Susannah L. Kurtz1, Swathi Sangli2, and Rupendra Swarup1
1 Icahn School of Medicine at Mount Sinai, New York, NY, USA
2 Allegheny General Hospital, Pittsburgh, PA, USA
Background
Definition of disease
Meningitis is an inflammation of the leptomeninges usually caused by an infection of the CSF surrounding the brain and spinal column. The presence or absence of alterations of consciousness and/or cognitive dysfunction distinguishes meningitis from encephalitis.
A brain or spinal cord abscess is a focal collection within the CNS parenchyma.
Disease classification
Meningitis and encephalitis are classified by duration of symptoms as acute, subacute (several weeks), or chronic (lasting at least 1 month).
Incidence/prevalence
Meningitis is one of the top 10 infectious causes of death worldwide.
Between 2003 and 2007 there were 4100 cases of bacterial meningitis with 500 deaths in the USA.
Worldwide data report an annual incidence of acute encephalitis ranging from 3.5 to 7.4/100 000 in adults.
The incidence of brain abscess in developed countries is as low as 1–2%, while in developing countries it is as high as 8%.
Etiology
Meningitis
Meningitis can be differentiated into community‐acquired and health care‐associated (includes penetrating trauma). The pathogen varies by age group. Health care‐associated meningitis is seen in post‐surgical patients and pathogens include Staphylococcus aureus, coagulase‐negative staphylococci, and aerobic gram‐negative bacilli (including Pseudomonas aeruginosa).
Common causes of community‐acquired bacterial meningitis
By age group
<1 month
Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes, Klebsiella species
1–23 months
Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b, S. agalactiae, E. coli
2–50 years
N. meningitidis, S. pneumoniae
>50 years
S. pneumoniae, N. meningitidis, L. monocytogenes
Other causes of meningitis
Bacterial
Spirochetes
Treponema pallidum, Borrelia burgdorferi
Tick‐borne
Rickettsia rickettsii, Erlichiosis
Tuberculosis
Viral
Non‐arthropod‐borne viruses
Picornavirus (RNA), enteroviruses (echovirus, Coxsackie A, Coxsackie B, enterovirus, poliovirus), herpes simplex virus type 2 (HSV‐2), mumps, HIV
Arthropod‐borne viruses
Togavirus (alphavirus, RNA), Eastern equine encephalitis (EEE), Western equine encephalitis (WEE), Venezuelan equine encephalitis (VEE), flavivirus (RNA), St. Louis encephalitis (SLE), West Nile virus (WNV), California encephalitis
Encephalitis is typically caused by viruses but also atypical bacteria, fungi, and parasites.
The most common cause of viral encephalitis is herpes simplex: HSV‐1 is most common in adults and HSV‐2 is most common in infants (Figure 47.1).
Causes of encephalitis
Viral
Herpes simplex, varicella‐zoster, Epstein–Barr, cytomegalovirus, enteroviruses, measles, mumps, rubella Vector‐borne: West Nile, St. Louis encephalitis, Eastern equine encephalitis, Western equine encephalitis, Japanese encephalitis, rabies
A pathogen enters through the bloodstream, crosses the blood–brain barrier (BBB), and replicates in the CSF space.
Many of the meningeal bacterial cell wall products (such as lipopolysaccharide and peptidoglycan) can induce an inflammatory host response.
Several CNS‐specific cells such as cerebromicrovascular endothelial cells, astrocytes, and microglia are capable of producing TNF‐α, IL‐1β, and IL‐6, which are early pro‐inflammatory cytokines. These in turn stimulate a downstream production of other cytokines, arachidonic acid metabolites, chemokines, and reactive nitrogen and oxygen intermediates.
In response, leukocytes migrate to the subarachnoid space and once activated release cytotoxic agents that cause direct cellular injury.
Bacterial DNA released during autolysis may have an additional inflammatory effect. Bacterial DNA can stimulate macrophages and pro‐inflammatory mediators such as TNF‐α.
The inflammatory response leads to edema, cerebral hypoperfusion, and elevated intracranial pressure in a vicious cycle of continued neuronal injury.
