Clinical manifestations

Presentation and course

Recurrent bacterial meningitis. The signs and symptoms of an individual episode of recurrent bacterial meningitis are identical to those seen in any isolated episode of meningitis of bacterial etiology. Onset of meningeal symptoms is usually rapid and may be fulminant (140; 41; 82; 75; 141; 77; 161). Patients almost always present with severe illness, fever, alteration in mental status, and nuchal rigidity. Seizures may occur. The condition is rapidly fatal if not treated.

Recurrent nonpurulent meningitis. Signs and symptoms of recurrent nonpurulent meningitis are much more variable. Onset may be fulminant, mimicking bacterial meningitis, but may also be insidious (43; 01). Patients may appear less critically ill at presentation than is the case with bacterial meningitis, and the course of illness is often less severe and more prolonged. Signs of meningeal irritation may be similar to those described in bacterial meningitis, although alteration in consciousness is much more variable and depends on the causative organism or condition. Recurrent exacerbations of meningitis in the setting of chronic fungal, bacterial, or Toxoplasma infections is often basilar, as may also be the case in sarcoid. Cranial nerve deficits, in particular involving cranial nerves 7 and 8 are common in this setting (38; 43; 28).

Prognosis and complications

Recurrent bacterial meningitis. Complications of recurrent bacterial meningitis are those of acute bacterial meningitis per se. Acute complications include intracranial hypertension, focal or generalized seizures, septic shock, and, occasionally, disseminated intravascular coagulation (75; 141; 161). Chronic sequelae include intellectual impairment, persistent epilepsy, and deafness or other cranial nerve deficits. In general, prognosis for recurrent bacterial meningitis is excellent if the individual episodes of meningitis are promptly and appropriately treated and if associated defects in skull base or spinal cord can be found and corrected.

Recurrent nonpurulent meningitis. The prognosis is highly variable, depending on the cause of the meningitis, the immune status of the host, and the duration and severity of the recurrent infections.

Clinical vignette

A 38-year-old female native of Mexico was in good health until approximately 3 years prior to admission, when she developed fever and neck stiffness requiring hospitalization and treatment with antibiotics. She recovered without sequelae, but 2 years later, had a second, similar episode and was hospitalized at another institution. Examination at that time revealed the patient to be febrile and stuporous, with prominent nuchal rigidity and Kernig and Brudzinski signs. Hematological studies showed a white blood count of 25,000 cells per cubic mm. Cerebrospinal fluid contained 550 cells per cubic mm; 90% of which were polymorphonuclear leukocytes. Cerebrospinal fluid protein content was 420 mg/dL, and cerebrospinal fluid glucose was 27 mg/dL with simultaneous blood glucose of 115 mg/dL. Streptococcus pneumoniae was isolated from cerebrospinal fluid. The patient recovered without sequelae but was lost to follow-up.

After the second episode of meningitis, the patient began to notice increasingly copious drainage of clear fluid from her right nostril whenever she leaned her head forward or lay down. The patient sought medical attention in this country after her nasal drainage became severe. On examination, the patient was without nuchal rigidity or focal neurologic deficit. The patient continually leaked clear liquid from her nose, however. This fluid was glucose-positive and was also positive for beta-2 transferrin. On CT scan, the right cribriform plate was not seen in its entirety, consistent with dehiscence. Dehiscence of the right cribriform plate was confirmed on Omnipaque CT cisternogram, and contrast medium was seen entering the right ethmoid air cells through this defect.

The patient underwent bicoronal craniotomy with watertight repair of the dura and with placement of a split calvarial graft placed using fibrin glue. The patient recovered from surgery uneventfully and thereafter remained without recurrent meningitis and without further rhinorrhea.

Biological basis

Etiology and pathogenesis

Recurrent bacterial meningitis. Recurrent bacterial meningitis is most commonly associated with defects allowing communication between the cranial cavity, or spinal canal, and the body surface, sinuses, or middle ear (39; 141; 144). Such defects may be congenital but are more often acquired. Congenital defects associated with recurrent episodes of bacterial meningitis usually involve the skull base and middle ear. These congenital defects include arachnoid cysts, Mondini dysplasia, Maffucci syndrome, meningoceles or encephaloceles, perilymphatic fistulae, congenital defects in the clivus, and other petrous bone abnormalities (115; 148; 101; 145; 138; 91; 124; 137; 117; 143; 05; 90; 133). Recurrent bacterial meningitis may also be associated with dermal sinus tracts caused by failure of the embryonic neural tube to close along its full length; these tracts provide communication between the meninges and overlying skin (97; 90). Recurrent meningitis may also result from neurenteric fistulae or cysts (61; 100).

