Bacterial meningitis
Author: MA Goldstein and CL Harden

Clinically relevant pathogens

Following is a taxonomic classification of neurologically relevant bacterial pathogens:

  • Aerobic gram-positive cocci
  • Streptococcus pneumoniae
  • Streptococcus agalactiae (group B)
  • Enterococcus
  • Aerobic gram-positive rods
  • Listeria monocytogenes
  • Aerobic gram-positive cocci
  • Neisseria meningitidis
  • Aerobic gram-negative rods
  • Escherichia coli
  • Haemophilus influenzae (type b)
  • Legionella pneumophila
  • Salmonella
  • Pseudomonas aeruginosa
  • Anaerobic gram-positive cocci
  • Peptostreptococcus
  • Anaerobic-gram positive rods
  • Actinomyces
  • Propionibacterium
  • Clostridium botulinum, Clostridium tetani, Clostridium perfringens
  • Anaerobic gram-negative rods
  • Bacteroides fragilis
  • Spirochetes
  • Borrelia burgdorferi (Lyme disease)
  • Treponema pallidum (syphilis)
  • Intracellular
  • Rickettsia (Rocky Mountain spotted fever)

The relationship of bacterial infections and epilepsy

A number of studies have investigated epileptic complications associated with bacterial infection of any type or severity. Iavanainen, et al. found that increased serum levels of various bacterial antibodies were more common in patients with recent seizures than in healthy control subjects (17 of 29 vs. 2 of 31; p <.001).6 In most of these cases, no infections were recognized clinically or bacteriologically. It is unclear whether seizure production was related to the bacterial infection or to a nonspecific immune response. Besides bolstering long-standing theories regarding the epileptogenic effect of infection in general, these results also suggest that epileptic seizures can be triggered by bacterial infections even when no clinically apparent infection is recognized.

During an investigation of an animal model for the study of the neurotoxicity of bacterial products, pentylenetetrazol (PTZ), a convulsant drug, was injected into mice.7 Increased seizure induction sensitivity to PTZ was used as an indicator of neurotoxicity. If the mice were given a preinjection of sonicates of Shigella dysenteriae or Escherichia coli, the seizure response to PTZ was enhanced: the mean convulsion score was higher, as was the number of mice responding to PTZ. The induction of seizures in animals pretreated with a subepileptic dose of PTZ was also increased.

In an attempt to formulate a quantitative means of predicting seizure risk in patients with serious acute infection, Guess and colleagues developed a predictive score of clinical risk for seizure occurrence based on records of intensive care unit patients with gram-negative infections.8 They devised an inventory of clinical risk factors with individual seizure risk weights (derived from regression coefficients determined by the frequency with which each clinical condition was associated with seizure occurrence in retrospective chart review):

Factor Risk index
weight
Before admission 
 Prior seizure history 2
 CNS tumor history 4
Concurrent factors (within 1 month) 
 Acute stroke (ischemic or hemorrhagic) 3
 CNS surgery 3
 CNS infection 3
While in intensive care unit  
 Coma or anoxic encephalopathy 1
 Renal impairment (serum creatinine >1.6 mg/dL) 2
 Acute hypotensive episode 1

They considered an index of 3 or more to be suggestive of relatively high seizure risk, whereas an index of 2 or less was considered low seizure risk.

To evaluate the predictive value of this scoring system, the authors applied it to a separate population of seriously ill inpatients with similar gram-negative infections. Seizure risk index scores and actual seizure occurrences were then compared. Positive predictive values were low (26%) but negative predictive values were high (³97%). Thus, this index better identifies patients at low risk for seizures than it predicts seizure occurrence in individual patients.

In another study,9 about 40% of patients with encephalopathy related to bacterial sepsis manifested seizures. Systemic sepsis may cause seizures by disturbing cortical function (e.g., synaptic transmission, cerebral energy production) via diffuse toxic or metabolic mechanisms. Autopsies revealed other potential causes of seizures, however:

  • bacterial intraparenchymal invasion with microabscess formation
  • cortical proliferation of astrocytes and microglia
  • microinfarcts
  • multiple small white-matter hemorrhages
  • central pontine myelinolysis

Seizure Complications of Bacterial Endocarditis

Neurologic complications occur in about 30% of all patients with bacterial endocarditis, and seizures are not uncommon. In one series of 218 patients with endocarditis, 39% had a neurologic complication. Of these, 58% died, versus 20% mortality among endocarditis patients without neurologic complications.

