Neurocritical Care

4. Fulminant Bacterial Meningitis

A 60-year-old woman presented initially to her family physician with a presumed sinusitis. She was treated with ciprofloxacin, but she did not complete a full antibiotic course. Over a matter of days she developed increasing headache and eventually nausea and vomiting. When she became less alert and confused, her husband brought her to the emergency room. On examination she was drowsy, but could follow a command when prompted. There was marked neck stiffness, but no other neurologic abnormalities were apparent. The emergency physician considered bacterial meningitis and proceeded with a CT scan that was normal. CSF showed 178 white blood cells per mm3 with predominantly polynuclear cells, protein of 710 mg/dl, glucose of 7 mg/dl. Gram stain and blood cultures were negative. She was treated with dexamethasone, vancomycin, and ceftriaxone. Several days later she became much sleepier and eventually was unable to protect her airway, requiring intubation prior to transfer. On arrival to our neurosciences intensive care unit, she is opening her eyes to loud voice, only localizes to pain, and displays considerable neck stiffness. The cranial nerve reflexes are normal, and there is no evidence of any focality on examination. CT scan shows a marked hydrocephalus and MR imaging shows marked gadolinium enhancement of the meninges (Figure 4.1).

What do you do now?

One of the most dreaded clinical scenarios is a patient deteriorating from bacterial meningitis despite—what seems—appropriate antibiotic coverage.

Here are some useful facts.

Streptococcus pneumonia (or pneumococcus) is the most common cause of bacterial meningitis in adults. CSF gram stain and cultures, but also blood cultures readily and rapidly identify the bacteria in most cases. Infection with Listeria monocytogenes will have to be considered in elderly patients (over 60 years) and alcoholics. Listeria monocytogenes can be adequately eradicated by adding ampicillin (or ciprofloxacin) to an initial already broad empiric regimen with vancomycin and a third-generation cephalosporin.

There is compelling evidence that corticosteroids used early in the clinical course improve outcome, and most recent information shows a 10% reduction in mortality. There is uncertainty about the duration of administration, dose, and why corticosteroids reduce mortality (reducing brain edema, reducing inflammation and vasculitis, reducing the effects of associated septic shock).

Although a Cochrane analysis found no benefit, a more recent study found considerable benefit from corticosteroids (using historical controls) in meningitis caused by Streptococcus pneumonia. The data in meningococcal meningitis in adults remain uncertain, with one European study showing no benefit of corticosteroids.

Corticosteroids in patients with acute bacterial meningitis, however, remains common practice irrespective of the organism. The lingering concern is that reduction of the blood brain barrier permeability (as a result of reducing inflammation) may reduce penetration of antibiotics (particularly vancomycin). This effect may be overcome by additional use of rifampicin, but this drug is not often used. On the other hand, high-dose corticosteroids may have an effect on reducing or stabilizing diffuse cerebral edema. The main priorities of the initial treatment of bacterial meningitis are listed in Table 4.1.

So how can we explain the deterioration in our patient, and why is she not improving despite broad spectrum antibiotics? There are multiple causes of deterioration in fulminant bacterial meningitis and they are summarized in Table 4.2.

Several causes of deterioration are treatable. A major medical urgency is the development of a cerebral venous thrombosis of the cavernous sinus after a suppurative mastoiditis, which requires immediate intervention by an otolaryngologist. In other patients the appearance of epidural empyema—commonly associated with sinusitis and sinus surgery and mimicking bacterial meningitis—may be difficult to recognize and can be missed on a noncontrast CT scan of the brain (MRI is definitive). This is a neurosurgical emergency and requires craniotomy. Microabscesses are more difficult to treat, but when they rupture into the ventricles exploratory surgery may be needed. Abscesses in the posterior fossa are most concerning and also require neurosurgical drainage.

