BACTERIAL AND FUNGAL INFECTIONS OF THE CENTRAL NERVOUS SYSTEM
John E. Greenlee, M.D.
INTRODUCTION AND OBJECTIVES:
Central nervous system infections are both diagnostic challenges and medical emergencies. They
are challenging because their onset may be fulminant or insidious and because clinical signs and
symptoms may be deceptively atypical. They are medical emergencies because delay in
diagnosis and institution of appropriate therapy will result in the patient's death or in permanent,
severe neurological injury. This lecture will serve as an introduction to this important area of
medicine and neurology. This lecture will review the following topics:
1. Meningitis: its pathogenesis, clinical features, and diagnosis
a. Acute bacterial meningitis
b. Tuberculous and fungal meningitis
2. Brain abscess
3. Space-occupying parameningeal infections: epidural abscess and subdural empyema
4. Indirect injury in central nervous system infections:
a. Injury to blood vessels
b. Immune-mediated demyelinating injury to the central nervous system or to
5. Diagnosis and treatment of CNS infections
Brain and spinal cord are poorly compliant in response to acute infections, and
progression to permanent injury or death may occur very rapidly. In chronic infections,
brain or spinal cord may be significantly displaced with very few symptoms. Once
compliance has been exhausted, however, clinical deterioration occurs very rapidly. This
has important implications: in chronic infection, you do not know how close the patient is
to brain herniation or spinal cord necrosis.
I ACUTE BACTERIAL MENINGITIS:
A. Is the most common of acute CNS infections. Infections involves meninges diffusely
and may also spread into ventricular system to cause an accompanying ventriculitis
B. Routes of CNS invasion: bacteria may reach the CNS by any of three routes
1. Most common: hematogenous spread
2. Less frequent: spread from sinuses, middle ear, mastoid, or other pericranial structures
3. Through congenital or acquired defects in the skull or spinal column:
a. Congenital defects: failure of the neural tube to close:
• Most common in cervical or lumbosacral spine
• May be marked by an overlying dimple or tuft of hair
b. Acquired defects: usually involves skull fractures (often basilar) involving the
thin bones separating the intracranial contents from the sinuses or middle ear.
c.. Important: suspect congenital or acquired defects in any patient having
recurrent episodes of meningitis.
• Note that injury causing skull defects may antedate the CNS infection by
months or even years.
D. Causative Organisms of bacterial meningitis: You should know the major groups of these
1. The agents of bacterial meningitis vary with host age and with the route of infection.
a. Neonates: E. coli and other gram negatives, and Beta-hemolytic streptococci, less
often Staph aureus, Listeria monocytogenes.
b. Age 6 months - 5 years: N. meningitidis and S. pneumoniae. Ten years ago,
Haemophilus influenzae type b was the leading cause of bacterial meningitis in the
United States, with 11,000 cases annually and with most cases occurring in children
in this age group. The advent of conjugate vaccines against this organism has led to
a 90% reduction in cases. H. influenzae remains an important cause of meningitis in
this age group in third world countries.
c. 5 - 40 years: Neisseria meningitis (45% of cases), pneumococcus (20%)
d. >40 y: pneumococcus, (50% of cases): Staph aureus (13%), Meningococcus. In the
elderly gram negatives and Listeria reappear.
e. Otitis, sinusitis, closed head injuries. Pneumococcus; H. influenzae, anaerobes.
f. Penetrating trauma: Staph aureus
2. Bacterial strain plays a major role in determining whether meningitis will occur
a. E. coli meningitis: strains carrying the K1 capsular antigen.
b. Group B streptococcal meningitis : >80% caused by Type III strains.
c. H. influenzae meningitis: Type B strains.
d. Meningococcal meningitis: Groups A, B, or C.
3. Important: S. aureus is a occasional - and highly lethal - organism at any age.
Specific therapy for S. aureus should be added if there is any suspicion that it its
C. Mechanisms of CNS injury in bacterial meningitis: In the past 10 years, there has been
an explosion in our knowledge about the pathophysiology of bacterial meningitis. This
new information has major implications for treatment. Major mechanisms of injury
are as follows:
1. Infection-mediated loss of capillary integrity: This is present in almost all bacterial
and fungal CNS infections and is the major cause of death:
a. Mechanism: Teichoic acid released from S. aureus, endotoxin released from
Gram-negative organisms, cause release of tumor necrosis factor and interleukin
2 from endothelial cells. These, in turn, cause both intravascular thrombosis and
loss of capillary integrity
b. Consequences: vascular occlusion with infarction; cerebral edema leading to
c. Important concept: antibiotics do not reduce cerebral edema during the
initial stages of treatment and may actually exacerbate vascular injury by
lysing bacteria, with release of additional teichoic acid or endotoxin.