Cerebral embolism is the most frequent and most clinically significant complication. It is particularly common in patients with mitral valve infection and with endocarditis due to virulent organisms (e.g., Staphylococcus aureus and enteric gram-negative bacilli). Emboli are important not only for their direct morbidity via cerebral infarction, but also because of their role as epileptogenic foci in the form of mycotic aneurysms and brain abscesses. Focal seizures are more commonly associated with acute emboli.29 Generalized seizures have diverse etiologies, with systemic (e.g., metabolic) and iatrogenic (e.g., drug-induced) seizures being most frequent.30

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

 

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Epidemiology
Author: MA Goldstein and CL Harden

About 25,000 cases of bacterial meningitis occur annually in the United States. Of these, about 70% occur in children younger than 5 years old.10

The relative frequency with which each bacterial species causes meningitis is age-related:

Organism Neonates Children Adults
Haemophilus influenzae + ++++ +
Neisseria meningitidis + +++ +++
Streptococcus pneumoniae + ++ ++++
Listeria species ++ + +
Group B Streptococci ++++ + +
Gram-negative bacilli (E. coli) ++++ + ++
Staphylococci + + ++
+ = infrequent; ++ = occasional; +++ = common; ++++ = most common

In a large review (n = 493) of adult bacterial meningitis cases managed at Massachusetts General Hospital from 1962 to 1988, 40% of cases were nosocomial, of which 33% were caused by gram-negative bacilli.11 In the 60% of cases that were community-acquired, the most common pathogens were:

Table adapted from KL Roos, AR Tunkel, WM Scheld. Acute bacterial meningitis in children and adults. In WM Scheld, RJ Whitley, DT Durack (eds), Infections of the Central Nervous System. Philadelphia: Lippincott–Raven, 1997;336–401.
Adapted from: Goldstein MA and Harden CL. Infectious states. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;83-133.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

 

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Diagnosis
Author: MA Goldstein and CL Harden

Clinical Presentation

The common neurologic manifestations of bacterial meningitis differ by age group.

Age group Neurologic manifestations
Child
  • Consciousness level change
  • Headache
  • Irritability
  • Photophobia
  • Nuchal rigidity
  • Seizures
  • Focal neurologic deficits
Adult
  • Headache
  • Consciousness level change
  • Photophobia
  • Nuchal rigidity
  • Seizures
  • Focal neurologic deficits
Elderly
  • Consciousness level change
  • Headache
  • Nuchal rigidity
  • Seizures, including nonconvulsive status epilepticus

Laboratory Diagnosis

Analysis of the cerebrospinal fluid (CSF) is the main test used in the diagnosis of acute bacterial meningitis. Other tests serve only as adjuncts to CSF analysis, but they can provide useful information about neurologic and systemic complications, including seizures.

CSF Analysis

The decision to perform a lumbar puncture (LP) is based on clinical presentation (i.e., meningitic signs). When the clinical threshold for LP has been reached, the clinician must first confirm that no focal intracranial mass lesion exists, before LP is performed. A mass lesion such as a tumor, abscess, or subdural empyema will increase intracranial pressure, which might predispose to brain herniation after LP. This precaution is especially relevant when the clinical presentation includes a seizure, particularly a seizure of focal onset. If history and neurologic examination (e.g., papilledema) suggest the existence of such a mass lesion, then LP must be delayed until neuroimaging is performed. If the need for neuroimaging imposes a significant treatment delay, then antimicrobial therapy must be started empirically.

Following is the typical CSF profile of bacterial meningitis:

Opening pressure >180 cm H2O
Glucose <40 mg/dL
Cerebrospinal fluid: serum to glucose ratio <0.31
Protein >50 mg/dL
Red blood cell Usually 0
White blood cell >10 to <10,000/mm2 (neutrophil predominance)
Gram’s stain Positive in >70% of cases
Culture Species-specific positive in 70–90% of untreated cases

Serologic Culture

Because bacterial entry into CSF is usually via a hematogenous route, blood cultures can be positive in up to 75% of cases of untreated meningitis.10,12

Neuroimaging

During acute bacterial meningitis, computed tomography (CT) can be normal or can demonstrate meningeal or ependymal enhancement, or both. It also may show widening of cortical sulci, basal cistern, or both, secondary to the accumulation of purulent exudate or bacterial meningitic complications (e.g., subdural effusion or empyema and diffuse cerebral edema). Development of a seizure (or focal neurologic signs) during meningitis is an additional indication for CT, besides the initial pre-LP screening.

Magnetic resonance imaging (MRI) is generally more useful than CT. MRI better images subdural effusions and empyemas, cortical infarctions, and the extent of leptomeningeal enhancement.