Encephalitis
Some viruses are transferred to humans from an infected animal bite or through exposure to their secretions. Some viruses may enter the CSF space by crossing the BBB, others travel along neuronal pathways.
Viruses enter neural cells causing cellular malfunction, perivascular congestion, hemorrhage, tissue necrosis, and trigger an inflammatory response that disproportionately affects gray matter.
When associated with evidence of meningeal irritation and CSF pleocytosis, it is referred to as meningoencephalitis.
Enteroviruses are the most common cause of viral meningoencephalitis (VME). During summer months, arboviruses commonly cause VME. Several herpetic family viruses can cause VME.
Brain abscess
This begins with cerebritis, an area of unencapsulated infection of the brain parenchyma that develops into a collection of pus. Abscesses are typically seen following trauma, surgery, hematogenous dissemination of organisms during systemic infection, or direct extension. Inflammation recruits neutrophils, which leads to vasogenic edema. After 2 weeks a vascularized capsule forms and the collection becomes walled off (Figure 47.2).
Abscesses may arise from direct extension from nearby structures such as teeth, bone, sinus mucosa, internal auditory canal, or cochlear structures. Otogenic infections are the most common source.
Less commonly, abscesses may develop from hematogenous spread from an infection in the lung, endocardium, pelvis, abdomen, or skin and soft tissues.
Spinal epidural abscess
Infection of the potential space between the dura mater of the spinal cord and the vertebral body, caused by hematogenous spread, direct extension from an adjacent structure, or from a procedure, trauma, or other manipulation of the spinal cord. In a minority of cases the mechanism is unknown.
A spinal abscess (Figure 47.3) may cause a neurologic deficit either from direct compression of the spinal cord or by vascular occlusion by microthrombi.
There is no recommended screening test for meningitis or encephalitis. Patients who have a personal or family history of two or more episodes of meningococcal or pneumococcal meningitis should have immunologic testing.
All patients with meningitis should be screened for HIV.
Patients with a recent history of neurosurgery, trauma, and evidence of rhinorrhea or otorrhea should have an investigation for CSF leak. Cranial bone defects are evaluated with high resolution CT scan. Diagnosing a CSF leak may require cisternography.
Patients who develop recurrent brain abscesses require evaluation for vascular malformations.
Primary prevention
There are vaccines available for three types of bacterial meningitis: Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenza type b (Hib) and for polio, measles, mumps, and rubella. Please refer to the CDC website for vaccine schedules: http://www.cdc.gov/vaccines/schedules/.
Persons who come into close contact with patients with meningococcal meningitis should be offered antibiotic prophylaxis.
Antibiotics may also be recommended for household contacts of a patient with a severe Hib infection.
Certain CNS infections require strict isolation:
Contact precautions: MRSA infections and disseminated HSV.
Droplet precautions: N. meningitidis, Hib, rubella, and mumps.
Airborne precautions: TB, varicella, and measles.
Secondary prevention
Indwelling devices such as ventricular drains or shunts, Ommaya reservoirs, or cochlear implants should be removed.
Bony defects or CSF leaks that cause recurrent infections may ultimately require surgical repair.
Diagnosis
Differential diagnosis
Meningitis, encephalitis, and brain abscesses can all mimic each other and so all should be considered for the patient.
