Meningitis – Why do we miss it… How do we improve?

Authors: Author: Nicholas J. Buffin, MD (EM Resident Physician, Mount Sinai Morningside-West, NYC, NY); Christopher Reverte, MD, (EM Attending Physician, Mount Sinai Morningside-West, NYC, NY) // Reviewed by: Michael Yoo, MD (EM Attending Physician, San Antonio, TX); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case

A 44-year-old male presents to your emergency department (ED) with subjective fever, headache, fatigue, generalized body aches, and nausea. He complains of associated photophobia and neck stiffness. He reports taking over the counter medications without much improvement. The patient lives alone. His vital signs are BP 122/75, HR 94, RR 14, SpO298%, T 101.2oF. Physical exam reveals an alert and oriented patient without neurologic deficits, with negative Kernig’s and Brudzinski’s signs. The patient was initially diagnosed with a viral infection and treated with ketorolac 15mg IV, 1L IV normal saline, and 10mg IV metoclopramide, with mild improvement in his symptoms; however, on reassessment, the patient now appears mildly confused. Given his clinical picture, what life-threatening conditions should you consider?


Background

Meningitis causes severe illness that can be difficult to diagnose. Without prompt treatment, meningitis can lead to long term sequelae or death. Throughout the world, meningitis affects 1.2 million people a year 1. The etiology can be bacterial, viral, fungal, parasitic, or non-infectious. Meningitis can be divided into bacterial meningitis or aseptic meningitis. Bacterial meningitis is irritation or inflammation of the meninges secondary to a bacterial infection with subsequent neutrophils being found in the CSF. Aseptic meningitis is a similar disease process but without any evidence of bacterial infection in the cell count or gram stain. Aseptic meningitis is further divided into infectious (viral, TB, and fungal) and inflammatory (systemic inflammatory diseases, malignancy, and drugs) 2.

Bacterial meningitis is associated with high adult mortality, cited as high as 16.4%, with increasing mortality with increasing age 3. It affects 1.2 million individuals worldwide per year 4. This increases in children, with a rate of 20 per 100,000 in patients <2 years old and 400 per 100,000 in neonates 4.

While significant advances in vaccinations have decreased morbidity and mortality 3, meningitis remains a significant health burden with devastating consequences.

In a study that looked at cases of bacterial meningitis found in the US in all age groups between 2003-2008, the most common bacterial causes are Streptococcus pneumoniae (58.0%), followed by Group B Streptococcus (18.1%), Neisseria meningitidis (13.9%), Haemophilus influenzae (6.7%), and Listeria monocytogenes (3.4%) 3. In neonates, Escherichia coli should also be considered 5. In patients who are immunocompromised, Mycobacterium tuberculosis is also a dangerous pathogen 5.


Why is the diagnosis often missed?

Meningitis can be difficult to diagnose due to the combination of fever and headache being a common symptomology in non-meningitis etiologies.  Specifically, 60% of patients with upper respiratory tract infections will experience a headache 6. Additionally, the classic triad of fever, headache, and neck stiffness is not common and can miss up to 66% of bacterial meningitis 7. However, 99% of patients will present with at least one of these findings, and 95% will present with two symptoms.  40% patients also report preceding pulmonary, otic, or sinus symptoms 8. Further complicating the diagnosis of bacterial meningitis, the classic triad can also be a presentation of drug-induced meningitis, carcinomatous meningitis, lymphomatous meningitis, inflammatory diseases (SLE, sarcoidosis, Bechet’s, or Sjogren’s), cerebral abscesses, and subarachnoid hemorrhage 8.

While altered mental status can be a manifestation of meningitis or lead to a lower threshold for a diagnostic workup, altered mental status itself is not specific for meningitis, as patients with sepsis, hypotension, and toxidromes may present with acute neurologic changes 8. Additionally, some toxidromes can present with fever and AMS such as anti-cholinergic and serotonin syndrome and a differential diagnosis should remain broad.