Acquired defects associated with meningitis most commonly involve the skull base, where only a thin layer of bone separates the meninges from sinuses, middle ear, or mastoid (140; 27; 85; 158; 165; 48; 141; 12; 144). Such defects are usually the result of closed head trauma, but may also follow neurosurgical procedures, be of nontraumatic origin (85; 158; 165), or occur spontaneously (96). Rarely, CSF leakage and meningitis may occur as a complication of idiopathic intracranial hypertension (68). In a review of the 363 cases of recurrent meningitis collected from the literature, 59% were related to anatomical defects or other problems, 36% to immunodeficiencies, and 5% to parameningeal infections (141). Traumatic and neurosurgical defects are usually accompanied by normal cerebrospinal fluid pressure. Nontraumatic acquired skull defects may occur in association with either normal or elevated cerebrospinal fluid pressure (158; 165). Normal pressure defects have also been associated with conditions causing erosion of the overlying skull, including meningiomas, epidermoid tumors, and encephaloceles (27; 76; 165; 36). High cerebrospinal fluid pressure defects may be associated with intracranial tumors or hydrocephalus (165). Congenital or acquired defects in the skull base may result in cerebrospinal fluid rhinorrhea or otorrhea (140; 85; 158; 165). Leakage of cerebrospinal fluid may be intermittent, however, and will not be present if meninges have herniated into a skull defect but are still intact. It is important to realize that a patient with congenital defects in the skull or spine may not develop recurrent episodes of meningitis until adulthood. Similarly, many years may intervene between trauma causing basilar skull defects and the onset of recurrent meningeal infections. In the series of patients by Friedman and colleagues, the average interval between head trauma resulting in a cerebrospinal fluid leak and the first episode of meningitis was 6.5 years (48).

In a minority of cases, recurrent episodes of bacterial meningitis are associated with congenital abnormalities in the complement pathway, including defects of C1, C3, C5, C6, C7, C8, and possibly C9 (152; 121; 105; 122; 22; 29; 132; 51; 130). Patients with such defects are particularly prone to recurrent episodes of infection by Neisseria meningitidis, usually with excellent response to treatment (152; 121; 105; 122; 130). Recurrent bacterial meningitis with Neisseria meningitidis has also been reported in Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia) (65) and, rarely, in association with other pulmonary vascular malformations. Recurrent cryptococcal meningitis has been reported in a patient with isolated idiopathic CD4 lymphocytopenia (162) and may occur in patients with selective IgM deficiency, X-linked IgM hypergammaglobulinemia, or common variable immunodeficiency (53; 47; 156).

The causative agents of recurrent bacterial meningitis are similar to those associated with bacterial meningitis in general (161). A retrospective study from the Netherlands identified 202 episodes of recurrent meningitis among 18,915 patients with meningitis identified in the Netherlands between 1988 and 2005 (149). Predominant organisms were S pneumoniae (40% of cases), Neisseria meningitidis (22% of cases), and nontype B H influenzae (9% of cases). In this study the proportion of episodes caused by meningococcus serogroups W135, Y, and Z was higher among patients with recurrent meningitis than among those with nonrecurrent meningitis. In studies over the years, Streptococcus pneumoniae has been the agent most often associated with recurrent bacterial meningitis, and it has accounted for more than 80% of cases in adults and 73% of cases in children (89; 72; 41; 82; 39; 161). As in the study from the Netherlands, a minority of cases were caused by Haemophilus influenzae or Neisseria meningitidis (72; 67). Occasional cases are caused by Streptococcus viridans or group A beta-hemolytic streptococci (72). Recurrent meningitis in adults due to Gram-negative organisms or Staphylococcus aureus is rare and usually associated with penetrating head injury (72; 74). Recurrent meningitis due to Salmonella has been reported in patients with AIDS (151). Recurrent meningitis in infants and young children may be due to Escherichia coli or other Gram-negative organisms, group B streptococci, Haemophilus influenzae or, rarely, Salmonella species (81; 72; 107; 115; 86; 15). Recurrent meningitis in children or adults with defects of the complement system is often due to Neisseria meningitidis (121; 33; 105; 122; 29; 08) or, less commonly, to Streptococcus pneumoniae (146; 51; 97).