Differential diagnosis
Features
Paraneoplastic encephalitis
Patients may present with classic syndromes associated with cancer with or without a cancer diagnosis: limbic encephalitis, subacute cerebellar degeneration, subacute sensory neuropathies, opsoclonus myoclonus ataxia, dermatomyositis, Eaton–Lambert syndrome
Autoimmune encephalitis
May present with a prodromal viral‐like illness. Neurologic findings are specific to the causal antibody. Should be suspected with associated non‐specific CSF findings. Anti‐NMDA receptor encephalitis can present with psychiatric manifestations, memory deficits, seizures, and stupor with catatonic features
Metabolic encephalopathy
Global cerebral dysfunction in the setting of a systemic illness. Common in the critically ill
Primary angiitis of the CNS
Should be suspected when a young person presents with recurrent TIAs or strokes. Requires neuroimaging and angiography
Drug‐induced meningitis
History of medication use: non‐steroidal anti‐inflammatory, sulfa antibiotics, intravenous immunoglobulins, antiepileptics, OKT3 antibodies
Leptomeningeal carcinomatosis
Typically has multifocal involvement
Subarachnoid hemorrhage
Classic presentation is of sudden severe headache – ‘worst headache of my life’
Subdural hematoma
Subacute or chronic hematomas will usually have a remote history of fall or trauma, may have an exacerbating acute component
Neurosarcoidosis
Patients typically have lung involvement, though not always
Toxidromes
Acute ingestion or drug use/abuse history
Post‐infectious acute disseminated encephalitis and encephalomyelitis
History of illness or vaccination days to months prior to onset of symptoms. Motor deficits predominate, but sensory deficits may also be present
Spondylitis, spondylarthritis, discitis
Neck or back pain that may worsen over weeks to months, usually worse with activity and relieved by rest
Typical presentation
Presentations of CNS infections can be as varied as the potential underlying etiologies. Common features of meningitis and encephalitis are fever and altered mental status. However, brain and spinal epidural abscesses often present without fever.
Signs of meningeal irritation, such as nuchal rigidity and photophobia, distinguish meningitis from other CNS infections.
Focal findings raise suspicion for encephalitis or abscess.
Point tenderness is an important feature of spinal epidural abscess.
Clinical diagnosis
History
The timeframe from onset of symptoms may differentiate the etiology. Acute onset <48 hours is often bacterial. A subacute onset is more typical of viral illnesses, while chronic or smoldering symptoms are more typical of fungal, parasitic, or non‐infectious causes.
Classic features of both bacterial and viral meningitis include fever, headache, stiff neck, and altered mental status. Other symptoms include photophobia, nausea, vomiting, poor appetite, and lethargy.
Brain abscesses will often present with headache, but lack the other features of fever and altered mental status. The physician should ask about subtle neurologic signs over past days or weeks.
Features of epidural abscess include back pain, point tenderness, with or without focal neurologic deficit.
It is very important to obtain history of HIV infection, other immunocompromised states, TB history or exposure, vaccination status, country of origin and travel, recreational activities, exposure to animals or insects, and occupational exposure. Medical and surgical history should include history of prior meningitis, brain or spine surgery, spine injections, and trauma.
Physical examination
Vital sign assessment for temperature and hemodynamic stability.
Complete neurologic exam should be performed: mental status, cranial nerves, motor and sensory examination, reflexes, and coordination. Focal findings indicate encephalitis or epidural or parenchymal abscess.
Altered mental status often indicates bilateral hemispheric or brainstem dysfunction and significantly limits the ability to determine if the patient’s neurologic evaluation is non‐focal.
An evaluation of nuchal rigidity, meningismus with decreased range of motion, Brudzinski’s sign (flexion at the neck elicits flexion at the hip or knees), and Kernig’s sign (with hips and knees flexed against abdomen extension on knees should elicit resistance). These signs have poor sensitivity and their absence does not exclude CNS infection.
Examination of the oral cavity, palate, and sinuses.
A thorough examination of the skin for rashes, purpura, erythema migrans, or vesicles.
Examination of spine for point tenderness in epidural abscess.
Disease severity classification
Bacterial meningitis carries a high risk of morbidity and mortality. Three clinical risk factors have been associated with adverse outcome: altered mental status, hypotension, and seizures.
Patients with no clinical risk factors are considered low risk for morbidity and mortality. Patients with one risk factor are at intermediate risk. Patients presenting with two or more risk factors carry a high risk.
A delay in initiation of appropriate antibiotics increases the risk of poor outcome.
A delay in draining an epidural abscess increases the risk of poor neurologic outcome.
Two sets of blood cultures. Blood cultures may be positive in S. pneumoniae and N. meningitidis.
Lumbar puncture:
The incidence of brain herniation following LP is low. Patients with focal findings or an immunocompromised state (including HIV infection) should undergo non‐contrast head CT to exclude a space‐occupying lesion prior to LP.
Opening pressure.
CSF studies: always obtain cell count with differential, glucose, protein, gram stain, and bacterial culture (Table 47.1).
CSF for HSV PCR.
