Aseptic meningitis has been defined as

Aseptic meningitis Chris Newton, MD
September 24, 1999

Aseptic meningitis has been defined as:

Meningitis with normal CSF glucose, normal to elevated protein and elevated cell count with a lymphocyte predominance
Nonbacterial meningitis
Meningitis with negative bacterial culture – old definition and not used much

Signs and Symptoms that may be present:

Fever

Headache, typically frontal or retro-orbital

Malaise

Myalgias

Anorexia

Nausea and/or vomiting

Abdominal pain

Diarrhea

Mild degree of lethargy or drowsiness

Need to think of something else if the patient has stupor, coma, marked confusion, seizures, cranial nerve palsies or focal neurologic symptoms

Photophobia

Pain on eye movement

Nuchal rigidity

Kernig’s and Brudzinski’s signs are generally absent

Etiologies:

Viruses – most common cause

Common	Less Common	Rare
Enteroviruses – 50-80% Arboviruses HIV-1 HSV-2	HSV-1 Lymphocytic choriomeningitis virus Mumps 10-20%	Adenovirus CMV EBV Influenza A,B Measles Parainfluenza Rubella VZV

Mycobacteria

Listeria
Syphilis
Leptospira
Toxoplasma
Fungi – Cryptococcus
Meningeal carcinomatosis
Meningeal reaction to nearby inflammation, destructive process or medications

Laboratory Diagnosis:

CSF Analysis typically gives a profile of lymphocytic pleocytosis (usually less than 1000 cells/mm³), slightly elevated protein level and normal glucose level

Reports estimate that 20-75% of patients with viral meningitis have neutrophil predominance in the first CSF specimen obtained, especially in enterovirus, mumps and arbovirus infections
A repeat lumbar puncture in 8-12 hours frequently shows a change from neutrophil to lymphocyte predominance, with the remainder taking place in 24-48 hours
Enterovirus, mumps, herpes simplex and lymphocytic choriomeningitis virus may have a mildly decreased glucose initially
Low glucose levels and a lymphocytic pleocytosis should suggest the presence of fungal, listerial, or tuberculous meningitis

CSF Culture for viruses can be done, but results may not be available for days or more

At least 2 ml of CSF should be obtained and transported to the microbiology lab quickly and processed in less than 24 hours
Viruses are unstable and will lose infectivity if stored in a freezer at –20° C, but may be stored at –70° C

Nucleic acid amplification of viral specific DNA or RNA from CSF using PCR may be done, especially looking for HSV-1, CMV and in picornavirus (coxsackie, polio, echo and enterovirus) it is the diagnostic procedure of choice

Other tests to consider include the following:

CBC with differential, Chem-7, LFT’s, CK, aldolase, amylase, lipase
MRI, CT, EEG, EMG, nerve conduction studies are generally not necessary

Differential Diagnosis for viral meningitis should include

Parameningeal infections or partially treated bacterial meningitis
Nonviral infectious meningitides where cultures may be negative – fungal, TB, parasitic, syphilitic disease
Pathogens that may clinically resemble encephalitis – Listeria, Brucella, Coxiella, Mycoplasma, Rickettsia
Neoplastic meningitis
Noninfectious inflammatory diseases – sarcoid, Behçet’s disease, uveomeningitic syndromes
Enterovirus – most common cause, especially in the summer months and a child <15 years old; look for exanthemata, hand-foot-mouth disease, herpangina, pleurodynia, myopericarditis and hemorrhagic conjunctiva on physical exam; PCR is diagnostic procedure of choice
Mumps – usually occurs late winter or early spring; 3:1 male:female ratio; may be associated with orchitis, oophoritis, parotitis or pancreatitis, but these findings are neither specific nor sensitive; 25% of cases may have PMN pleocytosis in CSF
LCMV – especially if in late fall or winter and there is a history of exposure to rodents (e.g. mice, hamsters) or their excreta; physical and laboratory exam may show rash, alopecia, parotitis, orchitis, myopericarditis, pulmonary infiltrates, leukopenia, thrombocytopenia or abnormal LFT’s
HSV-2 – affects ~35% of women and ~11% of men at the time of an initial episode of genital herpes; 20% will have recurrent attacks of meningitis during which cultures are invariably negative
EBV – patients may or may not have evidence of infectious mononucleosis syndrome; CSF may show atypical lymphocytes
VZV – should be suspected if concurrent chicken pox or shingles; patients may develop acute cerebellar ataxia, especially children
Arbovirus – typically occurs in summer months, has a geographic localization and occurs in epidemics; reflecting the transmission through insect vectors; history of tick exposure in the appropriate geographic area should suggest Colorado tick fever or Powassan virus infection
HIV – 5-10% of cases of primary exposure; cranial nerve palsies (especially V, VII and VIII) more common than other viruses

Treatment:

Symptomatic, hospitalization is often not required except in patients with deficient humoral immunity, neonates with overwhelming infection and patients in whom the clinical or CSF profile suggests the possibility of bacterial or non-viral causes
If bacterial meningitis is a possibility, then give empiric antibiotics pending culture results

Ceftriazone 2 g IV q12° or Cefotaxime 2 g IV q4°
Add Vancomycin if pneumococcal penicillin resistance is >5%
Could try acyclovir for HSV-1 or HSV-2, or severe EBV or VZV infections or antiretrovirals for HIV

Watch for hyponatremia as a consequence of SIADH

Prognosis is generally excellent in adults although rarely patients may have persisting headache, mild mental impairment, incoordination, or generalized asthesia for weeks to months

CSF Evaluation

Pressure - Normal pressure is 10-20 cm H₂0 and it varies directly with venous pressure.

