Viral Meningitis Case File

Viral Meningitis Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 26

A 28-year-old man presents to the emergency department with a headache for 2 days. The headache is located in the frontal and occipital regions and is associated with mild nausea. He has taken various over-the-counter analgesics without an improvement in the headache. His headache has gradually increased in intensity, prompting an evaluation, as he could no longer tolerate it. Besides nausea, he complains of a sense of tightness in his shoulders and neck. He does not have a history of head or neck trauma and is not known to have any other medical problems.

On examination, he is noted to have a temperature of 32.8°C (100.8°F), a blood pressure of 110/68 mm Hg, and pulse of 100 beats/min. He is awake, alert, and oriented. His Mini-Mental State Examination (MMSE) is normal; however, he takes a while to respond to questions. On general physical examination, no skin rashes are noted. He is noted to have a Kernig sign but no Brudzinski sign. Cranial nerves are normal except for a bilateral horizontal nystagmus. His motor, sensory, and cerebellar examinations are normal, with bilaterally downgoing toes (absent Babinski signs). His deep tendon reflexes are hyperreflexic throughout. A computed tomography (CT) of the brain without contrast is read as normal. His headache is now much worse than when he presented to the emergency department.

▶ What is the most likely diagnosis?

▶ What is the best next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 26:

Viral Meningitis                                                    

Summary: A 28-year-old man without a history of known medical problems presents with a 2-day history of a progressively worsening headache. Associated symptoms include nausea, stiffness of the neck and shoulders, and slowness in responding to questions. Physical examination is notable for a Kernig sign, horizontal nystagmus, and generalized hyperreflexia.

• Most likely diagnosis: Meningitis
• Best diagnostic step: Lumbar puncture (LP), usually done after CT imaging
• Next step in therapy: Start intravenous (IV) antibiotics and IV acyclovir

ANALYSIS

Objectives

1. Know the clinical presentation of meningitis.
2. Learn to develop a diagnostic strategy for the diagnosis of meningitis and understand the cerebrospinal fluid (CSF) findings in bacterial and viral meningitis.
3. Know the treatment strategy for meningitis in the emergency department.

Considerations

Any patient presenting with a progressively worsening headache associated with fever and nausea must prompt a clinician to suspect the possibility of an acute infective meningitis or encephalitis. Signs that further support our suspicion in this patient are a history of shoulder and neck tightness and the presence of a Kernig sign.

An LP and CSF study is the best way to diagnose and determine the etiology of meningitis, that is, whether it is bacterial or viral. But why did we choose to do a CT scan first? It is crucial to consider the long list of causes with the above presentation—of them, the most common are conditions that lead to increased intracranial pressure, either by impairing CSF drainage or due to a space-occupying lesion. Performing an LP first in these patients could potentially lead to cerebral herniation and death. CT scan or magnetic resonance imaging (MRI) of the brain are the imaging modalities of choice in these patients. However, although the MRI offers a better resolution of the brain than a CT scan does, the CT is chosen to be done first as it is quicker and generally more readily available. The presence of focal neurologic findings or papilledema are absolute indications to perform an imaging study before performing an LP.

Once it is determined that the risk of herniation is low, an LP is performed. LP analysis should include the following:

1. Opening and closing pressures.
2. CSF studies for glucose, protein, total and differential white cell count, Gram stain and culture, and fungal stains.
3. Latex particle agglutination, herpes simplex virus–polymerase chain reaction (HSV-PCR), enteroviral reverse transcriptase (EV RT-PCR), and Venereal Disease Research Laboratory for CSF (CSF-VDRL).
4. Extra CSF should be retained for additional studies.

Other tests to consider include chemistry panel, complete blood count (CBC) with differential and platelets, international normalized ratio (INR)/prothrombin time (PT)/partial thromboplastin time (PTT), human immunodeficiency virus (HIV), and blood cultures.

However, if there is a delay in obtaining an imaging study, treatment should not be deferred. Blood samples must be drawn and sent off for cultures, and empiric IV antibiotics should be started immediately. The initial choice of empiric therapy is customarily a third-generation cephalosporin (such as ceftriaxone or cefotaxime) plus vancomycin, IV dexamethasone; additionally, IV acyclovir is added if herpes simplex is suspected. The usage of antibiotics may confound the blood and CSF study findings and therefore should ideally be administered after the samples have been collected.

