20 Infections

10.1055/b-0038-160250

20 Infections

Marc Cabanne and Dan E. Miulli

Abstract

Rapid diagnosis and appropriate treatment of nervous system infections are paramount to preventing death and limiting neurologic disability. Infections of the central nervous system can spread rapidly through the cerebrospinal fluid and its spaces but spread more slowly through the substance of the brain, at times being present for months. The nervous system has a well-developed immune system, which can be compromised by a persistent attack of bacteria, viruses, fungal, and other foreign organisms in the adjacent structures of the blood, skull, ear, and mouth. Once symptomatic, as determined by the neurologic exam and constitutional signs, the infection must be treated empirically after a specimen is obtained through an invasive procedure and prior to the return of a definitive organism.

Case Study

A 14-year-old, right-handed girl is brought to the emergency room by paramedics with complaints of flulike symptoms over the past 3 or 4 days, followed by an abrupt change in mental status on the day of evaluation. The patient does not have any significant past medical or surgical history. Additionally, she does not have a history of recent travel. On initial evaluation, the patient is observed to be lethargic but arousable with deep stimulation. Her core temperature is 102.7°F. The remaining vital signs are normal. No nuchal rigidity is present. The patient’s Glasgow Coma Scale score is 8 without any focal neurologic deficits noted. Routine laboratory tests as well as blood cultures are drawn, with the only abnormality being a mildly elevated white blood cell count with many mononuclear cells. A computed tomographic scan of the brain was interpreted as normal. What is the patient’s diagnosis? What are the possible etiologies? What studies are needed to complete a thorough workup? What is the appropriate treatment?

See end of chapter for Case Management.

20.1 Introduction

Infections of the central nervous system (CNS) are relatively infrequent occurrences due to the protection of the blood–brain barrier and innate immune cells; however, when infections occur, they can cause significant morbidity and mortality. Rapid diagnosis and appropriate treatment are paramount to preventing death and limiting disability, particularly in immunocompromised patients. ¹ , ² , ³ , ⁴ This chapter provides information needed for prompt and accurate diagnosis and treatment of nervous system infections in the intensive care setting. The chapter will focus on the diagnosis and treatment of community-acquired infections of the nervous system, with a section near the end for the discussion of iatrogenic, or hospital-acquired, infections.

Nervous system infections can be divided into two broad categories: infection of the structures surrounding the nervous system (meningitis), and infection of the parenchyma of the brain and/or spinal cord (encephalitis, abscess).

The main and subtypes of infection are discussed here, along with the information necessary for the neurologic intensive care unit.

20.2 Bacterial Infections of the Skull, Meninges, and Brain

20.2.1 Bacterial Meningitis

Bacterial meningitis is an inflammatory response to bacterial invasion of the pia-arachnoid surrounding the CNS. Meningitis following neurosurgical procedures tends to be less severe than community acquired meningitis. Septic meningitis is more severe, with a greater risk for causing persistent neurologic deficits. ¹ , ² , ³ , ⁴ The result of infection is stagnant blood flow and cerebral ischemia.

Epidemiology: In 1998–1999 the overall incidence of bacterial meningitis in the United States was 2.0 per 100,000. In 2006–2007 this decreased to 1.38 per 100,000. ⁵

Risk factors: Alcoholism, splenectomy, human immunodeficiency virus (HIV), diabetes, immunosuppression, malignancy, dialysis, and sickle cell disease. ⁶ , ⁷ , ⁸ , ⁹

Predisposing conditions: Otitis media, mastoiditis, sinusitis, bacteremia, pneumonia, and bacterial peritonitis. ⁶ , ⁷ , ⁸ , ⁹

Most common organisms: Dependent on age; most spread by respiratory transmission (► Table 20.1).