Electroencephalography (EEG)

A full range of EEG abnormalities can be seen in the context of acute bacterial meningitis, from nonspecific slowing to status epilepticus. A corresponding variety of EEG findings can occur as part of the neurologic sequelae of bacterial meningitis.

Clinical presentation Table adapted from KL Roos, AR Tunkel, WM Scheld. Acute bacterial meningitis in children and adults. In WM Scheld, RJ Whitley, DT Durack (eds), Infections of the Central Nervous System. Philadelphia: Lippincott–Raven, 1997;336–401.
CSF profile Table adapted from KL Roos, AR Tunkel, WM Scheld. Acute bacterial meningitis in children and adults. In WM Scheld, RJ Whitley, DT Durack (eds), Infections of the Central Nervous System. Philadelphia: Lippincott–Raven, 1997;336–401; F Plum, JB Posner. Infectious and Inflammatory Disorders of the Nervous System. In TE Andreoli, CC Carpenter, F Plum, et al. (eds), Cecil Essentials of Medicine. Philadelphia: Saunders, 1990;806–816.
Adapted from: Goldstein MA and Harden CL. Infectious states. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;83-133.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

 

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Seizure complications
Author: MA Goldstein and CL Harden

Epidemiology and risk factors

In the first few days of illness, seizures occur in about 25% of children with bacterial meningitis and in more than 30% of adults with pneumococcal meningitis. Generalized convulsive seizures may occur as part of the presentation of bacterial meningitis, along with the classic triad of fever, headache, and stiff neck. Of bacterial pathogens, seizures are most often associated with Haemophilus influenzae.13

Early in the course of infection, generalized seizures and a depressed level of consciousness can result from inflammation and bacterial toxin accumulation in the subpial space. As the meningeal infectious process progresses, meningeal veins can become thrombosed, producing focal neurologic deficits including focal seizures.13

In a large meningitis case review performed at Massachusetts General Hospital,11 seizures occurred in 23% of patients with community-acquired meningitis. Seizure occurrence within 24 hours of presentation was a risk factor for death among those patients with single episodes of community-acquired meningitis.

Patients with bacterial meningitis who have been taking oral antibiotics can present with seizure as the sole initial sign or symptom; hence, all patients taking antibiotics who develop a seizure require a lumbar puncture to exclude meningitis. Rosenberg and colleagues reviewed the records of 187 patients with bacterial meningitis.14 Seizures were a presenting manifestation in 13%, and 28% of these patients had been taking antibiotics before diagnosis. Of the pretreated patients, 25% had no signs or symptoms other than seizure, whereas all patients without pretreatment had additional findings (p <.01). Patients with seizures had a poorer outcome than those without seizures.

Listeria represents an important cause of meningitis and meningoencephalitis, frequently complicated by seizures. In a large (n = 820) retrospective case review of CNS listeriosis (excluding pregnancy), patients with Listeria had a significantly lower incidence of meningeal signs than patients with acute meningitis secondary to other bacteria.15 Further, the CSF profile was significantly less likely to have a high white blood cell (WBC) count or elevated protein concentration, and Gram’s stains were negative in two-thirds. One-quarter of the patients with CNS listeriosis developed seizures. Mortality was 26% overall and was higher among the patients with seizures.

Of Rickettsial diseases, only Rocky Mountain spotted fever has significant epileptic comorbidity, with almost 10% of cases manifesting seizure as an acute illness component. Rickettsia rickettsii is transmitted via a number of different tick species. Treatment of infection is by tetracycline or doxycycline. After successful management of acute illness, CNS abnormalities, including EEG abnormalities, can persist in up to 50% of patients.16

Cerebral ischemia is a common complication of bacterial meningitis. Increased cerebral blood flow velocity (CBFV) in intracranial arteries, probably secondary to vasospasm, is a known finding in cerebral ischemia. In a prospective study of intracranial CBFVs via transcranial Doppler sonography in patients with bacterial meningitis, seizures were more frequent (43% vs. 7%) in patients with CBFV greater than 210 cm per second. Because transcranial Doppler sonography is an easily applicable, noninvasive technique for revealing vascular changes, even in severely ill patients, and because data suggest a greater seizure complication risk with increased CBFV, transcranial Doppler sonography could potentially be used to identify high-risk patients who may benefit from seizure prophylaxis.17

Neurologic sequelae in children

Neonatal bacterial meningitis is associated with significant neurologic sequelae. In a retrospective study of infants with culture-proven neonatal meningitis, a review of EEGs obtained during the acute phase of infection demonstrated that the degree of background abnormality was an accurate predictor of outcome.18 Infants who had normal or mildly abnormal backgrounds had normal outcomes, whereas those with markedly abnormal EEGs died or manifested severe neurologic sequelae at follow-up. When the EEG was considered in the context of presence or absence of clinical seizures and level of consciousness, an accurate prediction of neurologic outcome was obtained in 93% of cases.