APPROACH TO:

Suspected Meningitis                                        

DEFINITIONS

MENINGITIS: Inflammation of the meninges (membranes surrounding the brain and the spinal cord) caused by various pathogenic organisms—typically bacterial and viral in nonimmunocompromised individuals.

KERNIG SIGN: Pain and resistance to complete extension of the knee when the hip is flexed in the supine position. This is caused by a severe and usually painful spasm in the hamstring muscles due to an inflammation of the lumbosacral roots.

BRUDZINSKI SIGN: An involuntary flexion of the hips and knees upon flexion of the neck, which may indicate meningeal irritation.

LATEX PARTICLE AGGLUTINATION: A test utilizing the principle of antigen-antibody reactions: the surface of latex particles is coated with specific antigens or antibodies, thereby forming “sensitized latex.” When a sample containing complementary antigens or antibodies are mixed with the milky-appearing sensitized latex, visible agglutination is noted. It is used to detect Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis A, B, and C.

ENTEROVIRAL REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION (EV RT-PCR): EV RT-PCR is a technique in which complementary DNA (cDNA) is made from RNA via reverse transcription. The cDNA is then replicated and amplified through standard PCR protocols. Various viruses belonging to the enterovirus family can be detected using this technique.

HERPES SIMPLEX VIRUS POLYMERASE CHAIN REACTION (HSV PCR): PCR is a molecular technique that allows a small amount of DNA to be replicated and amplified. HSV is a possible viral cause for meningitis, and PCR can be used to detect HSV DNA in the CSF. HSV-PCR for CSF has an estimated sensitivity of 95% and specificity of almost 100%.

NYSTAGMUS: A rapid involuntary oscillatory movement of the eyes.

CLINICAL APPROACH

Etiology

Meningitis is typically bacterial or viral in etiology in nonimmunocompromised individuals.

Bacterial meningitis is typically more severe and carries a higher morbidity and mortality rate as compared to viral meningitis. The incidence of bacterial meningitis is approximately 3 to 5 per 100,000 people per year in the United States. Annually, approximately 2000 deaths are reported in the United States from bacterial meningitis. The relative frequency of specific bacterial species as a cause of meningitis varies with age. During the neonatal period Escherichia coli, Listeria monocytogenes, and group B streptococci account for most of the causes of neonatal meningitis. Following the neonatal period, H. influenzae, S. pneumoniae, and N. meningitidis account for 80% of cases. In 1987, widespread vaccination against H. influenzae type b led to a marked reduction in this pathogen causing meningitis in children. Streptococcal pneumonia and Neisseria meningitis are now the principal causes of meningitis following the neonatal period.

Of the viruses, Enteroviridae are the most common cause of viral meningitis in the United States. Approximately 75,000 cases of enteroviral meningitis occur in the United States each year. Coxsackie A9, B3 to B5, and echovirus 4, 6, 7, 8, 11, 18, and 30 are the most common causative strains. The infection primarily spreads by fecal-oral route, although a spread through the respiratory route may rarely be noted. Outbreaks may be associated with pharyngitis or gastroenteritis and typically occur in the late summer and early fall. A viral exanthem may be present. Other causes of viral meningitis include HSV, Arboviridae (St. Louis encephalitis virus, West Nile virus, Japanese encephalitis virus, Western equine encephalitis virus, Eastern equine encephalitis, and La Crosse virus), Arenaviridae, and Retroviridae. The Arboviridae are viruses that are transmitted to humans via arthropods, most commonly mosquitoes or ticks.

Clinical Presentation and Evaluation

Typical symptoms of meningitis include the classic triad of headache, fever, and neck stiffness. Other commonly associated symptoms include photophobia (eye pain or sensitivity to light), nausea, vomiting, myalgia, and confusion. Focal neurologic deficits (eg, cranial nerve palsies, hemiparesis, or dysphasia), seizures, and declining levels of consciousness (ranging from lethargy to coma) may occur in severe cases as a result of an ensuing encephalitis or ischemic strokes caused by secondary thrombosis or inflammation of cerebral vessels.

