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Keywords:

  • Bacterial meningitis;
  • Unprovoked seizures/epilepsy;
  • Risk factors

Summary

  1. Top of page
  2. Risk of Unprovoked Seizures and Epilepsy Following Bacterial Meningitis
  3. Risk Factors for Late Unprovoked Seizures
  4. Seizure Semiology, Course, and Prognosis
  5. Burden of Epilepsy Associated with Bacterial Meningitis
  6. Conclusions
  7. References

The high incidence and prevalence of epilepsy in developing countries has partly been attributed to an increased frequency of central nervous system (CNS) infections. Of the CNS infections, bacterial meningitis is endemic in many countries and several epidemics have also been reported in these regions. Unprovoked seizures and epilepsy (recurrent unprovoked seizures) can be long-term sequelae of bacterial meningitis. The probability of developing an unprovoked seizure or epilepsy varies according to the etiologic agent responsible for meningitis and this probability appears to be higher for Streptococcus pneumoniae. The risk factors for late unprovoked seizures/epilepsy include early seizures during the acute phase of meningitis and persistent neurological deficits other than sensorineural hearing loss. The majority of unprovoked seizures occur within 5 years of the meningitis episode and tend to be recurrent. The burden of epilepsy associated with bacterial meningitis depends upon the incidence of the latter and hence is to some extent preventable. Implementing vaccination programs against the three most important meningeal pathogens can reduce the incidence of bacterial meningitis. In developed countries, a decline in the incidence of bacterial meningitis has been accomplished with the implementation of vaccination programs.

Infections of central nervous system (CNS) are a common cause of symptomatic epilepsy. In population-based cohorts of survivors of CNS infections, the reported risk of developing unprovoked seizures is between 6.8% and 8.3% (Rantakallio et al., 1986; Annegers et al., 1988). In the cohort of survivors of CNS infections in Olmsted County, Minnesota, the ratio of observed to expected (O:E) cases of unprovoked seizures was 6.9 (Annegers et al., 1988). In developed countries, 1–5% of incident cases of epilepsy are presumed to be due to prior CNS infections (de Graaf, 1974; Hauser & Kurland, 1975; Bergamini et al., 1977). The high incidence and prevalence of epilepsy in developing countries has partly been attributed to the endemic CNS infections (Commission on Tropical Diseases of the International League Against Epilepsy, 1994; Murthy et al., 1998; Preux & Druet-Cabanac, 2005; Mac et al., 2007). However, no prospective community-based data is available to confirm these presumptions. CNS infections were the cause of epilepsy in 26% of patients in studies included in the systematic review of epilepsy in sub-Saharan Africa (Preux & Druet-Cabanac, 2005). In a university hospital-based study in south India, CNS infections accounted for 24.5% of established remote symptomatic etiologies of localization-related epilepsies (Murthy & Yangala, 1998). Seizures are a common complication of bacterial meningitis in the acute phase of illness, affecting one-third of patients (Pomeroy et al., 1990). Unprovoked seizures and epilepsy can be long-term sequelae of bacterial meningitis (Annegers et al., 1988; Bedford et al., 2001).

Risk of Unprovoked Seizures and Epilepsy Following Bacterial Meningitis

  1. Top of page
  2. Risk of Unprovoked Seizures and Epilepsy Following Bacterial Meningitis
  3. Risk Factors for Late Unprovoked Seizures
  4. Seizure Semiology, Course, and Prognosis
  5. Burden of Epilepsy Associated with Bacterial Meningitis
  6. Conclusions
  7. References

Very few studies have prospectively examined the association between bacterial meningitis and unprovoked seizures (Rantakallio et al., 1986; Annegers et al., 1988; Bedford et al., 2001). In the population-based cohort of 199 survivors of bacterial meningitis in Olmsted County, Minnesota, the 20-year risk of developing unprovoked seizures was 13% in those with early seizures and only 2% in those without early seizures. The O:E ratio for unprovoked seizures was 4.2 (Annegers et al., 1988). A nationwide survey in England and Wales, of children aged 5 years reported unprovoked seizures in 7.3% of those who developed meningitis in infancy in comparison to 2.7% of controls (relative risk: 2.7; 95% CI: 1.9–3.9; p < 0.001) (Bedford et al., 2001). Likewise, the risk of developing unprovoked seizures among survivors of neonatal meningitis is high (Jornada Krebs et al., 1996; Klinger et al., 2000). In a hospital-based study, this risk was 5.4% in comparison to 1.7% in matched controls (Stevens et al., 2003). A meta-analysis of the 19 prospective cohorts of bacterial meningitis in children between 2 months and 19 years of age from developed countries found that the mean probability of developing unprovoked seizures was 4.2% (Baraff et al., 1999). In cohorts that were either retrospectively assembled or from developing countries, this mean probability was 5%.

