Handbook of Neurosurgery 7th Ed

16. Infections

16.1. Prophylactic antibiotics

GENERAL PRINCIPLES³

1. antibiotics must be in tissues at time of contamination (thus, avoid “on-call” antibiotics; give 60 minutes prior to incision)

2. repeated administration is vital in prolonged procedures

3. typical infecting organisms are usually predictable. Coverage for these organisms is adequate (broadening spectrum is of no value)

4. in low risk operations (e.g. carotid endarterectomy, where infections rare and seldom life-threatening) may cost more to prevent than to treat

5. prolongation of antibiotics beyond first post-op day provides no additional protection (may not be true in patients with surgical drains)

6. theoretical side effects (alteration of patient’s flora, development of resistant strains in patient or hospital) have not been realized without prolonged administration of pre-op or post-op antibiotics

7. factors that increase risk of operative wound infection include:

A. systemic factors: malnutrition, reoperation, infection at secondary site (especially UTI when GU tract manipulated), prolonged administration of antibiotics

B. local factors: epinephrine, dehydration, hypoxia

SPECIFIC AGENTS FOR PROPHYLAXIS

1. cephalosporins:

A. agents of choice where skin flora (coagulase (–) or (+) staph) are likeliest pathogens

B. may safely be given even with history of mild, non-immediate manifestations of PCN allergy (e.g. “rashes”). Contraindicated if history of immediate or accelerated reaction (shock, bronchospasm, urticaria)

C. cefazolin (Ancef®, Kefzol®):

• effective, widely studied, therapeutic levels in brain tissue after systemic administration⁴, long half-life

• prophylactic dose: 1-2 gm (peds: 25 mg/kg up to 1 gm) IV 60 min before surgery, then q 6 hr x 24 hrs post-op

D. some S. aureus strains are efficient in ß-lactamase degradation of cephalosporins, and cefazolin is particularly susceptible. Lower infection rates may result with cefamandole (2 gm initially, and then 1 gm q 2-3 hrs intraoperatively)⁵

E. a semisynthetic penicillin may be more appropriate if good CSF penetration is necessary

2. vancomycin: alternative if cephalosporin contraindicated (incidence of anaphylactic reactions is too high for routine use). Dose (empiric): 15 mg/kg (up to 1 gm) IV pre-op, then 10 mg/kg q 8 hrs for 24 hrs post-op

3. penicillins: disadvantages: probably less safe, shorter half-life, may prolong bleeding times. Nafcillin is probably the best agent in this group

PROPHYLACTIC ANTIBIOTICS FOR SPECIFIC NEUROSURGICAL PROCEDURES

1. carotid endarterectomy: routine use not indicated (infection risk too low); when risk of infection is high, use cefazolin (as for general prophylaxis, see above)

2. craniotomy: risk of infection may be increased in prolonged or microsurgical procedures and in reoperations. No significant difference in the specific regimen used was detected in meta-analysis⁶. Options include:

• cefazolin (see above)

• clindamicin (300 mg IV) pre-op & q 4 hrs

• vancomycin (see above)

• some add gentamicin (80 mg IM) pre-op to any of these

3. CSF shunting procedures: efficacy has been documented when the infection rate is unusually high for some reason (e.g. ≈ 15%). Antibiotics possibly reduce early infections, i.e. ≈ first week post-op

A. for general use

1. select one of the following:

• cefazolin (see above)

• a 1st generation cephalosporin (e.g. cephapirin (Cefadyl®) 25 mg/kg (up to 1 gm)) IVP intra-op and 6 hrs post-op

• nafcillin 50 mg/kg (up to 2 g) IV 60 min before surgery and q 4 hrs post-op x 5 doses total

2. PLUS

• intrathecal gentamicin 4 mg injected into shunt at time of placement (no longer available in U.S., but preservative-free pediatric gentamicin may be diluted appropriately and used)

