Infections of the Central Nervous System

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I. Case presentation

A. Questions

1. What are two possible mechanisms of the patient's headache?
2. How might the patient's increased intracranial pressure be treated?
3. What is the possible significance of the patient's episodes of loss of consciousness?
4. What is the most common fungal infection of the CNS?
5. What antibiotic treatments are used for cryptococcal meningitis?
6. What illnesses or therapies predispose to cryptococcal meningitis?

B. Case notes

(2) Headache symptoms
Migraine headache is the most common type of headache for which patients seek medical treatment. Diagnosis is purely clinical--there is no laboratory test. Migraine headache is more common in women than in men, and there is often a family history of migraine. The essential symptoms of migraine headache are severe, throbbing headache with nausea. Other common symptoms include unilateral headache, photophobia, and phonophobia. The patient usually wants to lie down in a dark room, and if she can go to sleep, feels better on awakening.
    In migraine with aura the headache is preceded by visual symptoms. This may be as nondescript as vague black spots, or as dramatic as  "scintillating scotoma" or "fortification spectra"--brightly colored images with jagged lines. When clearly present, visual symptoms are invaluable for diagnosing migraine.
    Cluster headache is less common. The pain is nonthrobbing, unilateral, and retroorbital. An individual headache is brief, but recurs frequently, and the pain is said to be the most intense of all headache pain.
    Tension headache is very common, but not usually a cause for visits to the doctor's office. The pain is moderate, usually non-throbbing, and tends to be localized to the neck, occiput, and temples.
    Headache pain due to serious causes is variable. Most patients with intracranial neoplasm have a mild headache, not usually severe enough to seek medical attention. When present, it has symptoms reminiscent of tension headache, but it may worsen at night and awaken the patient from sleep. Patients with subarachnoid hemorrhage have a severe headache of sudden onset, often associated with temporary confusion and meningismus. Patients with bacterial meningitis often have a migraine-like headache with severe throbbing, nausea, and photophobia. Headache in pseudotumor cerebri is variable, but may have migraine-like qualities, and is often associated with transient blurring of vision that can, to the unwary, suggest migraine.

(3) Impaired consciousness
Sudden onset of impaired or loss of consciousness has two main causes: syncope and seizure.
    Syncope due to fall in blood pressure is most common. It may be preceded by a feeling of lightheadedness, as in orthostatic hypotension, vasovagal syncope, or vasodepressor syncope, or there may be no warning at all, as in sudden ventricular fibrillation. Onset in vasovagal or vasodepressor syncope is usually slow, and the patient may be able to remember the characteristic symptoms of lightheadedness followed by blindness prior to loss of consciousness. When consciousness is lost the patient collapses and falls. Usually there is quick recovery once the patient is recumbent, and there is no post-syncope confusion.
    The cause of loss of consciousness in syncope is global cerebral hypoperfusion--blood pressure drops, so the entire brain becomes ischemic for a brief time. Syncope is not due to primary brain disease, but if the hypoperfusion is prolonged for more than two minutes irreversible brain damage begins to occur.
    Seizure is also common. A generalized tonic-clonic convulsion is usually easy to diagnose from the history. A complex partial seizure is more difficult to diagnose. There often is a sudden alteration of consciousness, unresponsiveness, often with purposeless repetitive behaviors, followed by postictal confusion.
    Seizures are caused by the sudden onset of paroxysmal synchronous firing of neurons. Generalized seizures can be a symptom of a metabolic abnormality that only secondarily affects brain. Partial-onset seizures strongly suggest a specific abnormality of cerebral cortex.
    Increased intracranial pressure can cause syncope if the increase is large and sudden. Acute hydrocephalus, such as may occur with shunt malfunction or intermittent obstruction of the third cerebral ventricle due to "ball valve" tumors, may cause this. Loss of consciousness occurs in subarachnoid hemorrhage due to berry aneurysm because aneurysmal rupture causes intracranial pressure to temporarily equal arterial pressure, thereby reducing cerebral perfusion pressure to zero.

(4) Papilledema and increased intracranial pressure
The rigid skull makes the volume of the intracranial space constant. The major intracranial contents are:

1. Brain parenchyma
2. Cerebral spinal fluid
3. Blood, venous and arterial

1. Bulging fontanelle (infants)
2. Large head (infants)
3. Nausea
4. Projectile vomiting
5. Headache
6. Reduced retinal venous pulsations
7. Papilledema
8. Cranial nerve VI palsy
9. Bradycardia (severe cases)

Figure 1. Venous pulsations

    Venous engorgement and loss of pulsations occur because the central retinal vein drains into the cerebral circulation, so its pressure increases when ICP increases.
    Papilledema implies swelling of the optic disk. Features to look for with the direct ophthalmoscope are:

1. Blurring of the optic disk margins, especially the nasal margin
   
2. Loss of the optic cup
3. Engorgement of retinal veins
4. Obscuration of vessels passing through the disk margin
   
5. Flame-shaped hemorrhages in the nerve fiber layer

Figure 2. Normal optic disk	Figure 3. Papilledema

Figure 4. Cranial nerve VI	Figure 5. Bilateral VIth nerve palsies

C. More cases

1. Case 2: an infant with fever
2. Case 3: a man with headache

II. Syndromes of CNS infection, causes and treatment

A. Terminology

B. Acute bacterial (septic) meningitis

Signs and symptoms

• Headache
• Fever
• Meningismus
• Obtundation

Early in the course of the illness, the patient with a purely meningeal infection will be awake, and painfully aware of his symptoms, so you may simply ask him about them. Later in the illness, if untreated, the meningeal inflammation will have led to diffuse brain dysfunction, ischemia or infarction, and the patient will be stuporous.
    The classic signs of meningeal infection are fever, stiff neck (meningismus), and headache. Although characteristic of meningitis, headache and meningismus may occur in other infections, such as pneumonia. Photophobia, nausea, vomiting, malaise and lethargy are common. The latter are also common in "functional" headaches like migraine, and may confuse the unwary physician.

