Meningitis

Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Diagnosis of meningitis is made on clinical grounds with a thorough neurologic examination. CSF analysis is an important diagnostic tool, as it is difficult to identify the exact cause clinically. Management of meningitis includes immediate broad-spectrum antibiotics and supportive therapy to prevent complications. Specific treatment depends on the etiology of meningitis. Delay in treatment can lead to permanent neurologic defects and death.

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Overview

Definition

Meningitis is inflammation of the protective membranes of the brain and the spinal cord, collectively called the meninges, that is commonly caused by an acute infection.

Epidemiology

  • A significant decrease in frequency occurred after introduction of routine infant vaccinations against Haemophilus influenzae and Pneumococcus.
  • Since 2010, the peak incidence of bacterial meningitis shifted from children < 5 years of age to adults.
  • Meningococcal meningitis is observed in crowded accommodations.
  • Incidence is higher in developing countries owing to the lack of access to preventive measures.
  • Viral meningitis peaks in early fall and summer.
  • Meningitis can occur at any age and affects both sexes equally.

Etiology

Meningitis can be of infectious (most common) or noninfectious origin. Infectious meningitis can be community- or hospital-acquired.

Infectious meningitis

Bacterial meningitis:

  • The most common cause of bacterial meningitis is Streptococcus pneumoniae.
  • Relative frequency of occurrence varies according to the age group:
    • Neonates: Escherichia coli, Listeria monocytogenes, group B streptococci 
    • Infants and children: Haemophilus influenzae, Neisseria meningitidis 
    • Adults: S. pneumoniae, N. meningitidis (Meningococcus), L. monocytogenes  
  • Community-acquired bacterial meningitis is mainly caused by 5 organisms: 
    • S. pneumoniae (50%)
    • N. meningitidis (15%)
    • Group B streptococci (15%)
    • L. monocytogenes (10%)
    • H. influenzae (10%) 
  • Tubercular meningitis: 
    • Caused by Mycobacterium tuberculosis
    • Prevalent in developing countries
    • Predisposing conditions are:
      • History of previous exposure to tuberculosis
      • AIDS
      • Young age (children)

Viral meningitis:

  • Enteroviruses: 
    • Coxsackievirus
    • Echovirus
    • Human enterovirus
  • HSV-2 
  • Arthropod-borne viruses
  • HIV
  • Mumps

Fungal meningitis:

  • Cryptococcus neoformans: most common cause of fungal meningitis
  • Coccidioides immitis
  • Histoplasma capsulatum
  • Blastomyces dermatitidis
  • Candida species

Parasitic meningitis:

  • Angiostrongylus cantonensis
  • Gnathostoma spinigerum 
  • Acanthamoeba spp.
  • Naegleria fowleri 
  • Taenia solium 
  • Strongyloides stercoralis

Noninfectious meningitis

  • Systemic lupus erythematosus (SLE)
  • Malignancy
  • Sarcoidosis 
  • NSAIDs
  • IV immunoglobulins 
  • Behçet’s disease

Risk factors

  • Unvaccinated individuals or those who have skipped vaccinations
  • Children < 5 years 
  • Immunocompromised individuals with conditions like AIDS, diabetes, SLE
  • Immunosuppressant drugs
  • Pregnancy 
  • Outbreaks commonly occur in community accommodation settings. 
  • Pneumococci:
    • Other pneumococcal infections: pneumonia, sinusitis, otitis media
    • Splenectomy, asplenia 
    • Hypogammaglobulinemia
    • Complement deficiency 
  • N. meningitidis: 
    • Complement deficiency
    • B serotype
  • L. monocytogenes: 
    • Neonates < 1 month
    • Pregnant women 
    • Individuals > 60 years 
    • Immunocompromised individuals
3D image of a group of Gram-negative diplococci Neisseria meningitides

3-dimensional (3D) image of a group of diplococcal gram-negative Neisseria meningitidis

Image: “A 3D image of a group of diplococcal, Gram-negative, Neisseria meningitidis, bacteria” by Centers for Disease Control and Prevention. License: Public Domain

Pathophysiology

Direct inoculation of the infectious agent into the meninges is rare in meningitis. Usually, infection at an adjacent or remote site spreads to the brain.

Onset

Acute meningitis: 

  • Etiology: predominantly bacterial or viral
  • Symptoms develop in a few hours or within a day. 

