NERVOUS ORGANS SYSTEM COURSE

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 peripheral nerves 5. Diagnosis and treatment of CNS infections IMPORTANT! 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. (Staph aureus) 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 present.

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 brain herniation 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 meningitis) 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 obstructive hydrocephalus • 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 diagnosis 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 consciousness E. Bacterial meningitis may also present atypically: important points

1. Bacterial meningitis can be rapidly lethal Case Example 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 grew meningococci. • 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 spells. 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 patients 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 common. 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 systemic infection. 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 ischemic stroke. 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. Case Example 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 formation C. Location 1. Abscesses due to hematogenous spread a. Most common in area of middle cerebral artery but may involve any part of brain. 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 abscess Case Example 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 neurological deficit. Important Points: 1. Diabetes is a risk factor for bacteremia and abscess formation - including brain and parameningeal abscesses. 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 subdural empyema. 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 INFECTIONS 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 and otitis 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 Meningitis Meningitis Protein Elevated Mildly elevated Elevated (extreme) Elevated Glucose <50% blood Normal <50% blood glucose <50% blood glucose glucose Cells Poly's Lymphs Lymphs Lymphs +poly's Other Gram stain PCR AFB Stain India Ink Prep Culture Culture Cryptococcal antigen PCR (20 ml CSF) Culture (20 ml CSF) PCR (PCR) 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 bacterial meningiis 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

3. Hypothalamic/pituitary dysfunction: diabetes insipidus, inappropriate ADH secretion

REFERENCES General: 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 Classic Articles: 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. Meningitis: Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. NEJM 336:708-716, 1997 Sigurdardottir B et al. Acute bacterial meningitis in adults: a 20-year overview. Arch. Int. Med. 157:425-30, 1997. Coyle, PK. Glucocorticoids in central nervous system infections. Arch Neurol. 56:796-801. Leist TP et al. Tumor necrosis factor alpha in cerebrospinal fluid during bacterial but not viral meningitis. J Exp Med 167:1743-1748, 1988. Horwitz, Williams CPS, Swanson AG, Chapman JT Brain swelling with acute purulent meningitis. Pediatrics 34:220-227, 1964. Harper JR, Lorber J, Smith H, Bower's DB, Timing of lumbar puncture in childhood meningitis. Brit Med J 291:651-653, 1985 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. Hanigan WC, Asner NG, Elwood PW. Magnetic resonance imaging and the nonoperative 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)

Postinfectious syndromes: 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.

NERVOUS ORGANS SYSTEM COURSE

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