Recurrent nonpurulent meningitis. Recurrent nonpurulent meningitis may be associated with six different groups of disorders:

(1) Chronic meningeal infection. In these conditions, recurrent episodes of symptomatic meningitis occur as exacerbations of chronic meningeal inflammation. Recurrent symptomatic meningitis in this setting may be associated with Brucella, syphilis; Lyme disease; fungi such as Cryptococcus neoformans and Coccidioides immitis; or less common meningeal pathogens such as Histoplasma capsulatum and Blastomyces (108; 14; 45; 43; 25). The lymphocytic meningitis seen in HIV infection may also present with persistently abnormal cerebrospinal fluid and recurrent symptomatic episodes (16).

(2) Recurrent meningitis due to periodic reactivation of otherwise latent infection. In these conditions, cerebrospinal fluid usually returns to normal between episodes. The prototype of benign, recurrent lymphocytic meningitis is Mollaret meningitis. In Mollaret meningitis, symptoms of meningeal irritation come on abruptly, accompanied by fever, headache, photophobia, and at times, convulsions. Symptoms peak within 12 hours and may persist for 3 to 4 days. The patient remains normal until the next episode of meningitis, weeks to months later (23; 60). Meningeal symptoms are classically accompanied by a cerebrospinal fluid cellular response that may reach several thousand cells per cubic millimeter and consist of neutrophils, lymphocytes, and large, friable "endothelial" appearing cells (23; 81). Most cases of apparent Mollaret meningitis have been associated with reactivation of latent Herpes simplex virus type 2 (81; 142; 113; 87; 103; 136). In a retrospective review of 28 patients presenting with herpes simplex type 2 meningitis setting, CSF pleocytosis was found to range from 96 to 1860 white blood cells/ml, with moderate elevation of protein (60 to 258 mg/dL) and normal glucose; despite their historical presence in such cases, Mollaret cells were not detected (103). A small number of cases of recurrent meningitis have been associated with mononucleosis (109; 54), infection with human herpesvirus 6 (26), and with chemical meningitis due to leakage of epidermoid cysts or other tumors (32; 106). Rare instances have been associated with Toxoplasma gondii (59). Candida tropicalis, although usually associated with infections in infants or immunosuppressed children, has been associated with recurrent meningitis in an adult (37).

(3) Recurrent meningitis due to inflammatory disorders of unknown cause. This group includes sarcoidosis, Sjögren-Larsson syndrome, Behçet disease, Vogt-Koyanagi-Harada syndrome (111; 03; 28; 46; 56; 110; 95; 79). Recurrent episodes of cerebrospinal fluid pleocytosis, accompanied by signs of meningoencephalitis, may also be seen with migraine, with periodic disease, and Kikuchi Fujimoto disease (histiocytic necrotizing lymphadenitis) (52; 13; 83; 40). Rare cases of recurrent aseptic meningitis have also been reported in familial Mediterranean fever (163).

(4) Recurrent meningitis caused by atypical reactions to nonsteroidal anti-inflammatory agents or other medications. (See also the MedLink article “Drug-induced aseptic meningitis”). Cerebrospinal fluid pleocytosis in response to nonsteroidal anti-inflammatory medications usually occurs in patients with systemic lupus erythematosus or other collagen-vascular disease, but may occasionally be seen in apparently normal individuals, some of whom may subsequently develop autoimmune disease (157). The most common agents associated with meningitis are nonsteroidal anti-inflammatory drugs such as ibuprofen, naproxen, diclofenac, or sulindac (157). However, multiple other classes of pharmacological agents have been associated with meningitis, including phenazopyridine, intravenous immunoglobulin G; antibiotics including trimethoprim-sulfamethoxazole, amoxicillin, cephalosporins, rifampicin, and metronidazole; anticonvulsants such as lamotrigine or, less frequently, carbamazepine; monoclonal biological agents such as OKT3, cetuximab, infliximab, efalizumab, and adalimumab; and immune checkpoint inhibitors including the anti-CTLA-4 agent, ipilimumab or the PD-1 receptor antibodies, nivolumab, or pembrolizumab (66; 78; 147; 35; 157; 20). Cerebrospinal fluid pleocytosis in these cases is often polymorphonuclear with elevated protein, suggestive of bacterial meningitis; CSF glucose, however, is usually normal (157).

