The most common causes of viral meningitis in the U.S. are nonpolio enteroviruses (coxsackie and echovirus), which often occur in summer and early fall. Infection is by the fecal-oral route, with primary viral replication in the GI and upper respiratory tracts. Rarely, there is hematogenous spread of virus to the leptomeninges, where additional viral replication occurs. Other causes include mumps, arboviruses, herpes simplex type 2, lymphocytic choriomeningitis, and HIV at the time of seroconversion. HIV meningitis commonly presents during the acute flu-like illness that often accompanies seroconversion. However, meningitis due to HIV may occur at any time in the course of HIV infection, and must be distinguished from meningitis due to opportunistic infections. Asymptomatic CSF abnormalities including mild lymphocytic pleocytosis and elevated protein are common in HIV-infected patients.
Viral meningitis is usually a brief illness with an excellent prognosis. Most cases of aseptic meningitis are due to viruses. Aseptic meningitis refers patients with symptoms, signs and CSF findings indicating meningeal inflammation, but without evidence of bacterial, fungal or parasitic infection; or parameningeal infection (e.g. brain abscess). Typical symptoms include acute onset of fever, headache, malaise, and often myalgia, nausea and emesis. Changes in mental status do not usually occur. Signs may include photophobia and meningeal signs. The most important diagnostic test is lumbar puncture. This typically shows normal or elevated opening pressure, normal glucose, mildly elevated protein, and an elevated number of white cells. The cells are predominantly lymphocytes and are rarely in excess of 500/ml. A polymorphonuclear pleocytosis may be seen in the first 12 hours of infection and may produce confusion with bacterial meningitis. Noncontrasted computed tomography (CT) and magnetic resonance (MRI) scans are normal. MRI with intravenous contrast may show enhancement of the leptomeninges. Treatment is supportive, as the infection is self-limiting. Usual duration is 3-7 days.
Herpes Simplex Virus Type 1 Encephalitis
1. Pathogenesis
HSV-1 encephalitis is the most common cause of acute sporadic encephalitis in the U.S. It typically causes lip and mouth lesions (herpes labialis and stomatitis). Note the distinction from HSV-2, which causes genital lesions, and can also cause aseptic meningitis and congenital encephalitis in the neonate. HSV-1 is acquired by respiratory or salivary contact; humans are the sole reservoir. By adulthood 90% of the population is infected. Occurrence of HSV-1 encephalitis is not seasonal. Based on serologic studies, 30% of HSV-1 encephalitis is due to primary infection, and 70% is due to reactivation. Incidence is 2.3 cases/million/year. Initial replication of virus is at the mucosal surface. Viral particles then enter sensory nerve endings and undergo retrograde axonal transport back to the sensory neuron cell bodies in the trigeminal ganglia. HSV-1 remains latent within the sensory ganglion cells until it is reactivated; the precise trigger for reactivation is unknown. For those suffering encephalitis at the time of primary infection, it is believed that infection of the olfactory epithelial cells results in entry of the virus into the CNS. Initial spread is to the olfactory bulb, then along the olfactory tracts to olfactory cortex in the inferior and medial temporal lobes. For those with reactivation leading to encephalitis, there are two hypotheses. It is hypothesized that virus spreads along sensory axons from the trigeminal ganglion to the leptomeninges overlying the temporal and frontal lobes. These are the same sensory fibers that are responsible for transmitting the “headache pain” of meningeal inflammation. Alternatively, there may be HSV-1 virus already latent in neurons of the cerebral cortex, which could produce encephalitis if reactivated. The latter hypothesis is supported by discovery of HSV-1 DNA by hybridization in brain tissue obtained at autopsy from people with no clinical sign of HSV encephalitis.
2. Pathology Infection most typically involves the inferior and medial temporal lobes. The frontal lobes immediately above the orbits (orbitofrontal cortex) and the insula (cortex within the Sylvian fissure) are other regions that are commonly involved. There is gross necrosis and hemorrhage in these regions. Cowdry type A acidophilic intranuclear inclusions in neurons and glia may be seen during the second week of infection. Perivascular lymphocytic infiltrates are present.
West Nile Virus Encephalitis
1. Pathogenesis
This virus is a mosquito-borne flavivirus that is closely related to the St. Louis encephalitis virus, which was the initial diagnosis during the first outbreak in the Western Hemisphere during the summer of 1999 in New York City. The virus is spread by the bite of the female Culex mosquito that has been infected with the virus after feeding on an infected bird. Additional routes of transmission include transplacental (intrauterine), transfusion associated, and cases related to organ transplantation.