Meningeal signs

Diagnosis

1. Suspicious clinical symptoms and signs.
2. CT of head to rule out abscess or other space-occupying lesion, if it can be done quickly.
3. Lumbar puncture (see below).
4. Blood cultures.

Causes and therapy

• S. pneumoniae
• H. influenzae
• L. monocytogenes
• Group B streptococcus
• N. meningitidis

    Treatment and prevention
For many years, S. pneumoniae was reliably sensitive to penicillin. Meningitis caused by these strains responds to meningitis doses of penicillin, ampicillin, cefotaxime, or ceftriaxone.
    In recent years, penicillin-resistant strains have become common, and these constitute about 30% of cases in Springfield, Illinois. For the most part these strains remain susceptible to the third generation cephalosporins ceftriaxone and cefotaxime, which enter CSF in good concentrations [25]. For meningitis, a third-generation cephalosporin plus vancomycin is usually recommended for intial therapy until culture and sensitivity is available. No vancomycin-resistant strains have yet been documented, but vancomycin is not used alone because of its poor penetration into the CSF. There is some concern that dexamethasone may reduce blood brain barrier permeability to antibiotics. Because the organism is sensitive to rifampin, which easily passes the blood brain barrier, the addition of rifampin has been suggested [24].
    Like pneumococcal pneumonia, meningitis can be prevented with pneumococcal conjugate vaccine. In 2000, routine vaccination of children with pneumococcal vaccine was begin, but data are not yet available regarding changes in meningitis incidence. 

Hemophilus influenzae
H. influenzae is a small (1-2 micrometer diameter) Gram-negative coccobacillus (Click for micrograph [89k]). Strains causing meningitis in children almost all have an outer capsule, but non-meningitis-causing strains do not.
    The organism colonizes the upper respiratory tract of humans, who are its only natural host. Spread occurs through respiratory droplets or by direct contact with respiratory secretions. Risk factors for meningitis include head trauma, neurosurgery, paranasal sinusitis, otitis media and CSF leak.
    The case fatality rate for meningitis is approximately 6% [1] in children, higher in adults.

    Treatment and prevention
H. influenzae meningitis can be prevented by vaccination. Since the widespread use of H. influenzae conjugate vaccine in the 1990s, the incidence of H. influenzae meningitis has declined dramatically, with more than a 90% decline among children under 5 years old [2,3,4,1]. As with S. pneumoniae, beta-lactam and ampicillin-resistant strains are increasingly found, but resistance to ceftriaxone or cefotaxime are rare, and these are the drugs of choice.
    Rifampin is used for prophylactic chemotherapy to prevent secondary cases.

Listeria monocytogenes
Listeria monocytogenes is a facultatively anaerobic Gram-positive rod (Click for micrograph [137k]). The organism can be found in human feces, unpasteurized milk, cheeses, and other foods. Most cases are sporadic, and contaminated food is the source of infection. It may be difficult to diagnose clinically, because compared to other meningitides meningeal signs are less frequent, there is a lower CSF WBC count, less neutrophilic predominance, and lower protein [5,6]. Cranial nerve dysfunction may occur, and there are occasional cases of brainstem encephalitis [26].
    Listeria monocytogenes is a common cause of meningitis in infants less than 1 month old, and is also common in adults greater than 60 years old. Risk factors include pregnancy, advanced age, and immunosuppression. The case fatality rate for L. monocytogenes meningitis is 15% [1].

    Treatment and prevention
Listeria monocytogenes remains sensitive to penicillins, and ampicillin is the antibiotic of choice, but treatment must be prolonged--3 or 4 weeks. Trimethoprim-sulfamethoxasole is an alternative for the penicillin-allergic patient.
    Listeriosis results from food-borne transmission, so proper food handling measures markedly reduces infection risk.

Group B streptococcus
This is the most common meningitis in infants less than 1 month of age (70% of cases) (Click for micrograph [82k]). Transmission to the neonate usually occurs from mothers colonized by group B streptococcus in the genital tract. In adults, group B streptococcal infection is often nosocomial. The case fatality rate is 7%.

    Treatment and prevention
Beta-lactam-resistant strains of group B streptococcus have not emerged. Treatment is with penicillin and ampicillin. Neonatal meningitis can be prevented by therapies aimed at reducing maternal birth canal colonization, or by Caesarian section.

