CNS Infections

CLINICAL AND DIAGNOSTIC ASPECTS OF CNS INFECTIONS FOR UG/PG Medical Students

1. CNS Infections Dr. Suprakash Das

2. Anatomy of CNS Our bodies couldn’t operate without the nervous system - the complex network that coordinates our actions, reflexes, and sensations. Broadly speaking, the nervous system is organised into two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS is the processing centre of the body and consists of the brain and the spinal cord. Both of these are protected by three layers of membranes known as meninges . For further protection, the brain is encased within the hard bones of the skull, while the spinal cord is protected with the bony vertebrae of our backbones. A third form of protection is cerebrospinal fluid, which provides a buffer that limits impact between the brain and skull or between spinal cord and vertebrae.

3. Infections of CNS The central nervous system (CNS) may be infected by various agents, including viruses, bacteria, fungi, protozoa, and helminths . In addition, numerous noninfectious etiologies may account for syndromes that mimic CNS infections. These include neoplastic diseases, intracranial tumors and cysts, medications, collagen vascular disorders, and other systemic illnesses, and following various procedures that invade the CNS.

4. Infections of CNS The clinical presentation of a CNS infection may be acute, subacute , or chronic, depending on the virulence of the infecting agent and the location of the infection. Because CNS infections occur within the confines of the cranium or spinal column, they may be associated with significant morbidity and mortality, often necessitating emergent interventions to improve outcome.

5. Clinical Manifestations The clinical presentation of a specific CNS infection depends on the pathogenesis of spread of the infection to the CNS, the virulence of the etiologic agent, and the area of CNS involvement. Most patients with CNS infections present with the clinical features of fever, headache, altered mental status, or focal neurologic deficits. These findings are nonspecific, however, and not all patients with CNS infections develop all of these clinical manifestations. The likelihood of any specific clinical finding depends on the CNS syndrome caused by the infectious agent.

6. Acute Bacterial Meningitis DEFINITION Bacterial meningitis is an acute purulent infection within the subarachnoid space. It is associated with a CNS inflammatory reaction that may result in decreased consciousness, seizures, raised intracranial pressure (ICP), and stroke. The meninges , the subarachnoid space, and the brain parenchyma are all frequently involved in the inflammatory reaction ( meningoencephalitis ). EPIDEMIOLOGY- Currently, the organisms most commonly responsible for community acquired bacterial meningitis are Streptococcus pneumoniae (∼50%), N. meningitidis (∼25%), group B streptococci (∼15%), and Listeria monocytogenes (∼10%). H. influenzae now accounts for <10% of cases of bacterial meningitis in most series.

7. Acute Bacterial Meningitis Etiology- S. pneumoniae is the most common cause of meningitis in adults >20 years of age N. meningitidis Enteric gram-negative bacilli Group B streptococcus L. monocytogenes H. influenzae type b Staphylococcus aureus coagulase -negative staphylococci

8. P A T H O P H Y S I O L O G Y O F A B M

9. Acute Bacterial Meningitis CLINICAL PRESENTATION Meningitis can present as either an acute fulminant illness that progresses rapidly in a few hours or as a Subacute infection that progressively worsens over several days . The classic clinical triad of meningitis is fever, headache, and nuchal rigidity. A decreased level of consciousness occurs in >75% of patients and can vary from lethargy to coma. Nausea, vomiting, and photophobia are also common complaints.

10. Acute Bacterial Meningitis CLINICAL PRESENTATION Seizures occur as part of the initial presentation of bacterial meningitis or during the course of the illness in 20–40% of patients. Focal seizures are usually due to focal arterial ischemia or infarction, cortical venous thrombosis with hemorrhage, or focal edema. Generalized seizure activity and status epilepticus may be due to hyponatremia , cerebral anoxia, or, less commonly, the toxic effects of antimicrobial agents such as high-dose penicillin. Raised ICP is an expected complication of bacterial meningitis and the major cause of obtundation and coma in this disease. More than 90% of patients will have a CSF opening pressure >180 mmH2O , and 20% have opening pressures >400 mmH2O.

11. Acute Bacterial Meningitis CLINICAL PRESENTATION Signs of increased ICP include a- deteriorating or reduced level of consciousness, papilledema , dilated poorly reactive pupils, sixth nerve palsies, decerebrate posturing, and Cushing’s reflex ( bradycardia , hypertension, and irregular respirations). The most disastrous complication of increased ICP is cerebral herniation . The incidence of herniation in patients with bacterial meningitis has been reported to occur in as few as 1% to as many as 8% of cases.