B. Kaiser: suggests no antibiotics if infection rate low (< 10%). If high (> 20%) use trimethoprim (160 mg IV) plus sulfamethoxazole (800 mg IV) pre-op and q 12 hrs x 3 doses post-op (NB: this latter infection rate is very high, and results are thus questionable 7)

4. ICP monitors: see page 869

5. procedures involving incisions through oral or pharyngeal mucosa: gentamicin (1.7 mg/kg IV) and clindamicin (300 mg IV) pre-op & q 8 hrs post op x 24 hrs. Cefazolin & 3rd generation cephalosporin also effective when given over 24 hr period pre-op

6. spinal surgery: reduction of infection was suggested but was not statistically significant (low incidence would require large study)

A single blind prospective study⁷ showed the incidence of post-neurosurgical operative wound infections were reduced with cefazolin (1 gm IV) plus gentamicin (80 mg IV) given one hr before incision and q 6 hrs intra-op (none post-op) with significant results in patients without foreign implants (especially craniotomies; no significant difference for spinal operations, but numbers were small). All infections were Staph. aureus or epidermidis (makes use of gentamicin questionable).

16.2. Meningitis

Community acquired meningitis (CAM) is generally more fulminant than meningitis following neurosurgical procedures (the former tend to occur with more virulent organisms or impaired host defenses). Waterhouse-Friderichsen syndrome: occurs in 10-20% of children with meningococcal infection (usually disseminated infection in age< 10 yrs), produces large petechial hemorrhages in the skin and mucous membranes, fever, septic shock, adrenal failure (due to hemorrhage into adrenal glands) and DIC. Focal neurologic signs are rare in acute purulent meningitis. Meningitis is a medical emergency, and should be treated immediately. See Lumbar puncture on page 201for a discussion about when to perform an LP.

16.2.1. Post-neurosurgical procedure meningitis

1. usual organisms: S. aureus, Enterobacteriaceae, Pseudomonas sp., pneumococci

2. empiric antibiotics: vancomycin (to cover MRSA) + ceftazidime specifically: vancomycin (adult) 1 gm IV q 8 hrs: (check level before and after 3rd dose and adjust accordingly) + ceftazidime (Fortaz®) 1-2 gm IV q 8 hrs

3. for pseudomonas, add gentamicin (IV & IT)

4. if organism turns out to be non-MRSA S. aureus, change vancomycin to IV PRSP (e.g. nafcillin)

16.2.2. Post craniospinal trauma meningitis (post-traumatic meningitis)

Epidemiology

Occurs in 1-20% of patients with moderate to severe head injuries⁸. Most cases occur within 2 weeks of trauma, although delayed cases have been described⁹. 75% of cases have demonstrable basal skull fracture (see page 887), and 58% had obvious CSF rhinor-rhea.

Pathogens

As expected from above, there is a high rate of infection with organisms indigenous to the nasal cavity. The most common organisms in a series from Greece were Gram-positive cocci (Staph. hemoliticus, S. warneri, S. cohnii, S. epidermidis, and Strep. pneumonia) and Gram-negative bacilli (E. coli, Klebsiella pneumonia, Acinetobacter anitratus)⁸.

Treatment

1. also see CSF Fistula, Treatment on page 303

2. antibiotics: appropriate antibiotics are selected based on CSF penetration and organism sensitivities (adapted to the pathogens common in the patient’s locale; in the above series, all Gram-negative strains appeared resistant to ampicillin and third-generation cephalosporins, but were sensitive to imipenem and ciprofloxacin; Gram-positive strains were all sensitive to vancomycin). For empiric antibiotics see page 343

3. surgical treatment vs. “conservative treatment”: controversial. Some feel that any case of posttraumatic CSF rhinorrhea should be explored^{10, 11}, and that cases of spontaneous cessation often represent obscuration by incarcerated brain, so-called “sham healing” with the potential for later CSF leak and/or meningitis⁹. Others support the notion that cessation (possibly with the assistance of lumbar spinal drainage) is acceptable

4. continue antibiotics for 1 week after CSF is sterilized. If rhinorrhea persists at this time, surgical repair is recommended

16.2.3. Recurrent meningitis

Patients with recurrent meningitis must be evaluated for the presence of abnormal communication with the intraspinal/intracranial compartment. Etiologies include dermal sinus (either spinal or cranial, see page 252), CSF fistula (see page 300), or neurenteric cyst (see page 227).