West Nile virus encephalitis should be suspected and tested for in patients with fever, altered mental status, and acute flaccid paralysis during mosquito season (cases peak in the summer months).
According to CDC recommendations, in cases with suspected arbovirus encephalitis, serum and CSF samples should be obtained for serologic testing and cases should be reported promptly to state health departments.
Cryptococcal antigen.
HIV testing.
EEG: for patients with a persistent depressed level of consciousness despite appropriate therapy.
List of imaging techniques
CT scan to exclude a space‐occupying lesion or cerebral edema with associated mass effect: a non‐contrast study should be obtained prior to LP for any patient with an immunocompromised state (e.g. HIV infection, immunosuppressive therapy), history of CNS disease, new onset seizure, papilledema, abnormal level of consciousness, or focal neurologic deficit.
Contrast‐enhanced CT: a rapid way to determine size and location of brain abscesses. CT of the spine may reveal narrowing of the disc space or bone erosion indicating a discitis or osteomyelitis.
MRI with IV gadolinium: the diagnostic test of choice for both brain and spinal epidural abscesses.
Table 47.1CSF findings in various forms of CNS infection.
Algorithm 47.1Evaluation and management of suspected CNS infection
Potential pitfalls/common errors made regarding diagnosis of disease
Delay in diagnosis due to lack of history.
Presuming drug or alcohol as the cause of altered consciousness.
Treatment
Treatment rationale
Bacterial meningitis is a medical emergency. Prompt initiation of antibiotics within 60 minutes of arrival is crucial even before CSF gram stain and culture results are known (see Algorithm 47.1). Corticosteroids (dexamethasone 0.15 mg/kg every 6 hours for 4 days) are recommended before or at the time of antibiotic administration for suspected bacterial meningitis. Empiric antibiotics must cover all potential pathogens, based on age and immune status.
Viral meningitis requires supportive treatment and acyclovir for possible HSV.
Viral encephalitis typically requires hospitalization for supportive management. Prompt administration of acyclovir for possible HSV should be initiated in all suspected encephalitis. Any delay in acyclovir therapy worsens prognosis. Development of seizures is common and is an independent factor for increased morbidity and mortality. Management includes monitoring for signs of intracranial hypertension, maintaining normothermia, and avoiding hyponatremia. Conditions that mimic infectious encephalitis should be considered, particularly if no etiology is identified in the first week of hospitalization.
Brain and spinal epidural abscesses require antibiotics and may require drainage
Iatrogenic infections of the CNS are usually complications of neurosurgical procedures, LP, and spinal injections. Intracranial shunt infections require a complete antibiotic course and removal of infected shunt.
Managing the hospitalized patient
Meningitis
Empiric antibiotics should be administered within 60 minutes to all patients with bacterial meningitis (Table 47.2). Antibiotics should be modified based on gram stain and culture; after 48–72 hours, most routine CSF cultures will show preliminary results.
Antibiotic duration: although guidelines recommend the following duration of therapy, therapy must be individualized based on the clinical response to treatment:
N. meningitidis, H. influenzae: 7 days.
Streptococcus agalactiae, S. pneumoniae: 10–14 days.
b If dexamethasone is administered consider adding rifampin.
Repeat lumbar puncture: in patients with uncertain etiology and lack of clinical improvement.
Adjunctive dexamethasone: guidelines suggest dexamethasone administration before or at time of antibiotic administration to reduce unfavorable neurologic outcomes and death.
This benefit was seen in a subgroup of patients with pneumococcal meningitis, and not for meningitis caused by other pathogens.
Dexamethasone 0.15 mg/kg is given 20 minutes before or at the time of administration of antimicrobial agents, then continued every 6 hours for 4 days if S. pneumoniae is diagnosed. If cultures do not show S. pneumoniae, dexamethasone should be discontinued.
If antibiotics have already been given, guidelines recommend not giving dexamethasone.
If vancomycin is used for treatment of meningitis resulting from highly cephalosporin‐resistant S. pneumoniae, rifampin may be added, as dexamethasone may reduce the CSF concentration of vancomycin.
Encephalitis
Acyclovir must be administered parenterally (10 mg/kg IV every 8 hours with dose adjusted in patients with impaired creatinine clearance) to achieve therapeutic levels in brain parenchyma.
