Meningitis is an inflammation of the meninges (the inner membranes of the brain and spinal cord) that is most often caused by a viral or a bacterial infection. Distinguishing between a viral and a bacterial infection is difficult but essential because viral meningitis is usually benign and self-limited, whereas untreated or improperly treated bacterial meningitis may result in brain damage, learning disabilities, hearing loss, or even death. There are approximately 25,000 cases of bacterial meningitis and 12,500 cases of viral meningitis reported annually in the United States; of these, there are approximately 2,200 deaths and 4,000 to 5,000 patients with significant neurologic sequelae from bacterial infections. (Incidence rates vary in other countries. In the United Kingdom, for example, there were an estimated 3,500 reported cases of meningococcal meningitis [meningococcal disease being the most common cause of bacterial meningitis in children and young adults] in 1999.) Other types of meningitis include, but are not limited to, fungal (e.g. cryptococcus), tubercular, and chemical.

Bacterial Meningitis

• Before 1986, meningitis was most often caused by Haemophilus influenzae (45%), usually affecting infants and children under 6 years of age. Since the introduction of a vaccine, H. influenzae meningitis has virtually disappeared in the countries where the vaccine is administered.
• Neisseria meningitidis (meningococcal meningitis, 14% to 20%) now causes most cases of meningitis in children and young adults; it is the only type of meningitis that occurs in outbreaks.
• Streptococcus pneumonia (pneumococcal meningitis, 20%) is frequently seen in patients with a recent history of upper respiratory infection, pneumonia, otitis media, sinusitis, mastoiditis, or head injuries.
• Listeria monocytogenes (3% to 6%) meningitis often affects neonates who have been infected by their mothers or elderly patients, particularly those with preexisting medical conditions. 
• Group B Streptococcus (S. agalactiae, 3% to 6%) often affects neonates who have been infected by their mothers or by nursery personnel, or adults over 60 years of age. 
• Gram-negative bacilli (e.g., Escherichia coli, Proteus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella spp., Enterococcus spp.) meningitis often affects head trauma or neurosurgery patients. 
• Staphylococcus aureus affects head trauma or neurosurgery patients or patients with preexisting medical conditions. 

Viral Meningitis

• Common enteroviruses that cause meningitis (80% to 85%) include echoviruses 3, 4, 5, 6, 7, 9, 11, 21, and 30 and coxsackieviruses A₉, B₁, B₂, B₃, B₄, and B₅. These viruses, which are most common among infants and small children, are spread by the fecal-oral route, houseflies, wastewater, and sewage.
• Arboviruses are arthropod-transmitted and most often affect children. The most common variety is St. Louis encephalitis virus.
• Mumps virus is a very common cause of meningitis in nonimmunized individuals, usually children 5 to 9 years old.
• Lymphocytic choriomeningitis virus affects laboratory workers who have contact with hamsters, rats, and mice or with their excreta.
• Of all the herpesviruses (e.g., herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, herpesviruses 6 and 7), HSV-2 causes meningitis most often, especially following the primary genital infection (36% of women; 19% of men).
• Human immunodeficiency virus (HIV) meningitis occurs as part of the primary infection in 5% to 10% of patients.

Bacterial Meningitis

• Crowded urban areas or dormitory living (meningococcal disease) 
• Otitis media, mastoiditis, sinusitis, pneumonia
• Significant head injury
• Cerebrospinal rhinorrhea
• Sickle-cell anemia (in children) 
• Alcoholism
• Immunosuppression (pneumococcal disease) 
• Neurosurgical procedures, skull trauma, endocarditis, and cancer
• Lack of H. influenza vaccine availability or administration 

Viral Meningitis

• Children who have not been immunized with the measles, mumps, rubella (MMR) vaccine 
• Persons who do not follow safe sex practices and are therefore at risk for HSV-2 and HIV 
• Laboratory workers who handle rats, hamsters, and mice or their excreta 
• Children who attend daycare centers

• In neonates—irritability, high-pitched cry, poor feeding, vomiting, fever (only 60%), stiff neck (only 15%), headache, bulging fontanelle (only 30%), seizures
• In children and young adults—fever, headache, vomiting, stiff neck, upper respiratory infection, photophobia, drowsiness, Kernig's and Brudzinski's signs (50% of adults), petechiae or cutaneous hemorrhages (50% of patients with N. meningitidis), and then confusion, seizures (30%), obtundation, and loss of consciousness; N. meningitidis can result in acute fulminating septicemia known as Waterhouse-Friedrichsen syndrome, characterized by hypotensive shock from hemorrhage into the adrenal glands 
• In the elderly—an alteration in mental status and lethargy may be the only signs of meningitis; often there is no fever and signs of meningeal involvement are variable. 

