenpox occurs predominantly in the spring, whereas herpes zoster and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections occur year-round without seasonal predilection.

Diagnostic Paradigms and Cerebrospinal Fluid Analysis

Prompt evaluation of cerebrospinal fluid obtained via lumbar puncture remains the mainstay of diagnosis for viral aseptic meningitis and encephalitis. Typical CSF findings in uncomplicated viral infections feature a clear appearance, a predominantly mononuclear pleocytosis with cell counts usually under 100 cells/mm³ (though counts ranging from 50 to 1,000 cells/mm³ are common in enteroviral infections, and thousands of mononuclear cells can accumulate after mumps or LCM virus infections), a normal or mildly elevated protein concentration, and a normal glucose content. Early in the course of viral meningitis, polymorphonuclear leukocytes may transiently predominate before shifting to a mononuclear profile.

A critical diagnostic objective is distinguishing viral CNS infections from nonviral etiologies that present with mononuclear pleocytosis and hypoglycorrhachia (low CSF glucose content). While mild depression of CSF glucose occurs in approximately one-third of mumps and LCM virus meningitis cases, and rarely in HSV or VZV infections, its presence should immediately raise clinical suspicion for tuberculous (TB) or fungal meningitis (such as cryptococcosis or histoplasmosis), carcinomatous or lymphomatous meningitis, and neurosarcoidosis. Furthermore, viral aseptic meningitis can be mimicked clinically by granulomatous infections (syphilis, Lyme disease, Brucella, Mycoplasma pneumoniae, toxoplasmosis), vasculitides (Behçet syndrome, systemic lupus erythematosus, granulomatous angiitis), and drug toxicities resulting from nonsteroidal anti-inflammatory drugs or sulfonamides.

Molecular techniques, specifically nucleic acid amplification via PCR, have revolutionized viral identification in CSF due to high sensitivity and specificity. PCR is the gold standard for diagnosing HSV-1, HSV-2, VZV, and enteroviruses. However, clinicians must recognize that CSF PCR for HSV may yield false-negative results during the first few days of illness, necessitating clinical judgment and potential repeat sampling. Other essential laboratory methods include viral tissue culture, antigen and antibody detection in CSF, serologic testing (enzyme immunoassays and Western blot), and brain biopsy in refractory or atypical cases. Serologic titers often require two weeks or longer to demonstrate rising antibody levels, making them more useful for retrospective confirmation than acute diagnostic management.

Neuroimaging plays a supportive role in confirming brain involvement and excluding structural mimics. Computed tomography (CT) scanning in early viral encephalitis typically demonstrates non-specific effacement of cortical sulci and generalized brain swelling. Magnetic resonance imaging, particularly T2-weighted and Fluid-Attenuated Inversion Recovery (FLAIR) sequences, demonstrates higher sensitivity, revealing hyperintense signal alterations indicative of increased water content in mildly swollen tissue. Distinct neuroimaging patterns include bilateral medial temporal lobe involvement bounded sharply by the insular cortex in HSV-1 encephalitis, deep white matter and gray-white matter junction infarctions in VZV vasculopathy, signal abnormalities within the basal ganglia and thalamus in arboviral encephalitides, and ventricular ependymal enhancement in CMV ventriculoencephalitis.

Pathogen-Specific Clinical and Pathological Profiles

Enteroviruses and Poliovirus

Enteroviruses, belonging to the Picornaviridae family and comprising nearly 70 distinct serotypes including Coxsackieviruses and Echoviruses, are the leading cause of viral aseptic meningitis. Transmission occurs primarily via the fecal-oral route and occasionally through respiratory secretions. Clinical presentation frequently exhibits a biphasic fever pattern, where an initial phase characterized by constitutional and gastrointestinal symptoms resolves, only to be followed by a secondary fever accompanied by symptoms of meningeal irritation. While enteroviral meningitis is typically self-limited in immunocompetent individuals, agammaglobulinemic or hypogammaglobulinemic patients can develop chronic, progressive meningoencephalitis that persists for years and carries a high mortality rate, though successful management with intravenous immunoglobulin has been documented.

In rare instances, enteroviruses cause focal encephalitis, ataxia, opsoclonus-myoclonus, parkinsonism, and myelitis. During the enterovirus 71 epidemic in Taiwan, the predominant neurological complication was severe rhombencephalitis presenting with myoclonic jerks and brainstem signal changes on MRI. Enterovirus 71 has also emerged as a cause of acute flaccid paralysis and neurogenic pulmonary edema following poliovirus eradication. Regarding poliovirus, mass immunization has eliminated poliovirus encephalomyelitis across most regions. To prevent oral vaccine-associated paralytic poliomyelitis, official guidelines mandate the exclusive use of inactivated poliovirus vaccine (IPV) for routine childhood immunization in the United States, administered in a four-dose schedule at 2 months, 4 months, 6 to 18 months, and 4 to 6 years of age.