(Example: trials of intraventricular gentamicin for treatment of neonatal
d. Important concept: Agents to restore capillary integrity and prevent
cerebral edema are a major area of research in CNS infections. Only agents
currently in use are corticosteroids such as dexamethasone
2. Impairment of CSF flow and drainage:
a. Inflammation within the CSF space may block CSF reuptake by arachnoid villi,
causing communicating hydrocephalus (Common in bacterial meningitis).
b. Infection within the ventricles (ventriculitis) or at the base of the brain may cause
• Common sites of obstruction: Usually the base of the brain.
Occasionally the foramina of Luschka and Magendie at the base of the
brain, the aqueduct of Sylvius, or, less often, the foramina of Monro.
3. Cortical ischemia due to
a. Cerebral vasculitis with vascular occlusion
b. Loss of vascular autoregulation
4. Increased intracranial pressure. Caused by cerebral edema and by hydrocephalus. May
be severe enough to raise intracranial pressure above systolic perfusion pressure.
D. Important! Meningitis causes major changes in CSF. These changes are important in
1. Cell count rises: usually polymorphonuclear leukocytes
2. Protein rises d/t transudation across injured capillaries
3. CSF glucose falls due to decreased transport and increased utilization.
4. Pressure rises
D. Clinical features of bacterial meningitis = fever + stiff neck + impairment of
E. Bacterial meningitis may also present atypically: important points
1. Bacterial meningitis can be rapidly lethal
This 16 year old high school student was in excellent health until the day of admission,
when she complained to her parents of a slight headache and went to take a nap. She
was brought to the hospital 3 hours later after her parents could not awaken her for
dinner. Examination revealed extreme nuchal rigidity, midposition, fixed pupils, and
bilateral papilledema. MRI scan showed extensive cerebral edema with brain
herniation. Attempts to reduce intracranial pressure were unsuccessful, and support was
discontinued after EEG showed no cerebral electrical activity. CSF obtained at autopsy
• Never forget: that bacterial meningitis is one of the very few conditions that can kill
a previously completely healthy person within hours.
2. Meningitis in neonates may not have typical features of bacterial meningitis:
a. Typical clinical features of meningitis are often absent
b. Patient may be euthermic or hypothermic, eupneic, tachypneic, or have apneic
c. Seizures may occur, but infantile seizures do not always look like seizures
d. Diagnosis requires very low threshold for lumbar puncture
e. Mortality and sequelae are high in this condition.
3. Meningitis may be silent in alcoholics in the elderly, and in immunosuppressed
a. Meningitis is always a consideration - along with trauma, intoxication, etc. - in
the alcoholic presenting with altered mental status.
b. In the elderly, the only symptom of meningitis may be confusion in a previously
alert individual or deepened dementia
c. In the elderly and in alcoholics, as in infants, threshold for LP must be low.
Elderly patients and alcoholics are at risk for subdural hematoma, however,
which acts as a mass lesion and contraindicates lumbar puncture. The usual
approach in suspected meningitis in these two groups of patients is to begin
antibiotics, get a CT scan and then, if safe to do so, perform an LP.
IV. CHRONIC MENINGITIS
A. Tuberculous Meningitis:
1. Often considered the prototype of a chronic meningitis
a. Is usually subacute but may be as fulminant as any case of bacterial meningitis
b. Unless treated, usually proves fatal within days or, occasionally, weeks.
2. Should be suspected in AIDS, or in any patient, in particular a child or young adult,
known to have been exposed to tuberculosis or from an area in which tuberculosis is
3. Pathogenesis: Blood-borne
a. Meningeal infection follows rupture of a subependymal granuloma into the ventricles
or a submeningeal granuloma into the subarachnoid space.
b. Meningitis classically occurs during the first few months of primary infection
c. In developed countries, tuberculous meningitis is usually the consequence of
reactivated infection in lung or other organs
d. Rarely, meningitis results from reactivation of a granuloma within the nervous
system; in this case, tuberculous meningitis can develop with no signs whatever of
4. Characteristically produces a basilar meningitis. This has three consequences:
a. Hydrocephalus: due to obstruct of the foramina of Luschka and Magendi or the
aqueduct of Sylvius.
b. Vasculitis with arterial or venous occlusion: due to involvement of vessels within
inflamed meninges. Occasionally, tuberculous meningitis may present as an
c. Cranial nerve palsies: due to involvement of exiting cranial nerves in inflamed
basilar meninges. (In particular cranial nerves II, VII, and VIII).
d. CSF changes: Mixed pleocytosis with lymphocytic predominance, very low
glucose (may occur before cells are present), elevated protein.
