Meningitis, Bacterial Case File

Meningitis, Bacterial Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 43

A 20-year-old college student is the next patient in the emergency department. When you walk into the room, he is lying on the examination table on his side with his arm covering his eyes. The light in the room is turned off. His temperature is 102.3 °F, heart rate is 110 beats per minute (bpm), and blood pressure is 120/80 mm Hg. When you gently ask how he has been feeling, he says that for the past 3 days he has had fever, body aches, and a progressively worsening headache. The light hurts his eyes, and he is nauseated. He has not had any episodes of emesis. He has experienced rhinorrhea but denies diarrhea, cough, or nasal congestion. He has no known ill contacts. On examination, he has no skin rash, and his pupils are difficult to assess due to photophobia. Ears and oropharynx are normal. Heart, lung, and abdominal examinations are normal. Neurologic examination reveals no focal neurologic deficits. Passive flexion of his neck worsens his headache, and he is unable to touch his chin to his chest without pain.

▶ What condition concerns you the most?

▶ What diagnostic test would confirm this diagnosis?

ANSWERS TO CASE 43:

Meningitis, Bacterial

Summary: A 20-year-old college student presents with

• A 3-day history of fever, body aches, and headache
• Fever to 102.3 °F
• Photophobia and nausea
• Nuchal rigidity suggesting meningeal irritation

Most concerning condition: Meningitis (especially bacterial).

Diagnostic test to confirm diagnosis: Lumbar puncture (LP) for evaluation of the cerebrospinal fluid (CSF), in some cases (not this one) preceded by a computed tomographic (CT) scan of the head.

ANALYSIS

Objectives

1. Identify the clinical presentations of viral and bacterial meningitis. (EPA 1)
2. Discuss LP as the diagnostic test of choice for meningitis. (EPA 3)
3. Describe the CSF findings in different forms of meningitis. (EPA 3)
4. Recall the treatment for meningitis. (EPA 4)

Considerations

This 20-year-old college student has headache, nausea, photophobia, fever, and neck pain and stiffness, all suggestive of meningitis, which could be caused by different organisms. Prompt LP and analysis of CSF are essential to establish the diagnosis. Prior to the LP, a CT scan should be obtained if the patient is immunocompromised or has new-onset seizures, papilledema, altered mental status, or a focal neurologic deficit. In the event that an LP cannot be performed prior to antibiotic administration, blood cultures can be obtained; they are positive in 50% to 90% of patients with meningococcal meningitis. Two sets of blood cultures should be collected before the start of antibiotic therapy. In a patient without these signs and symptoms, a preceding CT scan may be unnecessary. A purpuric skin rash increases suspicion for Neisseria meningitidis. Antibiotic administration should not be delayed in suspected meningococcal infection because progression of the disease is rapid, and the mortality and morbidity are extremely high even when antibiotics are given in a timely manner. This seemingly immunocompetent patient does not have risk factors for fungal or parasitic organisms, and therefore empiric therapy with intravenous antibiotics such as vancomycin with cefotaxime or ceftriaxone should be initiated. However, patients at higher risk for opportunistic or unusual organisms should be managed differently; these patients include those with human immunodeficiency virus (HIV) and low CD4 counts, immunosuppression from chemotherapy or transplant antirejection agents, chronic antibiotic therapy, and status post brain/spinal surgery.

APPROACH TO:

Meningitis

DEFINITIONS

ENCEPHALITIS: Brain parenchymal injury and inflammation most often secondary to a viral etiology. When focal brain parenchymal infection is secondary to bacterial infection, it is usually termed cerebritis or abscess.

INFECTIOUS MENINGITIS: Inflammation of the subarachnoid space and meninges caused by bacteria, viruses, fungi, or protozoa; infection is the most common etiology of meningitis.

PAPILLEDEMA: Swelling of the optic nerve caused by increased intracranial pressure. On fundoscopic examination, the optic disc margin may appear hazy.

CLINICAL APPROACH

Epidemiology

Infections of the central nervous system involve either the meninges (meningitis) or the brain parenchyma (encephalitis). The incidence is dropping due to the more widespread administration of pneumococcal and Haemophilus influenzae vaccines. However, bacterial meningitis is still dangerous, with a case fatality rate of approximately 10% to 20% with treatment, and nearly 100% without any treatment. Serious sequelae, such as seizures, hearing loss, or brain damage, may occur despite adequate treatment. College students are at risk due to living in close quarters with other students.

