Continuing Education Activity

Streptococcal meningitis is an acute, purulent inflammation of the membranes surrounding the brain and spinal cord caused by bacteria from the Streptococci species. This condition requires prompt diagnosis and treatment to avoid the high morbidity and morbidity associated with its complications. This activity reviews the evaluation and treatment of Streptococcal meningitis and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Summarize the etiology of Streptococcal meningitis.
• Describe the typical history and physical of the patients with Streptococcal meningitis.
• Review the management options available for streptococcal meningitis.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients with streptococcal meningitis.

Introduction

Streptococcal meningitis is an acute inflammation of the membranes surrounding the brain and spinal cord caused by bacteria from the streptococcal species. Bacterial meningitis is a severe and life-threatening infection that may lead to death, especially when treatment initiation is overdue. Despite progress in diagnostic methods and treatment as well as the implementation of national immunization programs, bacterial meningitis is still one of the most burdening infectious diseases worldwide.

Etiology

Numerous Streptococcus bacteria can cause meningitis. The most significant one is Streptococcus pneumoniae, probably the leading etiologic agent of meningitis worldwide, both in adults and children. In the beta-hemolytic group, the most notable is group B Streptococcus (GBS) – the most common cause of meningitis in neonates and young infants. Other Streptococci, i.e., belonging to the S. viridans group or group A are very rarely causative pathogens of meningitis in adults or children.

Epidemiology

The etiologic agents causing streptococcal meningitis vary by age group. Streptococcus pneumoniae remains the most common etiologic agent of bacterial meningitis in children above one month and adults of all ages. In the U.S., the incidence of pneumococcal meningitis decreased from 0.8 per 100000 people in 1997 to 0.3 per 100000 people in 2010 (PCV 7 was introduced in 2000).[1] S. pneumoniae infection is also the most common cause of bacterial meningitis in children, ranging from 22.5% in Europe to 41.1% in Africa.[2] In the developing world, invasive pneumococcal disease (IPD) is a significant cause of morbidity and mortality, with up to 1.0 million deaths per year in children less than five years old.[3]

In neonates, S. agalactiae is one of the leading pathogens responsible for meningitis. In the U.S., from 2006 to 2015, early-onset disease (onset at 0 to 6 days of life, EOD) incidence decreased from 0.37 to 0.23 per 1000 live births, mainly due to intrapartum antibiotic prophylaxis. Late-onset disease (LOD) rates were stable in those years.[4] The global incidence of invasive GBS disease in infants is 0.49 per 1000 live births, with the highest numbers in Africa.[5] Other groups of streptococci rarely cause meningitis. S. viridans accounts for 0.3% to 3.0% of cases of bacterial meningitis in adults and 1% in children.[6] Group A streptococcal meningitis was diagnosed in 2% of the cases of community-acquired bacterial meningitis.[7]

Pathophysiology

Meningitis occurs when bacteria enter the bloodstream and then cross the blood-brain barrier or through direct contact of meninges with the skin or nasal cavity. The most frequent focus of the infection is the nasopharynx colonized by S. pneumoniae that evades the host immune system. During IPD, the bloodstream becomes invaded, and complement and coagulation systems are activated. Inflammatory mediators are released massively, which makes it easier for the bacteria to cross the blood-brain barrier. Inflammation is responsible for all the typical findings of bacterial meningitis, i.e., CSF pleocytosis.

History and Physical

Symptoms of bacterial meningitis, including Streptococcal, can develop either suddenly or over a few days. Typically they are present 3 to 7 days after exposure. There are no specific symptoms that allow recognition of causative agents of bacterial meningitis based solely on history taking and examination.