Clinical presentation: Headache, fever, nuchal rigidity, nausea/vomiting, neck or back pain; can have focal neurologic signs, altered level of consciousness, or seizures; onset of symptoms over hours to days. ⁶ , ⁷ , ⁸ , ⁹

**Table 20.1** Most common organisms in bacterial meningitis ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷
Organisms and characteristics	Age
Streptococcus pneumoniae: Most common organism in all age groups (40–50% of cases); most common organism causing meningitis in patients with cerebrospinal fluid leakage	> 7 years
Neisseria meningitidis: 20 to 30% of cases; associated with close living quarters	3–7years
Haemophilus influenzae: Prior to Haemophilus influenzae type B vaccination, most common organism in children < 5 years of age; now < 5% of cases	3 months–3years
Group B Streptococcus (agalactiae): Most frequent cause of neonatal meningitis; usually transmitted to infant during delivery; 10 to 15% of cases	< 3 months
Escherichia coli: 15% of neonatal cases; 3% of all cases	<3 months
Listeria monocytogenes: 5 to 10% of cases of meningitis in neonates <1 month; fecal-oral transmission: transmitted via mother at the time of birth from genital or gastrointestinal tract colonization	<1 month or>50 years + immunosuppression

Physical exam signs: Indicative of meningeal irritation.

Brudzinski’s sign: Passive flexion of the neck causes involuntary flexion of the knees and hips.

Kernig’s sign: Resistance to passive extension of the hip and knee.

Differential diagnosis: Includes viral meningitis, fungal meningitis, viral encephalitis, parenchymal abscess, epidural/subdural empyema, parasitic infection, neuroleptic malignant syndrome, and subarachnoid hemorrhage.

Diagnosis and studies: Cerebrospinal fluid (CSF) findings in bacterial meningitis: Opening pressure elevated, turbid, cloudy in appearance, red blood cell count > 200/mm ³ with predominance of neutrophils, glucose decreased, and protein elevated (► Table 20.2).

**Table 20.2** Cerebrospinal fluid analysis ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷
Parameter	Value
Opening pressure	4–15 mm Hg or 5.0–19.5 cm HO
Clarity	Cloudy: indicative of bacterial infection; WBC > 200/mm ³ for turbid CSF
Color	Reddish: subarachnoid hemorrhage via traumatic tap; RBC> 6000/mm ³ to appear red
	Yellowish: increased protein levels—usually > 150 mg/dL Xanthochromia: spin sample in centrifuge
Cell count and differential	WBC < 5/mm ³ ; may be higher in neonates ↑ neutrophils = bacterial infection ↑ lymphocytes = viral or fungal etiology RBC measured in successive tubes to differentiate subarachnoid hemorrhage from traumatic tap with clearing of CSF and decrease in the number of RBCs
Biochemistry: glucose and protein levels	Glucose ² /₃ blood glucose; CSF = normal values 45–60 mg/dL Glucose ↓ bacterial or fungal infections; normal in viral infections; protein = 15–40 mg/dL; ↑ not specific for type of meningitis
Gram stain/culture and bacterial antigen panels	Gram stain identifies the type, or identity of, the bacteria present in the CSF. ⁸ , ⁹
Abbreviations: CSF, cerebrospinal fluid; RBC, red blood cell count; WBC, white blood cell count.

Imaging: Has little role in the diagnosis of meningitis; is necessary to rule out hemorrhage, mass lesions, elevated intracranial pressure (ICP), or other nervous system infections

Lumbar puncture: If ICP is elevated, then the risk of herniation after lumbar puncture is significantly increased; however, it may be valuable for the evaluation of clinical sequelae of infection, such as subdural empyema, hydrocephalus, and infarction, because a lumbar puncture will be one of the most important tools in diagnosing meningitis.

Treatment: Duration of treatment 10 to 14 days, depending on clinical response. Dexamethasone can be used to reduce meningeal inflammation and pain associated with nuchal rigidity, as well as the incidence of hearing loss in patients with Streptococcus pneumoniae or Haemophilus influenzae type B meningitis (► Table 20.3).