Empiric antiviral treatment should be started immediately and continued until HSV‐1 has been reasonably excluded, which may require testing serial CSF samples.
HSV PCR may be negative on initial LP and should be repeated if suspicion persists.
Intravenous acyclovir is continued for 14–21 days.
Ganciclovir and foscarnet are administered for CMV encephalitis.
Brain abscess
Empiric antibiotic therapy should be started prior to surgical drainage (Table 47.3). HSV PCR may be negative on initial LP and should be repeated if suspicion persists.
Duration of treatment is usually 4–6 weeks if the abscess is drained or 6–8 weeks if not drained. Management should be guided by biweekly imaging up to 3 months until clinical recovery.
Abscesses of 2.5 cm should be surgically excised or drained stereotactically.
For abscesses <1.5 cm with a high risk of surgical complications and no neurologic deficits, medical therapy alone is often successful.
In HIV infected patient: pyrimethamine plus sulfadiazine plus folinic acid for empiric treatment of toxoplasmosis.
IV dexamethasone can be used for vasogenic edema.
Undrained abscess should have follow‐up imaging within days.
Mucormycosis in immunosuppressed and diabetic patients requires aggressive surgical debridement and early antifungal therapy.
Spinal epidural abscess
Patients presenting with spine pain, but no deficits and no risk factors for medical failure (advanced age, diabetes, MRSA infection, bacteremia), may be treated conservatively with antibiotics, but require close follow‐up for delayed neurologic deterioration.
If blood cultures are negative, CT‐guided aspirate should be done.
Patients with a neurologic deficit require surgical drainage.
Empiric antibiotics should include vancomycin and cefotaxime or ceftriaxone. If Pseudomonas is possible, cefepime or ceftazidime should be added to vancomycin.
Prevention/management of complications
Non‐neurologic complications
Hypotension and shock must be treated to maintain cerebral perfusion pressure.
Hyponatremia can contribute to brain swelling.
Coagulation disorders frequently occur with bacteremia. Patients with meningococcemia may develop fulminant disseminated intravascular coagulation.
Septic complications include endocarditis, pyogenic arthritis, and prolonged fever.
Elevated intracranial pressure
Management goals are to break the cycle of raised ICP and cerebral ischemia at the earliest, maintain an adequate cerebral perfusion pressure, and prevent brain herniation.
Patients with suspected intracranial hypertension should have an ICP monitor placed.
Treatment strategies include head‐of‐bed elevation, osmotic therapy with mannitol or hypertonic saline, sedation and analgesia with intubation and mechanical ventilation, therapeutic neuromuscular blockade, or CSF diversion.
Dexamethasone should be used in patients with vasogenic edema regardless of the suspected organism.
Patients without focal findings, but with persistent or late onset obtundation or coma may have developed brain swelling, subdural effusion, hydrocephalus, ventriculitis, cortical thrombophlebitis, or venous sinus thrombosis.
Patients with encephalitis and cerebral edema are best managed in an intensive care setting with close neurologic monitoring.
All patients with depressed consciousness require electroencephalography to diagnose or manage non‐convulsive status epilepticus.
Clinical pearls
Septic intracranial thrombophlebitis
Septic cavernous sinus thrombosis is the most common site of septic thrombosis. Staphylococcus is the most commonly identified organism. Symptoms include fever, periorbital pain, and swelling.
The infection reaches the cavernous sinus through venous spreading. Requires early imaging, and specific antibiotic therapy. Surgery is used to treat the nidus of infection, if required. The role of anticoagulation is not well established.