Adults

The classic triad of diagnostic symptoms of meningitis in adults includes fever, nuchal rigidity, and altered mental status; however, only 44% of adult patients with bacterial meningitis present with all three symptoms.[8] In the same study, nearly all patients had a minimum of two out of four symptoms among headache, fever, neck stiffness, and altered mental status.[8] Other complaints typically reported by patients are severe headache, intensified by head movements, nausea, vomiting, and photophobia. In the study by Lucht accuracy of clinical examination for the diagnosis of meningitis in adults was reviewed. Sensitivity for clinical signs like headache, vomiting, or fever was less than 30%, and for nuchal rigidity, 45%.[9] The study also showed that if two out of four signs among headache, fever, altered mental status, and neck stiffness are absent, the diagnosis of meningitis is extremely unlikely (with a negative predictive value of 95%). A Danish study enrolled adults with pneumococcal meningitis. On admission, researchers observed fever and an altered mental status in almost all cases. Back rigidity, headache, and convulsions were found less commonly (57%, 41%, and 11%, respectively).[10]

On physical examination, signs of meningeal irritation can be present - nuchal rigidity, Kernig's and Brudzinski's signs. Those signs have high specificity in patients with meningitis. However, their sensitivity is low. In a study conducted by Thomas et al. that analyzed adults with meningitis suspicion, researchers reported the specificity of 95% and sensitivity of 5% for both Kernig's and Brudzinski's signs and a sensitivity of 30% and specificity of 68% for nuchal rigidity.[11] Altered mental status is observable – confusion, decreased alertness, or even seizures.

Children

Clinical signs of neonatal and infant meningitis are usually non-specific, including irritability or lethargy, fever or hypothermia, poor feeding, and vomiting with diarrhea. More specific signs on the physical examination like bulging fontanel, nuchal rigidity, and seizures in neonates are usually late findings.[12] In the study of Amarilyo et al., half of the enrolled patients with meningitis with open fontanel had bulging fontanel.[13] This study enrolled children aged two months to 16 years with suspected meningitis - Kernig's and Brudzinski's signs had a sensitivity of 27% and 51%, respectively, with a high positive predictive value of 77% and 81%, respectively. Classic meningeal signs are often absent in infants less than six months. Weber et al. proved that reduced feeding, the appearance of being very sick, being lethargic or unconscious, neck stiffness, and a bulging fontanel are the variables associated independently with meningitis in children aged two months to 3 years.[14]

Evaluation

The pivotal test for the diagnosis of meningitis (including streptococcal) is cerebrospinal fluid (CSF) examination. It is required to confirm the diagnosis, identify the causative bacterial pathogen, and, therefore, to implement de-escalated treatment later on. CSF should be obtained as soon as bacterial meningitis is suspected unless contraindications for urgent lumbar puncture (LP) are present. Contraindications for immediate LP include risk of herniation, uncorrected coagulopathy, or critical condition of the patient. According to the Infectious Diseases Society of America guidelines, head CT before LP is warranted in the case of focal neurologic deficit, abnormal level of consciousness, papilledema, seizure within one week of presentation, history of central nervous system disease, and an immunocompromised state. During LP, samples of CSF are taken and sent for physical and chemical characteristics, cell count, Gram stain, latex agglutination test (LAT), culture, and, if available, polymerase chain reaction (PCR). CSF examination in patients with streptococcal meningitis usually shows neutrophilic pleocytosis (white blood count of 500/ microL or higher), elevated lactate level, and lowered CSF/serum glucose ratio. CSF leukocyte count less than 50/mm^3 and elevated CSF protein level (at least 660 mg/dL) were poor prognostic factors in children with pneumococcal meningitis.[15] CSF Gram staining results in the initial identification of bacteria. LAT detects antigens of few pathogens, among them S. pneumoniae. Results are provided in a short time. The causative pathogen is confirmed by positive culture from the CSF sample; however, in a study comparing traditional culture and antigen detection methods, less than half of the cases of bacterial meningitis were culture positive.[16] Another option was PCR, especially valid when previously using antibiotics. The use of the PCR test in determining the etiology of bacterial meningitis is increasing. However, it recognizes only several types of bacteria – the ones included in the primer mix. In the previously mentioned study, LAT proved to be more sensitive compared to conventional Gram stain and culture technique in identifying the specific organisms like H. influenzae, S. pneumoniae, and Group B Streptococcus. Nevertheless, the combination of culture, Gram stain, and LAT was more effective than any single method alone.[16]

Other laboratory tests include blood culture – necessary to take to increase the likelihood of identification of causative pathogen - as well as complete blood count, inflammatory markers (often much elevated), coagulation testing, markers of liver and kidney function. There should be no delays in instituting treatment because of all the diagnostic procedures.