(5) Recurrent meningitis during immune reconstitution during antiretroviral therapy in patients with AIDS. Recurrent episodes of meningeal inflammation have been reported as a response to residual infection with Cryptococcus neoformans in patients whose AIDS-induced immunosuppression was reversed during successful antiretroviral treatment (80; 21; 19; 71; 73).

(6) Recurrent chemical meningitis. Recurrent chemical meningitis may be caused by leakage of intracranial cholesteatomas or of intracranial or intraspinal epidermoid cysts, craniopharyngiomas, or other tumors (50; 32; 106; 94; 62). It should be kept in mind, however, that both dermoid and epidermoid cysts causing erosion of the skull can also be accompanied by recurrent bacterial meningitis (134; 27). Recurrent episodes of chemical meningitis have also been reported with neuroepithelial cysts (88). In small children, infection of midline nasal dermoid cysts can also lead to bacterial meningitis (112).

Recurrent nonpurulent (nonbacterial) meningitis is associated with a wide variety of conditions and, in consequence, a diverse array of biological mechanisms. Many cases of apparently recurrent meningitis, in particular those due to fungi, occur in the setting of defects in host lymphocyte-mediated immune response, at times in otherwise healthy individuals (125). Abnormal cellular immune response has also been found in recurrent meningitis due to Toxoplasma gondii (59) and is eventually always present in the meningitis that accompanies HIV infection (16). Recurrent meningitis due to Herpes simplex virus, on the other hand, appears to represent reactivation of latent infection in otherwise normal individuals (142; 87). Recurrent meningitis due to rupture of epidermoid cysts represents meningeal response to acute chemical irritation (06). The mechanisms that underlie noninfectious meningitis associated with chronic inflammatory conditions such as systemic lupus erythematosus (153), Sjogren syndrome (95), sarcoidosis (28), Behçet disease (111; 110; 46; 102), periodic disease, or Vogt-Koyanagi-Harada syndrome (56) are poorly understood, as is the pathogenesis of meningitis in response to nonsteroidal inflammatory drugs.

Benign recurrent meningitis of unknown cause. Occasional patients will develop recurrent attacks of nonpurulent meningitis over time, without identifiable cause, without fatal outcome, and often without permanent neurologic sequelae (23; 70). The diagnosis of benign recurrent meningitis is one of exclusion and is, by definition, a confession of ignorance, because cases of meningitis are excluded from this category once their cause is known.

Epidemiology

Between 1% and 9% of patients with bacterial meningitis will have recurrent episodes, usually in association with anatomical defects at the skull base (41; 02; 149; 144). Adriani and colleagues, in a prospective nationwide cohort study in the Netherlands, identified 34 episodes of recurrent meningitis (02). Men were more frequently affected (74% of cases). The most common predisposing conditions were remote head injury (53% of cases) and CSF leakage (32% of cases); this is consistent with similar studies by Tebruegge and Curtis and by Ter Horst and colleagues (141; 144). Comprehensive epidemiological data concerning the wide diversity of conditions associated with nonpurulent meningitis are not available. In most of these conditions, however, actual recurrent episodes of meningitis, separated by intervals of normal or relatively normal clinical status and cerebrospinal fluid findings, are unusual or rare. The majority of individuals with recurrent meningitis due to herpes simplex virus type 2 are women (103).

Prevention

Recurrent bacterial meningitis. Risk factors for recurrent bacterial meningitis include congenital or acquired defects in the skull or spinal column. Less common risk factors include abnormalities in the complement pathway or, rarely, congenital defects in humoral immunity (152; 121; 105; 141; 08). Prophylactic use of antibiotics in patients with skull base defects is controversial and not well supported by data.

Recurrent nonpurulent meningitis. This form is often, but not always, seen in the setting of defects in host cellular immune response, including HIV infection (55; 59). There is, however, no predictable association in general between recurrent nonpurulent meningitis and the presence or absence of specific host conditions, except for the frequent occurrence of both nonpurulent meningitis and chronic cryptococcal, or other opportunistic, meningitis in HIV infection. An attempt to treat recurrent attacks of herpes simplex type 2 meningitis, using 500 mg of oral valacyclovir twice daily, was not successful (09). Recognition that recurrent episodes of meningitis occur in association with the use of specific antibiotics or other pharmacological agents may be crucial in preventing further episodes.