Bacterial meningitis is the most common pus-forming intracranial infection, with an incidence of 1.38 per 100,000 persons. The microbiology of the disease has changed somewhat since the introduction of the H. influenzae type b vaccine in the 1980s. Now Streptococcus pneumoniae is the most common bacterial isolate, with N. meningitidis as a close second. Group B Streptococcus or Streptococcus agalactiae occurs in approximately 10% of cases, more frequently in neonates, patients older than 50 years, and those with chronic illnesses such as diabetes or liver disease. Listeria monocytogenes accounts for approximately 10% of cases and must be considered in pregnant women, the elderly, and patients with impaired cell-mediated immunity such as with acquired immunodeficiency syndrome (AIDS). H. influenzae is responsible for less than 10% of meningitis cases. Resistance to penicillin and some cephalosporins is currently a concern in the treatment of S. pneumoniae.

Pathophysiology

Bacteria usually seed the meninges hematogenously after colonizing and invading the nasal or oropharyngeal mucosa. Occasionally, bacteria directly invade the intracranial space from a site of abscess formation in the middle ear or sinuses. The gravity and rapidity of progression of disease depend on characteristics of both the host defense system and organism virulence. For example, patients with defects in the complement cascade are more susceptible to invasive meningococcal disease. Patients with CSF rhinorrhea caused by trauma or postsurgical changes may also be more susceptible to bacterial invasion.

Staphylococcus aureus and Staphylococcus epidermidis are common causes of meningitis in patients following neurologic procedures such as placement of ventriculoperitoneal shunts. The brisk host inflammatory response in the subarachnoid space may cause edema, vasculitis, and coagulation of vessels, leading to severe neurologic complications, including seizures, increased intracranial pressure, and stroke. Acute bacterial meningitis can progress over a matter of hours to days. Typical symptoms include fever, nuchal rigidity, and headache. Patients may also complain of photophobia, nausea and vomiting, as well as other nonspecific constitutional symptoms. Approximately 75% of patients will experience some confusion or altered level of consciousness. Less than 40% may experience seizures during the course of their illness.

Differential Diagnosis. The differential diagnosis of bacterial meningitis is fairly limited and can be narrowed down depending on the patient’s age, exposure history, and course of illness. Various viral infections may also cause meningitis. The most common include enteroviruses, which tend to be more common in the summer and fall. Patients may present with severe headache accompanied by symptoms of gastroenteritis. The CSF white blood cell (WBC) count will be elevated with a predominance of lymphocytes, and glucose and protein levels are usually normal. Herpes simplex virus (HSV) 1 or HSV-2 may cause a viral meningitis. The CSF of these patients will also have a normal glucose level, whereas protein and WBC counts will be elevated with a predominance of lymphocytes. Typically, these patients have a high CSF red blood cell (RBC) count, which is not seen in bacterial meningitis in the absence of a traumatic LP. In a patient with HIV infection, fungal meningitis, specifically Cryptococcus, should be considered. Tuberculous meningitis presents subacutely; it is more common in older, debilitated patients and patients with HIV. Rickettsial disease, specifically Rocky Mountain spotted fever, may also present with meningitis. Intracranial empyema, or brain or epidural abscess, should be considered if the patient has focal neurologic findings. The one nonsuppurative diagnosis in the differential is subarachnoid hemorrhage from bleeding intracranial aneurysms. These patients present with sudden onset of the “worst headache of their lives” in the absence of other symptoms of infection. They may have photophobia, and the CSF will be grossly bloody; the supernatant will be xanthochromic, reflecting the breakdown of blood into bilirubin.

Clinical Presentation

Some physical examination findings may be useful in the evaluation of a patient with suspected meningitis. Nuchal rigidity is demonstrated when passive or active flexion of the neck results in an inability to touch the chin to the chest. Classic tests include Kernig and Brudzinski signs. Kernig sign can be elicited with the patient on his or her back with the hip and knees flexed. The knee is then passively extended.

Abbreviations: AFB, acid-fast bacillus; CSF, cerebrospinal fluid; PCR, polymerase chain reaction; RBC, red blood cell; WBC, white blood cell.

If passive extension of the knee elicits pain, the test is positive. Brudzinski sign is positive if the supine patient flexes the knees and hips when the neck is passively flexed. Neither sign is very sensitive for the presence of meningeal irritation. However, if present, both are highly specific. Papilledema, if present, would indicate increased intracranial pressure. Focal neurologic signs, altered level of consciousness, or seizures may reflect ischemia of the cerebral vasculature or focal suppuration.

