Midnight Madness

Introduction References Patient Outcome Annotated Bibliography Questions

Midnight Madness: A crazy psychologist
in the ED late at night

Case Presentation

A 53-year-old woman arrived in the ED late at night. Her partner was concerned that she suddenly as not acting "right." The patient had complained of headache throughout the day but did complete her work schedule as a school psychologist and went to evening choir practice. She felt ill and went to bed early complaining of a headache. She awakened in the late night hours and seemed confused, repeating words, and not clearly recognizing her partner. EMS was called and she was transported to the emergency department.

Meaningful history could not be obtained from the patient and her partner was the initial historical source. The patient did not smoke and drank only occasionally. She reportedly did not use illicit drugs. Her past medical history was unremarkable and did not include a history of headaches. She was post-menopausal and took daily estrogen replacement therapy but no other medications. Surgical history was unremarkable except for a distant history of "sinus surgery." Family history was non-contributory. She had no known allergies and there were no known recent sick contacts.

Physical examination showed a confused woman who responded to questions only with monosyllabic, unintelligible responses. Airway was open and intact. Pulse was 108, BP 149/-, respirations 18/minute, and oxygen saturation of 97% on room air. Temperature was 38.3. The patient could not cooperate with physical examination. The patient moved all extremities and no facial asymmetry was seen. Pupils were equal, 4 mm, and reacted briskly to light. There were no skin rashes. Chest was clear and abdomen seemed soft. It was impossible to judge neck stiffness or other signs. The patient could localize painful stimuli.

With the fever and altered mental status, the possibility of a CNS infection was considered. Intravenous access was established and the patient received 2 grams ceftriaxone following laboratory work and blood cultures. CT showed sinus disease but no intracranial abnormalities. The LP was cloudy; the patient then additionally received acyclovir and vancomycin and was admitted to the ICU.

Key Clinical Questions

Acute bacterial meningitis has long been known to be a serious and often fatal disease; it was universally fatal prior to the introduction of antibiotics. Current estimates of mortality in acute meningitis caused by S. pneumoniae are still on the order of 20%-25% in developed countries. The majority of cases are due to three organisms: H. influenzae, Streptococcus pneumoniae, and Neisseria meningitidis. The frequency of meningitis due to H. influenza has dramatically dropped in the US with widespread vaccination programs. At the extremes of age other organisms are encountered, notably group B streptococcus (S. agalactiae) in neonates and Listeria monoctyogenes in infants and the elderly. (1) Risk factors for community-acquired meningitis in adults include diabetes mellitus, otitis media, pneumonia, sinusitis, and alcohol abuse. (2)

The emerging penicillin resistance of S. pneumoniae has altered the approach and therapy to meningitis. Isolates differ around the world with penicillin resistance varying from 0-40%. In one study from Australia, resistance increased from 0% to 20% during the 5-year study period in the late 1990's. (3) This has lead to the approach of assuming that penicillin resistance is present and covering with additional antibiotics (vancomycin) until culture results are available.

Acute bacterial meningitis may be thought to develop in several stages. Although some cases of bacterial meningitis develop from direct extension, in most cases the organism first proliferates within the nasopharynx, a state known as colonization. Infection implies invasion or proliferation in tissues; the infection may be asymptomatic (subclinical) or may cause symptoms (disease). It is interesting to note that of the many thousands of bacteria that have the potential to produce meningitis, only a few commonly produce the syndrome of acute meningitis.

Following colonization, a bacteremia may occur following microbial invasion of the intravascular space and bacterial survival and multiplication. Meningitis follows with live bacteria breaching the blood-brain barrier, surviving and multiplying in the subarachnoid space. Host immune responses ensue with reactions of disruption of the blood-brain-barrier and vasculitis with the resulting cerebral edema and neuronal injury.(4)
The blood-brain-barrier (BBB) is a structural and functional barrier formed by brain microvascular endothelial cells. Generally, the BBB excludes circulating microbes and toxins. There seems to be a threshold level of bacteremia required for meningeal invasion. Bacterial binding to the microvascular endothelial cells and invasion involve bacterial surface proteins. Once bacteria enter the CNS through the bloodstream, they multiply and induce the release of inflammatory and toxic compounds that result in pleocytosis, further BBB permeability, and neuronal damage. Neuronal injury results from many microbial and host factors; one current goal is attenuation of these specific host responses without adverse effects on other immunological functions. (4)

A vicious cycle of pathophysiologic responses may develop with endothelial cell injury and dysfunction leading to loss of cerebrovascular autoregulation, increased permeability of the BBB, development of cerebral edema, and decreasing cerebral perfusion. (5)

Acute bacterial meningitis has an imperfect triad of presentation - fever, neck stiffness, and altered mental status- but this triad is fully present in less than two-thirds of patients. (2)

The classic physical examination findings of Kernig's sign (pain in the posterior thigh or back when the knee is extended, or resistance to knee extension) and Brudzinski's sign (passive neck flexion produces flexion of the knees and hips in the supine patient) were described in the pre-antibiotic era and likely reflect advanced cases. These classic tests for meningeal irritation are thought to be insensitive but specific for meningitis. (6) In a prospective study of adults with suspected meningitis, Kernig's and Brudzinski's signs were found lacking and a plea was made for better bedside diagnostic tests. (7) A test that may be better-though the study population is small-is the finding of "jolt accentuation of headache." The patient is asked to turn his head to the left or right at a frequency of 2-3 times per second; a positive test is a subjective report of increased headache but most positive results are said to be evident to the observer. This is thought to be more sensitive than the other bedside tests of meningeal irritation, but again, study size is small. (6),(8)

Meningococcal meningitis may be associated with a petechial or purpuric rash reflecting accompanying systemic vasculitis.