TABLE 4.1 First Priorities in Bacterial Meningitis

Ceftriaxone 2 g IV every 12 hours

Vancomycin 20 mg/kg every 12 hours

Ampicillin 2 g every 6 hours

Dexamethasone 10 mg IV every 6 hours

Ventriculostomy with acute hydrocephalus

Acute hydrocephalus can be a major complication after bacterial meningitis (Figure 4.1). It station of a more severe infection and occurs more often in comatose patients. The presence of hydrocephalus has been shown to be associated with higher fatality rates. Blockage may be at the foramina of Magendie and Luschka rather than at the pacchionian granulations. A ventricular drain is needed and could result in neurologic improvement.

TABLE 4.2 Why Is the Patient with Bacterial Meningitis Deteriorating?

Wrong antibiotic

consider adding ampicillin for Listeria monocytogenes

Wrong diagnosis

consider epidural abscess

Wrong cause

consider nonconvulsive status epilepticus

Aggressive treatment needed

ventriculostomy, mannitol for brain edema, removal of cerebellar abscess after mastoiditis

Aggressive search for source needed

pneumonia, otitis media, mastoiditis, and sinusitis



FIGURE 4.1 CT scans shows early hydrocephalus (A) MRI shows dramatic meningeal enhancement. (B) Also, evidence of restricted diffusion in bilateral frontal temporal cortex indicative of additional laminar cortical necrosis due to infarction (C). MRA showed no evidence of arterial occlusions.

Cerebral edema is mostly cytotoxic and can have a particularly rapid onset with subsequent loss of some brainstem reflexes. Immediate aggressive use of osmotic diuretics and high dose of intravenous corticosteroids may turn the tide, but many patients may progress further to loss of all brainstem reflexes.

Several causes of deterioration are untreatable. The development of ischemic lesions—as shown in our case—may be due to vasospasm, vasculitis, or vasculopathy. Cortical infarctions are common and widespread and rarely lead to swelling or mass effect. These abnormalities on CT scan are often mislabeled as “cerebritis.” Vasculitis (or thrombotic vasculopathy) may lead to ischemia.

Brain injury can be rapid and permanent after an overwhelming infection. There is evidence that the brain may be an innocent bystander with leukocytes, macrophages, and microglia acting against invading bacteria, but at the same time releasing neurotoxic free radicals, proteases, cytokines, and other substances that result in neuronal cell death.

In our patient hydrocephalus was considered symptomatic despite the other areas of ischemic injury. A ventriculostomy was placed, and improvement of level of arousal occurred up to the point that extubation could be pursued. Nonetheless the patient remained severely impaired, uncommunicative, in need of gastrostomy and full nursing care. She died of a cardiac arrhythmia after the family had requested a do-not-resuscitate order.

Fulminant bacterial meningitis may be hard to treat effectively, and secondary manifestations (cerebral infarcts and hydrocephalus) may make recovery much less likely. Mortality in bacterial meningitis in the acute phase may be due to sepsis or multi-organ failure, but we suspect palliative care may be the most common reason of death in patients who remain comatose.


· Treat aggressively with corticosteroids and broad spectrum antibiotics as early as possible.

· MR imaging may explain neurologic condition.

· Patients may not improve due to cerebral infarcts or severe meningeal inflammation causing hydrocephalus.

· Cerebral edema may require osmotic diuretics and additional high dose corticosteroids.

Further Reading

Assiri AM, Alamari FA, Zimmerman VA et al. Corticosteroid administration and outcome of adolescents and adults with acute bacterial meningitis: a meta analysis. Mayo Clin Proc 2009; 84: 403-409.

Brouwer MC, Heckenberg SGB, de Gans J et al. Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis. Neurology 2010;75:1533-1539.

Kasanmoentalib ES, Brouwer MC, van der Ende A, van de Beek D. Hydrocephalus in adults with community-acquired bacterial meningitis. Neurology 2010;75:918-923.

Kim KS. Acute bacterial meningitis in infants and children. Lancet Infect Dis 2010; 10:32-42.

Muralidharan R, Rabinstein AA, Wijdicks EFM.Cervicomedullary injury after pneumococcal meningitis with brain edema. Arch Neurol. 2011;68:513-516.

Nudelman Y, Tunkel AR. Bacterial meningitis: epidemiology, pathogenesis and management update. Drugs 2009; 69:2577-2596.

