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Update on
Intracranial Infections
In today’s changing world, the clinical profile of intracranial infections is changing, too. The authors review the etiology, incidence, key findings, diagnosis, and treatment for four infections seen with increasing frequency in emergency departments.
By Scott C. Sherman, MD, FAAEM, and Matthew Y. Rhee, MD
With increased international travel, the spread of worldwide infectious agents, and a growing number of immunocompromised patients, the differential diagnosis and therapy for intracranial infections has expanded in the last 20 years. From West Nile virus to neurocysticercosis to intracranial abscesses, emergency physicians are more likely to encounter an unusual intracranial infection in their practices. Recognizing clues to certain disease processes and staying up to date on recent trends in intracranial infections will help prevent significant morbidity and mortality.
In this article, we will discuss four of the most common intracranial infections: toxoplasma encephalitis, neurocysticercosis, West Nile virus, and bacterial meningitis.
PATIENT PRESENTATION #1
A 34-year-old man with HIV/AIDS presents in the emergency department with progressive malaise and fever. On examination, he has a temperature of 102.2°F and left lower extremity weakness. A computed tomography (CT) scan of the head reveals a ring-enhancing lesion with surrounding edema (see image below).
 Toxoplasma encephalitis. Computed tomography scan of the brain showing a ring-enhancing lesion and surrounding edema.
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What is the most likely etiology?
The differential diagnosis of a focal brain lesion in a patient with HIV/AIDS is broad, so determining the exact etiology is usually not possible in the emergency department. However, clues exist to help narrow the differential so that treatment can be initiated. The first clue is the patient’s CD4 count. When it is more than 500/μl, brain tumors and metastases are 50 times more common than infectious masses. In patients with CD4 counts below 200/μl, however, opportunistic infections or central nervous system (CNS) lymphomas are more common.
The second clue is the CT scan image. Is there a mass effect or edema? If a mass effect is present, toxoplasma and CNS lymphoma are likely. These lesions tend to enhance on CT scan and may cause brain herniation, so prompt treatment with steroids is required, along with a neurosurgical consultation if there is a midline shift, clinical deterioration, or signs of impending herniation. If a mass effect is not present, consider progressive multifocal leukoencephalopathy (PML) or HIV encephalopathy. These lesions do not enhance on CT and do not cause brain herniation.
Although toxoplasma, CNS lymphoma, PML, and HIV encephalopathy are the four most common causes of a focal brain lesion in AIDS patients, other differential diagnoses include bacterial, fungal, viral, or mycobacterial diseases. Tuberculoma is especially common in developing countries.
Investigation of this patient’s past medical records revealed a CD4 count of 14/μl and immunoglobulin G (IgG) that was positive for toxoplasma. The patient stated he was not compliant with trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. Ring enhancement and the mass effect on the CT scan further supported the diagnosis of toxoplasma encephalitis. The decision was made to treat the patient empirically with pyrimethamine plus sulfadiazine. His symptoms improved dramatically within five days. The final diagnosis was toxoplasma encephalitis.
TOXOPLASMA ENCEPHALITIS
Toxoplasma gondii is a single-celled protozoa acquired by ingestion of cysts in undercooked meat or cat feces. The cysts are absorbed through the gut and are taken up by macrophages, where they differentiate into tachyzoites. From there, they enter cells in the brain, lungs, liver, eyes, and muscle. Further progression is limited by a competent immune system.
Incidence. Approximately 15% of people in the United States are seropositive for toxoplasmosis; in Europe, the prevalence is as high as 50%. In the absence of highly active antiretroviral therapy (HAART), there is a 33% per year risk of developing toxoplasmosis encephalitis in a seropositive patient with a CD4 count below 100/μl. The percentage of HIV/AIDS patients with focal brain lesions due to toxoplasma has decreased from 72% in 1991 to 19% in 1996 due to the advent of HAART and the use of TMP-SMX prophylaxis. However, this entity should still be suspected, especially in patients who are not compliant with drug therapy.
Clinical findings. Patients present in a variety of ways. A focal neurologic deficit is found in 69% of patients, headache in 55%, confusion in 53%, and fever in 47%. The median CD4 count at presentation is 50/μl, and 80% to 90% of patients will have positive IgG antibodies. A CT scan with intravenous contrast will show multiple lesions in 69% of patients, usually in the basal ganglia or thalamus. These lesions are generally ring enhancing.