Laboratory Evaluation. Blood cultures should be obtained in all patients with suspected meningitis. LP and CSF evaluation are critical to the diagnosis. Table 43–1 lists typical findings in the CSF from various etiologies of meningitis. The necessity of imaging of the head and brain prior to performing an LP should be individualized. CT scans are most useful in the initial presentation to exclude intracranial mass or bleeding or to evaluate for other signs of increased intracranial pressure. Performing an LP without a preceding imaging study in a patient with signs of increased intracranial pressure poses the risk for brain herniation following the LP procedure. However, studies have shown that in the patient with suspected meningitis who does not have papilledema, focal neurologic signs, or altered level of consciousness, an LP may be safely performed without preceding imaging. Furthermore, in instances in which performance of the LP may be delayed, antibiotics should be administered after blood cultures are obtained while awaiting the radiologic studies.

Ideally, the CSF should be examined within 30 minutes of antibiotics, but it has been shown that it takes up to 4 to 10 hours for the CSF to become sterile in a patient with pneumococcal meningitis. One exception is meningococcal meningitis, in which cultures convert to negative within 1 hour of antibiotic administration. If CSF is obtained, then a culture and Gram stain should be studied. CSF cell count, glucose, and protein levels should be measured. Though not very sensitive, latex agglutination tests for S. pneumoniae and H. influenzae are highly specific and can be useful in diagnosing the infectious agent in patients pretreated with antibiotics. If positive, they can establish the etiology. Polymerase chain reaction (PCR) testing is available for some bacteria; however, it may be more useful in the diagnosis of herpes simplex and tuberculous meningitis. In all, no more than 3.5 to 4 mL of CSF is necessary. The most critical issue in a patient with suspected bacterial meningitis is the initiation of antibiotics. The CSF examination and imaging studies can be deferred in this medical emergency.

Imaging. When HSV meningoencephalitis is suspected, magnetic resonance imaging (MRI) may demonstrate enhancement of the temporal lobes. In tuberculous meningitis, enhancement of the basal region may be seen. An electroencephalogram (EEG) may be helpful in patients suspected of HSV meningitis. Within 2 to 15 days after the start of the illness, periodic sharp and slow wave complexes originating within the temporal lobes can be demonstrated at 2- to 3-second intervals. On the other hand, if purpuric skin lesions are present, a skin biopsy may demonstrate N. meningitidis and can be helpful in confirming the diagnosis. The patient’s age may also provide clues regarding the etiology of the meningitis (Table 43–2).

Treatment

Treatment of meningitis often is empiric until specific culture data are available. Because of the growing incidence of antibiotic-resistant pneumococci and meningococci, the recommended empiric therapy in most regions is a high-dose third-generation cephalosporin given concurrently with vancomycin. In some cases, if the disease presentation is typical for meningococcus (with the characteristic rash), third-generation cephalosporins are sufficient. If the organism is proven to be susceptible to penicillin, therapy with high-dose penicillin G may be started. Ampicillin is added when there is a concern for listeriosis. Acyclovir should be started for suspicion of HSV, and antituberculosis therapy should be considered if the presentation is suspicious for tuberculous meningitis.

Glucocorticoids, when indicated, should be administered just before or concurrent with the first dose of antibiotics to reduce central nervous system inflammation and further neurologic deficits. One study in adults demonstrated decreased mortality in patients with S. pneumoniae meningitis who were also given glucocorticoids. There are stronger data supporting steroids for H. influenzae and S. pneumoniae meningitis in children. There is also some evidence for the benefit of steroids in severe tuberculous meningitis. A Cochrane database review in 2015 concluded that corticosteroids may help reduce the incidence of hearing loss and neurologic sequelae, but do not affect mortality.

Prevention. Prevention of meningitis can be achieved through the administration of vaccines and chemoprophylaxis to close contacts of the infected. Specific vaccinations are available for H. influenzae type b and some strains of S. pneumoniae and are now routinely administered to children. Meningococcal vaccination is recommended for those living in dormitories or close living quarters, such as college students and military recruits, but not for the general population. Rifampin given twice daily for 2 days or a single dose of ciprofloxacin is recommended for household and close contacts of an index case of meningococcemia or meningococcal meningitis.

