Aseptic Meningitis By: Seth Yandell

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Aseptic MeningitisBy Seth Yandell
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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.

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Case Presentation cont

• 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

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Case Presentation cont

• 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

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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)Inflam
  mation 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

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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).

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Common Symptoms

• Fever
• Headache
• Altered mental status
• Stiff neck
• Photophobia
• Nausea/vomiting

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Physical Exam

• Can vary depending on the etiology
• /- Fever
• /- Lethargy
• /- Kernigs sign
• /- Brudzinskis signs
• /- Jolt Accentuation of Headache sign

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Kernigs 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 patients 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."

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Kernigs Sign
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Brudzinskis signs

• Jozef Brudzinski was a Polish physician who
  described many meningeal signs in children in the
  early 1900s. 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)

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Brudzinskis Neck Sign
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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.

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Laboratory findings

• /- Leukocytosis
• Variable CSF Findings

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Differential Diagnosis
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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.

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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 gt50 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.

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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.

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Enterovirus Lab Findings

• CSF- findings typical of viral meningitis, with
  lymphocytic pleocytosis of generally lt250
  cells/mm3, with modest protein elevation
  generally lt150 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

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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
  

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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 Mollarets meningitis, which is a
  form of recurrent meningitis characterized by
  large monocytic/macrophage lineage cells in the
  CSF.

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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.

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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/valacyclo
  vir/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.

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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

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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.

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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.

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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 Jorges 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.

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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 gt 1000/mm3 are
  not unusual
• Diagnosis is made by documentation of
  seroconversion to the virus in paired serum
  samples.

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LCM Therapy

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

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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.

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Mumps Diagnosis

• CSF- similar to other viral causes, but like LCM
  it can induce a lymphocytic pleocytosis with cell
  counts gt1000/mm3 or a decreased glucose lt50mg/dl,
  can isolate the virus from the CSF
• Can document seroconversion
• Clinical correlation is very helpful, ex. If the
  patient has parotitis or orchitis.

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Mumps Treatment

• Most cases resolve without serious sequelae, and
  there is no specific therapy available

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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.

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Drug Induced Aseptic Meningitis (DAIM)
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DIAM Symptoms
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DIAM CSF Findings
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DIAM-Whos 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.

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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.

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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

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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.

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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 day2 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.

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References

• 1. Johnson, Paul R., Aseptic Meningitis,
  www.uptodate.com.
• 2. Saberi, Asif et.al., Meningeal Signs Kernigs
  Sign and Brudzinskis 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 Mar31(3)167-71.
• 4. Manning, Robert T., Kernigs 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, 20023546-52.
• 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 1532(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.

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Discussion/Questions