Differential diagnosis

Recurrent bacterial meningitis. Recurrent episodes of acute meningeal inflammation with neutrophilic cerebrospinal fluid pleocytosis, elevated protein, and low normal or depressed glucose may be seen in neurocysticercosis (98), chemical meningitis from ruptured epidermoid cysts (06), or occasionally in association with nonsteroidal antiinflammatory drug usage (157). Sarcoidosis, although usually causing a lymphocytic cerebrospinal fluid pleocytosis, may occasionally be accompanied by a mixed response that includes neutrophils, and by low cerebrospinal fluid glucose values (49; 110; 79).

Recurrent nonpurulent meningitis. The differential diagnosis of recurrent episodes of nonpurulent meningitis is extremely broad. Diagnostic concerns may be divided into two broad groups:

(1) Chronic meningitis with recurrent symptomatic episodes. In these conditions, cerebrospinal fluid rarely, if ever, returns to normal between clinical attacks. Fungal meningitis, in particular due to Cryptococcus neoformans or Coccidioides immitis, comprises the major treatable group of infections. Chronic meningitis with sporadic exacerbations may also be caused by Brucella, syphilis, or Lyme disease (43; 64). Noninfectious disorders include chronic inflammatory conditions such as sarcoidosis, Behçet disease, and Vogt-Koyanagi-Harada syndrome. HIV infection is often accompanied by a persistent lymphocytic meningeal response (16). It is extremely important to remember, however, that recurrent meningitis in patients with AIDS may represent sequential infections by different organisms (16).

(2) True episodic meningitis, Mollaret meningitis. In these conditions, episodes of nonpurulent meningitis are separated by periods in which cerebrospinal fluid returns to normal. As mentioned above, Mollaret meningitis was first described in 1944 as a recurrent meningitis illness whose CSF was described as containing “endothelial”-like cells as well as more conventional inflammatory cells (104). It is now recognized that the great majority of these cases are due to reactivated Herpes simplex virus type 2 or, rarely, Herpes simplex virus type 1 (135; 142; 113; 87; 129; 103). Rare episodes of recurrent episodes of lymphocytic meningitis, with normalization of cerebrospinal fluid between episodes, have also been reported in association with Epstein-Barr virus infection (54), with human herpesvirus 6 (26) and during chronic infection with Toxoplasma gondii (59). Noninfectious causes have included rupture of epidermoid cysts or teratomas (32; 106), nonsteroidal antiinflammatory drug use (157), and periodic disease (52).

Diagnostic workup

Recurrent bacterial meningitis. The diagnostic workup of recurrent bacterial meningitis is usually carried out in two stages. The initial concern of urgent importance at the time of clinical presentation is the prompt identification and appropriate antibiotic treatment of the offending organism. Lumbar puncture, unless contraindicated by evidence of severe intracranial hypertension, is crucial, and will usually show a neutrophilic cerebrospinal fluid pleocytosis, elevated protein, and depression of glucose levels to less than 50% of blood glucose, often to levels of 30 mg/dL or less. Reliable detection of bacteria on Gram stain requires greater than 100,000 organisms per cubic mL. Fluid should be submitted for appropriate aerobic and anaerobic cultures. Immunological methods to detect bacteria or use of the polymerase chain reaction to detect bacterial nucleic acids, if these techniques are available, may be used to achieve rapid diagnosis of the causative agent, especially if the patient has already been treated with antibiotics.