CASE CORRELATION

• See also Case 38 (Headache/Temporal Arteritis), Case 41 (Urinary Tract Infection and Sepsis in the Elderly), Case 42 (Vascular Catheter Infection in a Patient With Neutropenic Fever), and Case 45 (Syphilis).

COMPREHENSION QUESTIONS

43.1 An 18-year-old young man with a 3-day history of fever, headache, increasing confusion, and lethargy presents to the emergency department. His physical examination is normal, and he has no focal neurologic signs. The CT scan of his head is negative. An LP reveals a WBC count of 250/mm3, with 78% lymphocytes, and RBCs were 500/mm3 in tube 1 and 630/mm3 in tube 2, respectively. No organisms are seen on Gram stain. Which of the following is the best next step?

A. Careful observation with no antibiotics

B. Intravenous azithromycin

C. Intravenous ceftriaxone, acyclovir, and vancomycin

D. Intravenous fluconazole

43.2 A 55-year-old man with a long history of alcohol abuse has been hospitalized for 2 days. He was initially brought in by emergency medical services to the emergency center with a 3-week history of progressive confusion and stupor. On examination, he was afebrile, with heart rate 100 bpm and blood pressure 130/70 mm Hg. He was confused and drowsy but would open his eyes to verbal stimuli. On examination, he had a new right sixth cranial nerve palsy and tremulousness of all four extremities. An LP was performed, and his CSF showed 250 WBCs/mm3 (68% lymphocytes), 300 RBCs/mm3, protein level of 1070 mg/dL, and glucose 10 mg/dL. The serum glucose was 90 mg/dL. He was started on intravenous ceftriaxone, vancomycin, and acyclovir as empiric therapy. A purified protein derivative (PPD) placed on admission is positive today (48 hours), and bacterial cultures are negative at 48 hours. Which of the following would best help to confirm this patient’s probable diagnosis?

A. CT of the head with contrast

B. Gram stain of throat scrapings

C. Herpes simplex virus PCR

D. MRI of the head

E. Repeat LP after 48 hours of therapy

43.3 A 65-year-old man was diagnosed with stage III colon cancer, and after surgical staging, he was placed on a regimen of irinotecan, infusional fluorouracil, and leucovorin. His last course was 2 weeks previously. Today, he presents to the emergency center with a fever and severe headache of 3 days’ duration. His temperature is 101 °F. There is no papilledema or focal neurologic findings present. An LP is performed, and the Gram stain reveals gram-positive rods. Which of the following therapies is most appropriate for this patient?

A. Ampicillin

B. Ceftriaxone

C. Gentamicin

D. Metronidazole

E. Vancomycin

ANSWERS

43.1 C. This young man most likely has viral meningitis, given the modest CSF pleocytosis count with predominant lymphocytes. Given the high RBC count, the etiology might be HSV, so acyclovir should be instituted until more specific testing can be performed. However, because bacterial meningitis cannot be excluded based on the CSF analysis alone, empiric antibiotics should be given until culture results are known; culture results usually return within 48 hours. Moreover, the early CSF findings in bacterial meningitis may resemble those of viral meningitis. If in doubt, a second LP 24 to 48 hours later may be advisable. This patient does not exhibit signs of immunosuppression, so fluconazole (answer D) is not necessary to treat fungal meningitis. Careful observation without antibiotics (answer A) is inappropriate since untreated bacterial meningitis is associated with severe morbidity or mortality. Intravenous azithromycin (answer B) is a standard treatment for community-acquired pneumonia but has a very limited role in meningitis.

43.2 E. Tuberculous meningitis is extremely difficult to diagnose, and the index of suspicion should be high in susceptible individuals. Certain clinical findings, such as nerve palsies and CSF findings, including an extremely low glucose and high protein levels with a fairly low WBC count, are highly suggestive but not diagnostic. This patient has an elevated CSF protein level and low CSF glucose level. Mortality is high and correlates with the delay in instituting therapy. The only definitive test is acid-fast bacillus culture, but it can take 6 to 8 weeks to grow. PCR test for Mycobacterium tuberculosis is diagnostic if positive; however, the sensitivity is low, so a negative test does not rule out the disease. Findings such as a positive PPD or CSF cell counts and protein levels that do not change with standard antimicrobial or antiviral therapies can also suggest the diagnosis. Low CSF glucose is a hallmark of tuberculosis (TB) meningitis; if the glucose level falls at 48 hours, it is highly suggestive of TB. A CT scan (answer A) and MRI (answer D) may demonstrate basilar meningitis in TB, but this finding is not specific. TB meningitis is an extrapulmonary form of TB; as such, pulmonary involvement occurs concomitantly in 50% of patients. A chest x-ray can provide further data. Gram stain of the throat (answer B) would not have a role in this case. HSV PCR (answer C) should be performed on this patient since HSV can present atypically; however, the typical HSV meningoencephalitis usually yields CSF of mildly increased white cells (eg, 100 cells/mm3), glucose levels that are normal or mildly decreased (40 mg/dL), and protein levels in the range of 100 to 600 mg/dL.