Rosenstein NE, Perkins BA, Stephens DS, et al: Meningococcal disease. N Engl J Med 2001;344:1378-1388.

Van de Beek D, de Gans J, Tunkel AR, Wijdicks EFM. Community-acquired bacterial meningitis in adults. N Engl J Med 2006; 354:44-53.

5 Sorting Out and Treating Encephalitis

A 60-year-old woman was brought to the emergency department for evaluation of acute fever and confusion. She had psoriasis and rheumatoid arthritis, for which she was being treated with weekly doses of methotrexate and efalizumab and had recently received corticosteroids injections in her knees. Spiking fever had been first noticed one week before. Along with the fevers, she had been complaining of malaise and headache. Her primary internist suspected a urinary infection and had started her on levofloxacin two days before. She became more confused over the last 24 hours and was found in the neighbor’s garage at night. We are called to examine

her in the emergency department. She was tachycardic and had a temperature of 39.2˚ Celsius. She exhibited fluctuating level and content of consciousness. Her neck was rigid. Brainstem reflexes were preserved, and she had no lateralizing signs. CT scan showed low attenuation changes in the right temporal and insular regions (Figure 5.1 A and B).


FIGURE 5.1 Brain imaging in our patient with acute HSV-1 encephalitis. CT scan (A and B) showing low attenuation changes in the right temporal lobe and right insular region. Notice also the slightly hyperdense appearance in the Sylvian fissure, which may be confused for a fresh thrombus in the middle cerebral artery (A). The areas of brain swelling are much better visualized on the FLAIR sequence of the MRI (C and D), which also reveals the characteristic asymmetric bilaterality of the inflammation.

What do you do now?

The diagnosis of encephalitis as a syndrome is relatively straightforward. Patients present with headache, fever, confusion, and, when more advanced, abnormal consciousness. Seizures (focal or more generalized) are a common manifestation. Examination may show neck stiffness or focal deficits, but there may be no localizing signs. In fact the diagnosis may not even be considered if the patient is seen early in the course and is just “confused”. While the CT scan can be highly suggestive of certain forms of encephalitis (as illustrated by the temporal and insular areas of swelling in our patient with herpes simplex virus type 1 [HSV-1] encephalitis) (Figure 5.1), radiological changes are generally not characteristic of specific encephalitis etiologies. A brain MRI is far more helpful (Table 5.1). Cerebrospinal fluid (CSF) showing increased white blood cell count, and an increased protein concentration confirms the presence of encephalitis. A normal CSF strongly points towards alternative diagnoses (such as noninfectious limbic encephalitis).

TABLE 5.1 Causes of Acute Encephalitis with Characteristic Radiological Features


Characteristic radiological features

Herpes simplex virus type 1

Inflammatory lesions in temporal lobes, insula, and operculum

Varicella herpes zoster

Multifocal infarctions and irregularities of arterial lumen


Cerebellitis in children


Ventriculitis (subependymal enhancement). Brainstem inflammation

West Nile virus



Basilar meningitis

Fungal infections

Abscess formation**

Autoimmune limbic encephalitis

Inflammatory lesions in mesial temporal lobes

Acute disseminated encephalomyelitis

Bilateral white matter T2-hyperintense lesions. Corpus callosum involvement

Progressive multifocal leukoencephalopathy (JC virus)

Bilateral, confluent T2-hyperintense lesions in temporo-occipital white matter with involvement of U fibers and cortical sparing

* Presentation with acute flaccid paralysis may occur with or without radiological signs of myelitis.

 Also with fungal meningoencephalitis caused by Blastomycosis

** Aspergillus species is characterized by infarctions and hemorrhages

Recognizing a clinical presentation consistent with the diagnosis of acute encephalitis is just the first step. Encephalitis can be infectious, postinfectious, and noninfectious (Table 5.2). Autoimmune (paraneoplastic or not) and radiation-induced encephalitis are noninfectious examples. Defining the precise cause of the acute encephalitis is a much more difficult task that requires almost encyclopedic knowledge of neurological and infectious diseases, and working with a knowledgeable infectious disease consultant can be very helpful in these cases. Equally important is to narrow the differential diagnosis depending on the season, geographic area, specific exposures (including recent travel history) and risk factors.