The probability of developing unprovoked seizures varies according to the etiologic agent responsible for meninigitis. In a meta-analysis, this probability was the highest for Streptococcus pneumoniae meningitis (14.8%) in comparison to meningitis due to Haemophilus influenzae (6.1%) and Neisseria meningitides (1.4%) (Baraff et al., 1999). The risk of developing epilepsy among the survivors of bacterial meningitis is perhaps higher in developing countries. In the Sudan, 11% of infants who survived meningococcal meningitis developed epilepsy (Salih et al., 1991). Bacterial meningitis accounted for 2% of identified etiologies of epilepsy in a hospital-based study in Saudi Arabia (al-Rajeh et al., 1990) and it accounted for 0.9% of the remote symptomatic, localization-related epilepsies in a university hospital in South India (Murthy & Yangala, 1998).

Risk Factors for Late Unprovoked Seizures

  1. Top of page
  2. Risk of Unprovoked Seizures and Epilepsy Following Bacterial Meningitis
  3. Risk Factors for Late Unprovoked Seizures
  4. Seizure Semiology, Course, and Prognosis
  5. Burden of Epilepsy Associated with Bacterial Meningitis
  6. Conclusions
  7. References

A limited number of studies have examined risk factors that predispose to the development of a late unprovoked seizure or epilepsy (Annegers et al., 1988; Pomeroy et al., 1990; Chang et al., 2004). Seizures during acute phase of meningitis are associated with an increased risk for developing late unprovoked seizures. In the Olmsted County, Minnesota, the 20-year risk of developing an unprovoked seizure/epilepsy was 13% for those with bacterial meningitis and early seizures, and 2.4% for those with bacterial meningitis without early seizures (Annegers et al., 1988). Factors associated with seizures during acute phase of illness include disturbed consciousness on admission, abnormal neuroimaging findings, and low glucose and high protein concentration in the cerebrospinal fluid (Chang et al., 2004). In a hospital-based study, children with persistent neurological abnormalities other than sensorineural hearing loss demonstrated an increased risk of having at least one late unprovoked seizure (Pomeroy et al., 1990). The association of recurrent unprovoked seizures with persistent neurological deficits was striking. Other reported risk factors for developing late unprovoked seizures include electroencephalographic abnormalities, particularly focal slowing and sharp waves and an initial cerebrospinal fluid glucose concentration <20 mg/dl (Pomeroy et al., 1990). In the case of neonatal meningitis, no study has specifically analyzed the risk factors for development of late unprovoked seizures. In general, however, the duration of early seizures, presence of coma, use of inotropic agents, and leucopenia were the most important predictors of adverse outcome in the survivors of neonatal meningitis (Klinger et al., 2000).

Seizure Semiology, Course, and Prognosis

  1. Top of page
  2. Risk of Unprovoked Seizures and Epilepsy Following Bacterial Meningitis
  3. Risk Factors for Late Unprovoked Seizures
  4. Seizure Semiology, Course, and Prognosis
  5. Burden of Epilepsy Associated with Bacterial Meningitis
  6. Conclusions
  7. References

Seizures following bacterial meningitis are commonly of the focal-onset type with or without secondary generalization, though generalized seizures and myoclonic seizures may also occur (Rosman et al., 1985; Annegers et al., 1988; Pomeroy et al., 1990; Chang et al., 2004). In the Olmsted County study, the risk of focal-onset seizures after any CNS infection was increased 12-fold, while that of generalized-onset seizures was increased three-fold (Annegers et al., 1988).