**Table 20.3** Treatment of bacterial meningitis ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷
Empirical antibiotic treatment based on most common organisms for a particular age group
Treatment group	Antibiotic	Dosage
Initial treatment	Ceftriaxone or cefotaxime	2 g IV every 12 hours
	and	2 g IV every 6 hours
	Vancomycin
	Vancomycin	2–3 g IV every 8–12 hours (covers penicillin-resistant Streptococcus pneumoniae)
Penicillin allergy	Vancomycin or meropenem	2 g IV every 8 hours
	or
	Trimethoprim/sulfamethoxazole (use in place of cephalosporin)	5 mg/kg every 6–8 hours
Chronic diseases, immunosuppression, or alcoholism	Add ampicillin	2 g IV every 4 hours
Neonates group B: Streptococcus is suspected	Ampicillin and gentamicin or cefotaxime
Focused antibiotic treatment based on culture results
Streptococcus pneumoniae	Penicillin	4 million units IV every 4 hours
Neisseria meningitidis	Ceftriaxone	2 g IV every 12 hours
Haemophilus influenzae	Ceftriaxone (peds)	50 mg/kg IV every 12 hours
Group B Streptococcus	Penicillin	4 million units IV every 6 hours
Listeria monocytogenes	Ampicillin ± gentamicin	2 g IV every 12 hours 2 mg/kg loading dose then 1.7 mg/kg every 8 hours
Abbreviation: IV, intravenous.

20.2.2 Osteomyelitis of the Skull

Most infections are due to direct extension from infected sinuses, penetrating trauma, or intracranial empyema.

Most common organisms: Staphylococcus aureus, Staphylococcus epidermidis, and gram-negative bacilli—Escherichia coli must be considered in neonates.

Clinical presentation: Focal pain, fever, scalp erythema, swelling, and tenderness.

Differential diagnosis: Tumor, trauma, and epidural/subdural empyema.

Diagnosis and studies: Skull X-ray will occasionally show inflammation and edema in infected area (Pott’spuffy tumor). Computed tomographic (CT) scan can demonstrate infectious changes of the skull as well as associated areas of infection.

Treatment: Consists of a combination of surgical debridement and antibiotic therapy. Surgery involves a craniectomy of the infected skull, replacing it with mesh or acrylic cranioplasty ~ 6 to 12 months postoperatively if there are no signs of infection. Antibiotics are routinely given, such as vancomycin 1 g intravenous (IV) every 12 hours plus ceftazidime 2 g IV every 8 hours. The antibiotics are given for 6 to 12 weeks and are adjusted based on culture and sensitivities.

20.2.3 Subdural Empyema

Subdural empyema is usually the result of direct extension of local infection (e.g., sinus infection), spread via diploic veins in the skull. ¹⁰ It represents 15–20% of all intracranial infections. In children meningitis is an important predisposing condition, with subdural empyema occurring in 2–10% of patients. ¹ It can be seen in the epidural space and can be associated with osteomyelitis of the skull. Associated cerebral abscess is present in 20–25% of cases. ² It may also be postoperative, posttraumatic, or related to prior subdural hematoma. There is a 50 to 60% morbidity rate and a 10 to 20% mortality rate. ¹¹

Most common organisms: Aerobic and anaerobic Streptococcus species, S. aureus, and gram-negative bacilli.

Clinical presentation: Fever, headache, nuchal rigidity, focal neurologic deficits, mental status changes, seizures, and nausea/vomiting. Symptoms can be similar to other CNS infections, however more rapidly progressive with subdural empyema.

Differential diagnosis: Bacterial meningitis, viral meningitis, fungal meningitis, parasitic infection, viral encephalitis, parenchymal abscess, subarachnoid hemorrhage, HIV, and neuroleptic malignant syndrome.

Diagnosis and studies: CT/magnetic resonance imaging (MRI) with contrast shows fluid collection with a typical crescent shape as well as a degree of mass effect or the presence of midline shift. Lumbar puncture is not recommended due to suspected increased ICP and risk of herniation. When CSF is obtained, the findings are consistent with parameningeal infection. Usually there is an intraoperative culture swab (aerobic and anaerobic cultures).

Treatment: Emergent surgical evacuation via craniotomy; however, burr holes can be used in critically unstable patients if purulent material is liquefied. Antibiotics consist of vancomycin 1 g IV every 12 hours plus ceftazidime 2 g IV every 8 hours plus metronidazole 500 mg IV every 6 hours. The 4- to 6-week course of antibiotics is adjusted depending on culture and sensitivities. Antiepileptics can be given prophylactically and should be used if seizures are present.