16.2.4. Antibiotics for specific organisms in meningitis

Route is IV unless specified otherwise.

• S. pneumoniae: PCN G (2nd choice: chloramphenicol)

• N. meningitidis: PCN G (2nd choice: chloramphenicol)

• H. influenza:

A. non-penicillinase producing: ampicillin

B. penicillinase producing: chloramphenicol

• Group B strep: ampicillin

• L. monocytogenes: ampicillin

• S. aureus

A. initially before sensitivities known, or if MRSA or multiply resistant strains or resistant coagulase negative S. aureus prevalent or suspected: vancomycin + PO rifampin + PO trimethoprim

B. once it is known that the staph is not MRSA:

1. infant (< 7 d): methicillin

2. all others: nafcillin

3. PCN allergy: vancomycin or (cefazolin via both IV + IT)

• aerobic Gram negative rods (GNR)

A. ceftriaxone, or cefotaxime, or moxalactam (in order of preference, make alterations based on sensitivities)

B. if aminoglycoside required, intraventricular therapy is indicated after the newborn period

• P. aeruginosa

A. ceftazidime (Fortaz®) alone if not life threatening

OR

B. more serious infections require 2 agents (aminoglycoside gives more rapid kill, and may be used initially for 3 days and then stopped if sensitivities to ceftazidime are acceptable): ceftazidime + APAG + IT gentamicin 4 mg q 12 hrs (give via intraventricular route if ventriculitis is present)

OR

C. for overwhelming infection:

ceftazidime + tobramicin + ticarcillin

• candida spp.

A. premedicate with the following prior to amphotericin infusion:

1. IV bolus of NS (e.g. 500 ml) 2 hrs prior to amphotericin infusion to maintain renal blood flow

2. Demerol 50 mg IV q 1 hr during amphotericin therapy PRN for rigors

3. acetaminophen 650 mg po or per-NG 30 minutes prior to amphotericin infusion

B. amphotericin B deoxycholate (not the lipid form) 1 mg/kg IV over 4-6 hr, hold for hypotension (e.g. SBP < 90 mm Hg), cannot be given through peripheral IV because of phlebitis (central line or PICC line needed)

C. 5-fluorocytosine (5-FC) 25 mg/kg po or per-NG q 6 hrs

16.3. Shunt infection

Risk of early infection after shunt surgery: reported range is 3-20% per procedure (typically ≈ 7%).

Acceptable infection rate¹²: < 5-7% (although many published series have a rate near 20%¹³, possibly due to different patient population).

Risk factors for shunt infection

Many factors have been blamed. Some that seem to be better documented include:

1. young age of patient¹³: in myelomeningocele (MM) patients, waiting until the child is 2 weeks old may significantly lower the infection rate

2. length of procedure

3. open neural tube defect

Morbidity of shunt infections in children

Children with shunt infections have a increased mortality rate and risk of seizure than those without shunt infection. Those with myelomeningocele who develop ventriculitis after shunting have a lower IQ compared to those without infection¹⁴. Mortality ranges from 10-15%.

PATHOGENS

Over 50% of staph infections occur within 2 weeks post-shunt, 70% within 2 mos. Source is often the patient’s own skin¹². It is estimated that in ≈ 3% of operations for shunt insertion the CSF is already infected (therefore culture CSF during insertion).

Early infection

Most commonly:

1. Staph. epidermidis (coagulase-negative staph): 60-75% of infections (most common)

2. S. aureus

3. Gram-negative bacilli (GNB): 6-20% (may come from intestinal perforation)

In neonates E. coli and Strep. hemoliticus dominate.