Herpes Simplex Viruses

Herpes simplex virus type 1 is the primary cause of sporadic, focal necrotizing viral encephalitis in humans. Pathologically, HSV-1 demonstrates selective viral replication within the medial temporal lobes and orbital surfaces of the frontal lobes, accompanied by intense tissue inflammation and hemorrhagic necrosis. Patients present acutely with fever, headache, lethargy, irritability, confusion, and behavioral changes. Seizures—including complex partial, focal motor, and generalized tonic-clonic attacks—affect approximately 40% of patients. Dominant temporal lobe involvement causes prominent aphasia and focal motor or sensory deficits. Progressive hemorrhagic necrosis and local tissue edema can precipitate uncal herniation, signaled clinically by tachycardia, hyperventilation, flexor or extensor posturing, and an ipsilateral dilated pupil.

The CSF in HSV-1 encephalitis demonstrates mononuclear pleocytosis (ranging from 4 to 755 cells/mm³), elevated protein levels, and frequently red blood cells or xanthochromia, reflecting the hemorrhagic nature of the brain lesions. Electroencephalography reveals generalized or focal temporal slowing early in the disease course, progressing to widespread, stereotyped, periodic sharp-wave and slow-wave complexes repeating at regular intervals of 2 to 3 seconds. MRI is superior to CT, demonstrating early T1 signal decrease and T2/FLAIR hyperintensity in the medial temporal regions and cingulate gyrus. Early intravenous acyclovir therapy ($15-30\text{ mg/kg/day}$ divided every 8 hours for at least 10 days) reduces mortality from over 60% to under 30%. Management of associated cerebral edema includes fluid restriction to one-half or two-thirds maintenance, head elevation to 30 degrees, hyperventilation to a $PaCO_2$ of $25\text{ mmol/L}$, osmotic diuretics (mannitol $0.25-2.0\text{ g/kg}$ keeping serum osmolality $<310\text{ mOsm/L}$), and short courses of IV dexamethasone (10 mg initial dose, followed by $4-8\text{ mg}$ every 4 to 5 hours). Seizures are controlled with IV diazepam or lorazepam followed by fosphenytoin loading ($20\text{ mg/kg}$) and maintenance phenytoin.

Herpes simplex virus type 2 is the third most common cause of viral aseptic meningitis in the United States, accounting for 5% of cases. HSV-2 meningitis occurs year-round, produces a marked CSF lymphocytic pleocytosis, and is frequently preceded by genital vesicular lesions or pelvic pain. PCR testing confirms HSV-2 as the primary cause of benign recurrent lymphocytic meningitis (Mollaret meningitis). HSV-2 meningitis is self-limited and does not typically require antiviral therapy. However, HSV-2 encephalitis is a rare, severe condition affecting neonates and immunocompromised adults (especially AIDS patients), causing diffuse brain involvement rather than focal temporal lesions, and requiring IV acyclovir ($15-30\text{ mg/kg/day}$) followed by indefinite maintenance with famciclovir or valacyclovir in HIV-infected individuals. Both HSV-1 and HSV-2 can also cause dermatomal zosteriform eruptions and painful peripheral neuropathies, including recurrent sciatica.

Varicella-Zoster Virus

Varicella-zoster virus causes chickenpox during primary childhood infection and establishes latency in cranial nerve, dorsal root, and autonomic ganglia. Reactivation decades later produces shingles (herpes zoster), characterized by severe burning radicular pain and vesicular eruptions across one to three dermatomes. Herpes zoster affects over half a million individuals annually in the United States, with an incidence eight to ten times higher in individuals over 60 years of age. Complications include postherpetic neuralgia (PHN)—pain persisting longer than 4 to 6 weeks after rash onset, occurring in 46.9% of zoster patients over age 60—as well as zoster paresis, Ramsay Hunt syndrome (facial weakness with otic vesicles), and zoster sine herpete (prolonged radicular pain without cutaneous eruption, confirmed by CSF VZV DNA). Acute zoster is treated with valacyclovir ($1,000\text{ mg}$ three times daily) or famciclovir ($500\text{ mg}$ three times daily) for 7 days. PHN management includes gabapentin, amitriptyline, carbamazepine, lidocaine patches, and topical analgesics.

