- Rapid Reference
- Background: meningitis vs. encephalitis
- Droplet precautions
- Antibiotic selection
- Avoidance of fever
- Seizure prophylaxis & management
- Management of ICP & CPP
- Treatment failure & repeat lumbar puncture
- Questions & discussion
- PDF of this chapter (or create customized PDF)
approach to obtunded patient with suspected meningitis/encephalitis ✅
- Fingerstick glucose STAT.
- Electrolytes, complete blood count with differential, coagulation studies.
- Blood cultures x2.
- HIV screen as appropriate.
initial empiric therapy (more)
- 2 grams ceftriaxone IV
- 10 mg dexamethasone IV.
- 10 mg/kg acyclovir IV.
- Discontinue DVT prophylaxis to facilitate lumbar puncture.
- Head CT scan.
- Lumbar Puncture:
- MRI/MRV if possible (for the obtunded patient, this will generally require intubation).
- Scheduled acetaminophen (1,000 mg PO q6hr for most patients).
- External cooling if needed to achieve normothermia.
seizure control (more)
- If concern for seizures, obtain EEG.
- Consider levetiracetam for seizure prophylaxis.
is acyclovir needed for HSV?
background: meningitis & encephalitis
- Meningitis is inflammation of the subarachnoid space, the fluid bathing the brain. Most common causes are bacterial or viral.
- Encephalitis is inflammation of the brain tissue itself. Most common causes are viral or autoimmune.
- Focal neurologic findings and seizures are more characteristic of encephalitis, whereas meningeal irritation is more suggestive of meningitis.
- Among critically ill patients, meningitis and encephalitis are often indistinguishable. For example, patients are often obtunded and thus unable to participate in a detailed neurologic examination.
- The initial treatment approach should encompass the possibilities that the patient may have either meningitis or encephalitis.
when to suspect CNS infection
1) patients being admitted to ICU from the outpatient world
- Intensivists have a huge advantage with regards to diagnosing meningitis/encephalitis, because the patients that we see are all sick.
- In general, CNS infection should be considered when the following criteria are met:
- (1) Evidence of infection (e.g., fever/hypothermia, leukocytosis, or left-shift).
- (2) Evidence of neurologic involvement (e.g., altered mental status, severe headache, nuchal rigidity, photophobia, focal neurologic signs).
- (3) No well-established diagnosis to account for #1-2.
- When in doubt, it's generally better to err on the side of getting a lumbar puncture (especially among intubated patients who can't be closely observed for deterioration).
2) patients who have been in the hospital for awhile
- Fever and altered mental status are extremely common among patients admitted to the hospital.
- It is uncommon for a patient admitted with an unrelated problem to suddenly develop meningitis while in the hospital.
- In general, a lower index of suspicion is appropriate for patients who have been admitted to the hospital for a few days, unless they have a disease process that could cause meningitis (e.g., bacterial endocarditis, pneumococcal bacteremia, ventricular drain).
non-contrast head CT
- The goal here is to exclude an alternative diagnosis (e.g., hemorrhage) and ensure that it's safe to perform a lumbar puncture.
- There is some controversy about requirement for CT prior to lumbar puncture. However, this chapter refers to obtunded patients, who are recommended to receive a CT scan before lumbar puncture.(27828810)
MRI for the diagnosis of meningitis
- MRI is not typically used to diagnose meningitis, due to the time delay. However, MRI may be useful in some clinical circumstances (e.g., comatose patient with low index of suspicion for infection is undergoing an MRI to evaluate for other pathologies).
- Meningitis generates purulent exudates in the basal cisterns and superficial sulci, which appear isointense on T1 and T2 images and do not suppress on FLAIR, giving the appearance of “dirty” CSF.(31485117)
- Contrast enhancement can improve the sensitivity for meningitis on both FLAIR and T1 post-contrast sequences.(24977138) Most MRI protocols don't include a post-contrast FLAIR sequence, but this may be requested if there is concern for leptomeningeal inflammation.