Late infection (> 6 months after procedure)

Risk: 2.7-31% per patient (typically 6%). Almost all S. epidermidis. Tends to be internal type. 3.5% of patients account for 27% of infections¹⁵.

“Late” shunt infections may be due to:

1. an indolent infection due to Staph. epidermidis

2. seeding of a vascular shunt during episode of septicemia (probably very rare)

3. colonization from an episode of meningitis

Candida spp. infections

Candida spp. are responsible for the majority of fungal ventricular shunt infections. Usually occurs in children < 1 year age. Incidence: 1-7%¹⁶. The 4th leading pathogen causing meningitis in neurosurgical patients in 1 study¹⁷, possibly related to the use of prophylactic antibiotics used for ICP monitoring and CSF drainage. Higher incidence in VP shunt patients with abdominal infections and shunts placed in patients with previous bacterial meningitis¹⁸. CSF typically shows: elevated WBCs and protein, normal glucose. Management recommendations:

1. completely remove the contaminated shunt (may be more important than with bacterial infections)

2. place a fresh external ventricular drain (if patient is shunt dependent)

3. treat with antifungal therapy: see page 345

4. place a fresh shunt after ≥ 5-7 days of therapy and clinical response is apparent

5. continue antifungal agents for 6-8 weeks

PRESENTATION

Non-specific syndrome: fever, N/V, lethargy, anorexia, irritability; may mimic acute abdomen. May also present as malfunction; 29% of patients presenting with shunt malfunction had positive cultures. In neonates may manifest as apneic episodes, anemia, hepatosplenomegaly, and stiff neck¹⁹. S. epidermidis infections tend to be indolent (smoldering). GNB infections usually cause more severe illness; abdominal findings more common; main clinical manifestation is fever, usually intermittent and low grade. Erythema and tenderness along shunt tubing occurs occasionally.

Shunt nephritis²⁰: may occur with chronic low level infection of a ventriculovascular shunt causing immune complex deposition in renal glomeruli, characterized by proteinuria and hematuria.

Blood tests

WBC: < 10K in one fourth of shunt infections. It is > 20K in one third.

ESR: rarely normal in shunt infections.

Blood cultures: positive in less than one third of cases.

CSF: WBC is usually not > 100 cells/mm³. Gram stains may be positive ≈ 50% (yield with S. epidermidis is much lower). Protein is often elevated, glucose may be low or normal. Rapid antigen tests used for community acquired meningitis are usually not helpful for the organisms that tend to cause shunt infections. CSF cultures are negative in 40% of cases (higher culture yield if CSF WBC count is > 20K).

EVALUATION OF SHUNT FOR INFECTION

1. history and physical directed at determining presence of above signs and symptoms with emphasis on

A. history suggestive of infection at another site

1. exposure to others with viral syndromes, including sick siblings

2. GI source (e.g. acute gastroenteritis). Often associated with diarrhea. Diarrhea is a symptom that usually exonerates shunt infection

3. otitis media (check tympanic membranes)

4. tonsillitis/pharyngitis

5. appendicitis (peritoneal inflammation may impede VP shunt outflow)

6. URI

7. UTI

8. pneumonia

B. physical exam to R/O meningismus (stiff neck, photophobia…)

2. serum WBC count with differential

3. shunt tap: should be done in cases of suspected shunt infection. Shave and prep carefully to avoid introducing infection. GNB requires different therapy and has higher morbidity than staph, thus it is desirable to identify these rare patients: > 90% of these had positive Gram-stained CSF smear (only a few Gram-positive infections have positive results). GNB have higher protein and lower glucose, and neutrophils predominate in differential (unpublished data¹²)

4. CT: usually not helpful for diagnosing infection. Ependymal enhancement when it occurs is diagnostic of ventriculitis. CT may demonstrate shunt malfunction