When evaluating patients with meningitis, it is critical to differentiate between bacterial and viral meningitis. Certain findings on clinical examination can point toward a bacterial infection rather than a viral infection. For example, the presence of a very high fever, a widespread maculopapular rash, or the presence of purpura/ecchymosis suggests a bacterial infection such as Neisseria meningitis. CSF studies, however, are more definitive and help differentiate between viral and bacterial meningitis (Table 26–1).

Blood cultures pick up the causative organism of bacterial meningitis in 50% of cases. This emphasizes the fact that bacteremia is present early on, and it also explains why bacterial meningitis is a true medical emergency. Antibiotics administered up to 2 hours before an LP do not decrease the sensitivity of the CSF culture when done in conjunction with latex particle agglutination and blood cultures. Antibiotics administered more than 2 hours before an LP may decrease the chances of finding a positive CSF Gram stain or culture by 5% to 40%.

Viral CSF cultures have a relatively low sensitivity and a poor ability to grow. Furthermore, the clinical utility of this is limited by the amount of time required for the Enteroviridae to grow (days to weeks). On the other hand, the EV RT-PCR for CSF has 100% specificity and 95% sensitivity, and results are often available within 4 hours.

Neuroimaging studies in bacterial meningitis are often normal but can also reveal complications such as infarction, venous sinus thrombosis, communicating or noncommunicating hydrocephalus, and increased intracranial pressure.

CSF, cerebrospinal fluid; WBC, white blood cells.

Neuroimaging in most cases of viral meningitis is also normal. However, a key exception is HSV meningitis, where there can be evidence of hemorrhagic inflammatory damage in the temporal region.

Treatment

The key to reducing morbidity and mortality in patients with meningitis is rapid recognition so that treatment can be implemented as quickly as possible. This means identifying the causative agent as soon as possible. Many of the tests discussed previously take several hours before results are available, making it impractical to wait for the results before treatment is instituted. As a result, treatment with antibiotics and/or retrovirals are started while waiting for test results (Figure 26–1). Penicillin G

or ampicillin and a third-generation cephalosporin are typical first-line agents for the treatment of bacterial meningitis. However, drug resistance has started to become a major problem, so treatment should be adapted based on local resistance patterns. Ampicillin covers most pneumococci, meningococci, and Listeria. Third-generation cephalosporins, such as ceftriaxone or cefotaxime, cover gram-negative organisms as well as ampicillin-resistant H. influenzae. Vancomycin is added to third-generation cephalosporins to cover Staphylococcus aureus when patients have undergone recent neurosurgical procedures or have had head trauma. When the sensitivity for S. pneumoniae is unknown, adding vancomycin to a third-generation cephalosporin is appropriate. Penicillin G is used to treat gram-negative cocci and gram-positive bacilli. Aminoglycosides are added to treat gram-positive bacilli. Gram-negative bacilli are treated with third-generation cephalosporins and aminoglycosides.

Figure 26–1. Sample algorithm for the evaluation and management of possible meningitis.

Adjuvant therapy with IV corticosteroids for bacterial meningitis is clearly indicated in children. However, the use of IV corticosteroids in adults is not as clear. There is some evidence to suggest that the penetration of vancomycin into CSF is reduced by the administration of corticosteroids. Additionally, corticosteroids may mask clinical signs of antibody response. However, recent studies have shown that the administration of corticosteroids may help in the prevention of systemic complications as well as neurologic deficits in adult patients with S. pneumoniae meningitis.

As of yet, there is no effective pharmacologic treatment for viral meningitis, unless HSV meningitis is suspected. Herpes encephalitis is the most common cause of sporadic viral encephalitis, with a predilection for the temporal lobes. The clinical presentation can range from aseptic meningitis and fever to severe, rapidly progressive forms with significant mortality of the latter form. HSV meningitis is treated using IV acyclovir. Approximately 11% of men and 36% of women with genital herpes will exhibit symptoms consistent with HSV meningitis. HSV meningitis is, however, infrequently present in individuals at the time of their first episode of genital herpes. In adults, the prognosis for recovery is excellent, although some patients may have a residual headache. Sensorineural hearing loss can especially occur in children. Infants and neonates may have more serious long-term sequelae such as cognitive deficits or learning disabilities. In viral meningitis not caused by HSV, the treatment is generally supportive.

In cases where the etiology is unclear, empiric treatment should be initiated with a repeat LP in 6 to 24 hours. Further management depends on clinical improvement, CSF studies, and culture results.

