Table of Contents
Gold Standard Cerebrospinal Fluid Examination
Meningitis is defined as the infection and subsequent inflammation of the leptomeninges.
The various types of meningitis can be classified based on the cause of the infection:
- Bacterial meningitis: This is the most common cause of meningitis. It is a common disease in the developing world.
- Viral causes of CNS infections: This includes the herpes and varicella viruses. Encephalitis is also caused by viruses.
- Parasitic causes: These are very rare due to high hygiene standards. They have been associated with immunosuppression.
The main reason for classification according to etiology is to:
- Differentiate the pathogen classes and thus determine the accurate therapeutic approach; and
- To more easily diagnose meningitis in the future.
Treatment with antibiotics should only be considered if a bacterial central nervous system (CNS) infection is suspected!
The gold standard for the diagnosis of meningitis is a lumbar puncture with cerebrospinal fluid (CSF) examination for certain parameters. The following aspects are examined in the CSF:
- Cell count and cell differentiation
- Glucose and protein
- Microbiologic pathogen detection: direct pathogen detection with microscopy, polymerase chain reaction (PCR), antigen detection and cultivation, and indirect pathogen detection with intrathecal production of antibodies against pathogens
Overview of typical CSF findings in CNS infections
|Bacterial meningitis||Often > 1,000 cells/µL, dominantly granulocytic||↑ (100—200 mg/dL)||↓ CSF/serum glucose ratio < 0.3||↑|
|Tubercular meningitis||50–400 cells/µL, first granulocytes, later lymphocytes and monocytes||↑↑ (100—500 mg/dL)||↓ CSF/serum glucose ratio < 0.5||↑↑|
|Viral meningitis||< 1,000 cells/µL, dominantly lymphocytic||↑ (e.g., 50—150 mg/dL)||↔||Normal|
CSF/serum glucose ratio
The CSF/serum glucose ratio is a measurement of the glucose in the CSF compared with the blood glucose level.
Table: A. Bender et al. (2013). Mediscript Neurology. Elsevier. p. 191, Tab. 7.2.
Bacterial Infections of the Central Nervous System
Acute bacterial meningitis
Epidemiology of bacterial meningitis
In acute bacterial meningitis, the meninges and the subarachnoid cavity are infected. In Europe, the incidence is 2–6 cases per 100,000 people. The disease is significantly more frequent in the meningismus belt in the sub-Saharan regions of Africa. Empiric antibiotic therapy is administered based on the age-specific pathogens associated with the disease.
- Newborns: Enterobacteriaceae, Streptococcus pneumoniae, Listeria monocytogenes ⇒ Therapy: cefuroxime and ampicillin
- Children: Streptococcus pneumoniae, Neisseria meningitidis ⇒ Therapy: ceftriaxone
- Adults: Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes (in > 50-year-olds) ⇒ Therapy: ceftriaxone and ampicillin
Clinical picture of bacterial meningitis
Cardinal symptoms: headache, neck stiffness, fever, and decrease in vigilance (the symptoms do not always occur in this combination!)
Also, patients often present with the following symptoms: nausea, vomiting, vertigo, and photophobia. One-third of the patients display focal neurologic deficits such as cranial nerve palsies (mostly cranial nerves 3 and 6), sensitivity impairments and speech disorders; one-tenth also present with cranial nerve damage. Kerning’s sign and Brudzinski’s sign can be positive (see the article on neurologic examination). In infections with Neisseria, bleeding of the skin is possible in the context of Waterhouse-Friderichsen syndrome.
Diagnosis of bacterial meningitis
CSF examination: The diagnosis is based on the examination of the CSF. The pathogens in the CSF can be detected using the Gram stain, CSF cultures, antigen quick tests, PCR, and blood cultures. Cases of acute bacterial meningitis produce the following picture (before treatment):
- More than 1,000 cells/µL, granulocytes dominate
- Protein and albumin ↑
- Glucose ↓, CSF/serum glucose ratio < 0.3
- Lactate ↑
Blood: The differential blood count mostly shows leukocytosis with left shift, C-reactive protein (CRP) ↑ , and procalcitonin ↑.
