I. Central nervous system infections are usually life-threatening, necessitating immediate diagnosis and treatment to prevent death or significant residual brain damage.

• Headache with fever and signs of meningeal irritation (nuchal rigidity and Brudzinski's sign) strongly suggests infection which must be ruled out without delay; however, neonates or elderly individuals with central nervous system infection may not be able to report headache and fever, and signs of meningeal irritation may be absent.

 
• Predisposing factors for central nervous system infections include bacteremia (such as in bacterial endocarditis), debilitating conditions (such as chronic renal failure), immunologic compromise (such as from AIDS, lymphoma or immunosuppressive drugs), disruption of protective barrirers (such as following basilar skull fracture with associated cerebrospinal fluid rhinorrhea or following neurosurgical procedures such as cerebrospinal fluid shunt placement).

 
II. Cerebrospinal fluid (CSF) examination
• Most important test for identifying evidence of central nervous system infeciton is examination of cerebrospinal fluid.

 
• Cerebrospinal fluid study provides definitive evidence of infection along with opportunity for culture and identification of infection organism; must be performed prior to instituting antibiotic therapy in order to culture most organisms; culture of maternal obtained from sources other than cerebrospinal fluid (such as blood culture, urine culture, or wound culture) will usually either not yield organisms or yield organisms other than that producing central nervous system infection.

 
• Lumbar puncture (performed by attending physician) is preferred method for obtaining cerebrospinal fluid in most cases; however, cerebrospinal fluid can also be obtained by cisterna magna or lateral cervical puncture (performed by neurosurgeons under fluoroscopy) or by ventricular puncture (performed by neurosurgeons through cranial burr hole, except when cerebrospinal fluid shunt tubing is already in place, or through open fontanelle in neonates).

 
• Caution must be exercised in performing lumbar puncture in patient with signs of increased intracranial pressure (such as papilledema), since removal of cerebrospinal fluid from subarachnoid space may alter intracranial pressure dynamics precipitating brain herniation (transtentorial uncal herniation, central rostral-caudal herniation, or cerebellar tonsillar herniation).

• Since delay in diagnosis and treatment of central nervous system infection is usually fatal, attending physician must balance potential risks of lumbar puncture versus potential risk of delay in diagnosis.

 
• Radiologic imaging studies (such as CT scans) can quickly identify factors predisposing to herniation (such as mass effect or pre-existing early herniation).

 
• Inserting secure intravenous infusion apparatus prior to performing lumbar puncture permits infusion of hyperosmolar agents (such as mannitol) to reduce intracranial pressure if signs of herniation appear during lumbar puncture; additionally, antiobiotic therapy can be immediately instituted once appropriate cerebrospinal fluid samples have been obtained.

 
• Lumbar puncture should be performed using meticulous sterile technique, obtaining values for opening pressure and removing sufficient cerebrospinal fluid for all necessary studies.

 
• Normal opening pressure should be no more than 180 mm of water.

 
• It is incorrect that removing only minimal (1 mL) cerebrospinal fluid will prevent herniation; once arachnoid membrane is punctured, change in pressure dynamics will occur, since after removal of spinal needs, at least 40 mL or more of cerebrospinal fluid will continue to leak through puncture holes in arachnoid and dura (filling subdural and epidural spaces).

• Normal cerebrospinal fluid is thin, colorless, sparkling, crystal-clear fluid that does not cagulate; abnormal cerebrospinal fluid can be turbid (cloudy), colored, viscous, frankly purulent, or bloody; as few as 400 blood cells per cubic millimeter (microliter) result in turbidity.

 
• Tests performed on cerebrospinal fluid include:

 
• Glucose - normal cerebrospinal fluid glucose level is about 60% of blood glucose level; values of less than 50% of simultaneous blood glucose or values below 40 mg/dL are indicative of meningeal inflammation (as occurs with central nervous system infection); very low glucose values (less than 20 mg/dL) are indicative of granulomatous infections such as tuberculous meningitis.

 
• Protein - cerebrospinal fluid protein varies with central nervous system site and with age; protein elevation is found with variety of central nervous system disorders including inflammation, infection, tumor, or stroke.