Diagnosis. Sometimes it is difficult to differentiate toxoplasmosis and CNS lymphoma on imaging studies. Generally, CNS lymphoma has an irregular enhancement of the mass lesion, and lesions are greater than 4 cm. Magnetic resonance imaging (MRI), a polymerase chain reaction test, single proton emission CT, positron emission tomography, and brain biopsy can all aid in differentiating CNS lymphoma from toxoplasmosis.
Treatment. Recommended treatment of toxoplasma encephalitis includes 200 mg of oral pyrimethamine as a loading dose, followed by 75 mg/day, and 6 to 8 gm of oral sulfadiazine daily divided into four doses. Pyrimethamine should be given with folinic acid (10 to 25 mg/day) to prevent a drug-induced hematologic toxicity. Duration of therapy is six weeks.
Empiric treatment is frequently initiated before a definitive diagnosis is made. If the CD4 count is less than 100/μl, the patient is IgG positive, is not on prophylactic therapy, and multiple ring-enhancing lesions can be seen on the CT scan, there is a 90% probability of toxoplasma encephalitis. This infection responds rapidly with treatment. Clinical and radiographic improvement is generally seen within 10 to 14 days, with 91% of patients responding by day 14.
Following a full course of treatment, secondary prophylaxis is initiated with lower doses of sulfadiazine plus pyrimethamine and folinic acid. Primary prophylaxis is recommended for patients with CD4 counts below 100/μl who are T. gondii IgG positive.
PATIENT PRESENTATION #2: NEUROCYSTICERCOSIS
A 36-year-old woman who has had a headache and left-sided weakness for three days presents in the emergency department. She has no significant medical history and recently emigrated from Mexico. Physical examination reveals 2/5 strength in her left upper and lower extremities. A ring-enhancing lesion with marked edema in the right cerebral cortex lesion is noted on a CT scan (see image below).
 Neurocysticercosis in the colloidal stage. Computed tomography scan of the brain showing a ring-enhanced lesion with surrounding edema and marked edema of the right cerebral cortex.
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The causative organism in neurocysticercosis is Taenia solium, which is passed on to humans who eat infected pork containing larval cysts. These cysts develop into 2- to 4-meter-long flatworms that live in the intestines. Neurocysticercosis occurs with the ingestion of eggs in the feces of an infected individual. This results in the development of oncospheres (embryos), which cross the intestinal wall into the bloodstream and are carried into tissues, such as in the brain, muscles, or eyes, where they develop into larval cysts.
The lesions of neurocysticercosis are found in the brain parenchyma in 91% of patients. Other locations include the ventricles, subarachnoid space, and spine. There are four stages of infection:
• Vesicular stage. The cysts are 10 to 20 mm in diameter with a thin wall and clear fluid. Occasionally, the rounded head (scolex) is visualized within the cyst. Larval cysts inhibit the host immune response initially, so there is little inflammation evident in surrounding tissues. Patients are usually asymptomatic and may remain in this latent stage for months to years.
• Colloidal stage. The vesicular fluid becomes turbid with signs of degeneration. There is usually brain edema with a thick collagen capsule surrounding the cyst.
• Granular stage. The edema subsides.
• Calcified stage. A mineralized nodule forms (see image below). Multiple calcifications give a “starry sky” appearance with brain imaging.
 Calcified neurocysticercosis. Computed tomography scan of the brain showing the characteristic "starry sky" appearance.
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Incidence. Neurocysticercosis is endemic in most low-income countries, causing 50,000 deaths per year. It is extremely common in South America and Central America, where it is the culprit in 30% of all people with seizures. In California, it is found in 10% of all seizure patients who undergo neuroimaging in the emergency department. The disease is being diagnosed more frequently in high-income countries because of increased immigration and travel.
People at risk for neurocysticercosis are those with Hispanic ethnicity (relative risk, 17.1), those born outside the United States (relative risk, 11.1), and those living in or traveling to an endemic region (relative risk, 158).