- Basal meningitis (abnormalities centered on the basal cisterns, prepontine cisterns, and sylvian fissures) suggests unusual etiologies (e.g., tuberculosis, fungal meningitis, or sarcoidosis).(31731899)
MRI for the diagnosis of HSV encephalitis
- MRI is highly sensitive for HSV encephalitis, with sensitivity of 80-100%.(30921087)
- HSV encephalitis commonly affects the bilateral limbic system (anterior and medial temporal lobes, insular cortex, inferior frontal lobes, and cingulate gyri) in an asymmetric manner.(31485117)
- Findings may include:
- The classic finding is hyperintensity on T2/FLAIR images within the cortex and subcortex, with an indistinct grey-white junction. However, in severe cases hemorrhagic necrosis may occur, causing hypointensity on T2.(30921087)
- Diffusion restriction might be the most sensitive finding in the acute phase.(31485117, 30921087)
- GRE/SWI sequences may show hemorrhages.
- Swelling with mass effect can occur.
- Patchy or gyriform enhancement may be seen.(26046515) The differential diagnosis of gyriform enhancement includes PRES, postictal state, subacute ischemic stroke, and some malignancies.
- Hyperintense FLAIR signal in the thalamus may reflect seizures due to HSV encephalitis.(30921087)
MRI with MRV to evaluate for complications or underlying pathology
- Even among patients with known meningitis or encephalitis, there is a surprisingly high rate of abnormal findings which will alter management, including:
- Meningitis leading to cerebral venous thrombosis (which requires anticoagulation).
- Brain abscess or subdural empyema (which may require surgery).
- Anatomic portals of entry causing meningitis (e.g., encephalocele causing CSF leak, otitis media with extension into the brain).
- Anatomic distribution of encephalitis may suggest various pathogens (e.g., temporal lobe involvement suggests HSV).
lumbar puncture & CSF evaluation
cerebrospinal fluid tests to order
- Basic labs for all patients:
- ✅ Cell count with differential.
- ✅ Protein.
- ✅ Glucose.
- ✅ CSF lactate level.
- ✅ Gram stain & culture.
- ✅ PCR for VZV and HSV.
- Additional tests as indicated by the patient's epidemiology and clinical specifics, for example:
- Obese patients with impalpable landmarks may require ultrasound-guided lumbar puncture with a long LP needle (videos of this are here and here).
obtain an opening pressure
- Opening pressure is potentially very helpful in this scenario and should be measured. In a supine position, the opening pressure will equal the patient's intracranial pressure (ICP). This can be converted from cm water to mm mercury using the following formula:
- ICP in mm = 0.7(Opening pressure in cm water).
correction for RBCs
- Traumatic lumbar puncture will cause an increase in RBCs and WBCs, in a ratio equal to that present in the blood.
- An online calculator can be used to estimate the number of WBCs in the CSF prior to contamination with peripheral blood.
- If a CBC isn't available, a very rough estimation is that 1,000 RBCs correlates to 1 WBC.
- CSF lactate be useful to distinguish bacterial versus viral meningitis, in situations where other parameters are ambiguous. The optimal cutoff value for diagnosing bacterial meningitis seems to be greater than ~3.7-4 mM. However, bacterial meningitis has been reported with values as low as 3.2 mM.(31402154)
- Lactate is elevated in Listeria monocytogenes, which can help sort this out from viral infections that may have a fairly similar CSF profile.
- Lactate levels may also be elevated due to erythrocytes in the CSF sample, tuberculous meningitis, or fungal meningitis.
- A normal CSF lactate level supports the decision to discontinue antibacterial therapies.
CSF results can be grossly categorized into three patterns as shown above. Differential diagnosis of these patterns are explored below:
- Bacterial meningitis.
- Early meningeal response to any type of infection (early TB, fungal, viral, or drug-related meningitis).
- Parameningeal focus of infection (brain abscess, subdural empyema, epidural abscess).
- Naegleria fowleri.
- Early HSV infection.
- Further evaluation
- Some features are strongly suggestive of bacterial infection if present:(2810603)
- Glucose <34 mg/dL (1.9 mM).
- Protein >220 mg/dL.
- CSF WBC count >2,000/ul .
- CSF neutrophil count >1180/uL.
- In borderline cases, it may be helpful to repeat a lumbar puncture later on, to determine if this is an early response which shifts to a lymphocyte-predominant pattern over time.
- Some features are strongly suggestive of bacterial infection if present:(2810603)
- Viral meningitis (e.g., enteroviruses, HSV, HIV).
- Viral encephalitis.
- Listeria meningitis (although Listeria will elevated CSF lactate and may decrease the glucose, so it's not entirely a viral pattern).
- Partially treated bacterial meningitis.
- Spirochete infection (leptospirosis, lyme, syphilis).
- Rickettsial infection (rocky mountain spotted fever, ehrlichiosis).