• Subarachnoid hemorrhage 
• Brain abscess 
• Subdural empyema 
• CNS neoplasm 
• Various encephalopathies 
• CNS syphilis
• Neurologic manifestations of Lyme disease 
• Cerebral vasculitis 
• Neuroleptic malignant syndrome 
• Sarcoidosis 
• Rocky Mountain spotted fever 
• Multiple sclerosis 
• Atypical migraine headache 

Early diagnosis is the key to the successful treatment of meningitis. A detailed history— including information about pre-existing medical conditions; exposure to ticks, rodents, or birds; alcoholism; and neurosurgical procedures—can help to determine the most likely causative organism. When meningitis is suspected, lumbar puncture is performed emergently so that a thorough examination of the CSF can be done. Broad-spectrum antibiotic therapy is based on the physician's initial clinical impression, age of the patient, and the patient's underlying immunological status and is begun without waiting for culture results.

Bacterial Meningitis

• Lumbar puncture (LP)—to check opening pressure (>180 mm H₂O, up to 450 mm H₂O) and assess appearance of CSF (cloudy if >500 WBCs/mm³); WBCs (high; , between 100 and 100,000/mm³ with 80% PMNs); glucose (low; <1.9 mmol/L); protein (high; >100 mg/dL); Gram stain of CSF (positive in 60% to 90% of cases); CSF cultures are positive for the etiologic agent in 70% to 85% of bacterial meningitis. (Caution: If papilledema or focal neurologic symptoms are present, suggesting a mass lesion or mass effect, LP should be deferred until obtaining a CT scan or MRI. However, antibiotic therapy should not be delayed in the case of suspected bacterial meningitis even though this may render the CSF sterile; the other findings will remain consistent with bacterial meningitis.) 
• Measurement of serum creatinine, electrolytes, blood urea nitrogen—to determine renal function and electrolyte balance 
• Measurement of C-reactive protein concentration in the CSF (elevated in 95% of patients)—a normal value excludes a meningitis diagnosis 
• DNA polymerase chain reaction (PCR) for H. influenza, meningococci, streptococci, and Listeria 

Viral Meningitis

• Blood cultures 
• Lumbar puncture—CSF cell counts to detect pleocytosis (cell count of 100 to 1,000/mm³) with lymphocyte domination (although neutrophils may predominate in the first 48 hours; such a finding should raise suspicion of bacterial meningitis); virus is infrequently isolated from CSF; CSF protein will be slightly elevated; CSF glucose will be slightly decreased; main purpose of this diagnostic test is to distinguish from bacterial meningitis 

Bacterial Meningitis

• Nasopharyngeal colonization, mucosal invasion, and then entry of bacteria across the blood-brain barrier into the CSF where the host response is usually ineffective 
• Release of cytokines (e.g., tumor necrosis factor and interleukins 1 and 6) into the CSF, resulting in increased brain edema, increased intracranial pressure and decreased cerebral blood flow, leading to cerebral hypoxia 
• Increased permeability of the blood-brain barrier, leading to increased CSF protein levels 
• Decreased glucose transport, leading to decreased glucose levels in CSF 

Viral Meningitis

• Entry of virus through the skin (e.g., mosquito vector) or respiratory, gastrointestinal, or urogenital tracts 
• Replication of the virus outside the CNS, then spread hematogenously to CNS 
• Cell count of 100 to 1,000/mm³ with neutrophils predominating initially, then lymphocytes 
• Mildly increased CSF protein and mildly decreased CSF glucose 

Computed tomography (CT) or MRI—in patients with focal neurological findings to rule out an intracranial mass (e.g., cerebral abscess, subdural empyema); imaging should not delay start of antibiotic therapy.