• Cell count - cerebrospinal fluid normally contains no neutrophils or polymorphonuclear leukocytes and no more than five lymphocytes per cubic millimeter (microliter); more cells (cerebrospinal fluid pleocytosis) are abnormal; neutrophils are associated with infection, hemmorrhage, infarction (stroke), and tumor; eosinophils occur in small numbers in same circumstances as neutrophils, while large numbers are found with central nervous system parasitic infections, foreign bodies, allergies processes, malignant lymphomas, and post-myelography; plasma cells are found in viral disease, multiple sclerosis, in recovery phase of bacterial meningitis, and in luetic (syphilis) infection.

 
• Microbiology

 
• Light microscopy - if cerebrospinal fluid contains more than 100 organisms per milliliter, microscopic slide made from sediment obtained by centrifugation will reveal bacteria or fungi after Gram stain; tuberculous bacilli can be visualized in slides stained with acid-fast methods (Ziehl-Neelsen or fluorescent rhodamine stains); identification of Cryptococcus neoformans is possible in India ink preparations; amoeba can be detected as mobile trophozoites in wet mounts examined by phase interference microscopy; neutrophils containing keratin fragments can be identified using polarized light in chemical meningitis secondary to spillage of contents of epidermoid tumor, craniopharyngioma, or dermoid cyst.

 
• Serologic studies (antigen-antibody studies)

 
• Cryptococcal antigen (latex particle agglutination test)

 
• Elevated IgM levels can be detected in herpes simplex encephalitis

 
• Countercurrent immunoelectrophoresis (CIE) can rapidly detect polysaccharide antigens associated with meningococcal, pneumococcal, and Hameophilus influenzae (type B) meningitis

 
• Syphilis serology - VDRL procedure can identify up to 50% and fluorescent treponemal antibody absorption test (FTA-ABS) will identify over 90% of patients with neurosyphilis

 
• IgG and measles antibody titers are elevated in subacute sclerosing panencephalitis
• Culture

 
• Final identification and verification of organism type requires culture; however, contamination can lead to false positive results and negative culture results do not exclude organisms, since technical problems may prevent culture; false negative cultures result from antimicrobial drug treatment prior to cerebrospinal fluid collection (partially-treated meningitis).

 
• Culture of some organisms requires special media or collection techniques (for example, large quantities of cerebrospinal fluid are necessary for successful culturing of tuberculous bacilli and special transport media are necessary to preserve many viruses).

 
III Bacterial (suppurative; purulent) meningitis
• Organisms typically causing bacterial meningitis vary with age:

 
• Neonates (up to age 3 months)

 
• Lack of sufficient immunologic maturity to mount adequate immune response allows local infections to become disseminated to central nervous system; presenting signs and symptoms are non-specific (such as irritability, poor feeding, cyanosis, jitteriness, or lethargy); nuchal rigidity does not occur; fever is uncommon, and infected infant often is hypothermic.

 
• Infection by organisms of femal genital tract is acquired during passage through birth canal; such organisms include: enteric gram-negative rods (particularly Escherichia coli), group B B-hemolytic streptococci, and Listeria monocytogenes; such infections usually present during first week of life.

 
• Infections with Staphylococcus aureus, Pseudomonas, Proteus, andSalmonella are usually acquired after birth due to environmental contamination ( contact with contaminated articles or handling by infected individuals).

• Infants

 
• Immunologic system is mature enough by age 3 months to protect against most environmental pathogens, except those organisms surrounded by polysaccharide capsule: Haemophilus influenzae (particularly group B) and Streptococcus pneumoniae(pneumococcus); loss of protective maternal immunoglobulins (acquired through transplacental passage) against these organisms permits nasopharyngeal colonization to progress to localized infection (including otitis media), bacteremia, and in some infants, meningitis.

 
• Peak incidence at age 1 year; after age 4 years meningitis is uncommon (due to further maturation of immune system)

 
• Children and adolescents

 
• Because of large number of type specific capsular antigens and lack of cross immunity between types, Streptococcus pneumoniae(pneumococcus) remains common as cause of meningitis in all age groups after 3 years.

 
• Neisseria meningitidis (meningococcus) produces epidemic meningitis with rapid revolution of symptoms and associated petechial or purpuric skin rash.

 
• Adults

 
• Meningitis is rare and most often is associated with some underlying predisposing condition such as immunologic compromise, alcoholism, trauma, surgery, or systemic illness (such as pneumonia, septicemia, or endocarditis); recurrent meningitis (particularly pneumococcal) suggests abnormal communication between subarachnoid space and skin or nasopharynx; splenectomy or sickle cell anemia (with its associated auto-splenectomy) predisposes to pneumococcal sepsis and meningitis.