Neisseria meningitidis
Neisseria meningitidis is an encapsulated Gram-negative organism that appears in pairs on Gram stain (Click for micrograph [80k]). It commonly colonizes the nasopharynx, and can spread rapidly from person to person through respiratory droplets. N. meningitidis often occurs in epidemics among persons living in close quarters like dormitories or barracks.
    The course of the illness is usually rapid and dramatic. Initial non-specific fever, headache, and myalgia give way to distinctive signs of a petechial rash on the trunk and lower body that may coalesce into purpura [fifteen]. Septic shock, disseminated intravascular coagulation, and distal extremity necrosis may occur in disseminated meningococcemia. Although treatment is effective and the disease usually occurs in immunocompetent patients, nevertheless the case fatality rate is  3% [1] to 13% [five]. It is common to have non-lethal complications such as cutaneous scars, amputation, hearing loss, and renal injury.
    As with other encapsulated organisms, asplenia is a risk factor for infection.

    Treatment and prevention
Penicillin-resistant strains are uncommon, so drugs of choice are penicillin or ampicillin. Ceftriaxone or cefotaxime response is also excellent. A polysaccharide vaccine has been available for a number of years and routinely routinely recommended for all adolescents, such as college freshmen or military recruits. It has also been useful in patients with risk factors such as asplenia. Since 2005 a conjugate vaccine has been available [27], which should now be used instead of the polysaccharide vaccine.
    Close contacts of patients have a significantly increased risk of contracting infection, so antimicrobial prophylaxis is recommended for household members, day care contacts, and others. This should be done within 24 hours after exposure because secondary disease occurs within several days. For prophylaxis, rifampin is given twice daily for two days, but is contraindicated during pregnancy. One dose of ciprofloxacin or ceftriaxone is an alternative, and ceftriaxone can be given to pregnant patients.

Presumptive therapy for bacterial meningitis

(1) Ceftriaxone or cefotaxime
(2) Essential in areas with a high prevalence of penicillin-resistant S. pneumoniae.
(3) For patients with penicillin allergy, trimethoprim-sulfamethoxasole can substitute for ampicillin in treatment of L. monocytogenes.

Pathogen-specific therapy for bacterial meningitis

Adjuvant therapy

Comments

C. Viral meningitis

Signs and symptoms

• Headache
• Fever
• Viral syndrome
• Meningismus

This is the most common kind of meningitis, and the most benign. A systemic viral syndrome may be present, but fever and headache may suggest meningitis. Nuchal rigidity is usually present. It is highly unusual for focal neurologic signs to occur.
 

Diagnosis

Causes and therapy

Comments

D. Chronic meningitis

Signs and symptoms

• Headache
• Fever
• Meningismus
• Confusion
• Hydrocephalus.

Diagnosis

1. This is a difficult diagnosis because signs and symptoms are often non-specific. It can be suspected in any patient with a chronic encephalopathy, or a patient with new onset of hydrocephalus.
2. MRI or CT of head may show hydrocephalus or contrast enhancement of the basal meninges.
3. Lumbar puncture.

Causes

Infectious:

• Cryptococcus neoformans (common!)
• Human immunodeficiency virus (HIV)
• M. tuberculosis
• M. avium
• Treponema pallidum
• Nocardia sp.
• Candida sp.
• Aspergillus sp.
• Taenia solium (cysticercosis)
• Brucellosis
• Toxoplasma gondii

• Neoplasm (esp. breast, lung)
• Neurosarcoidosis
• Behcet's disease
• CNS vasculitis
• Mollaret's meningitis

    Cerebrospinal fluid
The CSF in tuberculous meningitis shows a lymphocytic pleocytosis with elevated protein and reduced glucose. Staining for mycobacteria is positive in 5 to 25%, and culture is positive in approximately 60% of cases. In some cases as many as four CSF examinations may be required to detect the organism, or it may be necessary to sample directly from ventricular fluid. CSF PCR may be useful.
    With treatment, the CSF returns to normal slowly. Glucose is the first to normalize, but it takes at least three weeks, and usually more [8].

    Imaging
Contrast-enhanced CT or MRI scans show a basilar meningitis, with contrast enhancement of the meninges in the suprasellar area, prepontine cistern, or interpeduncular fossa. Obstructive or communicating hydrocephalus may occur.

    Therapy
    Therapy is prolonged--isoniazid, rifampin and pyrazinamide daily for two months, then isoniazid and rifampin daily or twice weekly for four months [9]. Therapy may be even longer in patients who show a slow response.
    There is evidence that corticosteroids improve neurologic outcome [10].

    Prognosis and complications
Death occurs in 25% of cases. Complications of the disease include brain infarction in 25 to 40% due to involvement of perforating vessels at the base of brain. Infarction of the basal ganglia is especially common. Hyponatremia due to hypothalamic involvement may also occur.

Fungal infections
Depending on growth conditions, dimorphic fungi exist in a yeast (unicellular) form or in a filamentous (mold) form. In the filamentous form they have tubular structures called hyphae, which are divided into segments. Some segments have the ability to form spores.
    Most fungal infections begin with inhalation of spores, but may also come from indwelling catheters, mouth or GI tract (Candida), nasal sinuses (Aspergillus sp., Zygomycetes sp.) or skin (sporotrichosis).
    The most common organisms in CNS fungal infections are Cryptococcus neoformans (Click for micrographs [121k and 82k]), Coccidioides immitis, Histoplasma capsulatum, and Blastomycetes dermatididis. The clinical presentation is usually as a subacute or chronic meningitis, but fungal abscesses may also occur and cause focal neurologic signs.
    Risk factors include AIDS (Cryptococcus), organ transplantation  or diabetes (Aspergillus), or indwelling intravascular catheters (Candida). The likelihood of CNS disease is increased in the presence of systemic disease of kidney, lungs, or skin.