Neurological central nervous system involvement by VZV presents primarily as cerebral vasculopathy rather than primary encephalitis. VZV infects cerebral blood vessels of varying calibers, leading to two distinct clinical syndromes:

• Multifocal (small-vessel) vasculopathy: Predominantly affects immunocompromised individuals (cancer, AIDS, immunosuppressive therapy), presenting subacutely with headache, fever, altered mental status, seizures, and focal deficits. Brain MRI reveals multiple small and large ischemic or hemorrhagic cortical and deep white matter infarctions.
• Unifocal (large-vessel) vasculopathy: Predominantly affects immunocompetent elderly individuals, presenting weeks to months (average 7 weeks) after contralateral herpes zoster ophthalmicus as an acute stroke resulting from necrotizing granulomatous arteritis of large cerebral vessels (middle cerebral or internal carotid arteries).

Diagnosis of VZV vasculopathy relies on detecting CSF pleocytosis, oligoclonal bands, VZV DNA via PCR, or anti-VZV IgG antibodies in CSF combined with reduced serum-to-CSF antibody ratios. Treatment requires intravenous acyclovir ($15-30\text{ mg/kg/day}$ for 10 to 14 days) combined with corticosteroids to suppress arterial inflammation.

Cytomegalovirus and Epstein-Barr Virus

Cytomegalovirus causes congenital nervous system disease in infants, resulting in microcephaly, sensorineural hearing loss, seizures, spasticity, and intellectual disability. In immunocompetent adults, CMV infection is a major antecedent cause of Guillain-Barré syndrome and acute brachial plexopathy. In patients with advanced AIDS, CMV acts as an opportunistic pathogen causing subacute encephalitis (headache, seizures, progressive dementia), progressive myelitis, and cauda equina polyradiculopathy presenting with lower extremity weakness, sacral sensory loss, and urinary incontinence. CSF in CMV polyradiculopathy shows neutrophilic or mononuclear pleocytosis, high protein, and hypoglycorrhachia. MRI may show diagnostic periventricular ependymal contrast enhancement indicative of CMV ventriculitis. CMV CNS infections are treated with intravenous ganciclovir ($5\text{ mg/kg}$ every 12 hours for 2 weeks) followed by maintenance therapy ($5\text{ mg/kg/day}$ IV or $1,000\text{ mg}$ three times daily orally), or foscarnet.

Epstein-Barr virus is a ubiquitous herpesvirus that rarely causes neurological disease. When neuroinvasive, EBV presents as meningoencephalitis, acute cerebellar ataxia, choreoathetosis, cranial neuropathies, autonomic neuropathy, or myeloradiculitis. Cases of acute arcuate fiber demyelinating encephalopathy, recurrent aseptic meningitis, and basal ganglia calcification following active EBV mononucleosis have been documented. Diagnosis is confirmed by detecting EBV DNA in CSF via quantitative PCR or decreased serum-to-CSF EBV antibody ratios. Treatment is supportive, as no specific antiviral protocol exists.

Paramyxoviruses, Myxoviruses, and Emergent Pathogens

Mumps virus is a paramyxovirus transmitted via respiratory droplets. Aseptic meningitis occurs in up to 23% of mumps cases, whereas encephalitis occurs in 1 in 6,000 cases. Clinical clues include concurrent parotitis, pancreatitis (epigastric pain, elevated amylase), or oophoritis/orchitis. CSF analysis reveals prolonged mononuclear pleocytosis and hypoglycorrhachia. Because mumps virus replicates selectively within ependymal cells, aqueductal stenosis and obstructive hydrocephalus can develop months to years after recovery.

Influenza virus causes acute encephalopathy/encephalitis during winter epidemics, presenting with seizures, altered consciousness, and high mortality. Poor prognostic markers include severe thrombocytopenia and markedly elevated transaminase levels. Nipah virus, a paramyxovirus originating from Malaysian pigs, causes severe human encephalitis outbreaks with high case-fatality rates. Adenoviruses produce meningoencephalitis with mortality ranging from 26% to 38%. Arenaviruses, such as LCM virus acquired from domestic mice, cause aseptic meningitis or fatal meningoencephalitis featuring severe mononuclear pleocytosis and low CSF glucose. Hepatitis C virus has been associated with acute disseminated encephalomyelitis (ADEM) following blood transfusions, featuring symmetrical multifocal gray and white matter signal alterations responsive to high-dose dexamethasone.