Once the meningitis itself has been treated, evaluation of patients with recurrent bacterial meningitis involves identification of the factors that allow meningitis to recur. Consideration should be given to measuring serum levels of immunoglobulins and, particularly, in cases of recurrent meningitis associated with Neisseria meningitidis components of the complement system. Recurrent episodes of meningitis may also be associated with asplenia. Although this condition is usually thought of as being postsurgical, patients with congenital asplenia or functional asplenia, as in sickle cell anemia, are also at risk (116; 11). Cases of recurrent meningitis in children, especially due to N meningitidis, may warrant genetic testing for defects in the complement system up to and including whole genome sequencing (130). Recurrent meningitis due to defects in the skull or spinal column is far more frequent than are episodes due to abnormalities in the complement system. A major task in the evaluation of a patient with recurrent bacterial meningitis is, thus, identification of the site or sites of communication between subarachnoid space and sinuses, middle ear, mastoid, or skin. The patient's back should be evaluated for cutaneous dimples or tufts of hair suggesting a dermal sinus; these are most common at cervical and lumbosacral levels. Defects in the skull base may be suspected if there is a history or rhinorrhea or otorrhea, or if there is a history of recent or remote skull trauma (159). The presence of glucose in nasal or ear secretions provides evidence of a cerebrospinal fluid leak. Measurement of glucose in nasal secretions by glucose oxidase paper is unreliable, and quantitative measurement of glucose should be used (165). In general, a glucose level of greater than 30 mg/dL suggests a cerebrospinal fluid leak, as does a protein level of greater than 45 mg/dL (165). However, nasal secretions may occasionally contain glucose in the absence of cerebrospinal fluid rhinorrhea (158), and tests for glucose will be negative if cerebrospinal fluid glucose is depressed because of meningeal infection (58). Beta-2 (tau) transferrin is highly specific for cerebrospinal fluid and is not found in other body fluids. Although false-negative results have been reported, the presence of beta-2 transferrin levels in nasal secretions or material obtained at myringotomy, thus, provides strong evidence of a cerebrospinal fluid leak (160; 84). Measurement of beta trace protein has been shown to be a simpler and more sensitive measure of CSF leakage (07; 123). Beta trace protein, like glucose, may be depressed during the episode of meningitis itself. It should be remembered that basilar skull defects with exposure of the meninges may occur without causing a tear in the meninges. In such cases, the meninges remain intact, and cerebrospinal fluid rhinorrhea or otorrhea will not occur.

A number of diagnostic tests have been used to localize skull or spinal column defects in recurrent bacterial meningitis. The oldest of these employed introduction of radioisotope into the CSF followed by radionuclide scanning. Detection of basilar skull defects using this involves packing the nasal cavity and ears with cotton pledgets, injecting radioisotope into the subarachnoid space, and determining the amount of radioactivity in each of the pledgets after several 12- to 24-hour periods (165); this technique has also been used to identify defects along the spinal column. Radionuclide methods are cumbersome, give poor anatomical detail, are prone to error, and have largely been superseded by CT and MRI methods (127; 164). Radionuclide methods may still be useful, however, if minute or intermittent cerebrospinal fluid leakage is present because the test measures accumulation of radioactivity over time (138). More precise techniques include MRI, CT, MRI or CT cisternography, and, where basilar leaks are suspected, use of sodium fluorescein cisternography and endoscopic evaluation of cranial structures (114; 127; 164). MRI with gadolinium enhancement is the method of choice to examine brain, nerve roots, and meninges, and is also valuable because of its ability to image the spine over its entire length. MRI does not, however, image bone adequately, whereas high-definition computed tomography is highly reliable in detecting defects in the skull base (92). In many instances, the combined use of CT and MRI may provide information not obtainable by either study alone.

In some patients, however, neither MRI nor CT alone will be sufficient to identify sites of cerebrospinal fluid leakage. In such cases, precise localization of the site of injury may be achieved by cisternography using a nonionic contrast agent, followed by careful CT scanning (158; 165). MR cisternography involves enhancing CSF signal while simultaneously subtracting adjacent skull and background signal, thus, avoiding the need for lumbar puncture (42; 131). Meco and Oberascher have published an elegant comprehensive algorithm for the use of combined diagnostic modalities including beta-trace protein, beta-2 transferrin, sodium fluorescein tests, high-resolution computed tomography, and magnetic resonance cisternography to detect CSF fistulae (99); helpful guidance is also provided by the article by Yushvayev and colleagues (164). In a study, use of high-resolution MRI combined with intrathecally administered gadolinium resulted in localization of defects in six of eight patients with CSF leaks, three of five patients with recurrent bacterial meningitis and nine of 14 patients with spontaneous intracranial hypotension, possibly representing a significant advance in overall diagnostic sensitivity (150).