- Drug-induced meningitis (e.g., NSAIDs, trimethoprim-sulfamethoxazole).
- Paraneoplastic encephalomyelitis.
- SLE, multiple sclerosis, acute disseminated encephalomyelitis.
- 🔑 A viral pattern doesn't mean that the patient just has “some virus” and thus requires no specific therapy.
- Malignancy (leptomeningeal carcinomatosis).
- Tuberculosis, fungal meningitis.
- CNS vasculitis, neurosarcoidosis.
- Lymphochoriomeningitis virus (LCMV).
- Droplet precautions are indicated until meningococcal meningitis excluded.
- This is currently irrelevant, as staff is wearing masks anyways.
- The frequencies of various diseases in the United States is shown above.(28187808) A few points are notable:
- (1) Varicella zoster (VZV) occurs with reasonable frequency and should be tested for alongside HSV (especially because it's treatable).
- (2) Autoimmune encephalitis is common, and should also be routinely considered.
- Ordering an autoimmune encephalitis panel is generally more useful than ordering $5,000 worth of tests for every untreatable virus known to humankind.
- (3) Listeria only accounts for 2% of all patients with encephalitis/meningitis. However this may not be generalizable to other countries, for example Listeria accounts for 16% of meningitis cases among patients >65 years old in France.(31402154)
empiric regimen for undifferentiated CNS infection
basics of this regimen
- This regimen is for patients with suspected meningitis/encephalitis, prior to obtaining CSF results.
- If you're seriously suspecting meningitis, initiate therapy without delay. In particular, treatment should not be delayed until CT and LP can be performed, as these may take quite a while.
- Realistically, most of the patients treated with this regimen won't have meningitis or encephalitis at all.
components of the regimen (“2-10-10”)
- 2 grams ceftriaxone IV (or, alternatively, 2 grams of meropenem if patient has history of allergy to advanced generation cephalosporins).
- 10 mg dexamethasone 10 mg IV (or 60 mg IV methylprednisolone if that's all you have). Steroid should ideally be given simultaneously/before antibiotics, but it's still recommended up to four hours after the first dose of antibiotic per European guidelines, or up to twelve hours after antibiotic initiation per British and French guidelines.(27062097, 26845731, 31402154)
- 10 mg/kg acyclovir IV.
rationale for this regimen
- Many practitioners will also add vancomycin and ampicillin here. However, immediate administration of vancomycin and ampicillin is arguably unnecessary:
- The only reason to use vancomycin is for highly drug-resistant pneumococcus, whereas the only reason to use ampicillin is for listeria. Both of these pathogens are rare when we consider all patients with encephalitis/meningitis (~2% or less; see table above).
- Among patients with possible CNS infection, most of these patients won't actually end up having any CNS infection at all. At most, perhaps ~20% of such patients have a CNS infection.
- Multiplying 20% by 2% indicates that the likelihood that a patient with possible CNS infection has listeria or highly drug-resistant pneumococcus is <0.5%. This rate is so low that it arguably doesn't require empiric coverage.
- Patients will get a lumbar puncture within a few hours, so antibiotics can be broadened subsequently if the results suggest bacterial infection.
- ⚠️ The most common mistake made at this juncture is failing to include empiric dexamethasone.
empiric regimen for bacterial meningitis
basics of this regimen
- This regimen is for patients who have CSF results which indicate a bacterial meningitis.
- More on the bacterial pattern of CSF results above. This CSF pattern can also be caused by rupture of a brain abscess into the CSF, which would require a different antibiotic regimen – so adequate neuroimaging remains important.
components of the regimen:
- (1) Dexamethasone 10 mg IV q6hr for four days. Dexamethasone is supported best in meningitis due to Streptococcus pneumoniae or Haemophilus influenzae.(31402154) However, dexamethasone may be continued in all patients with bacterial meningitis, except those with Listeria monocytogenes.(34303412, 31402154)
- (2) Ceftriaxone 2 grams IV q12hr.
- If the patient has a history of allergy to advanced generation cephalosporins, may use meropenem 2g IV q8hr.
- (3) Listeria coverage in patients >50YO, pregnancy, or immunocompromise (e.g., diabetes, immunosuppressive medications, cirrhosis, malignancy).
- The usual coverage for listeria is ampicillin 2 grams IV q4hours. However, ampicillin isn't required for patients on meropenem (which covers Listeria).