5. abdominal U/S or CT: abdominal pseudocyst is suggestive of infection

6. ✖ LP: usually NOT recommended. May be hazardous in obstructive hydrocephalus (HCP) with a nonfunctioning shunt. Often does not yield the pathogen

TREATMENT

Antibiotics alone (without removal of shunt hardware)

Although eradication of shunt infections without removal of hardware has been reported^{21 (p 595-7), 22}, this has a lower success rate than with shunt removal²³, may require protracted treatment (up to 45 days in some), risks problems associated with draining infected CSF into the peritoneum (reduced CSF absorption, abdominal signs/symptoms including tenderness to full-blown peritonitis^{21 (p 235)}) or vascular system (shunt nephritis (see page 346), sepsis…), and often requires at least partial shunt revision at some point in most cases. Treatment with antibiotics without shunt removal is therefore recommended only in cases where the patient: is terminally ill, is a poor anesthetic risk, or has slit ventricles that might be difficult to catheterize.

Removal of shunt hardware

In most instances, during the initial treatment with antibiotics the shunt is either externalized (i.e. tubing is diverted at some point distal to the ventricular catheter and connected to a closed drainage system), or sometimes the entire shunt may be removed. In the latter case, some means of CSF drainage must be provided in shunt dependent cases; either by insertion of an external ventricular drain (EVD), or by intermittent ventricular taps or LPs (with communicating HCP). EVD allows easy monitoring of CSF flow, control of ICP, and repeated sampling for WBC determinations and cultures. In symptomatic patients or those with a positive CSF culture²⁴, any hardware removed should be cultured as only ≈ 8% are sterile in shunt infections. Skin organisms are fastidious and may take several days to grow.

If there is an abdominal pseudocyst, the fluid should be drained through the perito-neal catheter before removing it.

Empiric antibiotics

1. IV vancomycin used initially (penetration into CSF results in concentrations 18% that of serum).

2. PO rifampin may be added for increased coverage (10 mg/kg/day PO q 12 hrs)

3. when cultures return, change vancomycin to IV nafcillin unless patient is PCN allergic or cultures show MRSA (good penetration of inflamed meninges, lower toxicity than methicillin). If bactericidal activity is < 1:8, again consider adding rifampin

4. intraventricular injection of preservative-free antibiotics may be used in addition to IV therapy, clamp EVD x 30 minutes after injection

Treatment for specific organisms

Positive cultures from shunt hardware removed at the time of shunt revision in the absence of clinical symptoms or a positive CSF culture may be due to contamination and do not require treatment²⁴.

1. S. aureus and S. epidermidis

A. if sensitive (MIC ≤ 1.0 μg/ml): IT gent + (IV nafcillin, or cefazolin, or cephalothin, or cephapirin)

B. if resistant to nafcillin (i.e. MRSA), cephalothin, or cephapirin: PO rifampin + PO trimethoprim + IV & IT vancomycin

2. Enterococcus: IV/IT ampicillin + IT gent (if intravascular shunt: add IV gent)

3. other streptococci: either antistreptococcal or above enterococcal regimen

4. aerobic GNR: base on susceptibilities; both beta-lactam & APAG IV & IT indicated

5. Serratia marcescens: a rare cause of VP shunt infection²⁵ but the high morbidity may warrant aggressive antibiotic (IV + IT) and surgical therapy

6. Corynebacterium spp. & Proprionibacterium spp. (diphtheroids)

A. if PCN sensitive: use enterococcal regimen above

B. if PCN resistant: IV + IT vancomycin

7. Candida spp.: see page 346 for protocol, see page 345 for drugs

Intrathecal (IT) therapy

Yogev¹² cautions against high levels (caused neurologic effects in rabbits), he suggests striving for CSF concentrations comparable to peak blood values (e.g. 10-12 μg/ml for gent, or 25-30 μg/ml for amikacin).