• Organisms found in 10-30% of acid fast stains, 70% of cultures. PCR is the
diagnostic method of choice.
This 4 year old child was brought to the emergency room because of headache and
irritability. The child was diagnosed as having otitis media and begun on ampicillin.
She was rushed back to the emergency room the next morning after she was found in
coma. Neurological examination was nonfocal. Lumbar puncture was normal except
for a glucose of 5 mg/dl. A subsequent lumbar puncture revealed 150 cells, 60%
lymphocytes and 40% poly's, a protein of 300 mg/dl, and a glucose of 5 mg/dl. Acid-
fast organisms were seen on smear. The patient remained comatose despite
antituberculous therapy, and supportive measures were eventually discontinued. During
the week prior to admission, the patient's aunt had presented with granulomatous
hepatitis. Liver biopsy in the aunt subsequently revealed acid-fast organisms.
B. Chronic meningitis due to other agents
1. Major organisms: fungi (Cryptococcus neoformans, Coccidioides immitis, and less
frequently Histoplasma capsulatum, Blastomycoses species, Candida albicans and other
fungi.), spirochetes (syphilis, Lyme disease), and occasionally bacteria such as
Nocardia, Leptospira, or Brucella species or the protozoan Toxoplasma gondii
2. Virtually all are blood-borne
a. Exception: infections due to Mucor (Rhizopus) begin as nasopharyngeal
infections and spread along emissary veins.
3. All tend to cause basilar infection, and may cause hydrocephalus, cranial nerve palsies.
and, less often, inflammation and thrombosis of vessels at the base of the brain
4. Chronic meningitis due to fungi is most common in patients with defective T cell-
mediated immune response.
5. May pursue a fatal course over weeks but may also run an extremely protracted course
over months or years. Virtually all of these conditions cause major neurological injury,
however, and most are eventually fatal unless treated.
6. CSF changes are different from those of bacterial meningitis: Lymphocytic
pleocytosis, high protein, low glucose
a. Organisms may be very hard to detect or culture. PCR holds great promise
b. Cryptococcal antigen positive in 80%-90% of cases
V. FOCAL CNS INFECTIONS: BRAIN ABSCESS
A. Mechanisms of CNS Invasion
1. Hematogenous spread
2. Retrograde infection from sinuses, middle ear, mastoid
3. Penetrating trauma
B. Pathogenesis: Septic microvascular injury focal infection ("cerebritis") abscess
1. Abscesses due to hematogenous spread
a. Most common in area of middle cerebral artery but may involve any part of
b. Most common at gray-white junction.
2. Abscesses arising from infected sinuses or middle ear tend to involve contiguous brain
a. Sinuses involve frontal lobe (maxillary sinus may involve temporal lobe).
b. Middle ear and mastoid: involve temporal lobe or cerebellum
D. Production of CNS injury:
1. Abscesses both destroy and compress brain.
2. Accompanying cerebral edema increases the mass effect
3. Abscesses develop capsules which are thinner on their medial surface, This causes the
abscess to enlarge toward and rupture into the ventricles, causing meningitis and at
times, lethal changes in CSF pressure.
E. Etiologic organisms: Multiple organisms may be present. Major organisms are
1. Streptococcus milleri, Streptococcus anginosus, and other Gram-positive
microaerophilic or anaerobic organisms
2. Gram-negative aerobic and anaerobic organisms (Proteus, E. Coli, Bacteroides)
3. Staphylococcus aureus
F. Clinical Features: Focal neurological signs, (including seizures), increased intracranial
pressure with headache and papilledema.
1. Important: Focal signs, fever, headache are often absent
G. Diagnosis: MRI is the diagnostic procedure of choice, followed by CT.
H. Important: Lumbar puncture is contraindicated in brain abscess.
1. Information provided by LP is very limited, and CSF cultures are usually sterile
2. Brain herniation and death follow lumbar puncture in up to 20% of cases of brain
This 60 year old diabetic woman developed headache and mild confusion in mid-
January, 1993. Lumbar puncture showed increased lymphocytes, and the patient was
treated with antibiotics for suspected meningitis. In late March, the patient became
abruptly confused and was thought to have had a seizure. Outside CT scan suggested
brain abscess. On examination, the patient was stuporous, with mild right hyperreflexia.
