26.3 Acellular Diseases of the Nervous System

Viral Infections of the Nervous System

Viruses and prions both target the nervous system, but they do so in fundamentally different ways. Viruses use standard replication machinery inside host cells, while prions are misfolded proteins with no genetic material at all. Both can cause inflammation and destruction of brain and spinal cord tissue, leading to symptoms like paralysis, seizures, and cognitive decline.

Types of Nervous System Viral Infections

Several distinct clinical syndromes result from viral invasion of the nervous system. The key distinction between them is where the inflammation occurs.

• Meningitis: inflammation of the meninges (the protective membranes covering the brain and spinal cord). Common viral causes include enteroviruses (coxsackievirus, echovirus), herpesviruses (HSV-2, VZV), and arboviruses (WNV). Symptoms include headache, fever, stiff neck, photophobia, and altered mental status. Viral meningitis is generally less severe than bacterial meningitis.
• Encephalitis: inflammation of the brain parenchyma (the tissue itself, not just the coverings). Caused by herpesviruses (HSV-1, VZV), arboviruses (WNV, JEV), and rabies virus. Symptoms include fever, headache, altered mental status, seizures, and focal neurological deficits. Some of these viruses exhibit neurotropism, meaning they preferentially infect nervous system tissues.
• Myelitis: inflammation of the spinal cord. Caused by enteroviruses (poliovirus), herpesviruses (VZV, CMV), and West Nile virus. Leads to weakness, sensory changes, and autonomic dysfunction.
• Poliomyelitis: a specific form of myelitis where poliovirus (an enterovirus) infects the motor neurons in the anterior horn cells of the spinal cord. The hallmark is asymmetric flaccid paralysis, along with fever, headache, and stiff neck. Vaccination has nearly eradicated this disease globally.

Comparison of Arboviral Encephalitis Diseases

All arboviral encephalitides share a common theme: they're transmitted by mosquito bites, there's no specific antiviral therapy, and treatment is supportive. The differences lie in geographic distribution, severity, and vaccine availability.

• West Nile virus (WNV): Transmitted by Culex mosquitoes. Most infections are asymptomatic or mild (fever, headache, myalgia), but severe cases progress to encephalitis or meningoencephalitis. The most common arboviral disease in the United States.
• St. Louis encephalitis virus (SLEV): Also transmitted by Culex mosquitoes. Clinically similar to WNV, but SLEV disproportionately causes encephalitis in older adults.
• Japanese encephalitis virus (JEV): Transmitted by Culex mosquitoes, primarily in Asia. Severe cases carry a high mortality rate. Unlike the others listed here, a vaccine is available for prevention.
• Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV): Transmitted by Culiseta, Coquillettidia, and Culex mosquitoes. EEEV is particularly dangerous, with a case fatality rate of approximately 30–50% in symptomatic encephalitis cases. WEEV tends to be less severe.

Viral Neuroinvasion and Neuropathogenesis

Viruses don't just randomly end up in the brain. They use specific routes to get past the body's defenses:

1. Hematogenous spread: The virus enters the bloodstream and crosses the blood-brain barrier (BBB). This is the most common route for many arboviruses.
2. Retrograde axonal transport: The virus infects a peripheral nerve and travels along the axon toward the central nervous system. Rabies virus is the classic example, traveling from the bite site to the brain.
3. Olfactory route: The virus enters through the nasal cavity and travels along olfactory neurons directly into the brain, bypassing the BBB entirely.

Once inside the nervous system, viruses cause damage through direct destruction of infected cells, inflammation triggered by the immune response, and disruption of normal neuronal signaling.

Prion Diseases

Prions and Spongiform Encephalopathies

Prion diseases are unlike any other infectious disease you'll study. The infectious agent is not a bacterium, virus, or parasite. It's a misfolded protein.

Normal prion protein ($PrP^C$) is found on the surface of neurons and has a largely alpha-helical structure. The disease-causing form ($PrP^{Sc}$) has a beta-sheet-rich conformation. When $PrP^{Sc}$ contacts normal $PrP^C$, it induces the normal protein to refold into the abnormal shape. This creates a chain reaction: misfolded proteins accumulate, aggregate, and eventually kill neurons, leaving the brain riddled with microscopic holes. That sponge-like appearance is why these are called spongiform encephalopathies.

What makes prions so unusual as infectious agents:

• They contain no nucleic acids (no DNA or RNA)
• They're resistant to heat, chemical disinfection, and radiation (standard sterilization doesn't destroy them)
• They have long incubation periods, often months to years
• They can transmit within a species and sometimes between species

Examples of prion diseases:

Transmission routes for human prion disease vary by type:

• Variant CJD (vCJD): consumption of meat contaminated with BSE prions
• Iatrogenic CJD: exposure to contaminated surgical instruments, corneal transplants, or dura mater grafts (prions survive standard autoclaving)
• Familial CJD: inherited mutations in the PRNP gene that make the protein more likely to misfold
• Sporadic CJD: the most common form (~85% of cases), arising spontaneously with no identifiable cause

Symptoms progress rapidly and include dementia, myoclonus (sudden muscle jerks), ataxia (uncoordinated movement), and behavioral changes. Most patients die within a year of symptom onset.

Diagnosis relies on clinical presentation, characteristic MRI findings (cortical ribboning, basal ganglia signal changes), and detection of surrogate markers like the RT-QuIC assay in cerebrospinal fluid. Definitive confirmation of $PrP^{Sc}$ requires postmortem brain tissue examination.

There is no effective treatment or cure. Care is entirely supportive.