 
• Elderly individuals seem to be particularly susceptible to meningitis caused by same organisms as in neonates or infants.
• Complications

• Increased intracranial pressure

 
• Obstruction of normal subarachnoid cerebrospinal fluid circulation due to inflammation produces increased pressure that resolves as inflammation subsides with treatment.

 
• Cerebral edema may result from inflammation and bacterial toxins.

 
• Cortical venous thrombophlebitis or arteritis involving subarachnoid vessels can produce brain ischemia or infarction with resultant edema

• Syndrome of inappropriate antidiuretic hormone (ADH; vasopressin) secretion (cerebral salt wasting)

 
• Derangement (due to subarachnoid inflammation or cerebral edema) of hypothalamic mechanisms regulating blood volume and osmolality resulting in water retention with consequent dilutional hyponatremia

 
• Persistent ADH secretion despite fall in serum osmolality below normal values; diagnosis based upon finding hyponatremia with concomitant serum hypo-osmolality and urinary hyperosmolality

 
• Hyponatremia is usually not associated with clinical symptoms until serum sodium level falls below 120 meq/L and seizures and coma may occur with values approaching 100 meq/L levels

 
• Treatment involves fluid restriction; treatment with combination hypertonic saline infusion and diuretics can rapidly correct serum sodium level but also causes central pontine myelinolysis

 

• Brain infarction

 
• Thrombophlebitis - cortical venins encased in purulent exudate within subarachnoid space can become thrombosed resulting in venous infarction

 
• Arteritis - subarachnoid arteries encased in purulent exudate become inflamed (vasculitis) with consequent thrombosis and infarction
• Abscess - dead tissue in areas of infarction can become nidus for development of brain abscess

 
• Identified by radiologic imaging studies

 
• Must be differentiated from primary brain abscess which leaks organisms into subarachnoid space producing secondary meningitis

 
• Subdural fluid collection

 
• Subdural effusion - infants with meningitis are particularly susceptible to development of subdural fluid collections: differentiated from subarachnoid (cerebrospinal) fluid by high protein content of subdural fluid; signs of subdural fluid collection include increased irritability, lethargy, seizures, persistent fever, fullness of fontanelle, or increasing head circumference; small effusions resolve spontaneously, but large effusions require repeated percutaneous subdural taps to remove fluid utnil it no longer accumulate

 
• Subdural empyema - extremely rare complications of meningitis in which subdural effusion fluid becomes infected; treatment involves immediate neurosurgical drainage

 
• Seizures

 
• Frequent in infants and children presumably related to effects of subarachnoid inflammation and bacterial toxins on adjacent cerebral cortex; can also occur with subdural effusion or empyema (local pressure effect) or with metabolic derangements (such as hyponatremia from syndrome of inappropriate ADH section); seizures usually stop with successful treatment of meningitis and do not lead to epilepsy

 
• Can also occur due to cortical infarction or brain abscess; subsequent epilepsy is likely due to permanent cerebral damage

 
• Persistent fever - indicates inadequate antibiotic therapy, subdural effusion or empyema, brain abscess, or systemic infectious focus (such as abscess elsewhere in body or osteomyelitis)

• Hydrocephalus
1.  Acute - purulent material can obstruct cerebrospinal fluid pathways leading to ventricular enlargement; diagnosed by radiology imaging studies; usually resolves with treatment of infection
2. Communicating hydrocephalus - long-term complication due to subarachnoid fibrosis as reparative reaction following meningitis; fibrosis obstructs normal cerebrospinal flow toward arachnoid granulations (site of absorption into venous sinuses); diagnosed by radiologic imaging studies; necessitates cerebrospinal fluid shunt insertion after complete cure of infection.
• Persistent neurologic deficits
1. Cranial nerve palsies - palsies related to increased intracranial pressure (involving oculomotor, abducens, and facial nerve) usually resolve with treatment of infection; persistent damage to vestibuloacoustic nerve (cranial nerve VIII), particularly manifested as hearing loss, is common complication of meningitis in infants and children; visual disturbances are also common
2. Infarction or abscess results in permanent brain destruction with consequent neurologic deficits
3. Other long-term sequelae in children include mental retardation, behavioral disorders, and learning disabilities

• Recurrent meningitis - suggests communication between subarachnoid space and skin or mucous membranes, parameningeal focus of infection (such as cranial osteomyelitis), or inadequate antibiotic treatment