- (4) Coverage for cephalosporin-resistant pneumococcus:
- This is generally provided, although it may not be needed if there is a low local incidence of cephalosporin-resistant pneumococcus.(27828810)
- Either vancomycin or rifampin may be used for this, in conjunction with ceftriaxone.(27062097) For patients at risk of acute kidney injury, rifampin might be safer (600 mg q12hr). Rifampin may also offer some anti-inflammatory effects and superior meningeal penetration.(26306393)
empiric regimen for viral CSF pattern
basics of this regimen
- This regimen is for patients who have CSF results consistent with a viral pattern (more on this above).
- The differential diagnosis may include herpesviruses, listeria, and tick-borne encephalitides (depending on the patient's exposures and degree of immunocompromise).
components of the regimen:
- (1) Acyclovir 10 mg/kg q8hr is the cornerstone of this regimen (pending the return of HSV and VZV PCR results).
- If there is a very high suspicion for HSV encephalitis (e.g. based on MRI with temporal enhancement) and HSV PCR is negative, then repeat the HSV PCR after four days.(30921087) False-negative PCR is possible during the first 72 hours after onset.(30366550, 32778604)
- Discontinuation of acyclovir is explored in detail here and summarized in the algorithm below.
- (2) Consider doxycycline 100 mg twice daily if rocky mountain spotted fever or tick-borne encephalitis is possible.
- (3) Listeria can mimic a viral pattern, so listeria coverage might be considered in patients at risk for this (e.g., older or immunocompromised patients). If the CSF lactate level is normal, then listeria doesn't need to be covered.
definitive therapy based on culture & sensitivity
- Penicillin-sensitive (MIC <0.06-0.1 ug/mL)(27062097)
- Penicillin-resistant, but cephalosporin susceptible (MIC <1-2 ug/mL)(27062097)
- Cephalosporin-resistant (MIC ≧1-2 ug/mL)(27062097, 31021955)
- Duration of treatment: 10-14 days (27062097)
- Penicillin susceptible (MIC <0.064-0.1 ug/mL)(27062097; 31402154)
- Penicillin resistant (MIC ≧0.1 ug/mL)(27062097)
- Duration of treatment: 7 days (27062097)
- Standard therapy: Ampicillin or Penicillin.
- Alternative therapy: Trimethoprim-sulfamethoxazole, meropenem, linezolid.
- Duration of therapy: At least 21 days. Patients with rhomboencephalitis may require longer courses of therapy.
- Beta-lactamase negative, ampicillin sensitive:
- Beta-lactamase negative, ampicillin resistant:
- Standard treatment: Ceftriaxone.
- Alternative therapy: Ciprofloxacin.
- Beta-lactamase positive:
- Duration of treatment: 7-10 days.
- Methicillin-sensitive Staph. aureus (MSSA)(27062097)
- Methicillin-resistant Staph. aureus (MRSA)(27062097)
- Vancomycin resistant Staph. aureus (MIC >2 ug/mL)(27062097)
- Duration of treatment: At least 14 days.
Streptococcus agalactiae (Group B strep.)
More on meningeal penetration in the antibiotics chapter here.
- Patients who are truly obtunded/comatose due to CSF infection will usually require CT scan, lumbar puncture, and MRI. Intubation is often required to facilitate performing MRI safely.
- Patients may have elevated ICP, so there should be meticulous attention to:
- Avoiding hypercapnia.
- Avoiding hypoxemia.
- Avoiding hypotension (ideally keep MAP >75 mm; more on this below).
- However, excessive deviation from your usual intubation practice may also cause errors. High-quality rapid sequence intubation by an experienced operator with attention to blood pressure is generally a reasonable approach.
- Immediately following intubation, titrate end tidal CO2 to 30mm. An ABG may then be obtained, targeting normocapnia (pCO2 35-45 mm).
- More discussion on intubating the neurocritically ill patient here.
avoidance of fever
- There is no direct evidence for this in meningitis/encephalitis, but fever is generally harmful for neurocritically ill patients.
- Scheduled acetaminophen (usually 1 gram Q6hr) is a good first step, but this is often ineffective.
- Physical cooling (e.g., arctic sun or ice packs) may be needed as well.
seizure prophylaxis & management
- Seizures are common in severe meningitis and especially encephalitis. Seizure will make a bad situation much, much worse.
- If there is concern for non-convulsive status epilepticus, this should be excluded with EEG.