Elevation is due to increased intracranial pressure

Meningitis and Subarachnoid hemorrhage (SAH) are most common causes

Tumors and abscesses will increase pressure, but only after a variable period of days to weeks

Appearance - Normal is clear and colorless

Anything else is abnormal
Pink or red – many RBC’s
White and cloudy – many WBC’s (usually >400) or high protein content
Xanthochromia (yellowish color) – hemoglobin pigment from lysed RBC’s, protein levels > 150 may give faint yellowish color, jaundice

Glucose - Normal is about 60% of the serum glucose (about 45 mg/100 ml) or higher. It takes about 30 minutes to 2 hours for maximal changes in the CSF values after changing the serum level. Levels of 40-45 are equivocal.

Decreased levels (May be masked in diabetics or if IV glucose therapy is being given)

Classically meningitis from standard bacteria, tuberculosis and fungi

Hypoglycemia

Extensive meninges involvement by metastatic carcinoma

Protein - Normal is 15-45 mg/ 100 ml

Increased

Leukocytosis – Protein increases roughly proportionately to degree of leukocytosis

With a slight leukocytosis – Cerebral trauma, brain or spinal cord tumor, brain abscess, cerebral infarct or hemorrhage, CNS sarcoidosis, systemic lupus, lead encephalopathy, uremia, myxedema, multiple sclerosis, various hereditary neuropathies, chronic CNS infections, diabetic peripheral neuropathy

Blood – Introduces approximately 1 mg of protein / 1000 RBC’s and protein level may appear disproportionate with lysis of RBC’s

Markedly increased – Albuminocytologic dissociation

Guillain-Barre syndrome – 20% of patients have normal CSF protein levels, 25% have >200
Temporal arteritis

Increased gamma globulins

Multiple sclerosis

Cell Count - Normal is up to 5 cells / mm³, almost all of which are lymphocytes

Leukocytosis

Can result from any condition affecting the meninges. Degree depends on type of irritation, duration and intensity – highest counts in acute meningeal infections

PMN’s – generally predominate in bacterial infections

Lymphocytes or mononuclear cells – generally predominate in viral, CNS diseases, tertiary syphilis, TB
Eosinophils – always abnormal! and suggest parasitic infection

SAH or traumatic tap – approximately 1 WBC is added for every 1000 RBC’s

RBC’s

Normal is <10/mm³
Up to 100/mm³ and otherwise unexplained may be due to a traumatic tap
Increased – HSV encephalitis, SAH

Gram Stain and Culture

Gram stain is only ~70% sensitive but should be done in all cases in which bacterial meningitis is suspected

Culture suspected to detect 85% (54-100%) of cases of bacterial meningitis

Previous or concurrent antibiotic use decreases detection rates by 20% on Gram stain and 30% on culture

Disease	Pressure (mm H20)	Total WBC’s (cells / mm³)	Predominant Cell Type	Protein (mg / 100 ml)	Glucose (mg / 100 ml)
Normal	50 – 200	<5	Mononuclear	15 - 45	45 - 80
Acute Bacterial Meningitis	(/Nl)	>5 - >60000	PMN’s	100 - 500	5 - 40
Amebic Meningoencephalitis	/ (Nl)	>400 – 20000	PMN’s		¯ - Nl
Early Leptospira Meningitis			PMN’s		¯ - Nl
Brain Abscess	(/Nl)	>5 – 1000	Lymphocytes and PMN’s	Nl -	Nl
Early Coxsackievirus and Echovirus	Nl (/ )	>5	PMN’s	Nl -	Nl
Tuberculous Meningitis	(/Nl)	25 – 500	Lymphocytes	100 - 200	<45
Cryptococcal Meningitis	/ Nl	>5 – 800	Lymphocytes	20 - 500	~30
Meningeal Carcinomatosis	Nl -	>5 – 1000	Lymphocytes	Up to 500	¯ - Nl
Sarcoid	Nl to	0 - <100	Mononuclear	Slight	¯
Listeria			Lymphocytic		¯
Viral Meningitis	Nl to	>5 – 1000	Lymphocytes	Nl - <100	Nl
Syphilis	(/Nl)	~500	Lymphocytes	~100	Nl
Lead Encephalopathy		0 – 1000’s	Mononuclear	Nl to	Nl
Brain tumor	Nl to	>5 – 200	Mononuclear	up to 500	Nl - ¯¯
Cysticercosis		>5	Mononuclear 2-7% Eosino.	50 - 200	¯ in 20%
Sarcoid	Nl to	0 - <100	Mononuclear	Slight	¯
Brain tumor	Nl to	>5 – 200	Mononuclear	up to 500	Nl - ¯¯
Subarachnoid Hemorrhage	(/Nl)	Same as blood	Same as blood	(up to 2000)	Nl
Multiple Sclerosis		>5 in 30%	Mononuclear	in 25% cases
Lead Encephalopathy		0 – 1000’s	Mononuclear	Nl to	Nl
Cerebral Thrombosis	Nl (/ )	0 - <50		Nl - <100	Nl