Aseptic Meningitis By: Seth Yandell

1. Aseptic MeningitisBy: Seth Yandell

2. Case Presentation • HPI: 31 y/o WF who 3 days prior to presentation had finished a 5 day course of Telithromycin prescribed by her PCP for a URI, developed a severe HA approx 24 hours ago. The onset was sudden, the pain was located behind her eyes and in the back of her head, was throbbing in nature, and she rated it a 6/10 . She had some associated neck stiffness and lower back pain. The HA was not relieved by Naprosyn. No fevers or chills.

3. Case Presentation con’t • PMH: Notable for HSV2-her initial outbreak was four years ago with no lesions in the last 9 months. Pt states that about one week after her initial outbreak she developed meningitis and she was told it was secondary to her herpes outbreak. Also has well controlled asthma. • Current meds- Advair, Naprosyn, OCP • SH-no sick contacts, no recent travel, married and her husband was her only sexual partner, No IVDU

4. Case Presentation con’t • FH-non contributory, no migraine history, no h/o malignancy • ROS- +mild difficulty concentrating, +photophobia, otherwise negative • PE- afebrile, VSS only positive findings were mild nuchal rigidity, lower back pain on Kernigs manuever, and a positive Jolt accentuation sign

5. General Definition • Asepsis-Pronunciation: (a-sep'sis, a-)A condition in which living pathogenic organisms are absent; a state of sterility (2). Etymology: G. [a-] priv. + [sepsis,] putrefaction • meningitis - Pronunciation: (men-in-ji'tis)Inflammation of the membranes of the brain or spinal cord. • Aseptic meningitis – refers to patients who have clinical signs and laboratory evidence for meningeal inflammation with negative routine bacterial cultures

6. History of Meningitis • It has been recognized since as early as the 15th Century, when Hippocrates taught “If, in a fever, the neck be turned awry on a sudden, so that the sick can hardly swallow, and yet no tumour appear, it is mortal.-Aphorism XXXV.” • It was first described as a specific disease entity by British physician Thomas Willis (1621-1675) and Italian anatomist and pathologist Battista Morgagini (1682-1771) • The earliest suspected epidemic in the US occurred in Medfield, MA, in 1806 when on autopsy pus was noted between the patients dura and pia mater (thought to be bacterial meningitis).

7. Common Symptoms • Fever • Headache • Altered mental status • Stiff neck • Photophobia • Nausea/vomiting

8. Physical Exam • Can vary depending on the etiology • +/- Fever • +/- Lethargy • +/- Kernig’s sign • +/- Brudzinski’s signs • +/- Jolt Accentuation of Headache sign

9. Kernig’s sign • Vladimir Kernig was a Russian physician who first described his sign in 1882. This is Kernig's original description: "I have observed for a number of years in cases of Meningitis a symptom which is apparently rarely recognized although, in my opinion, it is of significant practical value. I am referring to the occurrence of flexion contracture in the legs or occasionally also in the arms which becomes evident only after the patient sits up....the stiffness of neck and back will ordinarily become much more severe and only now will a flexion contracture occur in the knee and occasionally also in the elbow joints. If one attempts to extend the patient’s knees one will succeed only to an angle of approximately 135°. In cases in which the phenomenon is very pronounced the angle may even remain 90°."

10. Kernig’s Sign

11. Brudzinski’s signs • Jozef Brudzinski was a Polish physician who described many meningeal signs in children in the early 1900’s. These include : • Symphyseal sign- pressure on the symphysis elicits a reflexive hip and knee flexion and abduction of the leg. • Cheek phenomenon- pressure on the cheek below the cheekbone elicits a reflexive rising and a simultaneous flexion of the lower arm. The phenomenon is somewhat analogous to the symphyseal sign for the lower extremity. • Contralateral reflex- With the patient supine, passive flexion of one knee into the abdomen results in flexion of opposite hip and knee. Reversely, a forced stretching of a previously flexed limb caused the other to stretch out. • Neck sign- With the patient lying on the back: if the neck is forcibly bended forward, there occurs a reflexive flexion of the knees. (the one we are most familiar with)

12. Brudzinski’s Neck Sign

13. Jolt Accentuation of HA Sign • Patient rotates head in horizontal plane two to three times per second, and the test is considered positive if this worsens the headache pain.

14. Laboratory findings • +/- Leukocytosis • Variable CSF Findings

15. Differential Diagnosis

16. Viral Meningitis • Enteroviruses • Herpes Simplex virus (HSV) • HIV • Lymphocytic Choriomeningitis virus (LCM) • Mumps • Other less common causes include West Nile, St Louis Encephalitis, and California Encephalitis (although most commonly assoc. with encephalitis). May also accompany primary VZV, outbreaks of herpes zoster, EBV, CMV, and adenoviruses.