MRI scan at our institution showed over 10 separate brain abscesses. Cultures of the
abscesses, (The patient had been on antibiotics) were negative. The patient was treated
with a four month antibiotics, at first in hospital and then at home and was monitored
with serial MRI scans. The abscesses resolved completely over a period of 4 months,
leaving the patient mentally unchanged from her premorbid state and without focal
1. Diabetes is a risk factor for bacteremia and abscess formation - including brain and
2. Even multiple brain abscesses may not cause focal deficit to suggest their presence
3. In some patients, cure of abscesses may be achieved with antibiotics alone
4. Response of a given abscess to antibiotics cannot be predicted in advance - you must
follow the patient's MRI or CT scan.
VI. FOCAL CNS INFECTIONS: PARAMENINGEAL INFECTION
A. Intracranial parameningeal infections
1. Anatomy: The outermost layer of the meninges - the dura - is tightly bound to the
overlying skull. Infections between the dura and skull - epidural abscesses - are tightly
contained and tend to be fairly small. Beneath the dura, however, lies a potential
subdural space within which infection can rapidly spread.
2. Pathogenesis of intracranial parameningeal infections:
a. Almost always arise from spread of organisms from sinusitis or otitis
b. Exception: bacteremia seeding of a preexisting subdural hematoma can cause
3. Clinical Features:
a. Intracranial epidural abscess: local pain, focal neurological signs, at times superficial
infection or swelling
b. Intracranial subdural empyema: rapid development of coma with signs suggesting
involvement of an entire cerebral hemisphere. Subdural empyema is an extreme
medical and surgical emergency.
B. Spinal parameningeal infections
1. Anatomy: In the spinal canal, the dura is surrounded by a fat-filled epidural space.
2. Pathogenesis of spinal parameningeal infections:
a. Spinal epidural abscess may arise by hematogenous spread, from adjacent
osteomyelitis, or by lymphatic spread of infection from deep abscesses.
b. Spinal subdural empyema is rare and is almost always due to bacteremia
3. Clinical Features: Spinal Epidural abscess
a. Risk factors: diabetes, i.v. drug abuse, pregnancy, back injury
b. Symptoms: occur in 4 stages
• Focal pain
• Radicular pain
• Long tract signs
• Signs of cord transection
4. Clinical Features: Spinal subdural empyema (rare): signs of cord and/or nerve root
injury at multiple levels.
VII. INDIRECT CNS INJURY IN BACTERIAL, MYCOBACTERIAL, AND FUNGAL
A. Due to injury of blood vessels: may result in ischemic injury or brain hemorrhage
1. Injury to arteries:: bacterial endocarditis, involvement of arteries in basilar meningitis
(example: tuberculous meningitis)
2. Injury to veins: septic venous thrombophlebitis: occurs as a complication of sinusitis
3. Injury to capillaries: Role in bacterial meningitis is discussed above. Other examples
include rickettsial infections: in this country Rocky Mountain Spotted Fever.
B. Due to immune reaction against neural tissue
1. Immune reaction against central myelin: may occur as a complication of
mycoplasma or viral infections, rarely as a complication of bacterial infections
2. Immune reaction against peripheral myelin or other nerve components: may occur in
response to a number of agents, in particular Campylobacter jejeuni. May cause
demyelination or axonal injury of nerve roots and peripheral nerves to cause severe
motor paralysis (Guillain-Barre syndrome).
Bacterial, Mycobacterial, or Viral Infection
Host immune reaction cross-reactive with neural antigens
Immune response to CNS antigens Immune response to PNS antigens
Acute CNS demyelination Acute PNS demyelination or axonal injury
(Postinfectious encephalomyelitis) (Guillain-Barre syndrome)
VIII. DIAGNOSIS OF ACUTE CNS INFECTIONS
A. Meningeal infections: the key to diagnosis is the lumbar puncture
Bacterial Viral Meningitis Tuberculous Fungal Meningitis
Protein Elevated Mildly elevated Elevated (extreme) Elevated
Glucose <50% blood Normal <50% blood glucose <50% blood glucose
Cells Poly's Lymphs Lymphs Lymphs
Other Gram stain PCR AFB Stain India Ink Prep
Culture Culture Cryptococcal antigen
PCR (20 ml CSF) Culture (20 ml CSF)