    Cerebrospinal fluid
The white blood cell count is usually moderately elevated, with 20 to 1000 cells per cu. mm. Lymphocytes usually predominate. Aspergillus, Blastomycetes, and Zygomycetes may cause a neutrophilic predominance, and Coccidioides may cause eosinophils to occur in the CSF. Special stains for fungi may demonstrate the organism.

    Cryptococcus neoformans, in addition to being the most common fungal meningitis, is the easiest to diagnose in the laboratory.  CSF culture for this organism, although growth is slow, is usually positive. For cryptococcus, a sensitive and specific test to detect capsular antigen is available and can be performed rapidly, so it is quite useful for clinical management. For initial diagnosis, test of the antigen in the CSF is most useful, but serum tests can be useful for following the course of therapy. The India ink test for cryptococcus, although quite specific, is not very sensitive, and no longer routinely performed by some laboratories.
    Antigen tests are not available for other fungi. Antibody tests are available, but immunosuppressed patients may not be able to mount a significant antibody response. PCR is not yet clinically available.

    Diagnosis
With Cryptococcus, diagnosis can usually be made from CSF studies. With other fungi, recovery of the organism from a non-CNS site such as skin, joint fluid, lung lesions, sinuses, bone marrow, urine, or blood is helpful. Often, brain biopsy is required. A diagnosis based on cultures from other body sites must be considered probable rather than definite.

    Treatment
The drug of choice for all fungal meningitides is amphotericin B, but it has several disadvantages. It must be given intravenously rather than PO because of poor gut absorption. It can be given intrathecally, but discomfort and toxicity are considerable with this route. It crosses the blood-brain barrier poorly and the dose that can be given is limited by renal toxicity. Intravenous doses cause a variety of unpleasant side effects including fever, chills, nausea, and vomiting, but adjunctive medications (diphenhydramine, ibuprofen, prochlorperazine) are used to control these symptoms. Life-threatening, but uncommon reactions include anaphylaxis, seizures, and cardiac effects. Drug treatment may have to be halted if rises in serum creatinine indicate renal toxicity. New lipid formulations of amphotericin B may reduce these toxicities.
    Fluconazole is also useful, and it can be given by mouth as well as intravenously, but the cure rate is lower than with amphotericin B. Fluconazole is standard for AIDS patients after a course of amphotericin is finished. Patients with C. neoformans, Candida sp., or Aspergillus sp. may also be given flucytosine, especially if the patient has AIDS.

    Complications
Half or more of patients with fungal meningitis develop complications. Communicating hydrocephalus is common (5  to 10% with cryptococcal meningitis), and may result either from blockage of CSF flow within the basal cisterns, or in the arachnoid villi of the sagittal sinus. Arachnoiditis can cause obstructive hydrocephalus by blocking outflow from the IVth ventricle. Stroke, cranial nerve palsies, seizures, and encephalopathy can also occur.

Other causes of chronic meningitis

•  Syphilis.  Caused by a spirochete, Treponema pallidum, CNS syphilis is a very rare cause of meningitis in the penicillin era. If CNS syphilis is a concern, a CSF VDRL should be checked.
• Lyme disease.  Lyme disease is rare in central Illinois, and Lyme meningitis or encephalitis is even rarer.
• Cysticerchosis.  A parasitic infection of brain, this is the most common cause of epilepsy worldwide, but is rather rare in the U.S. The diagnosis is usually first suspected when multiple cysticerci are detected on brain imaging studies.
• Carcinomatous meningitis.  This is associated with neoplasm such as breast cancer or lung cancer. It is uncommon, but not rare. Diagnosis requires a high index of suspicion, and is confirmed by finding malignant cells in CSF with cytologic examination.

E. Encephalitis

Symptoms and signs

• Confusion
• Personality change
• Altered mental status
• Fever
• Seizures

Diagnosis

1. History and physical
2. Brain imaging to rule out space occupying lesion
3. Lumbar puncture
4. Culture of CSF (some organisms)
5. Acute and convalescent titers of antibody
6. PCR of CSF for Herpes encephalitits
7. Brain biopsy in exceptional cases

Causes

• Herpes simplex viruses
• Varicella zoster virus
• Human immunodeficiency virus
• Rabies virus
• Many others

    Diagnosis
MRI of the head shows T2-bright lesions in the medial and inferior temporal lobes. EEG may show nonspecific slowing, or may show periodic discharges in the temporal leads on one or both sides.
    CSF examination may show an increased opening pressure if there is significant brain swelling. There usually is a lymphocytic pleocytosis of 5 to 500 cells per cu. mm and a mildly elevated protein. Red cells and xanthochromia are usually present. CSF viral cultures are usually negative. PCR of CSF to detect HSV nucleic acid is useful, though in our laboratory the result returns too slowly to be useful in deciding whether to use antiviral therapy. In addition, the reaction is inhibited by RBCs, so false negative results can occur.
    Brain biopsy demonstrates Cowdry A intracellular inclusions, and is relatively sensitive and specific for the condition, but is not usually performed if a probable diagnosis can be made without it.

    Treatment and prevention
Intravenous acyclovir (10 mg/kg every 8 hours for 2-3 weeks) is standard. Rarely, HSV is resistant to acyclovir, and must be treated with foscarnet [12]. Neonatal HSV-2 encephalitis can be prevented by Caesarean section.