20.2.4 Brain Abscess

Brain abscess is a localized suppurative infection of the brain parenchyma, ¹² with a male predominance. There is a slightly higher rate in children 5 to 9 years and adults > 60 years, with 25% of cases occurring in children. The infection is usually due to hematogenous spread from the chest or as a result of direct extension; in 25% of cases no source is identified.

Predisposing conditions: Otitis media, sinusitis, mastoiditis, oral infections, lung abscess, pulmonary abnormalities, cyanotic heart disease, bacterial endocarditis, penetrating trauma, and HIV. ¹³ , ¹⁴ , ¹⁵ Hematogenous spread will typically lead to multiple foci of infection versus a solitary lesion from contiguous spread from local infection. ¹

Most common organisms: Streptococcus species—aerobic, anaerobic, microaerophilic; Staphylococcus aureus most common secondary to trauma, surgery, or endocarditis ¹⁶ ; Staphylococcus epidermidis, Pseudomonas aeruginosa, Enterococcus, Bacteroides, Actinomyces, and Nocardia associated with immunosuppression due to HIV disease ¹⁷ ; Mycobacterium tuberculosis (TB)—most common cause of brain abscess in some developing countries; Cryptococcus—usually seen with meningitis; Aspergillus—seen in immunosuppressed patients from transplant; and Toxoplasma gondii.

Clinical presentation: Headache, fever, altered level of consciousness, visual changes, focal neurologic deficits—specific symptoms depending on location of lesion. Hemiparesis and seizures occur in 30–50% of patients.

Differential diagnosis: Bacterial meningitis, viral meningitis, fungal meningitis, parasitic infection, viral encephalitis, epidural/subdural empyema, intracerebral hemorrhage, subarachnoid hemorrhage, tumor, venous sinus thrombosis, and migraine headache.

Diagnosis and studies: Routine laboratory tests (complete blood count, basic chemistry panel) are usually not helpful. However, erythrocyte sedimentation rate (ESR) is usually elevated and can be used to follow the therapeutic response to antibiotics. C-reactive protein is also very sensitive and may be added as a test. Lumbar puncture is not usually indicated unless meningitis is suspected. When CSF is obtained, the findings are similar to those for other parameningeal infections, such as elevated white blood cell (WBC) count, normal glucose, and elevated protein. Cultures are usually negative.

Imaging: Contrast-enhanced CT or MRI scans show a characteristic rim-enhancing lesion with necrotic center surrounded by white matter edema. It can be difficult to differentiate from primary glial and metastatic tumors. Magnetic resonance spectroscopy can improve diagnostic accuracy. ¹⁸ The precise diagnosis of specific organisms requires pathological tissue from biopsy or resection.

Treatment: See ► Table 20.4, ► Table 20.5

**Table 20.4** Differentiating treatment for brain abscess: medical versus surgical ¹ , ² , ³ , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹
Indications for medical treatment	Indications for surgical treatment
Multiple lesions	Solitary lesion
Lesions < 3 cm	Lesions > 3 cm
Deep lesions	Proximity to ventricle
Poor surgical candidate	Significant mass effect or midline
	shift>0.5 cm
	Altered mental status
	Progressive neurologic deficit

**Table 20.5** Brain abscess management ¹ , ² , ³ , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹
Antibiotics	Vancomycin 1 g IV every 12 hours + ceftazidime 2 g IV every 8 hours + metronidazole 500 mg IV every 6 hours if anaerobes suspected
Duration	6–12 weeks
Repeat imaging	2–4 weeks after beginning antibiotic therapy
Surgery	Consider if no change in size of the lesion or if neurologic deterioration
Surgical options	Stereotactic biopsy via craniotomy for resection
Abbreviation: IV, intravenous.

20.3 Viral Infections of the Meninges and Brain

20.3.1 Viral Meningitis

Viruses are obligate intracellular parasites that can replicate only within a cell. They contain either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), and infection occurs via hematogenous spread as part of a systemic infection, usually from a respiratory (measles, mumps, varicella), gastrointestinal (enteroviruses), or oral/genital mucosa (herpes simplex) source or neuronal spread via nerve cells.