Recurrent nonpurulent meningitis. The objective here is to identify an infectious or noninfectious cause of meningitis from among a large number of diagnostic possibilities. A history of foreign travel, exposure to domestic or unusual animals, or ingestion of poorly cooked meat or unusual animals may be of value, as may a history suggesting association of episodes of meningitis with the use of nonsteroidal anti-inflammatory drugs. Evaluation should include meticulous general physical and neurologic examination, with a particular search for lymphadenopathy. Chest radiographs may provide evidence of sarcoidosis, as may careful neuro-ophthalmological examination for uveitis or retinal lesions, and evaluation of serum and urine levels of calcium and serum angiotensin converting enzyme. Ophthalmological examination may also be of value in Vogt-Koyanagi-Harada syndrome or Behçet disease, and examination for genital or mucosal ulcerations may be helpful in Behçet disease. Strong consideration should be given to testing for HIV, and skin tests should be carried out to determine the presence or absence of cutaneous anergy. In addition to routine blood tests, serological tests for Lyme disease, syphilis, and Toxoplasma gondii should be performed. PCR studies to detect herpes simplex virus type 1 and type 2 should be carried out in cases of recurrent lymphocytic meningitis. Metagenomic next-generation sequencing represents a novel technique that may be used to detect infectious agents in situations where more conventional techniques are unsuccessful (154). Metagenomic next-generation sequencing involves detecting nonhost DNA or RNA in clinical samples and comparing their nucleic acid sequences against databases of infectious agents. Use of metagenomic next-generation sequencing should be approached recognizing that sensitivity of the technique and sources of error are still being determined and that sensitivity and accuracy may vary depending on the laboratory. Despite the fact that herpes simplex virus type 2 is associated with recurrent episodes of genital infection, the great majority of patients presenting with recurrent meningitis due to this agent do not have evidence of genital reactivation (113).

Cerebrospinal fluid examination during and between attacks can be helpful in limiting diagnostic possibilities in recurrent nonpurulent meningitis. For the most part, recurrent episodes of symptomatic meningitis due to fungal agents, such as Cryptococcus neoformans, Coccidioides immitis, or Histoplasma capsulatum, or due to Brucella, Lyme disease, or neurosyphilis occur in the context of chronic, smoldering meningeal infection. Cerebrospinal fluid during attacks tends to show a lymphocytic pleocytosis with low glucose. Cerebrospinal fluid abnormalities may subside during remission, but cerebrospinal fluid rarely returns completely to normal. In contrast, recurrent episodes of meningitis due to Herpes simplex virus, rupture of epidermoid cysts, or idiosyncratic reactions to nonsteroidal anti-inflammatory medications are usually characterized by return to normal of cerebrospinal fluid between attacks. Intermittent episodes of lymphocytic meningitis with normal glucose and with return to normal of cerebrospinal fluid between episodes has also been observed with both periodic disease and with chronic infection with Toxoplasma gondii (59).

Careful thought and some advance planning are important in planning cerebrospinal fluid analysis in recurrent nonpurulent meningitis. The likelihood of identifying a causative agent is greatest during attacks but identification may occasionally be made during periods of remission. Routine cell count, culture and sensitivity, and glucose and protein levels should be obtained with each study. Examination of cerebrospinal fluid for the presence of oligoclonal bands should be carried out if multiple sclerosis is suspected; it must be kept in mind, however, that oligoclonal bands may be seen in a variety of chronic inflammatory disorders, and their presence does not confirm the diagnosis of multiple sclerosis. PCR studies to detect herpes simplex virus types 1 and 2 should be carried out. Fluid should be sent for cryptococcal antigen determination, and consideration should be given, based on the geographic locale, to serological tests for Coccidioides immitis. Similarly, serological evaluation of cerebrospinal fluid for antibodies to Borrelia burgdorferi may be helpful if meningitis is suspected as a complication of Lyme disease. Serological detection of active central nervous system infection by Toxoplasma gondii is often difficult because many normal individuals have circulating IgG antibody, and because detectable levels of IgM antibody may persist for over a year after initial infection. Where Toxoplasma meningitis is suspected, consideration should be given to testing cerebrospinal fluid antibody levels as well as polymerase chain reaction (118; 58). Large volumes of cerebrospinal fluid (up to 20 to 30 mL) should be submitted for fungal cultures and, if suggested by history, for culture for Brucella. Multiple large volumes of cerebrospinal fluid may need to be submitted over time before a specific diagnosis can be made, and specific diagnosis in occasional cases may require cisternal or high cervical puncture (17; 18; 123; 58; 57). Polymerase chain reaction amplification of Herpes simplex virus DNA may provide a diagnosis in cases of Mollaret meningitis (142; 87). Polymerase chain reaction methods have also been proven of value in other viral infections of the central nervous system, and in central nervous system Toxoplasma infections of the nervous system (58). Cerebrospinal fluid and serum should be saved frozen for further tests, as additional clinical data become available, and consideration should be given to sending CSF for metagenomic next-generation sequencing (154). Meningeal biopsy is almost never helpful, unless one is able to identify a specific site of inflammation using MRI or contrast-enhanced CT (31).