12. Acute Bacterial Meningitis CLINICAL PRESENTATION Specific clinical features may provide clues to the diagnosis of individual organisms . The most important of these clues is the- rash of meningococcemia, which begins as a diffuse erythematous maculopapular rash resembling a viral exanthem ; however , the skin lesions of meningococcemia rapidly become petechial . Petechiae are found on the trunk and lower extremities, in the mucous membranes and conjunctiva, and occasionally on the palms and soles.

13. Acute Bacterial Meningitis Laboratory Diagnosis- Samples needed- Blood (for culture and sensitivity) CSF ( Microscopy- For Organisms & Cell count / Biochemical analysis- Sugars/ Protein/ Chloride levels) CSF- Culture & sensitivity[ the yield of CSF cultures in suspected cases is low 28. Another disadvantage of CSF bacterial culture is that it requires up to 72 hours for final identification.] CSF- Molecular tests. Radiological diagnosis- CT MRI Obtaining CSF Sample- Lumber Puncture https://www.uptodate.com/contents/lumbar-puncture-technique-indications-contraindications-and-complications-in-adults

14. CSF Collection Kit Trans-Isolate (T-I) medium.

15. Work Flow Chart With CSF Samples

16. Acute Bacterial Meningitis Lab Diagnosis - Interpreting Glucose Levels - CSF glucose concentrations <2.2 mmol /L (<40 mg/ dL ) are abnormal, and a CSF glucose concentration of zero can be seen in bacterial meningitis . Use of the CSF/serum glucose ratio corrects for hyperglycemia that may mask a relative decrease in the CSF glucose concentration . The CSF glucose concentration is low when the CSF/serum glucose ratio is <0.6 . A CSF/serum glucose ratio <0.4 is highly suggestive of bacterial meningitis , but may also be seen in other conditions, including fungal, tuberculous , an carcinomatous meningitis.

17. Acute Bacterial Meningitis A broad-range PCR can detect small numbers of viable and nonviable organisms in CSF and is expected to be useful for making a diagnosis of bacterial meningitis in patients who have been pretreated with oral or parenteral antibiotics and in whom Gram’s stain and CSF culture are negative. When the broad-range PCR is positive, a PCR that uses specific bacterial primers to detect the nucleic acid of S. pneumoniae , N. meningitidis , Escherichia coli, L. monocytogenes, H. influenzae, and S. agalactiae can be obtained based on the clinical suspicion of the meningeal pathogen. The latex agglutination (LA) test for the detection of bacterial antigens of S. pneumoniae , N. meningitidis , H. influenzae type b, group B streptococcus, and E. coli K1 strains in the CSF

18. Acute Bacterial Meningitis The CSF LA test has a specificity of 95–100% for S. pneumoniae and N. meningitidis , so a positive test is virtually diagnostic of bacterial meningitis caused by these organisms. However, the sensitivity is only 70–100% for detection of S. pneumoniae and 33–70% for detection of N. meningitidis antigens, so a negative test does not exclude infection by these organisms. The Limulus amebocyte lysate assay is a rapid diagnostic test for the detection of gram-negative endotoxin in CSF and thus for making a diagnosis of gram-negative bacterial meningitis. The test has a specificity of 85–100% and a sensitivity approaching 100%. Thus a positive Limulus amebocyte lysate assay occurs in virtually all patients with gram-negative bacterial meningitis. Almost all patients with bacterial meningitis will have Neuro -imaging studies performed during the course of their illness. MRI is preferred over CT because of its superiority in demonstrating areas of cerebral edema and ischemia.

19. Acute Bacterial Meningitis Differential Diagnosis- (HSV) encephalitis Rocky Mountain spotted fever Ehrlichioses Subarachnoid hemorrhage cystic glioma or craniopharyngioma epidermoid sarcoid , systemic lupus erythematosus Behçet’s syndrome Drug hypersensitivity

20. ACUTE VIRAL MENINGITIS CLINICAL MANIFESTATIONS Patients with viral meningitis usually present with headache, fever, and signs of meningeal irritation coupled with an inflammatory CSF profile. The headache of viral meningitis is usually frontal or retroorbital and is often associated with photophobia and pain on moving the eyes. Nuchal rigidity is present in most cases but may be mild and present only near the limit of neck anteflexion . Constitutional signs can include malaise, myalgia , anorexia, nausea and vomiting, abdominal pain, and/or diarrhea.