Seizure can be another presenting finding. When a patient presents with fever and seizure, meningitis should be strongly considered. In adults, between 5% and 29% of patients had a seizure as part of their presentation of bacterial meningitis 9. In pediatric patients, 20-30% of patients with bacterial meningitis had a seizure prior to their final diagnosis 9.


High-risk groups

One way to improve our suspicion of meningitis is to recognize which groups are at increased risk. As always, a thorough history and exam is essential in identifying high risk populations. We highlight some of these groups below.

Immunocompromised

Immunocompromised patients are at higher risk for all types of infectious meningitis. While obvious populations include HIV positive patients, patients with autoimmune diseases, and cancer patients undergoing active chemotherapy or radiation therapy, patients with chronic steroid use, diabetes, obesity, chronic alcoholism, blood dyscrasias, and prior splenectomy patients should be considered immunocompromised. HIV patients have been shown to be 6 to 324-fold more susceptible to meningitis 10.

Age

Pediatric (particularly neonates) and elderly patients >age 65 are at increased risk for meningitis infections 11. Additionally, these patients can present with non-specific symptoms, such as trouble hearing or issues with balance 9. Neonates are especially susceptible to meningitis partly due to their cellular and humoral immune immaturity as well as increased permeability of the blood-brain barrier 12.  A potential confounder in the extremes of age may be the difficulty in obtaining an accurate medical history and disease course.  While there is an abundance of neonatal fever workups with geographic variances, typically, all patients under 21 to 28 days of life require a lumbar puncture 13.

Exposure

ENT infections increase the risk of meningitis, given the close proximity of the infection to the blood-brain barrier 14. Subsequently, an accurate history of recent head and neck infections or antibiotic use is important. Additionally, any history of neurosurgical procedures or placement of hardware such as a VP shunt, puts a patient at significantly increased risk 15. Cancer patients who underwent neurosurgery accounted for 75% of the cancer patients who developed meningitis 16. History of intravenous drug use, and a history of endocarditis can also increase a patient’s risk of meningitis 17. Travel to endemic regions of meningitis also increases the risk of meningitis, possibly due to the lack of regional vaccination 18. In addition, young adults living in close quarters to college freshmen or military recruits may also be at increased risk for some serogroup subtypes of Neisseria meningitides 19.

Vaccination History

Vaccination history is key in evaluating a patient with possible meningitis. Since the introduction of vaccines, rates of bacterial meningitis have dropped significantly 20. More recently the group B Neisseria meningitidis vaccine and the pneumococcal vaccine have led to decreased rates of meningitis in all age groups 20. The introduction of the PCV7 vaccine led to significant decreases in bacterial meningitis in children aged 1-23 months 3. Subsequently, patients electing to forego vaccinations are at higher risk compared to the general vaccinated population.


How useful are physical exam maneuvers?

As mentioned previously, no single physical exam finding is accurate enough to clearly identify meningitis.  However, a constellation of exam findings suggestive of meningitis in conjunction with laboratory and vital sign abnormalities may raise its suspicion.  For these reasons, we highlight some classic exam findings below.

Kernig Sign

The inability to straighten the leg past 135 degrees at the knee without pain, once the hip is flexed.

Brudzinski Sign

The involuntary flexion of the hips and knees in response to the neck being flexed.

Nuchal Rigidity

Resistance to passive flexion of the neck.

Jolt Accentuation

Worsening of headache when the head is rotated with a frequency of 2-3 times per second in the horizonal axis 21.

 

A 2019 meta-analysis of nine studies looked at the sensitivity and specificity of these 4 exam findings. The results are shown below 22:

The tests have low sensitivity and are poor at ruling out meningitis.  We emphasize that the absence of a specific sign should not prevent physicians from initiating a workup for meningitis.

Other notable findings on exam may include photophobia, phonophobia and a petechial rash on the extremities.