Chronic meningitis:  

  • Etiology: bacterial, viral, parasitic, fungal, or noninfectious 
  • Symptoms persist for > 4 weeks  
  • When taking a history, questions should be asked about recent travel, immune status, and animal exposure.

Pathogenesis of infectious meningitis

  • 1st step is usually mucosal colonization.
  • Sites of colonization:
    • Skin
    • Nasopharynx
    • Respiratory tract
    • GI tract 
    • Genitourinary tract 
  • Mechanisms of mucosal attachment vary depending on the organism:
    • N. meningitidis: type 4 pili 
    • S. pneumoniae: platelet-activating factor receptor, laminin, polymeric immunoglobulin receptors
  • Secretion of IgA protease by pathogens inactivates mucosal IgA and also helps epithelial attachment.
  • Organism invades the submucosa at the site of colonization and disrupts host defenses. The capsule is an important virulence factor in this process.
  • Viral pathogens usually multiply in regional lymph nodes before invading the bloodstream.
  • Invasion of the bloodstream and hematogenous spread to the CNS is the most common pathway: 
    • Polysaccharide capsule of the main pathogens inhibits complement attachment and phagocytosis.
    • Capsule is the major factor in intravascular survival. 
  • Other CNS access pathways: 
    • Retrograde neuronal transmission through olfactory or peripheral nerves 
    • Direct contiguous spread (due to otitis, sinusitis) 
    • Direct inoculation (rare)
    • Vertical transmission in newborns (from mother)
  • Organism seeds the meninges. 
  • Body defenses act against the pathogen to induce inflammation, causing a cascade of events, including edema of the meninges and brain parenchyma.
  • Parenchymal edema increases the intracranial pressure, which worsens the symptoms.

Clinical Presentation

Adults

  • The classic triad of symptoms:
    1. Altered mental status (Glasgow coma scale score, < 14)
    2. Fever > 38℃
    3. Stiff neck
  • Severe headache
  • Lethargy and drowsiness 
  • Nausea and vomiting 
  • Photophobia 
  • Aphasia 
  • Hemiparesis or monoparesis 
  • Seizures 
  • Ataxia 
  • Cranial nerve palsies 
  • Nystagmus 
  • Rash 
  • Papilledema (swelling of optic disc)
  • Meningitis due to L. monocytogenes:
    • Increased tendency to have seizures
    • Focal neurologic defects early in the infection
  • Meningitis due to N. meningitidis
    • Skin manifestations: petechiae, palpable purpura
    • Arthritis
Symptoms of meningitis

Clinical presentation of meningitis

Image: “Main symptoms of Meningitis” by Mikael Häggström. License: Public Domain

Newborns

  • High fever 
  • Irritability (constant crying) 
  • Excessive drowsiness 
  • Difficulty waking up
  • Lethargy 
  • Poor feeding 
  • Vomiting 
  • Bulge in the anterior fontanelle
  • Stiff body and neck

Diagnosis

History

  • Acute:
    • Preceding respiratory illness
    • Otitis/sinusitis
    • Immunodeficiency/HIV
    • Acute onset with quick symptom development (often < 24 hours)
  • Chronic:
    • Recent travel
    • Residence in certain endemic areas (e.g., coccidioidomycosis)
    • Exposure to animals
    • Tuberculosis or positive tuberculin skin test
    • Sarcoidosis

Physical exam

  • Fever
  • Patients appear ill.
  • Signs of meningeal irritation (low sensitivity for acute meningitis):
    • Kernig sign:
      • The patient is placed in a supine position or is seated on a chair. 
      • The hip and knees are flexed to 90 degrees and an attempt is made to extend the knee.
      • Maneuver causes pain in the neck or back.
    • Nuchal rigidity:
      • The patient is placed in a supine position. 
      • The patient’s chest is supported with 1 hand while the other is kept under the occiput.
      • The chin is moved toward the sternum.
      • Reflex contraction of neck muscle prevents the patient’s chin from touching the chest.
    • Brudzinski sign: 
      • The patient is placed in a supine position.
      • Flexion of the neck causes involuntary flexion of the hip and knees. 
  • Cushing reflex: 
    • Widened pulse pressure, bradycardia, and irregular respirations  
    • Indicative of increased intracranial pressure
  • Papilledema 
  • Abducens (6th nerve) palsy