17. Enteroviral Meningitis • Enteroviruses are thought to be the most common cause of viral meningitis • Are a diverse group of RNA viruses including Coxsackie A & B, Echoviruses, and polioviruses. • Account for >50% of cases and approximately 90% of cases in which a specific etiologic agent is identified. Majority of cases are in children or adolescents, but patients of any age can be affected. • As many as 75000 cases occur in US yearly • Transmitted primarily by fecal-oral route, but can also be spread by contact with infected respiratory secretions. • The incidence is increased in the summer months, but cases occur throughout the year. Sporadic outbreaks are generally associated with specific serotypes (eg, ECV-30), typically related to introduction of new virus strain to a region.

18. Enteroviral Meningitis Signs and Symptoms • Not very distinctive- typically include HA, fever, N/V, malaise, photophobia, and meningismus. Can also include rash, URI symptoms, abdominal pain, and diarrhea.

19. Enterovirus Lab Findings • CSF- findings typical of viral meningitis, with lymphocytic pleocytosis of generally <250 cells/mm3, with modest protein elevation generally <150 mg/dl, and normal glucose, viral cultures positive in 40-80% of cases but it usually takes 4-12 days to become positive, PCR is the most specific (close to 100%) and sensitive (97-100%) test and is positive in more than 2/3 of culture negative CSF in patients with aseptic meningitis • Can also culture throat and stool specimens but this typically leads to a significant number of false positive results

20. Enterovirus Meningitis management • Vast majority of patients have a self limited course and require nothing more than symptomatic therapy • In neonates or adult patients with hypogammaglobulinemia, IV immunoglobulin may be indicated • For severe enteroviral infections a new investigational drug named Pleconaril, which works by integrating into the capsid of picornaviruses, including enteroviruses and rhinoviruses, preventing the virus from attaching to cellular receptors and uncoating to release RNA into the cell, has been shown in limited use to be effective but is not currently FDA approved

21. Herpes Simplex Meningitis • Generally caused by HSV-2 (as opposed to encephalitis which is caused by HSV-1) • dsDNA virus • Increasingly recognized as a cause of aseptic meningitis, with improving diagnostic techniques and a continued increase in the transmission of HSV-2 • Can be due to primary or recurrent HSV infection • Between 13 and 36% of patients presenting with primary genital herpes have clinical findings consistent with meningeal involvement including HA, photophobia, and meningismus. Occasionally patients present with more severe signs including urinary retention, paresthesias, weakness of upper or lower extremities, or ascending myelitis. The genital lesions are typically present (85% of the time), and usually precede the CNS symptoms by seven days. • HSV meningitis can be recurrent, these patients may not have clinically evident genital lesions. For patients with benign recurrent lymphocytic meningitis, careful analysis has revealed that over 80% are due to HSV meningitis. It is also likely the cause of a large percentage of patients with Mollaret’s meningitis, which is a form of recurrent meningitis characterized by large monocytic/macrophage lineage cells in the CSF.

22. HSV Diagnosis • CSF- typical of a viral meningitis, with lymphocytic pleocytosis, modest elevation in protein, and normal glucose. Viral cultures are + in approx. 80% of patients with primary HSV meningitis, but less frequently positive in patients with recurrent HSV meningitis. HSV PCR of the CSF is the single most useful test for the evaluation of a patient with suspected HSV meningitis.

23. HSV Meningitis treatment • Most cases are self limited and will require only symptomatic treatment. • There are no published controlled trials for the use of antiviral agents for HSV meningitis. There have been anecdotal cases that suggest clinical improvement with acyclovir treatment. Antiviral therapy is recommended in patients with primary HSV infection or with severe neurological symptoms. (inpatient-IV acyclovir 10mg/kg Q8°, outpatient with high dose oral acyclovir/valacyclovir/or famciclovir) • Patients with frequent recurrences might benefit from acyclovir prophylaxis, although there are no studies of patients with recurrent HSV meningitis showing benefit from prophylaxis.

24. HIV meningitis • A subset of patients with primary HIV infection will present with meningitis or meningoencephalitis, manifested by HA, confusion, seizures or cranial nerve abnormalities. • ssRNA retrovirus

25. HIV Meningitis Diagnosis • Serum might reveal a atypical lymphocytosis, leukopenia, and elevated serum aminotransferases. Documentation of seroconversion or detection of HIV plasma viremia by nucleic acid techniques can be used for diagnosis. • CSF- might show a lymphocytic pleocytosis, elevated protein, and normal glucose. CSF cultures are often positive, but are not available in most centers.

26. HIV Meningitis Treatment • The meningitis associated with primary infection resolves in most patients without treatment, and patients are typically assumed to have a benign viral meningitis. This occasionally leads to missing the diagnosis of HIV.

27. Lymphocytic Choriomeningitis Virus • LCM is thought to be an underdiagnosed cause of viral meningitis, in one review it was noted to be responsible for 10-15% of cases. • ssRNA virus of the arenavirus group • LCM is excreted in the urine and feces of rodents, including mice, rats, and hamsters (that probably includes Jorge’s hamster Houdini). It is transmitted to humans by either direct contact with infected animals or environmental surfaces. Infection occurs more commonly in the winter months. • Symptoms generally include a influenza like illness accompanied by HA and meningismus. A minority of patients develop orchitis, parotitis, myopericarditis, or arthritis.