CASE CORRELATION

• See also Case 9 (Delirium from Hepatic Encephalopathy) and Case 18 (Migraine Headache)

COMPREHENSION QUESTIONS

26.1 A 42-year-old woman presents to the emergency department with a 1-day history of fever, neck stiffness, and a severe headache. Her examination reveals a widespread maculopapular rash. Which of the following is the most appropriate next step in management?

A. Obtain a STAT CT scan of the head followed by an LP.

B. Perform a STAT LP without obtaining a CT scan of the head.

C. Obtain a CBC with differential, blood cultures, chemistry 20, and INR, and begin IV penicillin G or ampicillin.

D. Obtain a CBC with D-P, blood cultures, chemistry 20, and INR, and begin IV ceftriaxone plus vancomycin.

26.2 A confused 21-year-old man is brought in by emergency medical services (EMS) to the emergency department. He has a severe headache and fever. His neurologic examination is notable for a Kernig sign and hyperreflexia. LP reveals a protein of 72 mg/dL, glucose of 50 mg/dL (serum glucose of 100 mg/dL), 235 white blood cells/μL (WBCs) with 60% lymphocytes, and cultures/Gram stain pending. These CSF studies are most consistent with which of the following?

A. Bacterial meningitis

B. Viral meningitis

C. Bacterial and viral meningitis

D. Cannot tell without knowing the result of the cultures and Gram stain

26.3 A 3-year-old boy is noted to have a stiff neck, fever, and photophobia. He and his family recently immigrated from a remote village in central America. The mother denies the child receiving any preventive care. Which of the following is most likely to be found on gram stain of CSF?

A. Gram positive diplococci

B. Gram positive chains

C. Gram negative diplococci

D. Gram negative coccobacilli

ANSWERS

26.1 C. The presence of maculopapular rash should cause the clinician to strongly suspect meningococcal meningitis in the patient. Because of the high morbidity and mortality with meningococcal meningitis, treatment should be started immediately. Until Gram stain and culture results are available, penicillin G and/or ampicillin should be started empirically. Serologic studies including blood cultures are necessary prior to starting antibiotics in case there is a delay in obtaining an imaging study.

26.2 B. The finding of an elevated CSF protein, normal glucose, and the predominance of lymphocytes is consistent with a viral meningitis. A predominance of polymorphonuclear cells may be seen early on in viral meningitis, making it easy to confuse viral and bacterial meningitis. However, a normal CSF glucose is uncommon in bacterial meningitis.

26.3 D. This child likely has a bacterial meningitis caused by H. influenza type B, which is the most common etiology of non-vacinnated children. Because of being from a remote village in Central America, vaccination is likely not received.

    CLINICAL PEARLS    

▶ Meningitis classically presents with the triad of altered mental status, fever, and neck stiffness. This is, however, seen in only about 44% of confirmed cases of meningitis. When headache occurs with one of the three symptoms, the sensitivity improves to 95%. ▶ Meningococcal meningitis is an emergency requiring prompt treatment and can be identified in the emergency room by the presence of a maculopapular rash. ▶ The key CSF difference between viral and bacterial meningitis is a normal CSF glucose despite a predominance of lymphocytes in viral meningitis. ▶ Nuchal rigidity is assessed in the supine position with both hips and knees flexed. Kernig sign is elicited by placing the hip and knee at a right angle to the trunk, followed by a passive extension of the knee. It is said to be positive if this maneuver is restricted, and the patient finds it painful. Brudzinski sign is elicited by flexion of the neck—a positive sign would produce an involuntary bilateral flexion of the hips and knees.

REFERENCES

van de Beek D, de Gans J. Dexamethasone in adults with community-acquired bacterial meningitis. Drugs. 2006;66(4):415-427. 

van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med. 2004;351(18):1849-1859. 

Debasi R, Solbrig M. Infections of the nervous system. In: Bradley WG, Daroff RB, Fenichel G, et al, eds. Neurology in Clinical Practice. 4th ed. Philadelphia, PA: Butterworth-Heinemann; 2003. 

Dorland’s Illustrated Medical Dictionary. 27th ed. Philadelphia, PA: WB Saunders; 1988. 

Tunkel AR. Aseptic meningitis in adults. In: Hirsch MS, Mitty J, eds. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/aseptic-meningitis-in-adults. Accessed February 22, 2016.

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