21. ACUTE VIRAL MENINGITIS Patients often have mild lethargy or drowsiness; however, profound alterations in consciousness, such as stupor, coma, or marked confusion, are unusual in viral meningitis and suggest the presence of encephalitis or other alternative diagnoses. Similarly, seizures or focal neurologic signs or symptoms or neuro -imaging abnormalities indicative of brain parenchymal involvement are not typical of viral meningitis and suggest the presence of encephalitis or another CNS infectious or inflammatory process.

22. Etiology of Viral Meningitis & Encephalitis

23. ACUTE VIRAL MENINGITIS Lab Diagnosis- Viral Culture- Poor sensitivity & specificity Serologic Studies- For some viruses, including many arboviruses such as WNV, serologic studies remain a crucial diagnostic tool. Serum antibody determination is less useful for viruses with high seroprevalence rates in the general population such as HSV, VZV,CMV, and EBV. Documentation of synthesis of virus-specific antibodies in CSF, as shown by an increased IgG index or the presence of CSF IgM antibodies, is more useful than serum serology alone and can provide presumptive evidence of CNS infection. Although serum and CSF IgM antibodies generally persist for only a few months after acute infection, there are exceptions to this rule. For example, WNV IgM has been shown to persist in some patients for >1 year after acute infection.

24. ACUTE VIRAL MENINGITIS Polymerase Chain Reaction Amplification of Viral Nucleic Acid- Amplification of viral-specific DNA or RNA from CSF using PCR amplification has become the single most important method for diagnosing CNS viral infections. In both enteroviral and HSV infections of the CNS, PCR has become the diagnostic procedure of choice. CSF PCR is also used routinely to diagnose CNS viral infections caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV), VZV, and human herpesvirus 6 (HHV-6). CSF PCR tests are available for WNV but are not as sensitive as CSF IgM . PCR is also useful in the diagnosis of CNS infection caused by Mycoplasma pneumoniae , which can mimic viral meningitis.

25. ACUTE VIRAL MENINGITIS Treatment- Treatment of almost all cases of viral meningitis is primarily symptomatic and includes use of analgesics, antipyretics, and antiemetics . Fluid and electrolyte status should be monitored. Oral or intravenous acyclovir may be of benefit in patients with meningitis caused by HSV-1 or -2 and in cases of severe EBV or VZV infection. Seriously ill patients should probably receive intravenous acyclovir (15–30 mg/kg per day in three divided doses), which can be followed by an oral drug such as acyclovir (800 mg, five times daily), famciclovir (500 mg tid ), or valacyclovir (1000 mg tid ) for a total course of 7–14 days. Patients who are less ill can be treated with oral drugs alone. HIV meningitis - highly active antiretroviral therapy.

26. VIRAL ENCEPHALITIS Definition- In contrast to viral meningitis, where the infectious process and associated inflammatory response are limited largely to the meninges , in encephalitis the brain parenchyma is also involved. Many patients with encephalitis also have evidence of associated meningitis ( meningoencephalitis ) and, in some cases, involvement of the spinal cord or nerve roots (encephalomyelitis, encephalomyeloradiculitis ).

27. VIRAL ENCEPHALITIS Clinical Manifestations- In addition to the acute febrile illness with evidence of meningeal involvement characteristic of meningitis, the patient with encephalitis commonly has an altered level of consciousness (confusion, behavioral abnormalities) or a depressed level of consciousness, ranging from mild lethargy to coma, and evidence of either focal or diffuse neurologic signs and symptoms. Patients with encephalitis may have hallucinations, agitation, personality change, behavioral disorders, and, at times, a frankly psychotic state.

28. VIRAL ENCEPHALITIS Clinical Manifestations- Focal or generalized seizures occur in many patients with encephalitis. The most commonly encountered focal findings are aphasia, ataxia, upper or lower motor neuron patterns of weakness, involuntary movements (e.g., myoclonic jerks, tremor), and cranial nerve deficits (e.g., ocular palsies, facial weakness). Involvement of the hypothalamic-pituitary axis may result in temperature dysregulation , diabetes insipidus , or the development of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

29. VIRAL ENCEPHALITIS Laboratory diagnosis- CSF Examination- same as Viral meningitis CSF culture- >95% culture negative Serology- HSV-1 & WNV- IgM CSF PCR- CMV, EBV,VZV, HHV-6, and enteroviruses MRI/ CT/ EEG

30. VIRAL ENCEPHALITIS Treatment- Vital functions, including respiration and blood pressure, should be monitored continuously and supported as required. In the initial stages of encephalitis, many patients will require care in an intensive care unit . Basic management and supportive therapy should include careful monitoring of ICP, fluid restriction, avoidance of hypotonic intravenous solutions, and suppression of fever . Seizures should be treated with standard anticonvulsant regimens, and prophylactic therapy should be considered in view of the high frequency of seizures in severe cases of encephalitis .