Management

Recurrent bacterial meningitis. Treatment of recurrent bacterial meningitis involves appropriate treatment of the individual episodes of meningitis and correction of cranial or spinal defects. The most common organism is Streptococcus pneumoniae. Although this organism has long been considered exquisitely sensitive to penicillin, increasing numbers of cases are found to be caused by penicillin-resistant organisms, and cases resistant to third-generation cephalosporins have also been reported. For this reason, initial therapy of Streptococcus pneumoniae meningitis should involve combined treatment with ceftriaxone plus vancomycin, until sensitivities are known (119; 120; 161). Penicillin G (or ampicillin) remains the treatment of choice for infections caused by Neisseria. Ceftriaxone or cefotaxime should be used if Haemophilus influenzae is suspected. These same agents, plus intravenous gentamicin to cover systemic infection, should also be employed in meningitis due to Gram-negative enteric organisms. Systemic administration of aminoglycosides, such as gentamicin, does not result in therapeutic CSF levels, even in the presence of meningeal inflammation. For this reason, adjunctive administration of intrathecal or intraventricular amikacin has been employed in cases involving resistant strains of Pseudomonas aeruginosa or other Gram-negative organisms (34). Nafcillin or oxacillin should be employed if infection by Staphylococcus aureus is suspected; vancomycin should be used if there is any question of nafcillin resistance. Meropenem, a newer carbapenem, has been shown to provide therapeutic outcomes similar to ceftriaxone in patients with bacterial meningitis (10).

Treatment of cerebrospinal fluid leaks may involve conservative therapy or surgery, and the proper role of each approach remains a matter of debate. In some instances, spontaneous closure of small cerebrospinal fluid leaks can be achieved by keeping the patient in a head-up position for days to weeks and avoiding activities that raise intracranial pressure, such as blowing the nose, coughing, or straining at stool (165). Conservative measures are particularly likely to be successful if cerebrospinal fluid leakage is associated with hydrocephalus or other states of increased intracranial pressure. Cerebrospinal fluid pressure may be kept low by repeated spinal taps or by placement of lumbar or subarachnoid shunts or catheters (04). Although CSF leaks may resolve, the 10-year risk of meningitis in children with skull base defects and CSF leaks has been estimated to be as high as 85%, and patients with traumatic CSF leak receiving conservative management alone have been reported to have a 25% to 29% risk of subsequent meningitis (155; 144). Where conservative measures are unsuccessful, surgical closure of the defect must be undertaken. Both extracranial and neurosurgical approaches have been employed (165; 126; 139). Currently, recurrent leaks occur in 6% to 7% of patients (126; 139).

Recurrent nonpurulent meningitis. Management of recurrent nonpurulent meningitis varies with the specific cause. Fungal infections may respond to amphotericin B, with or without 5-fluorocytosine or treatment with fluconazole. Optimal treatment of Brucella infections requires prolonged (4 months) treatment with doxycycline and rifampin. Treatment of syphilis requires intravenous therapy with 20 million units of penicillin per day over 10 to 14 days (69). Lyme disease should be treated with penicillin or ceftriaxone (63). Toxoplasma gondii may respond to sulfadiazine-pyrimethamine in the non-AIDS patient or to clindamycin in the AIDS patient. Recurrent episodes of Herpes simplex meningitis may be shortened by treatment with acyclovir; valacyclovir and famciclovir have also been used in this setting (129). Although not proven efficacious in controlled trials, use of these agents has also been reported to suppress recurrences of meningitis (129). An attempt to prevent recurrent episodes using valacyclovir was unsuccessful, although an adequate dosage may not have been used (09). Sarcoidosis may respond to treatment with methylprednisolone; agents such as chlorambucil, chloroquine, and hydroxychloroquine; or more aggressive immunosuppressive agents, such as infliximab or, less optimally, methotrexate or cyclophosphamide (110; 79; 93). Repeated courses of antimicrobial or steroid therapy may be required, and some patients may require chronic therapy.

Special considerations

Pregnancy

No differences exist in the incidence, clinical symptomatology, or treatment of recurrent bacterial or nonpurulent meningitis between pregnant and nonpregnant individuals.

Anesthesia

Acute bacterial meningitis and many forms of nonpurulent meningitis are accompanied by a significant elevation in intracranial pressure. The need for anesthetic administration in such individuals is uncommon. In such cases, however, the use of anesthetic agents such as halothane, methoxyflurane, or ketamine should be approached with caution. These agents cause intracranial vasodilatation and may, thus, possibly increase intracranial pressure and the risk of herniation.