Imaging: The CT of the skull reveals the following:
- Signs of increased cranial pressure as a result of diffuse brain edema or hydrocephalus
- Changes in density due to accumulations of purulence in the ventricles
- Inflammatory foci in the paranasal sinus and the mastoid
Treatment of bacterial meningitis
Important: Antibiotic therapy should start as soon as possible! The antibiotic therapy should—if possible—be started within 60 minutes after hospitalization.
Waiting for labs leads to a worse prognosis, so antibiotic therapy is initiated before final pathogen detection according to the age-specific pathogens associated with the disease (see Epidemiology above). Once the pathogen has been detected, antibiotic therapy can be adjusted. Of course, blood cultures should be taken BEFORE starting antibiotic therapy!
For adults with pneumococcal meningitis, adjuvant therapy with dexamethasone is currently (as of 2019) suggested. Studies show reduced mortality rates as well as a decrease in adverse effects such as hearing impairment.
Prognosis of bacterial meningitis
Bacterial meningitis is associated with high mortality rates. Twenty percent of all patients die of infections caused by the pathogens Pneumococci and Listeria. In acute bacterial meningitis caused by S. aureus, the mortality rates can be as high as 20–40%. Possible adverse effects are, among others, hearing impairment, neuropsychologic deficits, hemiparesis, epileptic seizures, and cranial nerve palsies.
Features of meningococcal meningitis
N. meningitidis is transmitted via droplet infection. In suspicious cases, the affected patients must be isolated until 24 hours after the start of antibiotic therapy. People who have had contact with the infected patients should be given post-exposure prophylaxis consisting of rifampicin and ciprofloxacin/or ceftriaxone.
Meningococcal meningitis is subject to mandatory reporting at the public health department.
Epidemiology of tubercular meningitis
The pathogens responsible for tubercular meningitis are mycobacteria of the Mycobacterium tuberculosis complex. This subacutely or chronically proceeding disease often presents as basal meningitis (infectious reaction is focalized to the basal cerebral areas, especially the brainstem).
Statistics for active tuberculosis:
- Tuberculosis is one of the top ten causes of death worldwide.
- In 2018, an estimated 10 million people were affected by tuberculosis.
Clinical presentation of tubercular meningitis
The clinical symptoms of tubercular meningitis are primarily fever, meningismus, headaches, nausea, and vomiting. In 50% of the patients, cranial nerve palsies, disorders in vigilance, and confusion syndromes occur. If encephalitis or tuberculomas occur, epileptic seizures are also possible.
Diagnosis of tubercular meningitis
CSF examination: Pleocytosis with 50–400 cells/µL, protein ↑↑, glucose ↓ (CSF/serum glucose ratio < 0.5), and lactate ↑.
Interferon-γ release assays: These assays measure the T cell release of interferon-γ, after being stimulated by antigens specific to tuberculosis.
Microbiology: When pathogen detection in CSF is performed with the Ziehl-Neelsen stain, Auramine stain, PCR, and cultures, acid-fast rods can be found. Do not wait until the final pathogen detection before beginning therapy (as with acute bacterial meningitis)!
Imaging: Cerebral changes in tuberculosis are often visible in magnetic resonance imaging (MRI) or computed tomography (CT) scans.
- Basal contrast agent accumulation
- Masses of CNS tuberculomas
- Ischemic infarction in cases of associated vasculitis
Treatment of tubercular meningitis
Anti-tuberculosis medications are administered in the following phases:
An intensive phase:
This is a four-fold-combination used as standard therapy that includes isoniazid, rifampicin, pyrazinamide, and ethambutol. The drugs are administered under direct supervision for compliance.
Dexamethasone is administered before or in combination with the initial dose. It has been shown to reduce mortality if properly administered as per the guidelines.