Understanding your LP

Once obtained, cerebral spinal fluid (CSF) should be analyzed with cell count, gram stain, glucose, protein, and cytology. Xanthochromia will often be determined by the laboratory technician or the operator of the lumbar puncture. Opening pressure, especially in cases where the patient is immunocompromised, can be helpful in the diagnosis of Cryptococcal meningitis23. Other less commonly used but potentially helpful tests include latex agglutination and polymerase chain reaction (PCR) panels. PCR panels may test for many different infections such as HSV, VZV, EBV, CMV, enterovirus, and tuberculosis but are often expensive and only available in large institutions. More advanced testing such as for West Nile Virus, Zika, Dengue and Chikungunya is often obtained in conjunction with infectious disease specialists in the setting of a known exposure.

Of note, the Biofire meningitis PCR panel can be helpful in assisting with diagnosis and need for hospitalization. Please see this ACEP Now article by Dr. David Talan.

Though slight variations may exist between references, the table below can help determine bacterial, viral, or malignant/fungal meningitides.


Scoring tools

There are scoring tools available to risk stratify patients who you are concerned may have meningitis, however they have not been fully validated and therefore must be used cautiously.

The “Bacterial Meningitis Score for Children” is designed to risk stratify patients between 29 days and 19 years old with concern for bacterial meningitis. The components of the tool are: positive CSF gram stain, CSF protein ≥80mg/dL, CSF absolute neutrophil count (ANC) ≥1000 cells/mm, peripheral ANC ≥10,000 cells/mm, and seizure at or prior to presentation 25. The goal of the decision tool is to determine which “high risk” patients have bacterial meningitis and need admission for IV antibiotics and which “low risk” patients have a non-bacterial meningitis, can receive a single dose of antibiotics in the ED and be discharged until the culture results. The sensitivity was 98.3% (95% CI 94.2-99.8%), and the NPV was 99.9% (95% CI 99.6-100%) 25. The cases that were missed were 2 cases of E coli meningitis in patients <2yo. Dr Nigrovic stated “The children who were misclassified by the Bacterial Meningitis Score were small babies with petechial rashes. So, I would be particularly cautious about applying the Score to babies under two months, especially those with a petechial rash” 25. As stated previously, more investigation is needed before this tool is used regularly, and clinical judgement should be used primarily.

The Step-by-step Rule is another rule designed to help determine which neonatal patients require an LP as part of their workup. It is to be applied to patients under the age of 90 days who present to the Emergency Department with a fever. Given these patient’s increased susceptibility to serious bacterial infections, all patients with a fever under the age of 21 days are recommended to have a full sepsis workup including blood cultures, urine cultures and chest Xray 27, however this varies depending on population and geographical area, so be sure to discuss with your local infectious and pediatrics department regarding their policy. For other patients <90 days of age, if they look well, have no leukocyturia, a procalcitonin <0.5, and CRP<20 and ANC <10,000, they are considered low risk. A patient must fulfil all of these criteria in order to avoid a full sepsis workup 27. As with the Bacterial Meningitis Score, this rule requires more validation before it’s use becomes mainstream. Be sure to use clinical judgment and have a low threshold for performing a lumbar puncture in patients < 90 days of age.


Treatment

In adults, the primary empiric therapy is 2g IV of either ceftriaxone or cefotaxime (due to concern for Neisseria meningitidis), with 15-20 mg/kg IV vancomycin (to cover for resistant Streptococcus pneumoniae). If the patient is immunocompromised or >50 years old, then 2g of IV ampicillin is added due to concern for Listeria monocytogenes.

Treatment of neonatal meningitis should cover both Group B Streptococcus, Listeria spp., and E. coli.  Often this is performed with 100mg/kg Q8H IV ampicillin, with gentamicin 4mg/kg Q24H IV.  For young infants (28-90 days), cefotaxime 100mg/kg IV can be an alternative to gentamycin 28.

For older infants, the recommended treatment is vancomycin 15mg/kg Q6H, with either ceftriaxone 50mg/kg Q12H or cefotaxime 100mg/kg Q8H 4.

Due to concern for HSV encephalitis, 20mg/kg IV acyclovir is also usually added if at all suspected. In neonates, if there is suspicion for HSV infection in the mother this should also be added 4.