Laboratory analysis

  • CBC:
    • Elevated WBC count
    • Differential diagnosis may help determine etiology:
      • Neutrophil proliferation in bacterial meningitis
      • Increase in lymphocytes in viral or fungal meningitis
  • Blood culture: to identify the cause of meningitis and test for antibiotic sensitivity
  • CMP: 
    • Compare serum glucose with CSF glucose levels.
    • Assess for metabolic disturbances.
    • Assess for organ dysfunction. 
  • HIV test: Test for immune status if there is no history of other immunocompromised conditions.
  • Coagulation profile (PT, PTT) prior to lumbar puncture: 
    • Chronic alcohol use
    • Chronic liver disease
    • Suspected DIC

CSF analysis

  • Lumbar puncture is performed in all patients with suspected meningitis unless contraindicated, such as with increased intracranial pressure or suspicion of a mass lesion.
  • CSF analysis establishes a definite diagnosis and aids in the provision of appropriate treatment. CSF is tested for:
    • Opening pressure
    • Leukocyte count
    • Differential leukocyte count
    • Glucose levels 
    • Protein 
    • RBCs 
    • Culture and sensitivity

Imaging

Imaging is not required for diagnosis but is usually indicated before performing a lumbar puncture if there is a concern about high intracranial pressure and to detect complications. 

  • CT or MRI can be performed.
  • Usually indicated in:
    • Immunocompromised state 
    • History of neurologic disease (lesion/stroke/focal infection)
    • Seizure within 1 week of presentation 
    • Papilledema 
    • Altered consciousness 
    • Focal neurologic deficit: dilated, nonreactive pupil/gaze palsy/arm or leg drift
    • To detect complications:
      • Hydrocephalus 
      • Cerebral infarct 
      • Brain abscess 
      • Subdural empyema 
      • Venous sinus thrombosis
Meningeal irritation evident on contrast-enhanced MRI

Meningeal irritation evident on contrast-enhanced MRI

Image: “Damaged Meninges” by National Institutes of Health (NIH). License: Public Domain

Management and Prevention

Management

Treatment is based on the type of meningitis. Supportive care is common for most patients. Broad-spectrum antibiotics are usually administered as an immediate measure while the cause is being determined.

Bacterial meningitis:

  • Antibiotics should not be delayed while awaiting results of CT scan or lumbar puncture.
  • Initially, broad-spectrum antibiotics are given.
  • Later, antibiotics are adjusted based on culture and sensitivity:
    • S. pneumoniae: vancomycin + ceftriaxone
    • N. meningitidis: 3rd-generation cephalosporin; penicillin G or ampicillin if susceptible
    • H. influenzae: 3rd-generation cephalosporin; penicillin G or ampicillin if susceptible
    • L. monocytogenes: ampicillin or penicillin G + gentamicin
    • Gram-negative bacilli (usually nosocomial): 3rd-generation cephalosporin
  • IV administration is used for maximum efficacy.
  • Penetration of blood–brain barrier is facilitated by active meningeal inflammation. 
  • Intrathecal administration of antibiotics is considered in patients who are unresponsive to IV antibiotics or in nosocomial meningitis.
  • Duration depends on the patient’s response and the pathogen.
  • Steroid administration: 
    • Corticosteroids, especially dexamethasone, are used as an adjunctive treatment for bacterial meningitis  
    • Decreases mortality
    • Decreases rate of neurologic complications (e.g., hearing loss)
  • Supportive management: 
    • Administration of IV fluids 
    • Bed rest 
    • Analgesics 
    • Antipyretics 
    • Anticonvulsants in care of seizures
    • Immunoglobulin administration in immunodeficient patients

Viral meningitis: 

Viral meningitis is usually self-limiting and requires only supportive management. Antiviral therapy is indicated only in selected and/or severe cases. 