B. Focal infections: Brain abscess and parameningeal infections
1. Lumbar puncture is contraindicated
2. Key to diagnosis is careful imaging - ideally MR scan.
TREATMENT OF ACUTE CNS INFECTIONS
A. Antibiotic therapy:
1. Agents chosen must cross blood-brain barrier
2. If two or more agents are used, they should be synergistic - or, if several antibiotics are
used to cover multiple possible organisms, they shouldn't cancel each other out
• Classic example: Lepper and Dowling: mortality in pneumococcal meningitis
treated with penicillin alone: 30%, with penicillin and tetracycline: 79%
B. Treatment of Cerebral Edema:
1. Dexamethasone has been shown to reduce mortality and deafness in H. flu meningitis.
Its role in other bacterial meningitides is less well established. Nonetheless, it is
probably the most effective current medical therapy
2. Other means of reducing ICP include hyperventilation, , osmotic diuretics, and, in
extreme cases, brain decompression. The efficacy of these has not been established in
3. Transcranial or intraventricular pressure monitoring devices; correlation of ICP with
arterial pressure to derive mean arterial cerebral perfusion pressure.
C. Evacuation of loculated infection: abscess of empyema
D. Treatment of hydrocephalus
E. Treatment of systemic infection
G. Treatment of metabolic consequences of infection
1. Septic shock
2. Disseminated intravascular coagulation
Mandell, Douglas and Bennett (editors). Principles and practice of infectious diseases, Fourth
Edition. John Wiley and Sons, New York, 1989. Chapters 60-67. Also for specific infections.
Scheld, Whitley, and Durack (editors). Infections of the Central Nervous System. Raven Press,
1997. (Excellent discussions of general approach to the patient, meningitis, and brain abscess.)
Roos, KL. Central Nervous System Infectious Diseases and Therapy: Marcel Dekker, Inc. 1997
Excellent, very practical book
Schwartz MN and Dodge PR: Bacterial meningitis. N Engl J Med 272:725, 779, 882, 898, 954,
1003, 1965. This remains a classic review of the clinical findings in meningitis.
Lepper MH and Dowling HF: Treatment of pneumococcal meningitis with penicillin compared
with penicillin plus aureomycin. Arch Intern Med 88:489,1951 (This classic article demonstrates
that therapy with two antibiotics is not always better than therapy with one).
Rich A and McCordock HA: The pathogenesis of tuberculous meningitis. Bull. John Hopkins
Hospital 52I:5, 1933.
Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. NEJM 336:708-716, 1997
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meningitis. J Exp Med 167:1743-1748, 1988.
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meningitis. Pediatrics 34:220-227, 1964.
Harper JR, Lorber J, Smith H, Bower's DB, Timing of lumbar puncture in childhood meningitis.
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Odio CM, Faingezicht I, Paris M, et al. The beneficial effects of early dexamethasone
administration in infants and children with bacterial meningitis. NEJM 324:1525-1531, 1991.
Silver TS, Todd JK. Hypoglychorrhachia in pediatric patients. Pediatrics 58:67-71, 1976.
Ellner JJ and Bennett JE: Chronic Meningitis. Am J Med 55:341-369, 1976. (Despite its age,
this is the best article ever written on this subject. The current edition of Mandell, Bennett, and
Douglass contains an update)
Brain Abscess and Parameningeal Infections:
Britt RH, Enzmann DR. Clinical stages of human brain abscesses on serial CT scans after
contrast infusion. J Neurosurg 59:972-989, 1983.
Darouiche RO, Hamill RJ, Greenberg SB, Weathers SW, Musher DM. Bacterial spinal epidural
abscess. Review of 43 cases and literature survey. Medicine 1992:71:369-385.
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treatment of spinal epidural abscess. Surg Neurol 1990;34:408-413.
Chacko AG, Chandy MJ, Diagnostic and staged stereotactic aspiration of multiple bihemispheric
pyogenic brain abscesses. Surg Neurol. 1997;48:278-82 (See also discussion: pp 282-3)
Johnson RT. Viral diseases of the nervous system. Second Edition. Lippincott-Raven, 1998.
(Highly readable. Probably the best overall book on viral CNS infections.
Fisher RS et al. Postinfectious leukoencephalitis complicating Mycoplasma pneumoniae
infection: Arch Neurol 40:109-113.
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