Clinical findings. Neurocysticercosis presents in a wide variety of ways. Seizures are most common (66% of patients), followed by headaches (15% to 44%), papilledema (28%), vomiting (27%), focal deficit (21%), and hydrocephalus (16%). Patients rarely develop fever or signs of meningeal irritation. Seizures are usually generalized tonic-clonic. Neurocysticercosis should be considered high in the differential diagnosis of any patient from Central America or South America with new-onset seizures.
Focal neurologic symptoms are related to the mass effect and increased intracranial pressure (ICP). Cranial nerve deficits are common when the basilar cisterns are involved. Arachnoiditis, ependymitis, or intraventricular cysts cause obstruction of cerebrospinal fluid (CSF), especially at the foramina of Monro or the cerebral aqueduct, leading to hydrocephalus.
Diagnosis. The diagnosis of neurocysticercosis is based on several criteria. Definitive diagnosis is made after a positive brain biopsy, when the scolex is visualized within the cyst on CT scan or MRI, or when subretinal parasites are visualized on funduscopic examination. Other criteria highly suggestive of the disease include the detection of anticysticercal antibodies, resolution with therapy, spontaneous resolution of a single lesion, or lesions highly compatible with neurocysticercosis on neuroimaging studies.
Treatment. Treatment depends on the location and type of lesion. Options include antiparasitic agents, antiepileptic drugs, surgical resection, or shunts. Antiparasitic agents have been available since 1978. A single course kills 60% to 85% of viable brain cysts, and treatment reduces the incidence of seizures. Albendazole, the drug of choice, is cheaper, has better CSF penetration, and has a higher parasiticidal effect than praziquantel. However, an antiparasitic agent should not be given to patients with encephalitis because it may cause a severe inflammatory reaction resulting in increased ICP and, possibly, death.
Intraparenchymal vesicular and colloidal cysts are treated with albendazole and steroids. Corticosteroids are administered with antiparasitic drugs to diminish swelling. Osmotic diuresis is recommended when encephalitis is present. Calcified lesions do not require treatment unless the patient has seizures. First-line agents used for seizure control are phenytoin and carbamazepine. Subarachnoid infections require albendazole and high-dose steroids. Ventricular cysts require surgical resection. Any patient presenting with hydrocephalus will need a ventricular shunt before administration of antiparasitic drugs.
PATIENT PRESENTATION #3:
WEST NILE VIRUS
An 82-year-old man presents in the emergency department during the late summer with altered mental status and fever. His wife states that for the past two days he has complained of worsening headaches and neck stiffness. She also mentions that a week ago, while her husband was gardening, he found a dead crow and was bitten by a mosquito.
West Nile virus is a single-stranded RNA virus of the Flaviviridae family. It is transmitted from an infected bird to a vector mosquito. There are high levels of viremia in crows, ravens, and jays that make transmission more likely, and 60 North American mosquito species have been found to harbor the virus. Almost all human cases of West Nile virus derive from mosquito bites, but transmission can also occur across the placenta, through breast milk, or during transfusion or organ transplantation.
Incidence. West Nile virus was first discovered in 1937, in the West Nile district of Uganda, Africa. It was first detected in the western hemisphere in New York City in 1999 and has gradually been progressing westward. Currently, it is the leading cause of arboviral encephalitis in the United States, with a seasonal incidence that starts in late May and peaks during the third week in August.
Approximately 85% of human infections occur in August and September. According to the Centers for Disease Control, there were 4219 cases of West Nile virus reported in 2006, with 161 fatalities. The incidence of death and neuroinvasive disease dramatically increases with age.
Clinical findings. The clinical syndromes range from asymptomatic infection to West Nile fever to neuroinvasive disease. About 80% of infections are asymptomatic.
West Nile fever occurs in 20% of all infected patients. It has an incubation period of 2 to 14 days and manifests with sudden onset of malaise, anorexia, nausea, vomiting, headache, myalgias, and symptoms of upper respiratory infection. Typically, symptoms last from three to six days. Only 50% of patients seek care. West Nile fever became a reportable disease
in 2005.