Arthropod-borne encephalitis
    West Nile Virus [18]
The West Nile Virus (WNV) first appeared in the U.S. in New York in 1999, and has since spread nationwide. In 2002, Illinois had the distinction of being the state with the most cases of WNV. In 2002 WNV was by far the most common etiology of viral encephalitis in the state. WNV's natural host is birds, especially crows and blue jays, and these animals develop a high titer viremia. It is transmitted from viremic birds to humans by Culex mosquitoes. Humans develop only low-level viremia, and human-to-human transmission by mosquitoes has not been documented. A few cases have been documented of WNV transmitted by blood transfusion, organ transplantation, breast feeding, by placental transmission, or by exposure of laboratory workers to infected sera or animals.
    The viral incubation period is 2 to 15 days. Most patients have an asymptomatic infection, but 20% will develop a fever, headache, backache, myalgia, and anorexia, lasting 3 to 6 days. About 50% develop a rash, and lympadenopathy can occur. About 1 in 150 infections will cause a severe illness with meningoencephalitis. Age is a strong risk factor, with the risk for 80 year olds almost 50-fold increased. Symptoms include flaccid weakness due to involvment of anterior horn cells, or less commonly parkinsonism, ataxia, polyradiculopathy, seizures, and cranial neuropathy. Mortality of the neurologic illness is about 10%, and recovery is rather poor in non-fatal cases.
    Radiologic findings are nonspecific. Diagnosis is based on clinical history, serology, and CSF findings. CSF shows a mild pleocytosis (30 - 100 cells/mm3), primarily lymphocytes, mild protein elevation, and normal glucose. Serologic tests are perfomed on both serum and CSF. WNV IgM is detectable in 90% of patients at 8 days, and persists for more than 6 months, so it is not an indicator of an acute infection. WNV IgM in the CSF indicates CNS infection. IgG antibodies increase between days 7 and 21.
    There is no specific treatment. Prevention relies on mosquito avoidance and control.

    Other arbovirides
The most common in the midwest U.S. are La Crosse virus and St. Louis encephalitis. They are transmitted by mosquitos and occur mainly in late summer and early fall. Symptoms are those of a flu-like illness, with evidence of brain involvement indicated by lethargy, confusion, irritability, tremors, or seizures. La Crosse virus may produce focal neurologic signs. St. Louis encephalitis may be associated with hyponatremia due to SIADH.
    CSF shows a lymphocytic pleocytosis. Diagnosis requires a fourfold rise in antibody titer between acute and convalescent sera, viral isolation from CSF, or demonstration of IgM antibody in CSF.
    Treatment is merely supportive--no specific antiviral therapy is available.

Other causes of encephalitis
Primary infection of meninges or brain by human immunodeficiency virus (HIV) is common, and causes meningitis or encephalopathy.  Rabies virus encephalitis is very rare, and almost invariably fatal. It can be prevented by immunization after exposure to a rabies-infected animal. In the immunosuppressed patient, varicella-zoster virus, Epstein-Barr virus, human herpes virus type 6, cytomegalovirus, measles and enterovirus can all occasionally cause encephalitis.

Therapy

• For herpes simplex encephalitis, intravenous acyclovir is curative.
• Varicella-zoster encephalitis can be treated with intravenous acyclovir.
• For HIV encephalitis, treatment for HIV is continued, but there is no specific treatment for the nervous system involvement by the virus.
• CMV encephalitis can be treated with ganciclovir.
• Rabies encephalitis can be prevented by vaccination after exposure to the rabies virus, but once the encephalitis has begun there is no effective treatment and death is practically certain.

Comments

F. Brain abscess and empyema

Brain Abscess

Symptoms and signs

1. Headache
2. Focal neurologic deficits
3. Fever, chills and other signs of infection usually do not occur
4. Papilledema (with increased ICP)
5. Nausea, vomiting (with increased ICP)

Diagnosis

1. Focal neurologic deficit or seizure suggests focal brain lesion
2. The patient may have a risk factor for abscess, such as:
• congenital heart disease with right to left shunt
• bacterial endocarditis
• lung abscess or bronchiectasis
• paranasal sinusitis
3. Contrast-enhanced CT or MRI may show a ring-enhancing lesion or lesions and surrounding brain edema
4. If the diagnosis is in doubt, a stereotaxic brain biopsy will confirm that the lesion is an abscess

Cerebrospinal fluid

Treatment

Etiology

Subdural empyema

G. Myelitis and spinal epidural abscess

Symptoms

• Fever
• Back pain
• Limb weakness or sensory changes
• Bowel or bladder dysfunction

Symptoms are those of spinal cord dysfunction: weakness, sensory changes, bladder or bowel dysfunction. In the case of epidural abscess, localized back pain and fever are very common.

Signs

Diagnosis

1. Characteristic signs and symptoms.
2. MRI of the spine at the level suggested by the clinical exam.
3. Lumbar puncture for suspected myelitis, but not for spinal epidural abscess.

Causes

Therapy

Comments

H. A slide show of organisms causing meningitis

This is a "Rogues Gallery" of microscopic images of organisms that cause meningitis. Images are courtesy of Dr. Joan Barenfanger.