• Counterimmunoelectrophoresis, latex agglutination test, enzyme-linked immunosorbent assay, and coagglutination—to detect antigens of meningeal microbes 
• Polymerase chain reaction (PCR)—to illuminate DNA from patients with meningitis from N. meningitidis and L. monocytogenes; to detect enteroviral RNA and HSV DNA 
• Echocardiogram, bone scan, or cultures of other body fluids—to evaluate potential coexisting medical conditions 

When a patient presents acutely ill with the signs and symptoms of meningitis, the following strategy may be warranted: (1) cultures should be taken immediately to identify the offending organism, including from the blood and CSF; (2) broad-spectrum antibiotics for presumed bacterial meningitis given immediately (within the hour) prior to return of culture results.

Currently, there is no specific antiviral therapy available for infection with enteroviruses, arboviruses, mumps virus, or lymphocytic choriomeningitis virus; treatment is supportive only. HSV meningitis may be treated with acyclovir, but it is not clear that the natural course of the disease is changed. HIV meningitis is not treated with antiretroviral agents such as zidovudine, didanosine, or dicalcitrine unless the CD4 lymphocyte count is below 500/mm³. Intravenous gamma-globulin is sometimes used as adjunctive therapy for enteroviral meningitis.

The length of treatment varies with the organism being treated, ranging from 7 days for a meningococcal infection to 21 days for a Listeria infection.

• For neonates with likely pathogens of S. agalactiae, E. coli, L. monocytogenes, and K. pneumoniae—ampicillin plus third-generation cephalosporins (e.g., cefotaxime, ceftriaxone) or ampicillin plus an aminoglycoside such as gentamicin 
• For infants with above pathogens plus S. pneumoniae, H. influenzae, or N. meningitidis—ampicillin (vancomycin substituted if PCN allergic) plus a third-generation cephalosporin (e.g., cefotaxime, ceftriaxone) 
• For children and young adults with S. pneumoniae, N. meningitidis, or H. influenzae—a third-generation cephalosporin plus vancomycin
• For adults with S. pneumoniae or L. monocytogenes—ampicillin plus third-generation cephalosporin (e.g., cefotaxime or ceftriaxone); third generation cephalosporin plus vancomycin for penicillin-resistant strains (25%); trimethoprim-sulfamethoxazole (TMP/SMX) and vancomycin for PCN allergy 
• For immunocompromised patients with S. pneumoniae, N. meningitidis, L. monocytogenes, and P. aeruginosa—vancomycin plus ampicillin plus ceftazidime; TMP/SMX for penicillin-allergic patients 
• For patients with recent head trauma or neurosurgery with likely gram-positive and gram-negative organisms—vancomycin plus ceftazidime 
• Corticosteroid therapy (e.g., dexamethasone, 0.15 mg/kg every 6 hours for 4 days, 2 to 3 hours before antimicrobial therapy)—to reduce neurologic sequelae
• For seizures—diazepam (5 to 10 mg in adults) and intravenous phenytoin 

Dosages: ampicillin 2 g every 4 hours (children 50 mg/kg IV q 12 hours); cefotaxime 2.0 gm IV every 4 to 6 hours; ceftazidime 2 g IV every 8 hours (children 50 mg/kg IV q 12 hours); ceftriaxone 2 g every 12 hours (children 50 mg/kg IV QD); gentamicin 2 mg/kg IV load, then 1.7 mg/kg every 8 hours; TMP/SMX 160 mg/800 mg every 6 hours; vancomycin 1 g IV every 8 to 12 hours (children 15 mg/kg IV q 6 hours).

• Surgical closure of CSF fistulas to prevent recurrent meningitis
• Surgical correction of CSF rhinorrhea

Bacterial meningitis has severe sequelae if not recognized and treated aggressively. Nutritional and herbal therapies should be used only in support of conventional treatment. Homeopathic remedies may be useful for symptomatic relief and some herbal studies suggest efficacious antimicrobial and immunomodulatory activities in the treatment of certain kinds of meningitis. Garlic, for example, has demonstrated activity against cryptococcal meningitis and appears to work synergistically with amphotericin B to treat this condition.

To understand better how CAM therapies may be useful, some studies implicate reactive oxygen species (ROS) and nitric oxide (NO) in the pathophysiologic changes seen in early bacterial meningitis, particularly:

• Increased intracranial pressure
• Increased cerebral edema
• Increased CSF WBC count

The theory is that antioxidants would help to attenuate this damage. However, results from studies of two antioxidants—vitamin C and N-acetyl-L-cysteine—have been mixed and fairly disappointing.