Bacterial infections
Bacteria
Important clinical points
Streptococcus pneumoniae
Most common cause of meningitis in patients >18 years of age
Neisseria meningitidis
Young people in communal living particularly at risk. Prophylaxis for people in close contact: ciprofloxacin, rifampin, or ceftriaxone
Listeria monocytogenes
Neonates, older adults, pregnant women, and immunosuppressed patients are at increased risk
Mycobacterium TB
Complication of primary TB Involves base of the brain Vasculitis and scarring
Treponema pallidum
Meningovascular syphilis: infectious small vessel endarteritis causing ischemic strokes. Middle cerebral artery is the most commonly affected with associated basal ganglia infarcts Tabes dorsalis: involves posterior root ganglia and posterior column; causes ataxia, absent deep tendon reflexes, Argyll Robertson pupil
Leptospira interrogans (leptospirosis)
Presents as two distinct clinical syndromes:
Anicteric leptospirosis has two well defined stages: septicemic stage (after 7–12 days incubation period) with conjunctival suffusion as the most characteristic physical finding, and immune stage that is characterized by aseptic meningitis
Icteric leptospirosis: potentially fatal syndrome with jaundice, renal failure, hypotension, and hemorrhage
Anthrax (meningitis)
Life‐threatening illness with meningeal component Initial non‐specific flu‐like symptoms followed by a second phase of hemodynamic collapse and multiple organ failure Add either penicillin or chloramphenicol
Viral infections
Virus
Important clinical points
Enteroviruses (meningitis and encephalitis)
Most common cause of viral meningitis. Coxsackie and echoviruses make up the majority of cases
Arboviruses (encephalitis)
Encephalitis can be fatal. They have both geographic and seasonal distributions. Usual vectors are mosquitoes and ticks
CMV (encephalitis)
Most common viral CNS infection in AIDS
Herpes simplex virus type 1 (meningitis and encephalitis)
Causes hemorrhagic necrosis of the temporal lobes
Human rabies (encephalitis)
The CDC recommends that human rabies should be considered in the differential diagnosis of patients presenting with unexplained rapidly progressive encephalitis Classic presentation is encephalitis with hypertonicity and hypersalivation
HIV (encephalitis)
Symptoms can be mistaken for progressive multifocal leukoencephalopathy caused by the JC virus
Fungal and parasitic infections
Fungus/parasite
Important clinical points
Cryptococus neoformans (meningitis and encephalitis)
Occurs in an immunocompromised host; most common fungal CNS infection in AIDS; budding yeast seen with India ink stain
Mucor species (frontal lobe abscess)
Occurs in diabetic ketoacidosis; spreads from frontal sinuses
Naegleria fowleri (meningoencephalitis)
Protozoa (amoeba) involves frontal lobes; contracted in freshwater lakes
Protozoa (hemoflagellate); transmitted by an infected tsetse fly Diffuse encephalitis: somnolence Treatment: pentamidine early; melarsoprol in encephalitis stage
Taenia solium (cysticercosis)
Helminth (tapeworm; cestode); transmitted by pigs Calcified cysts cause seizures and hydrocephalus Treatment: albendazole + dexamethasone
Toxoplasma gondii (encephalitis)
Protozoa (sporozoan); most common CNS space‐occupying lesion in AIDS; ring‐enhancing lesions on CT Treatment: pyrimethamine + sulfadiazine + folinic acid
Special populations
Pregnancy
Pregnant women are at increased risk of developing listeriosis. Infections can lead to miscarriage, stillbirth, premature delivery, and meningitis in the newborn.
Pregnant women should be screened for group B streptococci at 35–37 weeks of gestation. Women with positive culture should be treated with penicillin G (or clindamycin for a penicillin allergy) intra‐partum to avoid transmission to the newborn.
Children
<1 month: S. agalactiae, E. coli, L. monocytogenes, Klebsiella.
Treatment includes ampicillin plus cefotaxime or ampicillin plus an aminoglycoside.
1–23 months: S. pneumonia, N. meningitidis, S. agalactiae, H. influenza, E. coli.
Infections are an important preventable cause of neurologic disability in children. The key strategy for prevention is delivery of available vaccines.
Elderly
H. influenzae (>50 years) and L. monocytogenes (>60 years) infections are more common in elderly populations. Ampicillin should be included in the empiric antimicrobial regimen.
Prognosis of acute bacterial meningitis and acute viral meningitis is substantially worse in older adults.
The high prevalence of cervical spine disease in older individuals may result in false positive tests for nuchal rigidity.
Others
Patients with HIV infection: cryptococcal meningitis, toxoplasmosis brain abscess, and encephalitis must be considerations.
Prognosis
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