Rifampicin and isoniazid are continued for 6 more months and the cure must be confirmed before withdrawing the drugs.
|Medication||Duration of application||Side effects|
|Isoniazid||2 months initially and an additional 10 months (stabilization phase)||Hepatotoxicity, polyneuropathy (prophylaxis pyridoxine)|
|Rifampicin||2 months initially and an additional 10 months (stabilization phase)||Hepatotoxicity|
|Pyrazinamide||2 months initially||Hepatotoxicity|
|Ethambutol||2 months initially||Impaired vision (regular ophthalmologic controls are necessary)|
|Streptomycin||2 months initially||Ototoxicity|
Prognosis of tubercular meningitis
If no antibiotic therapy is administered, tubercular meningitis can be fatal. If appropriate treatment is administered, the mortality rate is reduced by roughly 20%. Approximately 30% of the affected people present with accompanying symptoms such as hydrocephalus, organic brain syndrome, cranial nerve palsies, ataxia, and epileptic seizures.
Etiology of brain abscesses
A brain abscess is a bacterial infection of the brain.
Brain abscesses can form in multiple ways: via the transmission of meningeal foci, via hematogenic transmission, and through iatrogenic causes during surgical interventions. The pathogens responsible are mostly streptococci, anaerobics, Gram-negative enterobacteria, Pseudomonas, and S. aureus. Fungi and parasites may also be responsible for immune deficiency–related abscesses.
Clinical presentation of brain abscesses
There is a broad variety of symptoms that can develop over the course of days or weeks. These include the following:
- Nausea and vomiting
- Epileptic seizures
- Neurologic examination: vigilance impairments and meningismus
Diagnosis of brain abscesses
Laboratory, microbiology, and imaging procedures: Among laboratory parameters, CRP is mostly increased. CSF examination is not necessary because the findings are too vague. It is extremely important to examine the abscess material via bacterial cultivation, PCR, and tests for fungi and mycobacteria.
Treatment of brain abscesses
|The three pillars of brain abscess therapy|
|Surgical removal of purulence
Computerized axial tomography (CAT)/MRI-controlled stereotactic aspiration
Goal: reduction of the mass and gain of material for microbiologic diagnostics
If necessary, excision of foreign bodies and division of abscesses
Before pathogen detection, empiric three-fold therapy:
⇒ Adjustment according to the antibiogram
|Elimination of the infectious foci
Thorough search for the focus (is the focus located distally?) with surgical elimination if needed
Prognosis of brain abscesses
With timely and appropriate therapy, the mortality is < 10%.
Epidemiology of neuroborreliosis
Neuroborreliosis is triggered by the bacterium Borrelia burgdorferi, which is transmitted by ticks. The incidence of this disease is 50–100 cases per 100,000 people. The regional dissemination of infected ticks is very different and should be taken into account for diagnosis.
Clinical features of neuroborreliosis
The symptoms of neuroborreliosis typically proceed in three stages:
Stage 1: Formation of erythema migrans—circularly limited skin reddening that mostly develops approximately 2 weeks after the tick bite. Only half of the patients who reach stage 2 present with erythema migrans.
Stage 2: Meningoradiculitis—searing, radicular pain (Bannwarth syndrome), partially radicular palsies, and palsy of the facial nerve. Joint involvement, myocarditis, pericarditis, and lymphadenosis cutis benigna are also possible.
Stage 3: Detection of antibodies against B. burgdorferi in the enzyme immune assay. The detection of antibodies must occur in both the serum and the CSF. Antibodies are not suitable for therapy assessment. The antibodies can circulate in the CSF over the course of months to years after successful antibiotic therapy.
Treatment of neuroborreliosis
Erythema migrans is treated with an oral 14-day antibiotic therapy of amoxicillin, cefuroxime, doxycycline, or penicillin. If neuroborreliosis has reached stage 2 or 3, oral therapy should be administered with doxycycline over 14 days. The alternative is intravenous (IV) treatment with ceftriaxone, cefotaxime, or penicillin.
Prophylaxis of neuroborreliosis
If a tick is removed within the first 12 hours after the bite, the risk of borrelia infection is decreased. There is no vaccination against borrelia.