III. Lumbar puncture

How to do it

• Position the patient. (This is like chess--position is half the battle.)
• Place the patient in the left lateral decubitus position with his back toward you. (That is, lying on his left side, with his head to your left.)
• Have the patient curl up into a ball, chin trying to touch the chest, knees pulled up to the chest. This tends to separate the spinous processes, and make it easier to get in. ("Arch your back like a mad cat!")
• Identify the L3/4 interspace. First, find the middle of the spine, marked by the spinous processes. The spinous processes stick out a little and are hard like bone. The interspaces are softer. Palpate the posterior superior iliac crest (the top of the pelvis). The L3/4 interspace is the one crossed by a perpendicular line dropped from the posterior superior iliac crest.
• Mark that space. I use a ballpoint pen to make lines on either side of it, pointing to it. (I don't want to introduce ballpoint ink into the CSF).
• Open the LP tray, put on your gloves, and perform a sterile prep and drape of the patient. This is extremely important but difficult to describe in words so I won't--observe the procedure once or twice, then do it yourself under supervision. Some people think that they don't need to use a drape, but I strongly advise that you do; it's just too easy to contaminate yourself without it, and if you have draped the patient, you can feel for landmarks like the iliac crest without breaking sterility.
• Prepare the kit. You'll need to set up a manometer to measure the pressure, and you'll have to loosen the caps of the tubes so that you can manipulate them with one hand. Keep the caps loosely over the tubes, so that if your assistant coughs it doesn't contaminate your sample.
• Ask the patient if they have an allergy to local anesthetics. If not, then anesthetize the interspace with 1% lidocaine. Make sure the air is out of the syringe, and if you anesthetize deeply, try withdrawing before you inject to make sure you're not in a vessel.  I anesthetize just the skin, and try to raise a orange-peel-like bleb with the anesthetic to ensure I get the epidermis, which is most pain-sensitive layer. Many physicians use a longer needle to anesthetize deeply, but I don't--I don't think it spares the patient any pain. If they are allergic to anesthetics, then I do it without anesthesia.
• Take the spinal needle, and orient it this way: bevel upward (to split, rather than cut, the fibers of the posterior longitudinal ligament); precisely perpendicular to the patient's back in a vertical direction; aim toward the patient's navel.
• Push the needle in. Don't try to be slow and "gentle"--it just hurts more to go slowly. If you hit bone, back up all the way to the skin and aim again. You may have to do this more than once. As you go through the posterior longitudinal ligament you sometimes feel a slight pop. If you think you may be in the thecal sac, pull out the stylet and see if you get CSF flowing out. If not, put the stylet back in and try again. You will often get blood return, because the thecal sac is surrounded by an extensive venous plexus. If blood clots in your needle you will need a new one. If the patient complains of back pain--well, there's nothing to do but reassure them it will be over soon. If the patient complains of pain in the hip or leg, ask them which one, because you are touching a spinal nerve root. If the pain is on the left side, your needle may be aimed too far down and you'll need to re-aim. If the right side, then you're too far up.
• Got fluid? If the fluid is bloody, waste the first 3 or 4 drops so that a bloody tap doesn't confuse you. Measure the opening pressure with your manometer. Collect approximately 2 cc of fluid in each tube for the usual diagnostic tests. If you want to culture for tuberculosis or fungi, collect 10 cc in one tube. If you want to test for abnormal cytology, then the more the better, but get at least 10 cc for the cytology alone.
• Done? Put the stylet back in, then withdraw. (Neurologic legend says you may vacuum up a nerve root with your needle if you don't put the stylet back in.)
• Having trouble? Try the L2/3 space.
• Still having trouble? Try sitting the patient up to do it--the interspaces may separate better and the lumbar CSF pressure will be higher.
• Still having trouble? Better ask a radiologist to do it under fluoroscopic guidance. If you possibly can, go watch the procedure so you can understand the anatomy better.

Looking at the sample with the naked eye

Looking at the sample with a microscope

Gram stain
For the truly devoted student of CSF, doing your own Gram stain is a must. For this, you will need, in addition to a microscope, a sink with running water, gloves, and the necessary staining paraphernalia. Instructions on this can be found elsewhere.
 

Tests to run on the sample

Glucose
CSF glucose is normally 2/3 that of the serum. Hence, for an accurate assessment, a simultaneous serum glucose is necessary.  Glucose is normal in viral meningitis, and may be normal in chronic meningitis, but is often very low in acute bacterial meningitis.

Protein
Protein is increased in any condition in which a leaky blood brain barrier occurs. Hence, it is increased in conditions affecting the spinal nerve roots (diabetes, Guillian-Barre syndrome), may be increased in neoplasms of the CNS, or infections of the brain, spinal cord, or meninges. Protein may be markedly elevated in cases of spinal block (for example, severe cervical stenosis or neoplasm), but LP is contraindicated in patients with these conditions because of the risk of producing spinal cord compression. Protein is also increased with normal aging--a rule of thumb is that a person is "allowed" 1 mg/ml of protein per year of age.
    In case of traumatic tap, protein is increased because of the inclusion of cells and serum in the sample. A rule of thumb is that 1000 cells imply a 1 mg/ml increase in protein concentration. If accuracy is imperative, then the amount of protein to be expected can be calculated if the patient's serum protein concentration, RBC counts, and WBC counts are known.