28. LCM Diagnosis • CSF- typical of other viral meningitis causes except that 20-30% of the time low glucose levels are present, and cell counts of > 1000/mm3 are not unusual • Diagnosis is made by documentation of seroconversion to the virus in paired serum samples.

29. LCM Therapy • Most patients will recover spontaneously • There is no specific anti-viral therapy available presently

30. Mumps Meningitis • Caused by paramyxovirus which is a ssRNA virus • Prior to the creation of the mumps vaccine in 1967, it accounted for 10-20% of all cases of viral meningitis. • Even now this virus causes a significant minority of cases in unvaccinated adolescents and adults. • In patients who do acquire mumps, CNS infection occurs rather frequently, with CSF pleocytosis detected in 40-60% of patients, and 10-30% of those have clinical signs and symptoms of meningitis.

31. Mumps Diagnosis • CSF- similar to other viral causes, but like LCM it can induce a lymphocytic pleocytosis with cell counts >1000/mm3 or a decreased glucose <50mg/dl, can isolate the virus from the CSF • Can document seroconversion • Clinical correlation is very helpful, ex. If the patient has parotitis or orchitis.

32. Mumps Treatment • Most cases resolve without serious sequelae, and there is no specific therapy available

33. Miscellaneous viruses • West Nile Virus, St Louis Encephalitis, California Encephalitis, primary VZV, outbreaks of herpes zoster,EBV,CMV, and adenoviruses. • Less common causes of meningitis, but they do occur. In most cases the course is self-limited, and the treatment is supportive in nature.

34. Drug Induced Aseptic Meningitis (DAIM)

35. DIAM Symptoms

36. DIAM CSF Findings

37. DIAM-Who’s at Risk • The only disease that seems to have a correlation is SLE, in whom DIAM appears to occur more commonly. • Recurrent DIAM does occur, although other than re-exposure to an offending agent (not necessarily the same agent that caused the initial episode) there is no other known risk factor for these patients.

38. DIAM Treatment • Treatment is simply to stop the offending agent and await resolution of the symptoms. Unfortunately, since this is a diagnosis of exclusion because of the seriousness of a missed bacterial meningitis, it is not an easy diagnosis to make until a bacterial infection can be ruled out.

39. Bacterial Infections that can present with negative cultures • Parameningeal bacterial infections (epidural, subdural abcess) • Partially treated bacterial meningitis or patients who develop meningitis while already on antibiotics • Leptospira species • Lyme disease (Borrelia burgdorferi) • M. Tuberculosis (look for signs of disease elsewhere in the body as a clinical clue) • Bacterial endocarditis

40. Malignancy as a cause of meningitis • It is also important to keep in mind that lymphoma, leukemia, and metastatic carcinomas and adenocarcinomas can occasionally present with an aseptic meningitis syndrome.

41. Back to our case • CT Head- no bleed or mass • WBC-7.07 with normal diff, CBC/Chem 14 WNL, HIV/RPR/ANA all neg. • CSF- Clear, 45 WBC with 98% lymphocytes, Protein 105, Glucose 50, GM Stain shows rare PMN/many lymphocytes/no organisms • CSF PCR for HSV was positive • Hospital course- pt was treated symptomatically initially. Her neurological symptoms were slowly improving but she developed a genital ulcer on hospital day#2 so she was started on oral acyclovir and was discharged on the following day with profound improvement in the HA and neck stiffness. She was counseled to discuss possible future prophylaxis with her PCP.

42. References • 1. Johnson, Paul R., Aseptic Meningitis, www.uptodate.com. • 2. Saberi, Asif et.al., Meningeal Signs: Kernig’s Sign and Brudzinski’s Sign, Hospital Physician, 7/04, pgs 23-24. • 3. Uchihara T, Tsukagoshi H., Jolt accentuation of headache: the most sensitive sign of CSF pleocytosis, Headache. 1991 Mar;31(3):167-71. • 4. Manning, Robert T., Kernig’s sign, www.whonamedit.com. • 5. Thomas KE, et al. The diagnostic accuracy of Kernig's sign, Brudzinski's sign, and nuchal rigidity in adults with suspected meningitis. Clin Infect Dis July 1, 2002;35:46-52. • 6. Attia, John, et al., Does this patient have acute meningitis?, JAMA, Vol 282, 7/14/1999, pgs 175-181. • 7. Rotbart HA; Webster AD, Treatment of potentially life-threatening enterovirus infections with pleconaril, Clin Infect Dis 2001 Jan 15;32(2):228-35. • 8. Moris, German, et al., The Challenge of Drug-Induced Aseptic Meningitis, Archives of Internal Medicine, 1999, June 14, Volume 159(11), pgs. 1185-1194. • 9. Johnson, Kimberly, et al., Lumbar puncture: Technique; indications; contraindications; and complications, www. Uptodate.com.

43. Discussion/Questions