Streptococcal Meningitis

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](A1)

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]