43.3 A. This patient should be placed on ampicillin as a minimum, and depending on his absolute neutrophil count, a broader antimicrobial regimen may be prudent. The organism identified by Gram stain is likely L. monocytogenes, a gram-positive rod that causes approximately 10% of all cases of meningitis. This infection is more common in the elderly and in other patients with impaired cell-mediated immunity, such as patients on chemotherapy. It is also more common in neonates. It is not sensitive to cephalosporins or aminogylcosides, and specific therapy with ampicillin must be instituted if the suspicion for this disease is high. Ceftriaxone (answer B) is a third-generation cephalosporin and is often chosen as a first-line agent for most community-acquired meningitis pending cultures; however, because this patient has likely Listeria meningitis, this agent would not be sufficient. Gentamicin (answer C) is an adjuvant antibiotic and offers some synergistic effect when used with another medication, such as a cephalosporin; gentamicin has no efficacy against Listeria. Vancomycin (answer E) is used as part of the empiric antibiotics covering staphylococcal infections. Metronidazole (answer D) covers for anaerobes and has little use in the therapy of meningitis.

CLINICAL PEARLS

▶ Generally, an LP should not be delayed in a patient who is suspected of having meningitis. If LP is contraindicated or impossible because of hemodynamic instability, empiric therapy should be started immediately after blood cultures are drawn.

▶ CT imaging of the brain prior to LP is not necessary in most cases, but it should be considered when the risk of brain herniation is high. These findings include new-onset seizures, signs suspicious for space-occupying lesions (eg, papilledema and focal neurologic signs), and moderate-to-severe impairment in consciousness.

▶ The most common cause of bacterial meningitis in adults is S. pneumoniae, followed by N. meningitidis. L. monocytogenes meningitis may occur in neonates and immunocompromised and older patients.

▶ Patients who have undergone neurosurgical procedures or who have been subject to skull trauma are at risk for staphylococcal meningitis.

▶ Hemorrhagic CSF with evidence of temporal lobe involvement by imaging or EEG suggests HSV meningoencephalitis; acyclovir is the treatment of choice.

▶ Corticosteroid use does not affect mortality but seems to reduce hearing loss and neurologic sequelae. It should be used just before or concurrent with antibiotic therapy.

REFERENCES

Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for bacterial meningitis. Cochrane Library. September 2015. http://www.cochrane.org/CD004405/ARI_corticosteroids-bacterial-meningitis. Accessed January 15, 2020. 

Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med. 2001;345:1727-1733. 

Pollard AJ. Meningococcal infections. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill; 2015:1211-1219. 

Roos KL, Tyler KL. Meningitis, encephalitis, brain abscess, and empyema. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw Hill; 2015:3410-3434. 

Thomas KE, Hasbun R, Jekel J, et al. The diagnostic accuracy of Kernig’s sign, Brudzinski’s sign, and nuchal rigidity in adults with suspected meningitis. Clin Infect Dis. 2002;35:46-52. 

Tunkel AR. Clinical features and diagnosis of acute bacterial meningitis in adults. Calderwood SB, Mitty J, eds. UpToDate. Waltham, MA: UpToDate; 2019 https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-acute-bacterial-meningitis-in-adults. Accessed June 10, 2019. 

Tunkel AR. Epidemiology of bacterial meningitis in adults. Calderwood SB, Mitty J, eds. UpToDate. Waltham, MA: UpToDate; 2019 https://www.uptodate.com. Accessed June 10, 2019. 

Tunkel AR. Treatment of bacterial meningitis caused by specific pathogens in adults. Calderwood SB, Sullivan M, eds. UpToDate. Waltham, MA: UpToDate; 2019 https://www.uptodate.com. Accessed June 10, 2019. 

Van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med. 2004;351:1849-1859.

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