- In the absence of clear evidence, seizure prophylaxis may be reasonable (e.g., 1 gram levetiracetam PO/IV Q12 hours). Seizure prophylaxis may be more beneficial in encephalitis than in meningitis.
management of ICP & CPP
adjust MAP target to obtain adequate cerebral perfusion pressure (CPP)
- Cerebral perfusion pressure (CPP) = MAP – ICP
- A reasonable target CPP may be >60 mm (ideal target unknown, sources vary between 60-70 mm).
- For patients with unknown ICP, targeting a generous MAP (e.g. >75 mm) may be reasonable.
- Once the ICP is known, MAP target can be adjusted accordingly:
- Target MAP > [60 mm + 0.7(lumbar puncture opening pressure measured in cm water)]
- Either norepinephrine or phenylephrine are reasonable to maintain MAP above target.
consider therapeutic drainage of CSF for patients with meningitis
- Patients with meningitis may benefit from therapeutic removal of CSF if they have the following:
- (a) Significantly elevated ICP (e.g., opening pressure >27 cm water).
- (b) Abnormal mental status.
- (c) No underlying structural brain abnormality (e.g. normal head CT).
- CSF drainage may serve to reduce the ICP and also drain off infected material (“source control”).
- Two ways of achieving CSF drainage:
- (a) Lumbar drain placement by neurosurgery.
- (b) Serial lumbar puncture (e.g., Q12 hr) with measurement of opening pressure, removal of ~20 ml, and measurement of closing pressure.
- This is controversial: evidence discussed here.(29088943)
treatment failure & repeat lumbar puncture
potential reasons for treatment failure may include:
- Failure of infection control:
- Inadequate antibiotics or antibiotic resistance.
- Anatomic focus of infection that requires drainage (e.g., abscess, mastoiditis).
- Neurological complication:
- Cerebral venous sinus thrombosis.
- Ischemic stroke, vasculitis.
- Hyponatremia precipitating edema and/or metabolic encephalopathy.
- Subdural effusion or empyema.
- Hypothalamic-pituitary dysfunction.(31306182)
- Patients recovering from HSV encephalitis may develop a subsequent anti-NMDA receptor encephalitis. This occurs in ~25% of patients, within five weeks.(30921087)
evaluations to consider may include:
- Definitive imaging (e.g. MRI/MRV) if not recently obtained.
- Repeat lumbar puncture (primarily used in meningitis; see below).
repeat lumbar puncture in meningitis (31402154)
- (1) The primary objective is to ensure that the CSF has been sterilized (this should occur within <24 hours of adequate antibiotic therapy). Other signs of an adequate response to therapy includes a rising glucose level and falling lactate level.
- (2) A secondary objective is to evaluate for communicating hydrocephalus.
- (3) If possible, drug levels within the CSF may be measured. However, this is generally not feasible.
- Potential indications for repeat lumbar puncture:
- (1) Organism with a high risk of treatment failure, most notably Streptococcus pneumoniae with cephalosporin resistance. Repeat lumbar puncture may also be considered for other unusual bacteria (e.g., MRSA).
- (2) Failure to clinically improve after 2-3 days of therapy.
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questions & discussion
To keep this page small and fast, questions & discussion about this post can be found on another page here.
- Failure to give steroid along with antibiotic. Steroid is recommended by both US and European guidelines, based on prospective RCTs proving reduction in long-term neurologic disability.
- Under-utilization of ultrasound-guided lumbar puncture for morbidly obese patients (if you're sending patients for IR-guided lumbar puncture, consider ultrasound).
- Delaying steroid/antibiotic therapy (e.g. for lumbar puncture, blood cultures, etc.).
- Failing to check VZV PCR (this is seen occasionally, so if you're going to get HSV PCR it's worth getting VZV also).(23566589)
- Keep in mind that antibiotics often require higher doses to penetrate the meninges (“meningeal dose”). Thus, simply because the patient is on an antibiotic doesn't mean that meningitis is necessarily covered adequately.
- Recognize that a patient with meningitis/encephalitis and obtundation is critically ill, and should usually receive care in an ICU.
- Neurocritical care of the comatose meningitis patient (PulmCrit)
- Severe CNS infections (EMCrit)
- Meningitis Pearls & Pitfalls (Aaron Tiffee and Marc Zosky, emDocs)
- Bacterial Meningitis, Encephalitis, anti-NMDA receptor encephalitis, HSV encephalitis (Chris Nickson, LITFL)
- Neurocritical care intubation (EMCrit)
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