Most common organism: Enterovirus, consisting of echovirus, coxsackievirus, and nonparalytic poliovirus, is the most common viral meningitis infection type in the United States. It is transmitted by fecal–oral spread. Peak incidence occurs in August–September.

Clinical presentation: Headache, fever, nausea/vomiting, nuchal rigidity, photophobia. However, patients are usually not as ill as with bacterial meningitis.

Differential diagnosis: Bacterial meningitis, fungal meningitis, viral encephalitis, parenchymal abscess, epidural/subdural empyema, severe frontal or sphenoid sinusitis, vaccination, intrathecal administration of drugs, HIV, subarachnoid hemorrhage, migraine headache, parasitic infections, sarcoidosis, and neuroleptic malignant syndrome. The diagnosis of viral meningitis is usually one of exclusion.

Diagnosis and studies: CSF findings in viral meningitis: Opening pressure usually normal; CSF usually clear/colorless; WBC elevated but usually < 200/mm ³ . There is initially a predominance of neutrophils with a shift toward mononuclear cells after 12 to 24 hours. The glucose is normal, and the protein is elevated. Gram’s stain and routine cultures are negative; for this reason, viral meningitis is also referred to as aseptic meningitis. Viral cultures for Enterovirus are positive in 30 to 50% of cases; therefore, serological testing for the diagnosis of Enterovirus is not recommended. Polymerase chain reaction (PCR) can be used for diagnosis, but it is available only in specialized laboratories and is expensive.

Imaging: Usually unremarkable.

Treatment: Currently there is no treatment for enteroviruses, and treatment is symptomatic. Only if varicella-zoster or herpesvirus is suspected is acyclovir usually recommended.

20.3.2 Viral Encephalitis

Most common organisms: The majority of epidemic cases of encephalitis are caused by arboviruses with spread by vector transmission (infected mosquitoes).

Arbovirus types are St. Louis encephalitis, California encephalitis, western equine encephalitis, eastern equine encephalitis, West Nile virus, and La Crosse encephalitis. Encephalitis from arbovirus will peak in August and September when mosquitoes are most active.

Herpes simplex virus is a latent virus found in dorsal root ganglion; it is spread via the neuronal route. The majority of cases are caused by type I virus. CNS infection involves the mesial temporal lobes bilaterally, with one side affected worse than the other. Autopsy studies show a predilection of the olfactory and limbic systems. ¹⁹

Clinical presentation: Most common presentation is altered level of consciousness in the setting of acute febrile illness with possible focal neurologic signs, usually meningeal involvement. Between 5 and 15% of patients with acute viral encephalitis will die, with persistent neurologic deficit occurring in 20–35% of patients. ¹

Differential diagnosis: Bacterial meningitis, viral meningitis, fungal meningitis, parasitic infection, epidural/subdural empyema, parenchymal abscess, tumor, subdural hematoma, HIV, lupus cerebritis, adrenal leukodystrophy, Reye’s syndrome, and neuroleptic malignant syndrome

Diagnosis and studies: CSF analysis similar to aseptic meningitis; viral cultures of arboviruses and herpes simplex virus are available only at a specialized laboratory. Electroencephalogram (EEG) can show characteristic periodic lateralizing epileptiform discharges in the case of herpes simplex encephalitis.

Imaging: Critical for diagnosis of encephalitis. Focal hyperintense lesions seen in inconsistent distribution on T2-weighted images and FLAIR (fluid attenuated inversion recovery) sequences on MRI, especially in eastern equine encephalitis, asymmetric bitemporal distribution possibly with hemorrhage in herpes simplex encephalitis.

Treatment: No known treatment for arbovirus infections; herpes simplex encephalitis can be treated with acyclovir 10 mg/kg IV every 8 hours for 14 to 21 days and should be started as soon as possible to attempt to avoid long-term neurologic sequelae. If viral encephalitis is suspected, empirical treatment with acyclovir is indicated, as better outcomes are seen with early institution of antiviral therapy.

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