2. Clinical features Less than 1 percent of people infected by this virus develop severe symptoms, including encephalitis. Approximately 20% of seropositive patients have reported a febrile illness that probably could be attributed to the WN virus. Of the original 59 patients that required hospitalization, the most common presenting abnormalities were fever (90%), muscle weakness (54%), headache (46%), and altered mental status (44%). Neurologic syndromes encountered were encephalitis with muscle weakness (39%), encephalitis without muscle weakness (22%), and aseptic meningitis (32%). The findings of severe, diffuse muscle weakness should substantially increase the suspicion of WN virus in a patient with meningoencephalitis, which can now bw confirmed by CSF-PCR. The case fatality rate among hospitalized patients in NYC was 12%, with all deaths occurring over the age of 65. Over 9000 human cases in 230 deaths were reported as result of the 2003 West Nile virus outbreak. Nearly 3000 cases were reported in Colorado. 79% had West Nile virus fever, 13% developed meningitis, and 8 percent developed encephalitis. Severe neurologic damage was documented both in elderly patients and in organ transplant recipients.
3. Pathology Perivascular mononuclear infiltrates accompanied by microglial nodules in the gray and white matter is described in fatal cases. Brain stem involvement, especially medullary inflammation, was prominent. Endoneurial inflammation of cranial nerve roots was described in two out of four cases in which it was sought.
Human Immunodeficiency Virus Infection
1. Pathogenesis
The CNS is a major target of HIV infection, and HIV is the most common cause of chronic viral encephalitis. HIV is carried into the brain by infected monocytes from the blood stream. Microglia are the predominant cell type infected in the CNS. Microglia, as part of the monocyte/macrophage lineage, express CD4 receptors. These bind HIV gp120, resulting in direct infection. Viral products or soluble factors from infected microglia induce neurologic disease. HIV gp120 may directly damage neurons, and gp41 can induce neurons to produce nitric oxide. Soluble factors from microglia that may injure neurons include interleukins (IL-1, IL-6) and TNF-a.
2. Clinical Syndromes
Primary neurologic manifestations of HIV infection such as dementia and myelopathy occur late in the course of HIV infection. Opportunistic infections and neoplasms affecting the CNS are AIDS-defining illnesses according to the Centers for Disease Control criteria. They are signs of severe immunosupression, and typically occur with CD4 counts of less than 200/ml. In contrast, HIV meningitis usually presents at the time of seroconversion. HIV-associated dementia. This is a distinct clinical syndrome with typical cognitive, behavioral and motor findings. Features include cognitive slowing, poor concentration and memory, apathy and social withdrawal, slowing of rapid movements, spasticity, hyperreflexia, and gait disorder. Up to 10% of patients develop psychosis. There is gradual progression to a mute, quadriparetic, incontinent state. MRI shows diffuse cerebral atrophy and abnormal signal in the cerebral white matter. AZT seems to help prevent the condition, and may even result in some improvement. Preliminary results suggest that HAART can bring about cognitive improvement in early HIV-associated dementia. Progressive childhood encephalopathy. This syndrome occurs in congenital HIV infection, within in the first years of life. Cardinal features are loss of developmental milestones, symmetric motor signs (weakness, spasticity, dystonia, or gait dysfunction), and microcephally due to impaired brain growth. Imaging shows cerebral atrophy; calcification of the basal ganglia is common in infants. Vacuolar myelopathy. Presents as gradually progressive lower extremity weakness, proprioceptive loss, spasticity, and incontinence, occurring late in the course of HIV infection. MRI is usually normal or shows spinal cord atrophy. There is no specific treatment.
3. Pathology
The classic lesion of HIV encephalopathy is the microglial nodule containing multinucleated microglial cells. These are found predominantly in the white matter and basal ganglia. As discussed above, these infected microglial cells secrete evil humors, which diffuse into the adjacent cortex, resulting in neuronal dysfunction. Vacuolar myelopathy looks like it sounds. Microglial nodules are not seen, and it is unclear whether resident cells are virally infected in this disorder. While there is some resemblance to changes seen in subacute combined degeneration (B12 deficiency), these patients usually have normal B12 levels. In addition, vacuolar myelopathy has also been seen in non-AIDS immunosuppressed patients.