WBC count
This is a critical number in cases of meningitis. The meninges are everywhere close to the spinal fluid spaces, and early in the course of illness, inflammatory cells spill from the meninges into the CSF. The WBC count is normally 5/cu. mm or less. It is increased into the tens and hundreds or thousands by septic meningitis.
    The differential can help in determining the type of infection. In aseptic meningitis, mononuclear forms, especially lymphocytes, predominate. In septic meningitis, polymorphonuclear forms predominate. If the overall count is normal the differential is not meaningful.
    A number of non-infectious conditions can produce small increases in CSF WBC counts, including:

• Seizures. Cell counts of 25 or so are common immediately after a generalized seizure.
• Multiple sclerosis. During an acute exacerbation, cell counts in the dozens are common.
• Stroke. Stroke, especially embolic stroke, may be associated with cell counts in the dozens. This is even more likely if the stroke is caused by bacterial endocarditis.

Bacterial cultures
Cultures are the "gold standard" for diagnosis of bacterial meningitis. Normal CSF is always sterile, so if cultures grow the patient either has an infection, or the specimen was contaminated. In bacterial meningitis, cultures are positive in the large majority of cases: 80% for S. pneumoniae, 90% for N. meningitidis, 94% for H. influenzae. False-positive results occur if the culture is contaminated by skin organisms such as coagulase-negative staphylococcus, but this organism often is the infectious agent in cases of shunt infection. False-negative results are often obtained if the meningitis has been partially treated with antibiotics before the CSF specimen is obtained.
    It is worth noting that patients with meningitis are often also bacteremic, so blood cultures are usually positive as well.
    A drawback of CSF cultures is that it takes 24 to 48 hours for the organism to grow and be identified.

Gram stain
Gram stain is an essential part of the CSF examination whenever meningitis is considered. In addition to being practically 100% specific, it has a sensitivity of 60 to 80% for bacterial infection [13,14].

Bacterial antigen tests
Rapid bacterial antigen tests are available for S. pneumoniae, N. meningitidis, and H. influenzae.

Other tests
Other tests may be useful in particular clinical situations:

•  Traumatic tap. Do cell counts on tubes #1 and #4. If the RBC count goes down significantly, traumatic tap is likely.
•  Chronic meningitis. Add a VDRL to check for syphilis, an acid-fast bacillus stain for M. tuberculosis, and fungal cultures.
•  Multiple sclerosis. Collect 10 cc for CSF electrophoresis to detect the characteristic oligoclonal bands.
•  Carcinomatous meningitis. Collect as much CSF as possible for cytologic examination. The more CSF is available, the more likely it is that the spun-down specimen will contain malignant cells.
• Pseudotumor cerebri.  No further tests on the fluid are required, but the clinician may want to obtain large amounts of fluid to lower the pressure, measure a closing pressure to ensure that the pressure has been decreased, and determine whether the procedure provides relief from headache.
• Aseptic meningitis.  Viral cultures are worthwhile when positive, but detect less than 25% of cases [15,16]. Acute and convalescent antibody titers in the serum may be useful.
• Encephalitis. The most common organism is herpes simplex. CSF PCR may be useful for confirmation of the diagnosis, but in my area at the time of this writing the test cannot be obtained rapidly enough to use a negative result to select patients who needn't be treated with acyclovir--so clinical diagnosis is still paramount. PCR is available for HSV I, CMV, VSV, EBV and enterovirus, and has a sensitivity and specificity of 90-100% in each. Consider ordering a viral culture as well--although it is usually negative, it may become positive before the PCR result returns from the lab you sent it to.

Typical CSF formulas

Relative contraindications to lumbar puncture

1. Space-occupying intracranial lesions or obstructive hydrocephalus. The risk is that removing fluid from the lumbar space would exacerbate a pressure differential between intracranial compartments and lead to brain herniation. This is uncommon, but is a definite concern. Careful examination of the patient for signs of increased intracranial pressure (e.g. papilledema) is indicated. An emergency non-contrast CT scan of the head is also indicated. If a scan is not immediately available, your choice is between (a) presumptive treatment and no lumbar puncture, or (b) puncture without scan. Either may be the most reasonable depending on the clinical situation. Brain absess is thought to be especially likely to be associated with herniation. Papilledema and increased intracranial pressure are not by themselves a contraindication to LP. In fact, LP is a good therapy for the increased intracranial pressure of pseudotumor cerebri.
2. Bleeding dyscrasia. If necessary, give two units of fresh frozen plasma and do the LP right away. But the risk of serious complication here is low, so do not delay long if you suspect bacterial meningitis--the two hours you delay may mean the difference between a normal life or a brain-damaged one.
3. Spinal epidural abscess. Do not put a lumbar puncture needle through the abscess--you may seed the subarachnoid space with bacteria and cause a meningitis.

Possible complications

1. Headache. Occurs in 20% of patients, caused by leakage of fluid through the hole made in the dura. Diagnosis is obvious--the headache is severe when standing but immediately goes away on lying down. Treatment is bedrest with the head lower than the hole, and drink plenty of fluids.
2. Meningitis. Rare. Should occur only if there is some break in sterile technique--which is to say it should never occur.
3. Contamination of the CSF sample. This is really bad form. Do not cough into your sample. You and the patient went to a lot of trouble--keep it sterile.
4. Disk herniation? There are rare reports of disk herniation thought to be caused by a previous LP that punctured an intervertebral disk.
5. Impalement of nerve roots. Not likely in a conscious patient, who will inform you quickly if he has lancinating pain shooting down one leg. It is more likely in an unconscious patient, so you may have to take the blame for it if the patient wakes up and finds he has a numb spot on his leg. But you may also get the credit for the patient waking up.
6. Impalement of spinal cord. There is a popular misconception that paralysis is a possible complication of LP. This is not possible unless you do a thoracic or cervical puncture because the spinal cord ends at the L1/L2 disk. On the other hand, it is entirely possible if you do C1/C2 punctures, or err during thoracic epidural anesthesia.