The majority of unprovoked seizures following bacterial meningitis occur within 5 years of the acute illness (de Graaf, 1974; Bergamini et al., 1977; Sell et al., 1977; Rantakallio et al., 1986; Annegers et al., 1988; Pomeroy et al., 1990; Chang et al., 2004). Unprovoked seizures following bacterial meningitis tend to be recurrent (Rosman et al., 1985; Annegers et al., 1988; Pomeroy et al., 1990). There are virtually no data on the long-term prognosis of epilepsy associated with bacterial meningitis. Remission rates following antiepileptic drug therapy are perhaps similar to other epilepsies with remote symptomatic etiology, i.e., ∼50% (Pomeroy et al., 1990). Patients with medically refractory, localization-related epilepsy and prior history of meningitis often have underlying mesial temporal sclerosis. In such cases, if imaging reveals unilateral hippocampal sclerosis, the seizure outcome following surgery (anterior temporal lobectomy) is good (Marks et al., 1992; O'Brien et al., 2002).

Burden of Epilepsy Associated with Bacterial Meningitis

  1. Top of page
  2. Risk of Unprovoked Seizures and Epilepsy Following Bacterial Meningitis
  3. Risk Factors for Late Unprovoked Seizures
  4. Seizure Semiology, Course, and Prognosis
  5. Burden of Epilepsy Associated with Bacterial Meningitis
  6. Conclusions
  7. References

Burden of bacterial meningitis

The burden of epilepsy associated with bacterial meningitis depends on the incidence of bacterial meningitis and also to some extent on the pathogen causing meningitis. The estimated incidence of bacterial meningitis in developed countries is 0.6–4/100,000 adults/year and might be up to ten times higher in other parts of world (Fitch & van de Beek, 2007). The estimated incidence of bacterial meningitis in children is 1.5/100,000/year in developed countries and 20/100,000/year in developing countries. Worldwide, at least 890,000 cases of bacterial meningitis (500,000 in Africa; 210,000 in Pacific countries; 100,000 in Europe and 80,000 in the Americas) are estimated to occur annually. The annual incidence of meningococcal meningitis in the African 'meningitis belt' that extends from the Gambia in West Africa to Ehiopia and Sudan in East Africa is ∼20/100,000 population/year. In addition, epidemics of meningococcal meningitis frequently occur in the African meningitis belt (Anonymous, 1995; Tikhomirov et al., 1997). A systematic review of 36 studies from the world's developing nations estimated that there are 126,000 cases of neonatal meningitis annually (Stoll, 1997). Neisseria meningitides, H. influenzae type b (Hib) and S. pneumoniae are responsible for over 80% cases of meningitis (Anonymous, 1995; Tikhomirov et al., 1997). In the neonatal age group, gram-negative bacilli, such as Escherichia coli and Klebsiella species are the common pathogens (Stoll, 1997).

Projected burden of unprovoked seizures/epilepsy

The calculated mean probability of unprovoked seizures among survivors of bacterial meningitis is 4.2% and specifically in N. meningitides-meningitis is 1.4% (Baraff et al., 1999). Worldwide, about 890,000 cases of bacterial meningitis occur each year; hence an estimated 37,000 people are at risk of developing unprovoked seizures following bacterial meningitis. In Africa, with an estimated 250,000 cases of meningococcal meningitis each year (Tikhomirov et al., 1997), there would occur approximately 3,500 cases of unprovoked seizures due to meningococcal meningitis.

Can the burden of epilepsy associated with bacterial meningitis be reduced?

Bacterial meningitis is a preventable cause of epilepsy. Implementing vaccination programs against the three most important meningeal pathogens can reduce the burden of bacterial meningitis and probably thereby associated epilepsy. Besides, it is plausible that early diagnosis and effective antibiotic therapy along with adjuvant therapies that down-regulate the mediators involved in the induction of neuronal injury may reduce the risk of subsequent development of epilepsy in the survivors of bacterial meningitis.

Prevention of bacterial meningitis

In developed countries, a decline in the incidence of meningitis due to the three most important meningeal pathogens has been accomplished with the implementation of vaccination programs against the common meningeal pathogens (Dery & Hasbun, 2007). In the United States, the incidence of bacterial meningitis has decreased by 55% since the introduction of H. influenzae type b (Hib) conjugate vaccine in 1990 (Dery & Hasbun, 2007). An impressive drop in the incidence of meningococcal disease has also been witnessed; the incidence of meningococcal disease decreased from 23.6/100,000 in 1964 to 1.3/100,000 in 1998 by implementing routine vaccination of military recruits with the meningococcal polysaccharide vaccine (Brundage et al., 2002). In addition, implementation of guidelines for group B streptococcal infection surveillance and antibiotic prophylaxis in pregnancy has had a positive impact, with lower incidence rates of early-onset invasive disease (Schrag et al., 2002; Kainer et al., 2005).