The most common viruses that cause CNS infection are herpes simplex virus (HSV), varicella zoster virus (VZV), human immunodeficiency virus (HIV), Epstein-Barr virus (EBV), and enteroviruses.
Herpes simplex encephalitis
Epidemiology of herpes simplex encephalitis
Herpes simplex encephalitis is a rare disease, but it has a rapid onset and develops very quickly. It occurs when the herpes simplex virus enters the brain. The incidence of this disease is 1 per 250,000 people.
Clinical features of herpes simplex encephalitis
Besides possible aphasia, ataxia, hemiparesis, cranial nerve palsies, and visual field deficits, these are the most common cardinal symptoms of herpes simplex encephalitis:
- High fever
- Personality changes
- Epileptic seizures in 60% of the patients
- NO meningismus
Diagnosis of herpes simplex encephalitis
CSF: CSF findings mostly show a typical pattern of lymphomonocytic pleocytosis, elevated protein and albumin, and non-decreased glucose (see above table concerning typical CSF findings in bacteria and viruses).
Microbiology: Herpes simplex virus (HSV) DNA is detected in the CSF using a PCR assay.
Imaging procedures and EEG: In most cases, the temporal lobe is affected. Necrosis and hemorrhages are typical signs. The electroencephalogram (EEG) often shows temporal slowdowns.
Treatment and prognosis of herpes simplex encephalitis
The treatment consists of the IV injection of acyclovir five times a day for 14 days. Despite timely therapy, 20% of all cases result in death. Most survivors have consequential diseases.
Epidemiology of viral meningitis
The incidence of viral meningitis is 6–10 per 100,000 people. Enteroviruses are the most common causative pathogens, accounting for around 85% of all cases of viral meningitis. Human herpesvirus-6 (HHV-6), VZV, measles viruses, mumps viruses, and EBV should also are also associated with viral meningitis.
Clinical features of viral meningitis
Viral meningitis causes the typical picture of a meningitic disease: fever, neck stiffness, and headache. Often, patients also display flu-like symptoms.
Diagnosis and therapy of viral meningitis
The CSF findings show the typical picture for viruses, with elevated protein and non-decreased glucose levels. PCR and indirect serologic pathogen detection are used for the microbiologic analysis.
If viral meningitis is caused by VZV or HSV, treatment with acyclovir is reasonable. If, however, enteroviruses are the cause, only symptomatic treatment is recommended.
Herpes zoster: shingles
Etiology of herpes zoster
If a past VZV infection (chickenpox) is reactivated, herpes zoster develops. This is often an expression of immunodeficiency. However, herpes zoster may also occur in immunocompetent people.
Typically, after a painful phase, skin reddening with blister formation occurs over the dermatome of a nerve root. It is especially severe if the infection develops in the facial dermatomes, where it is classified as herpes zoster oticus and herpes zoster opthalmicus. A frequent complication is post-herpetic neuralgia that is accompanied by pain and allodynia.
Diagnosis and therapy of herpes zoster
The diagnosis of herpes zoster is most often made on the basis of the dermatologic picture. Rarely, pathogen detection with blister secretion and biopsy material is used.
The virostatics acyclovir, brivudin, or famciclovir can be used orally for the treatment of uncomplicated herpes zoster. In severe cases, IV therapy is indicated.
Early summer meningoencephalitis (ESME)
Etiology of ESME
ESME is actuated by the flavivirus, which is—like borrelia—transmitted by ticks.
Clinical features of ESME
ESME proceeds in two phases:
- Phase 1: 8–10 days after the infection; the patient has flu-like symptoms
- Phase 2: 1-week fever-free interval, then vigilance disorders, confusion syndrome, stance and gait ataxia, intention tremor, and extrapyramidal symptoms
Diagnosis, treatment, and prevention of ESME
Typical clinical features for ESME are: CSF syndrome with lymphocytic pleocytosis, blood-liquor barrier disorders, positive detection of ESME-immunoglobulin M (IgM) and immunoglobulin G (IgG)-antibodies, and intrathecal ESME-specific antibody production 2 weeks after disease onset.