N-acetyl-L-cysteine (NAC)

N-acetyl-L-cysteine (NAC), an antioxidant, and S-methylisothiourea, an inhibitor of inducible NO synthase (iNOS), have both been shown to limit early pathological events in the course of bacterial meningitis. In view of these results, an animal study was undertaken to evaluate the protective effects of NAC and S-methylisothiourea against occurrences of advanced bacterial meningitis. Treatment with NAC significantly reduced CSF white blood cell counts but did not modulate CSF bacterial titers. In addition, although NAC did modulate early brain changes in the rats with meningitis, the antioxidant did not affect later brain manifestations of the disease. It is difficult to know what to conclude from this information except, perhaps, that NAC may confer some antioxidant properties against ROS early in the disease process, but does not seem to impact upon the disease process during advanced stages in animals (Koedel and Pfister 1997).

Vitamin C

Because vitamin C may be depleted in cases of infectious disease, it was hypothesized that administering supplemental dosages of this vitamin might be beneficial for patients with meningitis. However, in a controlled clinical trial of this antioxidant, 42 children and infants hospitalized with acute meningeal disease (either bacterial or viral) were randomly assigned to vitamin C or placebo. The experimental group received an IV infusion of vitamin C, 100 mg/kg up to a maximum of 3,000 mg infused over 30 minutes, followed by 50 mg/kg every 8 hours for a total of 9 doses over 3 days. Treatment failed to show any beneficial effect on the clinical course of either form of meningitis compared to placebo (Destro and Sharma 1977).

Vitamin B₁₂ 

In a study of neurochemical markers in patients with aseptic and tuberculous meningitis, decreased levels of vitamin B₁₂ and significantly increased levels of homocysteine were found only in CSF of patients with tuberculous meningitis; no changes were noted in CSF of aseptic meningitis patients (Qureshi et al. 1998). More research is needed to determine whether measures to supplement vitamin B₁₂ or decrease homocysteine can influence the course of disease in patients with tuberculous meningitis.

Vitamin A

A study investigating meningococcal disease found that stores of vitamin A were depleted in 41 children in sub-Saharan Africa; it is unknown whether vitamin A supplementation would be beneficial for this condition (Semba et al. 1996).

Garlic

In vitro experiments have demonstrated antifungal properties of garlic (Allium sativum) as well as synergistic activities when garlic is administered with amphotericin B. A concentrated garlic extract exhibited fungistatic and fungicidal activities against three different isolates of C. neoformans. On a weight basis, this concentrated extract of garlic was determined to be as potent as fluconazole, ketoconazole, or 5-fluorocytosine but was 60 times less potent than amphotericin B. Synergistic activity observed between amphotericin B and the concentrated garlic extract was comparable to that between amphotericin B and 5-fluorocytosine (Davis et al. 1994).

A small human case study of five patients with meningitis from Cryptococcal neoformans suggests that the antifungal properties of garlic seen in vitro may be conferred to people. In this study, commercial garlic extract was administered to each of the five patients intravenously (1 mg/kg body weight per day diluted into 500 ml saline over 4 hours) and no other antimicrobial medications were given. Fungistatic activity was demonstrated in three of the patients while fungicidal activity was demonstrated in the other two (Davis et al. 1990).

More research is needed to fully evaluate both safety and efficacy of garlic administration in the case of meningitis, as well as whether garlic has activity against other kinds of meningitis; ideas for future study in this area are intriguing.

Echinacea

Echinacea (Echinacea purpurea) has been shown to enhance nonspecific immunity in immunosuppressed mice against systemic infections of L. monocytogenes. In the immunosuppressed animals infected with L. monocytogenes, echinacea extract reduced bacterial counts in the spleen and liver to about 5% of the number in the untreated control animals and significantly increased survival rates (Steinmuller et al. 1993). This study is consistent with earlier results showing protection against a lethal dose of L. monocytogenes in mice treated with polysaccharide extract of echinacea soon after infection (Roesler et al. 1991).