 
• Waterhouse-Friderichsen syndrome - fulminant meningococcemia can produce septic shock and vasomotor collapse associated with hemorrhagic infarction of adrenal glands; often rapidly fatal

 
• Ventriculitis - infection of intraventricular cerebrospinal fluid; uncommon except associated with abscess that ruptures into ventricle or with neurosurgical opening to ventricles (as with cerebrospinal shunt tubing); often rapidly fatal except when caused by low virulence organisms such as Staphylococcus epidermidis or enterococcus (group D streptococci)

• Treatment

 
• Bacterial meningitis requires immediate treatment (medical emergency)

 
• Antibiotic therapy must be administered intravenously and at high doses; minimum treatment is for 10 days (or 7 days after becoming afebrile), but for relatively resistant organisms (such as gram-negative bacteria) treatment for 3 weeks or longer often is necessary

 
• Cerebrospinal fluid is examined from lumbar punctures performed 24-48 hours after initiating antibiotic therapy and 24-48 hours after cessation of antibiotics;

 
1. Cerebrospinal fluid should be sterile by 48 hours after beginning therapy for relatively sensitive infection organisms (such as Neisseria meningitidis, Haemophilus influenzae, or Streptococcus pneumoniae)

 
2. Positive culture at 48 hours can sometimes still be obtained in relatively resistant organisms (such as gram-negative enteric bacteria), necessitating repeat lumbar puncture at 72-96 hours after antibiotic initiation, at which time cerebrospinal fluid should be sterile

 
3. With successful antibiotic therapy, cerebrospinal fluid differential cell count changes to predominantly lymphocytes

 
4. Persistence of organisms identifiable by culture or persistent neurophilic predominance in cell count signifies inadequate antibiotic therapy or parameningeal focus with continue seeding of cerebrospinal fluid

• Antibiotic choice

 
• Initial therapy (prior to culture results) should be based upon assumptions concerning likely organism based upon patient age, environmental exposure, and risk factors; combinations of antibiotics covering a wide-range of potential pathogens is preferred

 
1. Combination therapy with ampicillin/gentamycin or ampicillin/cefotaxime for neonates

 
2. Combination therapy with ampicillin/ceftriaxone or ampicillin/chloramphenicol for infants, children, adolescents, and adults

 
• Once culture results are available, therapy should be changed to antibiotic to which organism is sensitive

• Prophylaxis

 
1. All infants should receive immunization against Haemophilus influenzae type B

 
2. Immunization against many serotypes of pneumococcus is available for elderly and immunocompromised individuals

 
3. During epidemics of meningococcal meningitis, contacts should receive prophylactic antibiotics

 
IV. Tuberculous (Mycobacterium tuberculosis) infection

• Since organism culture takes as long as four weeks, diagnosis must be based upon finding evidence of central nervous system infection (such as elevated cerebrospinal fluid cell count) along with active pulmonary tuberculosis, positive purified protein derivative (PPD) skin test, and microscopically identifiable acid-fast organisms in cerebrospinal fluid sediment or brain tissue biopsy

• Tuberculous meningitis

1. Gradual onset of nonspecific symptoms of malaise, low-grade fever, and anorexia followed later by lethargy, seizures, cranial nerve palsies focal (often brain stem) neurologic signs, and evidence of increased intracranial pressure (papilledema); meningeal signs (such as nuchal rigidity) are uncommon

 
2. Cerebrospinal fluid obtained by lumbar puncture usually shows increased numbers of lymphocytes, low glucose (often less than 20 mg/dL), and elevated protein (sometimes fluid will form clot or pellicle)

• Tuberculoma - granuloma involving brain parenchyma (can be single or multiple); must be differentiated from tumor or abscess, necessitating neurosurgical biopsy with culture and histologic identification of tuberculous organisms

 
• Treatment requires long course of combination antituberculous medications; initial medication regimen must be modified when culture results establish sensitivity

 
• Complications

 
1. Medication-induced neurologic sequelae include:

 
1. Isoniazid-induced neuropathy - can be avoided by pyridoxine supplementation

 
2. Streptomycin-induced damage to cranial nerve VIII (with consequent deafness and vestibular dysfunction

 
3. Ethambutol-induced optic nerve damage

 
4. Cycloserine-induced seizures

 
2. Hydrocephalus - very common due to dense subarachnoid fibrosis surrounding brain stem and interfering with normal cerebrospinal fluid flow