As with any critically ill patient, multiple laboratory studies will be obtained. With establishment of intravenous access, it is usual to obtain a CBC, serum chemistries, coagulation studies, and blood cultures, though none of these will guide decision to treat or the type of therapy.

CSF sampling confirms the diagnosis and guides therapy with culture results. The typical CSF formula of the patient with acute bacterial meningitis is the presence of leukocytes of segmented forms. Lymphocytic predominance of CSF suggests but is not conclusive of a viral or fungal infection. Elevated CSF protein is common in meningitis of any type. Low CSF glucose (two thirds or less of the serum glucose) is suggestive of bacterial infection as is an elevated CSF lactate. (8) At times, though the CSF may be clearly inflammatory, it may be inconclusive as to whether the infection is bacterial or viral. Bacterial antigens, if available, may be helpful as may PCR testing for HSV (Herpes simplex virus) in selected cases. Gram stain is commonly obtained and may show bacteria suggesting a causative organism.

Controversy continues about the need for cranial CT prior to lumbar puncture in cases of suspected acute bacterial meningitis. The fear is the theoretical risk of cerebral herniation if lumbar puncture is performed in the presence of a mass lesion such as cerebral abscess. This must be weighed against the therapeutic delays inherent in obtaining imaging and interpretation. No consensus exists on this point and there are proponents and opponents on each side with no randomized studies to tip the argument to one side. Retrospective studies have shown that delays in antibiotic administration are physician-generated and often involve imaging studies. One clinical axiom has emerged-do not delay antibiotics in cases of suspected bacterial meningitis pending imaging studies. If cranial CT is to be pursued, empirically determined antibiotics (and perhaps steroids) should be administered to the patient to avoid delay in initiating therapy.

The unequivocal way to establish meningitis is to sample the CSF or the meninges themselves; except in rare instances, lumbar puncture is the means to sample the CSF. Typically, noncontrast cranial CT scanning is performed. One expert recommendation is that in cases of suspected acute meningitis, LP may be safely performed except in patients with coma, papilledema, or focal neurological findings. Should imaging be performed with the inherent delay, the recommendation is to obtain blood cultures and initiate antibiotic therapy before CT and LP. (1)

Recognition and prompt treatment are key. In meningitis, at times this is quite straightforward but at times it is not. The patient with altered mental status may not give a meaningful history and fine examination for nuchal rigidity or other abnormalities may be difficult. Fever is not initially present in some cases.

When the diagnosis of acute bacterial meningitis is suspected, antibiotics should be promptly administered and not be delayed for imaging or procedures (see discussion above). Initial antibiotic treatment is largely based on risk factors. In the absence of recent trauma or neurosurgical procedures, known contacts, or a pathognomonic rash, treatment will be empiric based mainly on the patient's age. In general, this means treatment with a third generation cephalosporin (ceftriaxone or cefotaxime) and vancomycin. Additionally, ampicillin is often recommended for children less than three months of age or for adults over 50.

A recent prospective study in adults with bacterial meningitis has strengthened the argument for administering steroids early in treatment; in the study protocol steroids were administered 15-20 minutes before antibiotics. (9) The accompanying editorial recommends steroid administration either just before or at the time of steroid administration.(10) There is the concern that steroids, through limiting meningeal inflammation, may interfere with penetration of vancomycin into the CNS but this is not thought to be of clinical significance.

It is important to remember to treat close contacts of patients with meningitis from Neisseria meningitidis; rifampin (pediatric dose 10 mg/kg; adult dose 600mg) PO q12h X 4 doses or ciprofloxacin (adults 500 mg PO once) are the recommended medications.

In general, ICU admission is recommended until patient condition improves because of the potential for early complications such as seizures or stroke symptoms. Typically consultation with infectious disease services is recommended when meningitis is discovered. Meningitis may be a reportable illness to local public health authorities though often this is done by laboratory personnel.

The initial management of acute bacterial meningitis is clearly the province of the emergency physician and initial therapy should not be delayed pending imaging, consultation, or lumbar puncture. When the diagnosis is established or at the time it is strongly suspected, empiric antibiotics based on patient age and other risk factors should be administered. Currently, administration of dexamethasone (10 mg in adults; 0.15 mg/kg children) is recommended in most cases either moments before or at the time of antibiotic administration. (9) (10)

Diagnosis: Acute bacterial meningitis from S. pneumoniae with predisposing condition of post-surgical encephalocele.

The patient received ceftriaxone 2 grams intravenously prior to neuroimaging. CT showed sinus disease with diffuse mucosal thickening but no other abnormalities. Following the lumbar puncture that showed cloudy fluid evident to visual inspection, the patient additionally received vancomycin and acyclovir.

Lumbar puncture cell count showed 16,000 WBC, 99% segmented forms. CSF glucose was less than 10; protein was 522. Gram stain showed white cells but no bacteria. Lactic acid was 10.9. Peripheral WBC 18,500 and routine chemistry was normal.

The patient was admitted to the ICU for one day; mental status improved but headache persisted. Blood cultures were all positive for Streptococcus pneumoniae, sensitive to penicillin. Other medications were discontinued except for pain medications. The patient was discharged home where she completed a two-week course of antibiotics.

The patient returned to work three weeks after admission without sequelae. At ENT consultation one month later for persistent sinusitis, endoscopic examination and further imaging established the existence of a right encephalocele, a complication of earlier elective sinus surgery (FESS). This was electively repaired.

2. Which of the following is the best test for meningeal irritation and predicting the need for lumbar puncture?

3. The most common organism in adult meningitis in the US is which of the following?

4. Initial antibiotic therapy for acute bacterial meningitis in adults less than 50 years of age …?

5. Current innovations in treatment of acute bacterial meningitis are mainly directed along the lines of which of the following?