In developing countries, where routine vaccination for Hib is available, there has been a decline in the incidence of Hib meningitis (Peltola, 1997; Cowgill et al., 2006; Daza et al., 2006). In Egypt, the administration of meningococcal serogroup A polysaccharide vaccine reduced the incidence of meningococcal disease from 10.2/100,000/year to 1.2/100,000/year (Wahdan et al., 1977). In sub-Saharan Africa, where serogroup A N. meningitidis accounts for majority of the large-scale epidemics (Greenwood, 2006), serogroup A and C meningococcal polysaccharide vaccines have been used to control epidemics. However, little progress has been made in the last 30 years in further developing and implementing meningococcal vaccination in most of Africa (Dery & Hasbun, 2007).

Prevention of neurological sequelae including epilepsy

Despite effective antibiotic therapy, patients with bacterial meningitis continue to experience significant morbidity and mortality in the long term (Fitch & van de Beek, 2007). Early diagnosis and institution of appropriate antibiotic therapy are important steps to optimize outcome (Auburtin et al., 2006). The intense inflammatory response to bacterial infection is believed to be responsible for significant morbidity and mortality despite effective antibiotic therapy (Koedel et al., 2002). Several mediators contribute to increased permeability of blood–brain barrier and the migration of leucocytes across the blood–brain barrier during bacterial meningitis. Down-regulation of these mediators and targeting of pathways involved in the initiation of neuronal injury are promising adjuvant therapeutic strategies for bacterial meningitis (Kim, 2003). Corticosteroids constitute one such adjuvant therapeutic strategy. A systematic review in adults with community-acquired acute bacterial meningitis showed that adjunctive corticosteroid treatment reduced neurological sequelae. The proportion of patients with neurological sequelae was smaller in the corticosteroid group (14%) than in the placebo group (22%), with borderline statistical significance (relative risk: 0.6; 95%CI: 0.4–1.0; p = 0.05) (van de Beek et al., 2004). No study has specifically examined the effect of adjuvant corticosteroid therapy on subsequent epilepsy. However, since persistent neurological deficits have been identified as risk factors for late unprovoked seizures following bacterial meningitis, it may be conjectured that corticosteroid administration may also impact the incidence of late unprovoked seizures/epilepsy (Pomeroy et al., 1990; van de Beek et al., 2004). Future prospective studies will be needed in order to establish whether early adjuvant corticosteroid therapy would reduce the risk of subsequent development of unprovoked seizures/epilepsy.

Conclusions

  1. Top of page
  2. Risk of Unprovoked Seizures and Epilepsy Following Bacterial Meningitis
  3. Risk Factors for Late Unprovoked Seizures
  4. Seizure Semiology, Course, and Prognosis
  5. Burden of Epilepsy Associated with Bacterial Meningitis
  6. Conclusions
  7. References

Unprovoked seizures/epilepsy are long-term sequelae of bacterial meningitis and the association between bacterial meningitis and late unprovoked seizures/epilepsy has been demonstrated in both, prospective and retrospective studies. The probability of developing unprovoked seizures/epilepsy varies according to the etiologic agent responsible for meningitis and this probability appears to be higher for S. pneumoniae. The burden of epilepsy associated with bacterial meningitis depends on the incidence of bacterial meningitis. The burden of epilepsy is preventable to quite an extent by implementing vaccination programs against the three most important meningeal pathogens. In developed countries, a decline in the incidence of meningitis has been accomplished with the implementation of vaccination programs.

Conflict of interest: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The authors have declared no conflicts of interest.

References

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  2. Risk of Unprovoked Seizures and Epilepsy Following Bacterial Meningitis
  3. Risk Factors for Late Unprovoked Seizures
  4. Seizure Semiology, Course, and Prognosis
  5. Burden of Epilepsy Associated with Bacterial Meningitis
  6. Conclusions
  7. References
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