  • Supportive management: 
    • Administration of IV fluids 
    • Bed rest 
    • Analgesics 
    • Antipyretics 
    • Anticonvulsants in care of seizures
    • Immunoglobulin administration in immunodeficient patients
  • Indications of antiviral therapy:
    • Patients with HIV 
    • Herpes simplex meningitis: acyclovir
    • Cytomegalovirus meningitis: ganciclovir, foscarnet 
    • Cases associated with encephalitis 

Fungal meningitis: 

  • The most common type is cryptococcal meningitis.
  • Antifungal drugs administered are:
    • Amphotericin B 
    • Fluconazole 
    • Itraconazole 
  • Raised intracranial pressure is a common complication of fungal meningitis and is managed by:
    • Regular lumbar punctures to drain the excess fluid 
    • Placement of a lumbar drain 

Other types of meningitis: 

  • Tubercular meningitis is treated with antitubercular therapy:
    • Isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin 
    • Recommended duration of treatment is 9–12 months.
  • Parasitic meningitis: 
    • Antimicrobials: amphotericin B, miconazole, rifampin, miltefosine
    • Parasitic meningitis is fatal, and immediate treatment is essential.
    • The drugs are administered in high doses, and some are administered intrathecally. 
  • Noninfectious meningitis:
    • Allergic or autoimmune meningitis is managed with corticosteroids.
    • Meningitis due to cancer is managed by treating the underlying condition.

Prognosis

  • Mortality increases with age:
    • 18–34 years old: Case fatality is 8.9%.
    • > 65 years old: Case fatality is 22.7%.
  • Neurologic complications (hearing loss, intellectual impairment, focal deficits) affect up to 28% of patients.

Prevention

Vaccinations can protect against certain types of meningitis: 

  • Haemophilus influenzae type B (Hib) vaccine 
  • Pneumococcal conjugate vaccine 
  • Meningococcal vaccine

Differential Diagnosis

  • Stroke: damage to the brain due to interrupted blood supply: Stroke presents with neurologic defects, blurred vision, slurred speech, and paresthesia. Stroke is diagnosed by history, neurologic examination, and imaging. Management depends on the type of stroke. 
  • Brain abscess: collection of pus in response to an infection or trauma: Brain abscess presents with fever, headache, seizures, nausea, and vomiting. Diagnosed by evaluation of signs and symptoms, blood tests, and imaging. Management includes antibiotic therapy and surgery to drain the abscess. 
  • Encephalitis: inflammation of the brain parenchyma due to infection: Encephalitis presents with fever, headache, pain in muscles and joints, and fatigue. Diagnosed by imaging, CSF analysis, lab tests, and electroencephalography. Encephalitis rarely presents with nuchal rigidity and photophobia. Seizures are common. Supportive management, anti-inflammatory drugs, and antiviral drugs are used to manage encephalitis. 
  • Subdural empyema: collection of pus between the dura mater and the arachnoid mater: Subdural empyema presents with fever, headache, lethargy, focal neurologic deficits, and seizures. This condition is diagnosed by imaging, most commonly with contrast-enhanced MRI. Subdural empyema is managed surgically and with antibiotics.
  • Delirium tremens: severe form of ethanol withdrawal that presents clinically with global confusion, agitation, hallucinations, fever, and diaphoresis. Diagnosis of delirium tremens is made by history and signs and symptoms and management is with supportive therapy and thiamine. 
  • Subarachnoid hemorrhage: bleeding within the subarachnoid space that occurs spontaneously or following head trauma: Subarachnoid hemorrhage presents with neck and shoulder pain, numbness throughout the body, seizures, confusion and irritability, diplopia, and sudden headache. Diagnosis is by history, signs and symptoms, imaging, and cerebral angiography. Subarachnoid hemorrhage is managed surgically. Antihypertensive agents are recommended.

References

  1. Hasbun R. (2021). Pathogenesis and pathophysiology of bacterial meningitis. UpToDate. Retrieved April 26, 2021, from https://www.uptodate.com/contents/pathogenesis-and-pathophysiology-of-bacterial-meningitis
  2. Cassoobhoy A. (2020). Meningitis. WebMD. https://www.webmd.com/children/understanding-meningitis-basics#2-7
  3. Hasbun R. (2019). Meningitis. Medscape. https://emedicine.medscape.com/article/232915-overview#a3
  4. Mayo Clinic. (2020). Meningitis. https://www.mayoclinic.org/diseases-conditions/meningitis/symptoms-causes/syc-20350508
  5. Meningitis (2017). Healthline. https://www.healthline.com/health/meningitis#symptoms
  6. Chabria SB, Patel M. (2019). Bacterial meningitis in adults. VisualDx. https://www.visualdx.com/visualdx/diagnosis/bacterial+meningitis?diagnosisId=50164&moduleId=101
  7. Hasbun R. (2021). Clinical features and diagnosis of bacterial meningitis in adults. UpToDate. Retrieved April 26, 2021, from https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-acute-bacterial-meningitis-in-adults

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