The EEG patterns in these infants were generally nonspecific, but some abnormalities suggested more specific pathology:

Thus, the EEG was valuable both for recognition of subtle and subclinical seizures and for predicting long-term prognosis of infants with neonatal bacterial meningitis.18

Inoue and colleagues compared seizures occurring in the acute phase of aseptic and bacterial meningitis in children. Of the study sample with aseptic meningitis, approximately 5% had seizures. Of this group, 80% developed seizures within 24 hours of onset of the initial symptom (which was fever in 60%), and 60% had repeated seizures on the first day. Of the study sample with bacterial meningitis, approximately 17% had a seizure, which in all cases occurred on the second day of illness.

All the children with bacterial meningitis who had seizures had abnormal head CT. The authors inferred that seizures occurring in the acute phase of aseptic meningitis tend to reflect transient cortical dysfunction secondary to nonstructural mechanisms such as fever or syndrome of inappropriate secretion of antidiuretic hormone (SIADH), whereas seizures complicating bacterial meningitis tend to be associated with structural factors.19

To study risk factors for adverse outcomes from pediatric bacterial meningitis, Grimwood and colleagues prospectively studied 166 cases for 5 to 9 years, employing neurologic, neuropsychologic, audiologic, and behavioral assessments. Statistical analysis revealed that seizures complicating the acute episode were associated with an adverse outcome.20

Baraff and coworkers performed a meta-analysis of reports of pediatric bacterial meningitis to determine the frequency of neurologic sequelae in children 2 months to 19 years of age. Of approximately 1,600 children with acute bacterial meningitis who were evaluated for at least one sequela after hospital discharge, 4.2% had epilepsy as a likely consequence of having had childhood bacterial meningitis.21

In what turned out to be a study of a long-term complication of childhood bacterial meningitis and febrile seizure, Cascino and colleagues performed a prospective investigation of temporal lobe pathology in 13 patients with facial asymmetry and intractable partial epilepsy of temporal lobe origin.22 All patients had a history of childhood bacterial meningitis or febrile seizure. Facial weakness occurred primarily during emotional expression (i.e., spontaneous smiling). Ictal EEG recordings showed that seizure origin was always in the temporal lobe contralateral to the side of facial weakness. Hippocampal atrophy was present in all epileptic temporal lobes, as measured by MRI volume studies. Thus, facial asymmetry and partial epilepsy associated with mesial temporal sclerosis can occur as long-term sequelae of childhood bacterial meningitis.

Adapted from: Goldstein MA and Harden CL. Infectious states. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;83-133.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

 

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Treatment
Author: MA Goldstein and CL Harden

Antibiotic choice is affected by complicated factors:

  • etiologic bacterial species
  • blood-brain barrier penetration
  • antibacterial activity within purulent CSF
  • drug metabolism
  • potential drug interactions
  • host defense status

The following general guidelines are well developed, however:

Organism Antibiotic
Streptococcus pneumoniae
Penicillin-sensitive Penicillin G or ampicillin
Partial penicillin-sensitive Third-generation cephalosporin
Penicillin-resistant Vancomycin + third-generation cephalosporin
Neisseria meningitidis Penicillin G or ampicillin
Haemophilus influenzae
Beta-lactamase negative Ampicillin
Beta-lactamase positive Third-generation cephalosporin
Enterobacteriaceae Third-generation cephalosporin
Pseudomonas aeruginosa Ceftazidime
Listeria monocytogenes Penicillin G or ampicillin
Staphylococcus aureus
Methicillin-sensitive Nafcillin or oxacillin
Methicillin-resistant Vancomycin
Staphylococcus epidermidis Vancomycin

Table adapted from KL Roos, AR Tunkel, WM Scheld. Acute bacterial meningitis in children and adults. In WM Scheld, RJ Whitley, DT Durack (eds), Infections of the Central Nervous System. Philadelphia: Lippincott–Raven, 1997;336–401.
Adapted from: Goldstein MA and Harden CL. Infectious states. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;83-133.
With permission from Elsevier (
www.elsevier.com).

Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.

 

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