IV. References

A good general review is:

Specific references are:

 2 Progress toward eliminating Haemophilus influenzae type b disease among infants and children--United States, 1987-1997, MMWR, 47 (1998) 993

 3 Adams, W.G., Deaver, K.A., Cochi, S.L. and et al, Decline of childhood Haemophilus influenzae type b (Hib) disease in the Hib vaccine era, JAMA, 269 (1993) 221

 4 Murphy, T.V., White, K.E., Pastor, P. and et al., Declining incidence of Haemophilus influenzae type b disease since introduction of vaccination, JAMA, 269 (1993) 246

 5 Mylonakis, E., Hohman, E.L. and Calderwood, S.B., Central nervous system infection with Listeria monocytogenes: 33 years' experience at a general hospital and review of 776 episodes from the literature, Medicine (Baltimore), 77 (1998) 313

 6 Southwick, F.S. and Purich, D.L., Intracellular pathogenesis of listeriosis, N Engl J Med, 334 (1996) 770

 7 Gray, B.M., Converse, G.M.D. and Dillon, H.C.J., Epidemiologic studies of Streptococcus pneumoniae in infants, J Infect Dis, 142 (1980) 923

 8 Bishburg, E., Sunderam, G., Reichman, L.B. and et al., Central nervous system tuberculosis with the acquired immunodeficiency syndrome and its related complex, Ann Intern Med, 105 (1986) 210

 9 Cassleman, E.S., Hasso, A.N., Ashwal, S. and et al., Computed tomography of tuberculous meningitis in infants and children, J Comput Assist Tomogr, 4 (1980) 211

 10 Dooley, D.P., Carpenter, J.L. and Rademacher, S., Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature, Clin Infect Dis, 25 (1997) 872

 11 Fodor, P.A., Levin, M.J., Weinberg, A. and et al., Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF, Neurology, 51 (1998) 554

 12 Whitley, R.J., Kimberlin, D.W. and Roizman, B., Herpes simplex viruses, Clin Infect Dis, 26 (1998) 541

 13 Carpenter, R.R. and Petersdorf, R.G., The clinical spectrum of bacterial infection, Am J Med, 33 (1962) 262

 14 Dunbar, S.A., Eason, R.A., Musher, D.M. and et al., Microscopic examination and broth culture of cerebrospinal fluid in diagnosis of meningitis, J Clin Microbiol, 36 (1998) 1617

 15 Atkinson, P.J., Sharland, M. and Maguire, H., Predominant enteroviral serotypes causing meningitis, Arch Dis Child, 78 (1998) 373

 16 Gorgievski-Hrisoho, M., Schumacher, J.D., Vilimonovic, N. and et al., Detection by PCR of enterviruses in cerebrospinal fluid during a summer outbreak of aseptic meningitis in Switzerland, J Clin Microbiol, 36 (1998) 2408

 17 McIntyre, P.B., Berkey, C.S., King, S.M. and et al., Dexamethasone as adjunctive therapy in bacterial meningitis: a meta-analysis of randomized clinical trials since 1998, JAMA, 278 (1997) 925

18 Sampathkumar P., West Nile Virus: Epidemiology, Clinical Presentation, Diagnosis, and Prevention, Mayo Clin Proc, 78 (2003) 1137-1144

19 de Gans J., van de Beek D. for the European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators, Dexamethasone in adults with bacterial meningitis, N Engl J Med. 347 (2002) 1549-56.

20 Hanson R.A., Ghosh S., Gonzalez-Gomez I., Levy M.L., Gilles F.H. Abducens length and vulnerability? Neurology, 62 (2004) 33-36.

21 Kahn E.A., Cherry G.R. The clinical importance of spontaneous retinal venous pulsations. Univ Mich Med Bull 16 (1950) 305-398.

22 Cochlear implants may increase risk for bacterial meningitis. Public Health Rep 119 (2004) 97-98.

23 Cohen N, Ramos A, Ramsden R, Baumgarten W, Lesisnski A, O'donoghue G, Lenarz T, Fraysse B International consensus on meningitis and cochlear implants. Acta Otolaryngol 125 (2005) 916-917.

24 Yogev R, Guzman-Cottrill J Bacterial meningitis in children: critical review of current concepts.  Drugs 65 (2005) 1097-1112.

25 Goldwater PN Cefotaxime and ceftriaxone cerebrospinal fluid levels during treatment of bacterial meningitis in children. Int J Antimicrob Agents 26 (2005) 408-411.

26 Antal EA, Loberg EM, Dietrichs E, Maehlen J Neuropathological findings in 9 cases of listeria monocytogenes brain stem encephalitis. Brain Pathol 15 (2005) 187-191.

27 Harrison LH Prospects for vaccine prevention of meningococcal infection. Clin Microbiol Rev 19 (2006) 142-164.

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