Vector-Borne Arboviruses

Arthropod-borne RNA viruses (Togaviridae, Flaviviridae, Bunyaviridae, Orbiviridae) are transmitted to humans via mosquito or tick bites during late summer and early autumn. Clinical manifestations include headache, photophobia, fever, confusion, seizures, tremor, and focal deficits. Diagnostic methods include viral isolation, CSF virus-specific IgM detection, rising serum IgG titers, and CSF PCR.

• St. Louis Encephalitis (SLE): Transmitted by mosquitoes, causing encephalitis with prominent opsoclonus, body tremulousness, and brainstem dysfunction; 15% present with aseptic meningitis.
• West Nile Virus (WNV): A flavivirus transmitted by mosquitoes, blood products, or organ transplants. Neurological manifestations are protean, including meningoencephalitis, rhombencephalitis, opsoclonus-myoclonus cerebellar ataxia, unilateral brachial plexopathy, Guillain-Barré syndrome, and acute flaccid paralysis due to anterior horn cell myelitis. MRI reveals characteristic deep-seated basal ganglia and thalamic hyperintensities.
• Bunyaviruses (La Crosse Virus): Common cause of pediatric encephalitis in the United States; 50% experience seizures, and focal deficits occur in 20% to 40%.
• Eastern Equine Encephalitis (EEE): Highly fatal ( $>50\%$ mortality); over 80% of survivors suffer permanent mental, visual, auditory, or motor deficits. MRI shows focal basal ganglia and thalamic signal increases distinguishing EEE from HSV.
• Western Equine Encephalitis (WEE): Case-fatality rate near 10%; produces transient parkinsonism.
• Powassan Virus: Tick-borne flavivirus producing encephalitis accompanied by near-total ophthalmoplegia.
• Colorado Tick Fever: Orbivirus causing acute febrile neurological disease following tick exposure.

Other Opportunistic Pathogens

Human herpesvirus type 6 (HHV-6) causes limbic encephalitis primarily in bone marrow and stem cell transplant recipients, confirmed by CSF PCR DNA amplification. Papovavirus BK, related to JC virus, causes encephalitis in immunosuppressed and occasionally immunocompetent patients. Human Immunodeficiency Virus (HIV) infects the meninges early, causing self-limited acute aseptic meningitis at seroconversion (verified by p24 antigenemia), followed years later by subacute progressive HIV encephalitis.

Pathophysiological Pathways and Host Immunity

The biological mechanism of viral entry into the central nervous system proceeds via two primary routes: hematogenous dissemination and neural retrograde transport. Hematogenous spread occurs when systemic viral replication produces high-grade viremia. Viruses traverse the blood-brain barrier by directly infecting cerebral capillary endothelial cells, passing through fenestrated endothelium, or riding inside infected circulating leukocytes—a mechanism known as the "Trojan horse" pathway. Enteroviruses, arboviruses, and HIV utilize hematogenous routes to access the meninges and brain parenchyma. Conversely, neural retrograde transport involves viral entry into peripheral motor or sensory nerve terminals, followed by retrograde axonal transport along peripheral nerves directly into the central nervous system. HSV-1, HSV-2, and VZV utilize retrograde transport along trigeminal, dorsal root, or autonomic nerve axons.

Parenchymal brain injury during acute viral infection results from a combination of direct cytopathic viral replication and secondary host immunopathology. Direct viral entry and replication inside neurons, glial cells, or endothelial cells trigger cell lysis, apoptosis, and severe tissue necrosis. Concurrently, the host immune response—mediated by cytotoxic T-lymphocyte activation, microglial proliferation, and inflammatory cytokine cascades—contributes to local edema, vascular occlusion, and bystander tissue destruction. In VZV vasculopathy, viral replication within the arterial adventitia and media incites a necrotizing granulomatous arteritis with multinucleated giant cells, leading to focal luminal narrowing, thrombosis, and downstream ischemic or hemorrhagic cerebral infarction.

Host immunocompetence fundamentally alters the pathological expression of neurotropic viral infections. In immunocompetent individuals, cellular immune responses restrict viral replication, often confining damage to specific neuroanatomical regions, such as the medial temporal lobes in HSV-1 encephalitis or single dermatomes in herpes zoster. In contrast, patients with impaired cell-mediated immunity—such as individuals with AIDS, bone marrow or solid organ transplant recipients, or patients receiving cytotoxic chemotherapy—lacks the capacity to contain viral dissemination. In these vulnerable populations, viral neuroinvasive diseases manifest as diffuse, non-focal encephalitides, multifocal small-vessel vasculopathies, progressive leukoencephalopathies, or severe necrotizing polyradiculopathies, carrying substantially higher morbidity and mortality rates.