31. VIRAL ENCEPHALITIS Acyclovir- HSV/VZV/EBV- Adults should receive a dose of 10 mg/kg of acyclovir intravenously every 8 h (30 mg/kg per day total dose) for a minimum of 14 days. it is recommended that neonates with HSV encephalitis receive 20 mg/kg of acyclovir every 8 h (60 mg/kg per day total dose) for a minimum of 21 days. Ganciclovir and foscarnet , either alone or in combination, are often utilized in the treatment of CMV-related CNS infections, although their efficacy remains unproven. Cidofovir may provide an alternative in patients who fail to respond to ganciclovir and foscarnet .

32. CHRONIC AND RECURRENT MENINGITIS Chronic inflammation of the meninges ( pia , arachnoid , and dura ) can produce profound neurologic disability and may be fatal if not successfully treated. The condition is most commonly diagnosed when a characteristic neurologic syndrome exists for >4 weeks and is associated with a persistent inflammatory response in the cerebrospinal fluid (CSF) (white blood cell count >5/ μL ). The causes are varied, and appropriate treatment depends on identification of the etiology. Five categories of disease account for most cases of chronic meningitis: (1) MENINGEAL INFECTIONS, (2) MALIGNANCY, (3) NONINFECTIOUS INFLAMMATORY DISORDERS, (4) CHEMICAL MENINGITIS, AND (5) PARAMENINGEAL INFECTIONS.

33. BRAIN ABSCESS Definition- A brain abscess is a focal, suppurative infection within the brain parenchyma, typically surrounded by a vascularized capsule. The term cerebritis is often employed to describe a nonencapsulated brain abscess. Predisposing conditions include otitis media and mastoiditis , paranasal sinusitis, pyogenic infections in the chest or other body sites, penetrating head trauma or neurosurgical procedures, and dental infections.

34. BRAIN ABSCESS Etiology- Associated with Mastoiditis - streptococci, Bacteroides spp., Pseudomonas spp., Haemophilus spp., and Enterobacteriaceae . Associated with paranasal sinusitis - streptococci (especially S. milleri ), Haemophilus spp., Bacteroides spp., Pseudomonas spp., and S. aureus . Dental infections - streptococci, staphylococci, Bacteroides spp., and Fusobacterium spp.

35. BRAIN ABSCESS Heamatogenous - brain abscesses that develop as a complication of infective endocarditis are often due to viridans streptococci or S. aureus . Abscesses associated with pyogenic lung infections such as lung abscess or bronchiectasis are often due to streptococci, staphylococci, Bacteroides spp., Fusobacterium spp., or Enterobacteriaceae . Abscesses that follow penetrating head trauma or neurosurgical procedures are frequently due to methicillin -resistant S. aureus (MRSA), S. epidermidis , Enterobacteriaceae , Pseudomonas spp., and Clostridium spp. Enterobacteriaceae and P. aeruginos a are important causes of abscesses associated with urinary sepsis .

36. BRAIN ABSCESS Diagnosis is made by neuroimaging studies. MRI is better than CT for demonstrating abscesses in the early ( cerebritis ) stages and is superior to CT for identifying abscesses in the posterior fossa . Microbiologic diagnosis of the etiologic agent is most accurately determined by Gram’s stain and culture of abscess material obtained by stereotactic needle aspiration . Aerobic and anaerobic bacterial cultures and mycobacterial and fungal cultures should be obtained . Up to 10% of patients will also have positive blood cultures.

37. BRAIN ABSCESS Diagnosis- LP should not be performed in patients with known or suspected focal intracranial infections such as abscess or empyema ; CSF analysis contributes nothing to diagnosis or therapy, and LP increases the risk of herniation . About 50% of patients have a peripheral leukocytosis , 60% an elevated ESR, and 80% an elevated C-reactive protein. Blood cultures are positive in ∼10% of cases overall but may be positive in >85% of patients with abscesses due to Listeria .

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