Treatment / Management

Streptococcal meningitis requires immediate treatment with antibiotics. Delays in implementing treatment are not acceptable.

S. pneumoniae

Initial treatment for pneumococcal meningitis consists of vancomycin plus one of the third-generation cephalosporins: cefotaxime or ceftriaxone. The antibiotic therapy can undergo review after antibiotic sensitivity is available – if bacteria is penicillin-susceptible, switch to penicillin is acceptable. For patients with a history of anaphylaxis to cephalosporins or penicillins, chloramphenicol is an option. Adjuvant therapy with dexamethasone is recommended - research showed a significant reduction in mortality and all unfavorable outcomes in patients with pneumococcal meningitis compared to sole antibiotic treatment.[17][18]

S. agalactiae

Penicillin G monotherapy is suitable for the treatment of meningitis caused by GBS. Ampicillin is an acceptable alternative.

S. viridans, Group A Streptococcus

Penicillin G is effective for the treatment of meningitis caused by S. viridans or group A Streptococcus.

Supportive care, including fluid management, reduction of intracranial pressure, antipyretics, and analgesics, are valid parts of the therapy.

Differential Diagnosis

Diseases that merit consideration in the differential diagnosis are other neural infections. Meningitis of different bacterial etiology (i.e., meningococcal) can be mistaken for streptococcal meningitis. It is impossible to establish the etiology taking into consideration only the clinical picture. CSF culture is indispensable in making a precise diagnosis. Viral and fungal etiologies of meningitis must also be ruled out. Encephalitis is another disease that can present itself very similarly to meningitis. Although encephalitis can affect meninges as well, evidence of brain inflammation is the distinguishing feature absent in meningitis. All other causes of altered mental status and coma should be ruled out, including stroke, intoxication, hypoglycemia, and electrolyte disturbances.

• Brain abscess
• Brain tumors
• Subdural/epidural abscess
• Central nervous system (CNS) leukemia
• Hypersensitivity to drugs
• CNS tuberculosis
• Disorders associated with vasculitis (e.g., Kawasaki disease and collagen vascular disease)
• Lead encephalopathy
• Encephalitis
• Cerebrovascular accident
• Hypoglycemia
• Intoxication
• Viral meningitis
• Fungal meningitis

Prognosis

Prognosis in streptococcal meningitis is always serious. In a Danish study of pneumococcal meningitis, the overall case-fatality rate was 21%, with a 10-fold higher mortality rate in adults than in children.[10] The causes of death were neurological, such as brain herniation, cerebrovascular complications (41% of the patients), systemic causes like septic shock, multiple-organ dysfunction (nearly one-fourth), other causes (8%), and roughly one-third died due to a combination of systemic and neurological complications.[10] Advanced age, presence of lung focus, convulsions, having a CT scan before lumbar puncture, and need for assisted ventilation were prognostic factors associated with a fatal outcome within 100 days. The otogenic focus was associated with better survival.[10] Retrospective analysis showed that the initial presentation of coma, respiratory failure, shock, and leukopenia (WBC less than 4,000/mm^3) were poor prognostic factors in children with meningitis.[15] Mortality rates for GBS meningitis in neonates decreased following the introduction of intrapartum chemoprophylaxis. However, it remains high (11.4% among 848 patients enrolled).[19] Neurological and systemic sequelae in survivors are common.

Complications

The incidence of neurological sequelae in survivors of pneumococcal meningitis remains high. Kastenbauer et al., in their study of adults, showed that meningitis-associated intracranial complications concerned 74.7% of the patients after pneumococcal meningitis and systemic complications touched over one-third of the patients. Some of the complications were seizure (27.6%), diffuse brain swelling (28.7%), hearing loss (19.7%), ischemic or hemorrhagic brain damage (21.8%), and hydrocephalus (16.1%).[20] In Van De Beek's study, researchers found focal neurological deficits in 65% of the patients with pneumococcal meningitis, with the most common one being hearing impairment.[8]

In children, the developmental delay was the most common long-term post-pneumococcal meningitis sequelae concerning 43% of the enrolled children.[21] In almost one-third of survivors, seizures were observed at one year postinfection. Hearing loss occurred in 29% of the children.