Traditional Chinese Medicinal Herbs

Studies in Japan have used an animal model to demonstrate the efficacy of traditional Chinese medicines in augmenting host resistance to L. monocytogenes. Xiao-chai-hu-tang (Japanese name: Shosaiko-to) and Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to) were shown to enhance macrophage-mediated protection (Yonekura et al. 1990; Yonekura et al. 1992). The latter remedy contains:

• Angelicae archangelica (Angelica root)
• Atractylodis macrocephalae (Largehead atractylodis)
• Tuckahoe (Poria cocos)
• Rehmannia glutinosa (Rehmannia root)
• Panax ginseng (Asian ginseng)
• Cinnamomi aromaticum (Cinnamon bark)
• Citrus aurantium (Orange peel bitter)
• Paeoniae lactiflora (Peony root)
• Polygalae tenuifolia (Thinleaf Milkwort root) 
• Astragalus membranaceus (Milk vetch) 
• Scisandrae chinensis (Chinese Magnoliavine fruit)
• Glycyrrhizae radix (Licorice root)

Shosaiko-to contains:

• Bupleurum falcatum L (Bupleurum) 
• Pinellia ternata (Pinelliae tuber) 
• Scutellariae baicalensis (Skullcap root)
• Zizyphi jujube (Jujube)
• Panax ginseng (Asian ginseng)
• Glycyrrhizae radix (Licorice root)
• Zingiber officinale (Ginger root) 

Traditionally, these remedies have been used in combination. Direction of treatment, using herbal therapies as adjuncts to other medical care, is best directed by a trained, licensed, and certified specialist.

Clinical trials evaluating the safety or efficacy of homeopathy for meningitis have not been documented to date; there are certain remedies, though, used in clinical practice as adjuncts to treat meningitis that are reportedly beneficial in helping to alleviate symptoms. Remedies include Apis, Arnica, Bryonia, Helleborus, and Hyoscyamus (Morrison 1993).

• Apis—for meningitis in children with intense head pain that drives them to bore their head into the pillow. Infants for whom this treatment is appropriate may have a bulging fontanelle.
• Arnica—for meningitis following surgery or head trauma. The appropriate patient will often insist that there is nothing wrong.
• Bryonia—for meningitis with delirium and a characteristic movement of the mouth in which the jaw moves side to side quite rapidly in a somewhat contorted manner.
• Helleborus—for meningitis with stupefaction and apathy, although patients may also be anguished and pleading for help. Delirium and shaking or rolling of the head may be present.
• Hyoscyamus—for meningitis with convulsions that occur with shrieking and grinding of the teeth.

Patients must be monitored in the intensive care unit for 24 to 48 hours for the following reasons: to be sure that the antimicrobial agent is having an effect; to observe for seizure activity; and to prevent aspiration. CSF examination should be repeated after 24 to 48 hours if there is no clinical improvement.

• For chemoprophylaxis—rifampin (600 mg, adults; 5 mg/kg, children every 12 hours for 4 doses) is given to household contacts to eradicate nasopharyngeal colonization of meningococcal infection
• Meningococcal vaccine (groups A, C, Y, W135)—to immunize during epidemics and for persons traveling to endemic areas
• H. influenzae type B (HIB) vaccine—for pediatric population
• Pneumococcal vaccine—to prevent pneumonia in elderly and debilitated patients; not effective in children under 2 years of age; given post-splenectomy as well
• Live, attenuated mumps vaccine—for pediatric population

• Sensorineural hearing loss (10% of children)
• Seizures (20% to 30% of patients), which may be reversible
• Cerebral edema (25% of fatal cases)
• Hemiparesis, dysphasia, visual field defects, gaze disturbances (25% of adults)
• Intellectual deficits, ataxia, and blindness
• Loss of airway reflexes, vasomotor collapse, and respiratory arrest
• Recurrent meningitis (most common in patients with head trauma) is most often due to S. pneumoniae but occasionally to H. influenzae.
• Vancomycin is contraindicated as a single agent because of its erratic CSF penetration; CSF levels of vancomycin may be reduced by dexamethasone.
• Imipenem and meropenem are effective against pneumococcal meningitis but have epileptogenic activity.
• Corticosteroids should not be used when patients present with severe sepsis or septic shock.

Although there are many new antimicrobial agents used for bacterial meningitis, the morbidity and mortality are still unacceptably high. Approximately 25% of adults who contract bacterial meningitis will die, and 60% of infants who survive the infection will have neurologic sequelae or developmental difficulties. Most patients recover completely from viral meningitis without sequelae.

Pregnant women often carry L. monocytogenes and S. agalactiae asymptomatically in their genital tract or rectum and transmit these infections to their children during birth. Pregnant women should not take rifampin for prophylaxis as risks to the fetus have not been determined.

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