| Infectious | |
|---|---|
| Enterovirus | Echovirus Coxsackievirus A and B Poliovirus Enterovirus 68–71 |
| Herpesvirus | Herpes simplex virus (HSV) 1 and 2 Varicella-zoster virus Epstein–Barr virus Cytomegalovirus HSV-6 |
| Paramyxovirus | Mumps virus Measles virus |
| Togavirus | Rubella virus |
| Arbovirus | Eastern equine encephalitis virus Western equine encephalitis virus Venezuelan encephalitis virus |
| Flavivirus | Japanese encephalitis virus Murray Valley encephalitis virus St. Louis encephalitis virus West Nile virus Powassan |
| Bunyavirus | California encephalitis virus LaCrosse encephalitis virus Jamestown Canyon virus |
| Reovirus | Colorado tick fever virus |
| Arenavirus | Lymphocytic choriomeningitis virus |
| Rhabdovirus | Rabies virus |
| Retrovirus | Human immunodeficiency virus Human T-cell lymphotropic virus (HTLV)-I |
| Adenovirus | |
| Mycoplasma | Mycoplasma pneumoniae |
| Fungi | Cryptococcus neoformans Coccidioides immitis Histoplasma capsulatum Candida spp. Aspergillus Blastocystis Sporothrix schenckii |
| Mycobacteria | Mycobacterium tuberculosis |
| Rickettsia | Rickettsia rickettsii Anaplasma |
| Spirochetes | Treponema pallidum (syphilis) Borrelia burgdorferi (Lyme) Borrelia recurrentis (relapsing fever) Leptospira spp. (leptospirosis) |
| Parasites | Angiostrongylus cantonensis (eosinophilic meningitis) Toxoplasma gondii Gnathostoma spinigerium |
| Taenia solium (cysticercosis) Trichinella spiralis Taenia canis (visceral larva migrants) Negiceria fowleri Acanthamoeba spp. | |
| Bacteria | Partially treated bacterial meningitis Listeria monocytogenes Brucella Nocardia Acute or subacute bacterial endocarditis Parameningeal focus (brain or epidural abscess) Chlamydia spp. Actinomyces spp. |
| Noninfectious | |
|---|---|
| Drug reactions | Nonsteroidal anti-inflammatory agents Antineoplastic agents Antibiotics (trimethoprim–sulfamethoxazole) Immunosuppressants (orthoclone, azathioprine) Isoniazid Immunoglobulin |
| Malignancy | Primary medulloblastoma Metastatic leukemia Hodgkin’s disease |
| Collagen vascular disease | Lupus erythematosus Behçet’s/adult-onset Still’s disease |
| Trauma | Subarachnoid bleed Traumatic lumbar puncture neurosurgery |
| Chemicals | Lead, mercury Contrast agents Disinfectants, glove powder |
| Neurologic disorders | Cerebral vascular lesions Epidermal cysts Brain tumors |
| Systemic disorders | Sarcoidosis Vasculitis |
| Miscellaneous | Serum sickness Mollaret’s meningitis Meningeal carcinomatosis Vaccination Postinfectious viral syndromes Post-transplantation lymphoproliferative disorder Kikuchi syndrome |
Etiology
Infectious agents
The most common causes of viral meningitis are the enteroviruses, herpesviruses, and HIV. Some viruses passively enter through the skin or respiratory, gastrointestinal, or urogenital tract and may cause initial infection at the entrance site. Some viruses spread through nerve endings by retrograde transmission via neuronal axons (i.e., poliovirus, rabies virus, herpesvirus). Enteroviruses, LCM, mumps, and arthropod-borne viruses replicate initially in muscle cells or mesodermal cells. Other viruses enter via the nose, cause infection of the submucosa, and then enter the subarachnoid space. Most viruses probably enter the CNS following viremia with primary replication at the site of entry and dissemination into the systemic circulation to either anchor and grow in the choroid plexus or pass directly through it into the CNS. Enteroviruses and HIV are carried by this route.