 
3. Arteritis - involves vessels at base of the brain, producing infarctions
V. Brain abscess

1. Slowly progressive onset of symptoms suggesting intracranial mass lesion, including headache, focal neurologic signs, lethargy, and increased intracranial pressure; seizures are frequent, but fever and leukocytosis often are absent; predisposing conditions include sinusitis, mastoiditis, bacterial endocarditis, or lung abscess

 
2. Diagnosis suggested by radiologic imaging studies (particularly "doughnut" lesion consisting of low density area with encircling higher density capsule and marked surrounding cerebral edema); confirmation requires neurosurgical exploration and drainage (with biopsy and culture to determine organism)

 
3. Lumbar puncture can be dangerous due to potential for inducing herniation, and cerebrospinal fluid study generally is not helpful (culture is usually negative, cell count normal, and protein only slightly elevated)

 
4. Evolution of brain abscess - initial phase is cerebritis (poorly marginated area of infection and edema); followed by central necrosis and liquefaction which is then walled off by margin of dense fibrosis and gliosis (evident as "doughnut" lesion on radiologic imaging studies)

 
5. Treatment involves neurosurgical drainage and high dose intravenous antibiotics


VI Fungal infection

1. Can present either as chronic meningitis (mimicking tuberculous meningitis) or as parenchymal infection (mimicking brain abscess)

 
2. Most often affects ummunocompromised individuals (although cryptococcal meningitis can occur in otherwise healthy individuals and candidal meningitis can affect neonates)

 
3. Selected common pathogenic organisms

 
• Cryptococcus neoformans - symptoms of meningitis can be rapidly progressive and fatal or indolent over many months; large volumes of cerebrospinal fluid (40 mL or more) are often necessary to establish diagnosis by culture, microscopic examination (Gram stain and India ink preparation), or antigen assay

• Candida albicans - usually produces both meningitis and multiple parenchymal abscesses (granulomas) in patients with candidal sepsis; antecedent predisposing illnesses include severe burns, anatomic disruptions of urinary tract (such as hydronephrosis), peritonitis, or following prolonged broad spectrum antibiotic treatment

• Rhinocerebral phycomycosis (zygomycosis; mucormycosis) - vasoinvasive organisms spreading from paranasal sinuses into retroorbital tissues and brain to cause fatal multifocal hemorrhagic brain infarction; usually associated with poorly controlled diabetic hyperglycemia and acidosis
• Aspergillosis - increasingly common infection found in immunocompromised individuals (particularly in AIDS); due to embolization of vasoinvasive fungal hyphae from lung infection; fungal emboli obstruct brain vesses resulting in infarcts which then serve as culture media for organism proliferation

• Treatment consists of antifungal medication: amphotericin B, 5-fluorocytosine, or ketoconazole depending on specific organism sensitivity; however, in most cases unless underlying disease or immunologic compromise can be reversed, antifungal therapy is not successful

 

 
 
 

VII. Neurosyphilis

1. Neurologic disease from infection by spirochete Treponema pallidum can occur in all patients with inadequately treated syphilis, producing various types neurologic damage over many years; this complication is completely avoidable by adequate early antibiotic treatment

 
2. Diagnosis based upon examination of cerebrospinal fluid

 
VIII. Cysticercosis
 
1. Multiple brain cysts produced by larval (embryo) form of pork tapeworm Taenia solium; larva migrate from intestine into circulation to be transported to muscle, eye, and brain; associated with intense in inflammatory reaction and calcification

 
2. Often asymptomatic; most common clinical symptom is seizures; radiologic imaging studies demonstrate multiple intracranial calcifications and ring-enhancing lesions; treatment with praziquantel (broad-spectrum antinematode drug) kills surviving organisms


IX. Rickettsial infection

1. brupt onset of fever, headache, myalgias, stiff neck, confusion. seizures, lethargy and subsequent coma; associated with maculopapular rash development two to four days after onset of fever; death results from pneumonia, renal failure, or circulatory collapse

 
2. Pathology consists of generalized necrotizing vasculitis resulting in petechial hemorrhages and focal necrosis scattered throughout brain

 
3. Causative agent include Rickettsia prowazekii (typhus; transmitted by body lice); Rickettsia tsutsugamushi (scrub typhus; transmitted by chiggers)

 
4. Diagnosis is based upon signs of neurologic disturbance associated with characteristics skin rash and history of insect bite: Weil-Felix reaction (antibody test) positive during second week of illness

 
5. Treatment involves prompt administration of antibiotics, either intravenous chloramphenicol or oral tetracycline