Therapeutic Strategies and Neuro-Intensive Management

The management of acute viral central nervous system diseases requires a dual approach combining targeted antiviral pharmacotherapy with neuro-intensive supportive care. Bed rest, fluid monitoring, and strict isolation procedures are indicated if highly contagious or hemorrhagic pathogens (such as Ebola virus) are suspected. Parenteral or nasogastric nutritional support is necessary for patients with altered consciousness or impaired brainstem swallow function.

Suspected Acute Viral CNS Infection

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  ├── Initiated Immediately: Empirical Intravenous Acyclovir (15-30 mg/kg/day)

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  ├── Diagnostic Workup: Lumbar Puncture (CSF Pleocytosis, Protein, Glucose, PCR), Brain MRI, EEG

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  ├── Neuro-Intensive Care & Monitoring

  │     ├── Fluid Restriction (1/2 to 2/3 maintenance) & SIADH Monitoring

  │     ├── ICP Control (Head elevation 30°, Hyperventilation to PaCO2 25 mmHg, Mannitol, IV Dexamethasone)

  │     └── Seizure Management (IV Diazepam/Lorazepam -> Fosphenytoin Loading -> Phenytoin Maintenance)

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  └── Pathogen-Specific Targeted Antiviral Therapy

        ├── HSV-1 / HSV-2 / VZV: IV Acyclovir (15-30 mg/kg/day for 10-14+ days)

        ├── CMV: IV Ganciclovir (5 mg/kg q12h) + Foscarnet -> Maintenance Oral Ganciclovir

        ├── Chronic Enterovirus: Intravenous Immunoglobulin (IVIG)

        └── Acute Zoster / PHN: Valacyclovir (1000 mg TID) or Famciclovir (500 mg TID)

Because viral thermolability means modest fever may serve as a natural host defense, mild antipyresis is used only when clinically necessary. Headaches are managed with acetaminophen, ibuprofen, codeine, or meperidine. Passive range-of-motion exercises, footboards, and frequent patient turning prevent contractures and decubitus ulcers. Patients with encephalitis frequently develop the syndrome of inappropriate antidiuretic hormone secretion (SIADH), predisposing them to water intoxication, hyponatremia, worsening cerebral edema, deepening coma, and seizures. Regular monitoring of serum and urine electrolytes and strict fluid restriction are essential. Elevated intracranial pressure and cerebral edema are managed by elevating the head of the bed to 30 degrees, hyperventilating intubated patients to a $PaCO_2$ of $25\text{ mmol/L}$, administering osmotic diuretics such as mannitol ($0.25-2.0\text{ g/kg}$ IV keeping serum osmolality $<310\text{ mOsm/L}$), and using short courses of IV dexamethasone ($10\text{ mg}$ initial bolus, followed by $4-8\text{ mg}$ every 4 to 5 hours for 3 days). Seizures are aborted with IV diazepam ($2\text{ mg/min}$ up to $15-20\text{ mg}$) or lorazepam ($2\text{ mg/min}$ up to $5-10\text{ mg}$), followed by fosphenytoin loading ($20\text{ mg/kg}$ at $150\text{ mg/min}$) under continuous blood pressure and ECG monitoring.

Conclusions and Future Outlook

Acute viral central nervous system diseases remain a challenging area in neuro-infectious disease medicine, carrying high risks of mortality and persistent neurological disability if unrecognized or undertreated. Clinical outcomes depend on rapid clinical differentiation, prompt lumbar puncture with CSF molecular testing, early neuroimaging, and immediate administration of empirical antiviral therapy. The integration of CSF PCR testing has transformed diagnostic speed and accuracy, allowing targeted treatment of specific herpesvirus and enterovirus infections while avoiding unnecessary prolonged broad-spectrum anti-infective coverage.

The global landscape of viral neuroinvasive disease is changing rapidly. Annual international travel involving over 500 million passengers, global labor migration, and population displacements enable neurotropic pathogens and their vector species to cross international borders within a single incubation period. Recent outbreaks of West Nile virus across North America, enterovirus 71 rhombencephalitis in Asia, and Nipah virus paramyxoviral encephalitis highlight the potential for emerging zoonotic and vector-borne viruses to produce widespread neurological morbidity. Maintaining a high index of suspicion, expanding viral diagnostic panels, developing novel therapeutic antivirals, and establishing robust global epidemiological surveillance are essential priorities to protect human populations against emerging neurotropic viral threats.