Viral infection is the most common cause of acute encephalitis in adults. Epidemic outbreaks can be produced by the seasonal spread of arboviruses (i.e., viruses transmitted by arthropod vectors, such as mosquitoes). Most of these agents are constrained to specific geographical locations, but there are exceptions such as the West Nile virus or H1N1, which has been identified as a cause of outbreaks of encephalitis in all continents. Viral encephalitis can also be sporadic. Sporadic cases can occur in the immunocompetent and the immunodepressed patient.

HSV-1 is the most frequent cause of sporadic viral encephalitis in immunocompetent patients. HSV-1 encephalitis has a predilection for the temporal lobes, insula, and operculum. Consequently, it should be suspected when a febrile patient develops confusion or drowsiness associated with seizures or focal deficits referable to those locations. Aphasia, amnesia, hallucinations, agitation, visual field deficits and oral apraxia can be seen. When present, the typical distribution of swelling on brain MRI (Figure 5.1 C and D) strongly supports the diagnosis. Yet, the diagnosis should be established by confirming the presence of the virus in the CSF. Polymerase chain reaction (PCR) can detect HSV-1 DNA in the CSF with great sensitivity and specificity. If PCR is negative but the clinical-radiological presentation is suspicious for HSV-1 infection, the test should be repeated on a new CSF sample after 3–5 days.

TABLE 5.2 Main Causes of Acute Encephalitis, Diagnostic Test, and Principal Aspects of Management



Ab, antibodies; CMV, cytomegalovirus; CSF, cerebrospinal fluid; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; HSV-1, herpes simplex virus type 1; IMF, immunofluorescence; NMDA = N-methyl D-Aspartate; PML, Progressive multifocal leukoencephalopathy; PMN, polymorphonuclear; TPO, thyroid peroxidase; VZV, varicella-zoster virus; WNV, West Nile virus

*Serum antibodies are more sensitive than CSF antibodies.

 Bacterial infections that may present with acute encephalitis include Bartonella, Listeria (which characteristically causes a rhombencephalitis), Mycoplasma, and Tropherima whippeli.

** Sensitivity may not be optimal.

 Intrathecal amphotericin B may be necessary in severe cases.

Electroencephalography (EEG) should be performed in patients with HSV-1 encephalitis. It is not infrequent to see patients with encephalitis who exhibit fluctuating levels of alertness and awareness. In these cases we often pursue continuous EEG monitoring. Continuous EEG monitoring should also be considered in comatose patients with encephalitis. Nonconvulsive seizures are not uncommon but should be differentiated from periodic lateralized epileptiform discharges (PLEDs). Nonconvulsive seizures must be treated with antiepileptic drugs. When PLEDS are frequent or tend to become rhythmic, we also favor the use of antiepileptics to prevent seizures.

The role of brain biopsy has been relegated to very few selected cases thanks to the high yield of PCR. Brain biopsy in unexplained encephalitis is only considered once all noninvasive diagnostic alternatives have been exhausted and the patient continues to decline despite treatment with adequate doses of acyclovir. It is also advisable to search for other biopsy targets before invading the brain. Detailed physical examination with especial attention to the skin and lymph node chains; CT scans of chest, abdomen, and pelvis; and PET scan can deliver a more accessible site for tissue sampling. Brain biopsy should be guided by MRI findings, and we favor inclusion of a meningeal sample. When neuroimaging is unrevealing, the yield of random brain biopsy is much lower, but pathology may still be diagnostic in these cases. The most salient issue about the evaluation of unexplained encephalitis is how much of it may be without results—an intimidating assignment to say the least.