West Nile virus neuroinvasive disease includes cases of meningitis, encephalitis, and acute flaccid paralysis. Patients present with fever, often associated with weakness, gastrointestinal distress, or headache. Some patients have movement disorders, tremors, myoclonus, or parkinsonism. Acute flaccid paralysis represents 6% of neuroinvasive disease cases and is due to destruction of the anterior horn cells in the spine. Generally, the paralysis is asymmetric and affects both upper and lower limbs. Patients are hyporeflexic or areflexic, without any sensory complaints. Over a third of patients require mechanical ventilation and only 37% recover fully after one year.
Diagnosis. Diagnosis is based on clinical suspicion but is further confirmed by serum or CSF detection of immunoglobulin M antibody. A new test developed in 2005 using a microsphere immunoassay produces results within three hours, compared to 24 to 36 hours for the ELISA method. Antibodies persist in an infected patient’s serum for more than 500 days. About 75% of patients are positive within four days of symptoms and more than 90% after eight days. The antibody does not cross the blood-brain barrier, so its presence in CSF suggests neurologic infection.
Treatment. The treatment for West Nile infection is supportive. A greater emphasis is placed on preventive measures, such as mosquito repellents, protective clothing, and the draining of standing water. The blood supply has been screened since 2003, after it was shown that the virus could be transmitted through blood transfusion. Research to develop a vaccine is ongoing.
PATIENT PRESENTATION #4:
BACTERIAL MENINGITIS
A 45-year-old woman presents in the emergency department with headache, malaise, fever, and neck stiffness. She states that light bothers her eyes. On examination, her temperature is 100.8°F and there is mild nuchal rigidity, but Kernig’s and Brudzinski’s signs are negative. A CT scan of the head does not show any acute abnormalities or mass lesions. She undergoes a lumbar puncture, which demonstrates cloudy CSF indicative of bacterial meningitis (see image below).
 Bacterial meningitis. Tube contains cloudy cerebrospinal fluid (indicative of bacterial meningitis) obtained after a lumbar puncture.
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Neisseria meningitidis remains the most common cause of bacterial meningitis in patients aged 2 to 18. The introduction of a meningococcal conjugate vaccine containing serogroups A, C, Y, and W-135 for adolescents and other high-risk patients will reduce the incidence of meningitis from this pathogen. Group B streptococcus accounts for 70% of cases in neonates, while Listeria monocytogenes is most common in adults over age 60.
Incidence. The incidence of bacterial meningitis has changed rapidly over the last 15 years. Since the introduction of the vaccine in 1990, the incidence of Haemophilus influenzae type B meningitis has declined 94% in children under age 5. The median age increased from 15 months in 1986 to 25 years in 1995. Likewise, there has been a 59% reduction in the incidence of pneumococcal meningitis in children under age 5 since the introduction of the pneumococcal vaccine (Prevnar) in 2000.
Clinical findings. The signs and symptoms of bacterial meningitis vary (see table below). The classic triad of fever, neck stiffness, and altered mental status is present in less than half of patients, but the absence of all three rules out the diagnosis. However, 95% of patients have two, three, or all four of the following symptoms: fever, neck stiffness, altered mental status, and headache. The jolt accentuation test is 100% sensitive for meningitis, with 54% specificity in one small study. A positive test occurs when patients shake their heads back and forth and the headache worsens.
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Diagnosis. Computed tomography is useful to exclude space-occupying lesions that might contribute to herniation following lumbar puncture (LP). Up to 25% of patients with suspected meningitis who undergo a CT scan have some abnormality, but absolute contraindications to LP are present in only 2% to 5%. Clinical features associated with an abnormal CT scan are age over 60, abnormal neurologic examination, history of immunocompromise, history of CNS disease, and seizure within the last seven days. When these features are absent, one study found that LP is safe without a CT scan. If a CT scan is deemed appropriate, obtain a set of blood cultures and treat the patient for bacterial meningitis while awaiting the results of the scan.
When a CT scan of the brain is ordered, the clinician should look for specific findings on the imaging study to determine whether it is safe to proceed to LP. Theoretically, increased ICP and an obstruction of CSF flow from the brain to the thecal sac must be present to cause herniation. Without a pressure gradient, increased pressures rarely cause herniation. Therefore, absolute contraindications to LP include evidence of unequal pressures across the midline or between the supratentorial and infratentorial compartments. When a lateral shift of midline structures occurs, LP may result in compression of the ipsilateral temporal lobe and uncal herniation. When the pressure gradient is between the tentorial compartments, bilateral uncal herniation may occur. Last, when there is a posterior fossa mass, LP could cause cerebellar tonsillar herniation.