In addition to use of antibiotics and antivirals, steroids have been shown to reduce CSF inflammation, reduce morbidity and mortality in adults 28, and reduce downstream neurologic dysfunction in children 29. The dose is 10mg IV dexamethasone (0.6mg/kg for pediatric patients) every 6 hours for adults. If bacterial meningitis is suspected and the patient is ill appearing or has neurologic findings such as altered mental status or seizures, administration of steroids should be given before or with the first dose of antibiotics. Ideally an LP would be performed prior to administration of antibiotics to obtain an appropriate specimen for culture and sensitivity results, but if an LP cannot be performed in a timely manner do not delay administration of therapeutic medications.


Pearls:

  • Fever with headache, neck stiffness, and altered mental status are concerning for meningitis.
  • The symptoms of meningitis can be found in many other disease states, making it a difficult diagnosis to make, requiring a high clinical suspicion.
  • There are many factors that can put you at increased risk of meningitis. It is imperative that we know these and ask directly about them, to properly risk stratify.
  • Use physical exam maneuvers with the knowledge that their sensitivity is low. They should not be used to rule out meningitis.
  • We have a decision tool for ruling out bacterial meningitis in children (and now adults), however this requires CSF results and is less applicable when attempting to increase our sensitivity for the disease.
  • Make sure that you are covering your patients with appropriate medications for the different organisms they are at risk for, depending on their age and risk factors.
  • Continue to educate patients on the importance and safety of vaccines.

From Dr. Katy Hanson at Hanson’s Anatomy:


References/Further Reading:

  1. Organization WH. Control of epidemic meningococcal disease. 1988. WHO Practical Guidelines Second Edition.
  2. Mace SE. Acute bacterial meningitis. Emerg Med Clin North Am. May 2008;26(2):281-317, viii. doi:10.1016/j.emc.2008.02.002
  3. Thigpen MC, Whitney CG, Messonnier NE, et al. Bacterial meningitis in the United States, 1998-2007. N Engl J Med. May 26 2011;364(21):2016-25. doi:10.1056/NEJMoa1005384
  4. Tintinalli JE, Stapczynski JS, Ma OJ, Yealy DM, Meckler GD, Cline DM. Tintinalli’s emergency medicine: a comprehensive study guide. 9th. ed. McGraw-Hill Education; 2019:pages cm.
  5. Parikh V, Tucci V, Galwankar S. Infections of the nervous system. Int J Crit Illn Inj Sci. May 2012;2(2):82-97. doi:10.4103/2229-5151.97273
  6. Eccles R. Understanding the symptoms of the common cold and influenza. Lancet Infect Dis. Nov 2005;5(11):718-25. doi:10.1016/S1473-3099(05)70270-X
  7. Tabatabai RR, Swadron SP. Headache in the Emergency Department: Avoiding Misdiagnosis of Dangerous Secondary Causes. Emerg Med Clin North Am. Nov 2016;34(4):695-716. doi:10.1016/j.emc.2016.06.003
  8. Brouwer MC, Thwaites GE, Tunkel AR, van de Beek D. Dilemmas in the diagnosis of acute community-acquired bacterial meningitis. Lancet. Nov 10 2012;380(9854):1684-92. doi:10.1016/S0140-6736(12)61185-4
  9. Kaplan SL. Clinical presentations, diagnosis, and prognostic factors of bacterial meningitis. Infect Dis Clin North Am. Sep 1999;13(3):579-94, vi-vii. doi:10.1016/s0891-5520(05)70095-7
  10. Brouwer MC, Tunkel AR, van de Beek D. Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clin Microbiol Rev. Jul 2010;23(3):467-92. doi:10.1128/CMR.00070-09
  11. van de Beek D, Brouwer M, Hasbun R, Koedel U, Whitney CG, Wijdicks E. Community-acquired bacterial meningitis. Nat Rev Dis Primers. Nov 3 2016;2:16074. doi:10.1038/nrdp.2016.74
  12. Baud O, Aujard Y. Neonatal bacterial meningitis. Handb Clin Neurol. 2013;112:1109-13. doi:10.1016/B978-0-444-52910-7.00030-1
  13. Baraff LJ. Management of infants and young children with fever without source. Pediatr Ann. Oct 2008;37(10):673-9. doi:10.3928/00904481-20081001-01
  14. Geyik MF, Kokoglu OF, Hosoglu S, Ayaz C. Acute bacterial meningitis as a complication of otitis media and related mortality factors. Yonsei Med J. Oct 2002;43(5):573-8. doi:10.3349/ymj.2002.43.5.573
  15. Chen CH, Chang CY, Lin LJ, et al. Risk factors associated with postcraniotomy meningitis: A retrospective study. Medicine (Baltimore). Aug 2016;95(31):e4329. doi:10.1097/MD.0000000000004329
  16. Pruitt AA. CNS infections in patients with cancer. Continuum (Minneap Minn). Apr 2012;18(2):384-405. doi:10.1212/01.CON.0000413665.80915.c4
  17. Brouwer MC, Keizerweerd GD, De Gans J, Spanjaard L, Van De Beek D. Community acquired Staphylococcus aureus meningitis in adults. Scand J Infect Dis. 2009;41(5):375-7. doi:10.1080/00365540902744766
  18. Memish ZA, Goubeaud A, Broker M, Malerczyk C, Shibl AM. Invasive meningococcal disease and travel. J Infect Public Health. Dec 2010;3(4):143-51. doi:10.1016/j.jiph.2010.09.008
  19. Neal KR, Nguyen-Van-Tam J, Monk P, O’Brien SJ, Stuart J, Ramsay M. Invasive meningococcal disease among university undergraduates: association with universities providing relatively large amounts of catered hall accommodation. Epidemiol Infect. Jun 1999;122(3):351-7. doi:10.1017/s0950268899002368
  20. van Ettekoven CN, van de Beek D, Brouwer MC. Update on community-acquired bacterial meningitis: guidance and challenges. Clin Microbiol Infect. Sep 2017;23(9):601-606. doi:10.1016/j.cmi.2017.04.019
  21. Afhami S, Dehghan Manshadi SA, Rezahosseini O. Jolt accentuation of headache: can this maneuver rule out acute meningitis? BMC Res Notes. Oct 30 2017;10(1):540. doi:10.1186/s13104-017-2877-1
  22. Akaishi T, Kobayashi J, Abe M, et al. Sensitivity and specificity of meningeal signs in patients with meningitis. J Gen Fam Med. Sep 2019;20(5):193-198. doi:10.1002/jgf2.268
  23. Williamson PR, Jarvis JN, Panackal AA, et al. Cryptococcal meningitis: epidemiology, immunology, diagnosis and therapy. Nat Rev Neurol. Jan 2017;13(1):13-24. doi:10.1038/nrneurol.2016.167
  24. Nigrovic DL. Bacterial Meningitis Score Children. https://www.mdcalc.com/bacterial-meningitis-score-children
  25. Nigrovic LE, Kuppermann N, Macias CG, et al. Clinical prediction rule for identifying children with cerebrospinal fluid pleocytosis at very low risk of bacterial meningitis. JAMA. Jan 3 2007;297(1):52-60. doi:10.1001/jama.297.1.52
  26. Mintegi DS. Step by Step Approach to Febrile Infants. https://www.mdcalc.com/step-step-approach-febrile-infants
  27. Gomez B, Mintegi S, Bressan S, et al. Validation of the “Step-by-Step” Approach in the Management of Young Febrile Infants. Pediatrics. Aug 2016;138(2)doi:10.1542/peds.2015-4381
  28. van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet. Nov 10 2012;380(9854):1693-702. doi:10.1016/S0140-6736(12)61186-6
  29. Brouwer MC MP, de Gans J, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. 2010. Cochrane Database of Systematic Reviews.

One thought on “Meningitis – Why do we miss it… How do we improve?”

  1. I am from Ethiopia.an a PGY2 of emergency medicine and critical care at jimma university medical school.i am following this blog for the past one and halve year and I found it very interesting.i thank you for unlimited effort of teaching me.
    Thank you again!!!

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