In ESME, only symptomatic treatment is recommended. People living and working in high-risk areas should be vaccinated.
Progressive multifocal leukoencephalopathy (PML)
Etiology of PML
The pathogen responsible for PML is the John Cunningham (JC) virus, which leads to demyelination of white matter in infected areas. Mostly, the disease occurs due to immunodeficiency, such as T cell defects. While it almost exclusively affected HIV-patients in the past, PML now also frequently affects people who are immunosuppressed due to multiple sclerosis.
Clinical features of PML
Depending on the localization of the demyelination focus, symptoms such as behavioral problems, cognitive deficits, palsies, visual impairments, vigilance disorders, and speech disorders can be observed.
Diagnosis and treatment of PML
The JC virus can be detected in the CSF via PCR. In the MRI scan, the typical signs of PML are confluent demyelination foci without contrast agent accumulation.
Only an improvement of immunocompetence is possible with the available treatments. Antiviral therapy does not (yet) exist. Affected patients with PML do not have a good prognosis: Often, patients die within 2 years.
Cytomegalovirus (CMV) infection
CMV infection occurs in HIV-infected patients with very severe immunosuppression. In imaging procedures, the infection shows micronodular changes in the brain and/or hydrocephalus. The viruses can be detected in CSF using PCR. Ganciclovir is used for therapy.
Protozoan and Fungal Infections of the CNS: Facts Overview
The following overview allows quick access to facts concerning the most important CNS diseases caused by protozoa and fungi.
|Etiology||AIDS-defining disease, parasite: Toxoplasma gondii||AIDS-defining disease, fungal infection, especially with Cryptococcus neoformans||Mold fungus infection with Aspergillus fumigatus, does not occur without severe immunosuppression||Consumption of contaminated meat and infection with eggs of tapeworm Taenia solium; causes cysts in the brain|
|Clinic||Personality change, palsy sensations, sensibility disorders, visual impairments (toxoplasmosis-choriorenitis), speech disorders, epileptic seizures, and headaches||Meningoencephalitis with headaches, fever and vigilance disorders, focal neurologic deficits such as palsies, sensibility disorders, and visual impairments||Depending on the location of the manifestation, frequent affliction of the lung and the paranasal sinuses: dyspnea, hemoptysis, sinusitis, lung infiltration, and bronchial asthma||Depending on the location of the cysts: often epileptic seizures|
|Diagnosis||Imaging: multiple circular contrast agent accumulating lesions
Laboratory: antibodies for toxoplasmosis
|Imaging: inconspicuous MRI, germ detection in tusche specimen, with PCR, cultures, positive antigen detection in blood and CSF||Imaging: abscess in the brain, ischemic and hemorrhagic infarctions Laboratory: Aspergillus antigen in blood and CSF, cultures, and PCR, histologic detection in biopsy material||Imaging: detection of cerebral cysts and detection of the head of the worm (scolex) Laboratory: Intermittent eosinophilia is frequent.|
|Therapy||Sulfadiazine or clindamycin and pyrimethamine for at least 4 weeks, then reduced dose for 6 months||Amphothericin B and fluconazole for 6 weeks, then continuation therapy with fluconazole||Voriconazole prognosis: Mortality rate is high in invasive CNS aspergillosis.||Praziquantel (stationary due to edema formation); surgical, if cysts are operable|
Opportunistic Infection in Patients with HIV/AIDS
Immunosuppression in AIDS patients leads to several diseases that manifest in the CNS. Mostly, the diagnosis of AIDS is made on the basis of so-called AIDS-defining diseases. They occur if CD4 cells drop to certain levels.
- CNS: toxoplasmosis (at < 100/µL)
- Primary CNS: lymphomas (no limit)
- Cerebral Cryptococcus infections (at < 100/µL)
- CNS: tuberculosis (no limit)
- CMV: encephalitis (at < 50/µL)
- PML (at < 250/µL)