Cerebrospinal fluid with more than five white blood cells/mm3 or the presence of neutrophils is consistent with meningeal inflammation. Other findings consistent with bacterial meningitis include a CSF protein level above 100 mg/dl and a CSF glucose reading that is less than 50% of the serum glucose level. Neutrophilic predominance has not been shown to reliably distinguish between a bacterial and viral etiology. A CSF gram stain is 40% to 60% sensitive but more than 90% specific. Bacterial antigen detection is not routinely recommended because it is associated with more false positives than true positives, is not cost effective, and rarely changes management of the disease. When antibiotics have not been previously administered, CSF cultures are 70% to 85% sensitive, but are less than 50% sensitive if antibiotics were given before LP.
Treatment. Administration of antibiotics should not be delayed while awaiting the results of diagnostic testing. There is strong evidence that a delay in administering the first antibiotic dose increases adverse outcomes. The addition of vancomycin to a third-generation cephalosporin is currently recommended due to the increasing resistance of pneumococci to these drugs (21% of patients have intermediate resistance and 14% have high resistance). In patients over age 50 or those with conditions associated with cell-mediated immunodeficiency, the addition of ampicillin is recommended to cover L. monocytogenes.
The use of steroids in bacterial meningitis has been debated in the literature for the past 50 years. Steroids are believed to blunt the host inflammatory response that is stimulated by debris produced by bacterial death from antibiotics. In children, studies reveal reduced morbidity if steroids are given early to patients with bacterial meningitis caused by H. influenzae and Streptoccus pneumoniae, without an increase in adverse events. However, studies show no benefit for meningococcal meningitis. In adults, 10 mg of dexamethasone administered 15 to 20 minutes before antibiotic administration, or with antibiotics, reduces unfavorable neurological outcomes (relative risk, 0.59) and mortality (relative risk, 0.48).
Patients require 24 hours of respiratory isolation in case the causative agent is found to be N. meningitides. People with close contact to these patients require chemoprophylaxis with rifampin, ciprofloxacin, or ceftriaxone.
KEEPING UP TO DATE
This article has discussed how to recognize and manage four intracranial infections seen with increasing frequency in the emergency department. Keeping up to date is the key to making the correct diagnosis and giving the best, most expeditious treatment.
Suggested Reading
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Attia J, et al.: The rational clinical examination. Does this adult patient have acute meningitis? JAMA 282(2):175, 1999.
de Gans J and van de Beek D?: Dexamethasone in adults with bacterial meningitis. N Engl J Med 347(20):1549, 2002.
DeGiorgio CM, et al.: Neurocysticercosis in the United States: review of an important emerging infection. Neurology 64(8):1486, 2005.
Garcia HH, et al.: A trial of antiparasitic treatment to reduce the rate of seizures due to cerebral cysticercosis. N Engl J Med 350(3):249, 2004.
Hasbun R, et al.: Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med 345(24):1727, 2001.
Nash D, et al.: The outbreak of West Nile virus infection in the New York City area in 1999. N Engl J Med 344(24):1807, 2001.
Negrini B, et al.: Cerebrospinal fluid findings in aseptic versus bacterial meningitis. Pediatrics 105(2):316, 2000.
Ong S, et al.: Neurocysticercosis in radiographically imaged seizure patients in U.S. emergency departments. Emerg Infect Dis 8(6):608, 2002.
Perkins MD, et al.: Rapid bacterial antigen detection is not clinically useful. J Clin Microbiol 33(6):1486, 1995.
Petersen LR, et al.: West Nile virus. JAMA 290(4):524, 2003.
Swartz MN: Bacterial meningitis--a view of the past 90 years. N Engl J Med 351(18):1826, 2004.
van de Beek D, et al.: Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 351(18):1849, 2004.
Wallin MT and Kurtzke JF.: Neurocysticercosis in the United States: review of an important emerging infection. Neurology 63(9):1559, 2004.
Whitney CG, et al.: Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 348(18):1737, 2003. |
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