All patients with presumed acute encephalitis should be started immediately on intravenous acyclovir (10 mg/kg every 8 hours; longer intervals between doses in case of reduced glomerular filtration rate). This antiviral agent is the first choice for treating HSV-1, HSV-2, and varicella-zoster virus. Cytomegalovirus infection requires the combination of ganciclovir and foscarnet; these patients should also be tested for HIV infection. Ganciclovir and foscarnet are also the treatment for HSV-6 infection in immunosuppressed patients. No antiviral has proven effective against West Nile virus infection. HIV-infected patients must receive highly active antiretroviral therapy. In cases of progressive multifocal leukoencephalopathy (JC virus), the treatment consists of reversing immunosuppression. Main treatment measures for nonviral causes of encephalitis are summarized in Table 5.2.

Patients who develop severe brain swelling might require intracranial pressure monitoring. Intraparenchymal monitors are preferable when the ventricles are compressed by brain edema. Head of bed elevation and osmotic agents (mannitol, hypertonic saline) are the first step in cases of intracranial hypertension. The most severe cases may demand decompressive craniectomy. Corticosteroids do not have a role in the treatment of viral encephalitis.

The management of acute encephalitis may require admission to an intensive care unit. The major issues are recognition and treatment of seizures requiring video/EEG monitoring, mechanical ventilation in patients unable to protect the airway (due to abnormal consciousness or requirement of anesthetic drugs to control seizures or agitation), and treatment of brain swelling and medical complications. Even when the cause of the encephalitis is not treatable, aggressive supportive care increases the chance of a favorable outcome.

Our patient was started on intravenous acyclovir in the emergency department. An MRI of the brain (Figure 5.1 C and D) was obtained to delineate the degree of temporal lobe swelling before proceeding with lumbar puncture. The CSF contained 14 white blood cells (predominantly lymphocytes), a protein concentration of 58 mg/dL, and normal glucose level. Shortly after arrival to the ICU she was intubated because of progressive stupor and inability to protect the airway patency. Levofloxacin was stopped (it can reduce seizure threshold) and she was prophylactically started on intravenous levetiracetam. EEG demonstrated frequent periodic epileptiform discharges arising from the right temporal region but no electrographic seizures. Within hours we received confirmation that the PCR for HSV-1 was positive. She began to improve within the following 5 days. Two weeks later she was discharged home, where she continued recovering and completed a 21-day course of acyclovir. Her systemic immunosuppressive regimen was permanently stopped. Six months later she had regained full function.


· Always consider the diagnosis of encephalitis in a febrile and confused patient, regardless of the presence of meningealsigns or focal deficits.

· Start intravenous acyclovir in all patients with suspected viral encephalitis.

· PCR for HSV-1 should be performed in all CSF samples of patients with presumed encephalitis. If PCR is negative but the diagnosis is still suspected (clinical or radiological localization to the temporal lobes or insular/opercular region), acyclovir should be continued and PCR should be repeated after 3-5 days.

· MRI with gadolinium is the most informative neuroimaging modality for patients with suspected encephalitis.

· Every patient with HSV-1 encephalitis should have an EEG. In patients with fluctuating consciousness the option of continuous EEG monitoring should be considered to exclude nonconvulsive status epilepticus.

Further Reading

Barnett GH, Ropper AH, Romeo J. Intracranial pressure and outcome in adult encephalitis. J Neurosurg 1988; 68:585-588.

Kastrup O, Wanke I, Maschke M. Neuroimaging of infections of the central nervous system. Semin Neurol 2008; 28:511-522.

McGrath N, Anderson NE, Croxson MC, Powell KF. Herpes simplex encephalitis treated with acyclovir: diagnosis and long term outcome. J Neurol Neurosurg Psychiatry 1997; 63:321-326.

Rosenfield MR, Dalmau J. Update on paraneoplastic and autoimmune disorders of the central nervous system. Semin Neurol 2010; 30:320-33.

Steiner I, Budka H, Chaudhuri A, Koskiniemi M, Sainio K, Salonen O, Kennedy PG. Viral meningoencephalitis: a review of diagnostic methods and guidelines for management. Eur J Neurol 2010; 17:999-1009.

Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Hartman BJ, Kaplan SL, Scheld WM, Whitley RJ; Infectious Diseases Society of America. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2008; 47:303-327.

Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens. Lancet 2002, 359:507-513.