Enteroviruses are the most common cause of viral meningitis, occurring mostly during summer and fall but may continue to cause CNS infection also during the winter. The presentation is not distinctive, and the disease presents with abrupt onset and fever, nausea, vomiting, and photophobia. Rash and upper respiratory symptoms may be present. Another increasingly common cause of viral meningitis is represented by herpes simplex virus (HSV). Although HSV encephalitis is mostly caused by HSV-1, meningitis is generally caused by HSV-2. In patients presenting with HSV meningitis genital lesions may be present, and one-quarter of the cases presenting with primary genital herpes have meningeal involvement. However, in the case of recurrent Mollaret’s meningitis, which is due to HSV-2 in 80% of cases, genital lesions are usually absent. Primary HIV can present as aseptic meningitis with headache, nausea, vomiting, fever, and stiff neck. This disease is self-limiting and can be the only manifestation of HIV for many years. Unfortunately, if patients are not diagnosed at the time of their acute illness, they may infect a number of sexual partners before the diagnosis is established. Interestingly, early onset of aseptic meningitis has not been associated with late neurologic manifestations in HIV-1 infection, and treatment is symptomatic. Other than during the acute phase, aseptic meningitis may also be present during different stages of the disease. The diagnosis may be later complicated by the fact that cerebrospinal fluid (CSF) pleocytosis is less common with advanced immunosuppression. Exposure to excretions of rodents can cause exposure to the LCM, a human zoonosis caused by a rodent-borne arenavirus. The infection, more common during the winter, presents often as an influenza-like syndrome.
Nonviral causes of meningitis often have a more complicated course than viral meningitis and must be recognized because they may have specific therapy. Agents such as bacteria, mycobacteria, and fungi enter the body through the respiratory tract, including the pharynx, sinuses, skin, or lung, and travel to the CNS via the bloodstream. Pneumonitis may be followed by fungemia or bacteremia. Coccidioides meningitis has to be considered in patients with indolent symptoms such as persistent fever and headache who live or traveled from the Southwestern United States and Central or South America. Meningitis is frequently not recognized in this population and may be lethal. Treponema pallidum and Borrelia burgdorferi enter the CNS after bloodstream invasion.
West Nile virus (WNV) is a bird virus and is spread within the avian reservoir by mosquitoes. The main vectors, Culex pipiens, C. restuans, and C. tarsalis, are abundant and ubiquitous in water in puddles and containers, sewers, storm drains, and catch basins.
It usually causes mild flu-like symptoms 3 to 14 days after infection.
However, 1 in 150 cases will develop serious manifestations, mainly meningoencephalitis, meningitis, or encephalitis. CSF invariably shows a pleocytosis, with a predominance of neutrophils in up to half the patients. Laboratory diagnosis involves testing serum or CSF for viral-specific neutralizing antibodies. Several WNV IgM ELISA kits are available in the USA.
Because the ELISA can cross-react between flaviviruses (e.g., systemic lupus erythematosus, dengue, yellow fever, WNV), it should be viewed as a screening test only. Initial serologically positive samples should be confirmed by neutralization test.
Diagnostic workup
In establishing a diagnosis, clues in the history, physical examination, and CSF examination (Table 75.2) are important.
| Clinical evaluation |
|---|
| History |
| Season (summer, enteroviruses, Rocky Mountain spotted fever) Geographic area (Colorado tick fever, babesia, Anaplasma, Lyme disease) Exposure to other patients (mumps, varicella) Tick, mosquito bites (malaria, Lyme disease), tsetse fly (trypanosomiasis) Exposure to animals (rabies, hantavirus, LCM) Sexual history (HIV, HSV, syphilis) IVDU (endocarditis) Drug reactions (immunoglobulin, OKT-3, NSAIDs, antibiotics) |
| Physical examination |
|---|
| Spinal fluid |
| Opening pressure Leukocyte count predominance a. Neutrophils (initial echo, polio, HSV, Mollaret’s, TB) b. Lymphocytes (Coxsackie, enterovirus) c. Eosinophils (Angiostrongylus, Gnathostoma) d. Abnormal cells (Mollaret’s, lymphoma, WNV) Protein ≤ 40 mg/dL Glucose ≤ 40 mg/dL or ≤ 50% serum Gram stain, AFB smear, Papanicolau stain (Mollaret’s meningitis) Cryptococcal antigen, India ink Immunoelectrophoresis Wet mount (toxoplasmosis, amebae) Bacterial, mycobacterial, fungal cultures PCR for enterovirus, HSV, VZV (in immunocompromised patients), CMV, EBV Antibodies to Borrelia burgdorferi, Brucella, Histoplasma capsulatum antigen and anti-histoplasma antibody testing by complement fixation, beginning with undiluted CSF, complement-fixing IgG antibodies, or immunodiffusion tests for IgM and IgG for Coccidioides immitis (chronic or recurrent presentation) |
| Serologic testing |
| Cryptococcal antigen Histoplasma urinary and serum antigen (MiraVista Diagnostics) Lyme disease ELISA, Western blot Rocky Mountain spotted fever indirect fluorescent antibody test (state health departments) ANA HIV-I/HIV-2 antibody HTLV-1 Serum and CSF VDRL |
| Other |