Long-term morbidity in survivors of GBS meningitis is significant. One-fourth of the children with GBS meningitis had a mild-to-moderate impairment; almost 20% showed severe impairment when assessed later.[22]

Deterrence and Patient Education

Patient education about Streptococcal meningitis, including alarming symptoms, is vital to provide the best possible outcome. Treatment delay is an unfavorable factor in bacterial meningitis. Pregnant women should be informed by their obstetrician about possible intrapartum chemoprophylaxis.

Pearls and Other Issues

Transmission

S. pneumoniae spreads through respiratory droplets from people with Pneumococcal disease or healthy carriers with the bacteria in their nasopharynx. However, there is a little chance of having pneumococcal meningitis even after close contact. There are individual factors that make the person vulnerable to the development of pneumococcal meningitis, including immunocompromised, especially patients with asplenia, diabetes, leak of cerebrospinal fluid, cochlear implant, history of meningitis, cigarette smoking, and alcohol use.

GBS is a common finding in gastrointestinal and genital tracts. Women who become colonized with this bacteria can pass it on to their newborns during labor. In adults, most of the GBS meningitis is found in patients with comorbid conditions.

Prevention

Among all streptococcal meningitides, only pneumococcal is a vaccine-preventable condition. Two types of vaccines exist against Streptococcus pneumoniae: older pneumococcal polysaccharide vaccine (PPSV) and newer pneumococcal conjugate vaccines (PCV). PPSV is composed of 23 pneumococcal capsular polysaccharides, and it covers the broadest range of antigens out of all pneumococcal vaccines. Children less than two years old do not respond to this vaccination, though it is suitable only for patients over two years of age. In the meta-analysis by Falkenhorst et al., PPSV23 efficacy against IPD caused by any serotype was reported to be 73% in a pooled analysis of all included clinical trials enrolling adults aged above 60 years living in industrialized countries.[23] PCV contains pneumococcal capsular polysaccharides linked to a carrier protein that allows the immune system of infants to produce antibodies. The recommendation is to use PCV in the children's routine immunizations. There are two types of PCV available with a different number of serotypes: PCV10 and PCV13. Lucero et al. conducted a meta-analysis of six randomized trials of different valencies of PCV. In children of less than two years of age, the efficacy of PCV for preventing vaccine-type IPD was 80%, and 58% for preventing IPD caused by all serotypes.[24] The CAPiTA trial assessed the efficacy of PCV13 with immunocompetent adults above 65 years of age enrolled. Results demonstrated about 75% efficacy against the vaccine-type invasive pneumococcal disease.[25]

Meningitis caused by group B streptococci is also preventable by testing all pregnant women at 35 to 37 weeks of gestation for vagina and rectum colonization with GBS and using antibiotic chemoprophylaxis in colonized women. Approximately half of the colonized women will pass the bacteria to their neonates during labor or after membranes rupture. If not for intrapartum antibiotic prophylaxis, up to 2% of those newborns will develop GBS EOD.[26] Since the implementation of national guidelines in the USA for intrapartum prophylaxis, statistics show a reduction in the occurrence of GBS EOD of more than 80% between the early 1990s and 2010.[27]

Enhancing Healthcare Team Outcomes

Streptococcal meningitis is a severe, life-threatening infection. It may pose a diagnostic challenge, especially in infants, because these patients may exhibit non-specific signs. The most vital for a patient outcome is fast diagnosis and treatment. Doctors who work in primary care facilities should educate their patients about alarming symptoms of meningitis. While the pediatrician or internist is almost always involved in the care of patients with streptococcal meningitis, it is essential to cooperate with other specialists that include infectious disease experts or anesthesiologists if needed. The nurses are also vital members of the interprofessional group, as they will monitor the patient's vital signs. Laboratory professionals play an essential role in establishing the diagnosis of causative agents. A physiotherapist is also needed to reduce the neurological burden of streptococcal meningitis. A board-certified infectious disease pharmacist can review antibiotic choices with the clinician, using the latest antibiogram data. They can also check for interactions, verify dosing and duration, and communicate with the rest of the team regarding potential adverse events. Interprofessional team efforts are necessary to improve outcomes for patients. [Level 5]