Subsequent management

Once the CSF is sterile x 3 days, convert the EVD to a shunt (if an EVD was not used, it is still recommended that the shunt be replace with new hardware). Continue antibiotics an additional 10-14 days.

MANAGING VENTRICULOPERITONEAL SHUNTS IN PATIENTS WITH PERITONITIS

Peritonitis may occur as a result of:

1. perforation of a viscus (sometimes as a result of penetration by the peritoneal catheter tip²⁶, more common with obsolete Raimondi wire-reinforced tubing)

2. spontaneous bacterial peritonitis (SBP): absence of an identifiable intraabdominal source. Most commonly diagnosed in patients with cirrhotic ascites²⁷

3. or as a result of seeding through a VP shunt in a patient with a shunt infection: predominantly gram-positive, cutaneous organisms²⁸

Concerns following en episode of peritonitis in a patient with VP shunt:

1. ascending infection into the CNS: uncommon, especially in the acute setting while on appropriate antibiotics with shunts containing a 1-way valve (as most do). CSF grows predominantly mixed, gram-negative intestinal flora²⁸

2. contamination of the distal shunt: prevents permanent eradication of infection (appendicitis in the absence of peritonitis does not produce shunt infection²⁸)

3. shunt malfunction due to distal shunt obstruction: often as a result of walling off of the catheter tip, usually by omentum in reaction to the infection

Management recommendations following an episode of peritonitis (many viable options):

1. immediate appropriate treatment of peritonitis, usually managed by general surgeon (e.g. for ruptured appendix: appendectomy and appropriate antibiotics), with initial attempt to address shunt not being mandatory

2. anecdotally, cases have been managed successfully by cleaning off the peritoneal catheter with bacitracin solution, and then wrapping the catheter in a bacitracin soaked lap sponge until the time to close the abdomen

3. if the peritonitis was diffuse or if the shunt catheter is believed to have been contaminated, an option is to externalize the distal catheter, preferably once the patient has stabilized from the peritonitis (afebrile, stable vital signs, normal WBC)

A. externalization is done in a manner to avoid pulling contaminated catheter up towards hopefully sterile portions of the shunt. This can be accomplished by reopening the skin incision used for inserting the peritoneal catheter, and making a second incision over the shunt tubing, well above this entry point. The catheter is then divided at the upper incision. The catheter is grasped at the lower incision and is pulled, extracting both ends (the peritoneal end and the end just cut). The remaining catheter coming from above is connected to an external drainage system

B. CSF cultures are monitored daily

C. if 3 consecutive cultures are negative, a new distal catheter may be implanted

D. if cultures continuously grow organisms, then the shunt may be contaminated and should then be replaced with an entirely new shunt system

E. when it is time to replace the shunt, some authors^{29, 30} recommend using an alternative site other than the peritoneum, but this is not mandatory²⁸

16.4. Wound infections

16.4.1. Laminectomy wound infection

Occurs in 0.9-5% of cases³¹. May range from superficial to severe dehiscent wound infection. The risk is increased with age, long term steroid use, obesity, and possibly DM. Intraoperative mild hypothermia (as commonly occurs in the operating room) may also increase the risk of wound infection (as demonstrated with colorectal resection³²). Most are caused by S. aureus.

MANAGEMENT

1. culture the wound and/or any purulent drainage

2. start the patient empirically on vancomycin plus a third generation cephalosporin (e.g. ceftazidime)

3. modify antibiotics appropriately when culture and sensitivity results available

4. debride wound of all necrotic and devascularized tissue and any visible suture material (foreign bodies). Superficial wounds may be debrided in the office or treatment room, deep infections must be done in OR

5. shallow defects may be allowed to heal by secondary intention, and the following is one possible regimen

A. pack the wound defect with 1/4” Iodophor® gauze

B. dressing changes at least BID (for hospitalized patients, change q 8 hrs), remove and trim ≈ 0.5-1” of packing with each dressing change

1. while wound is purulent, utilize 1/2 strength Betadine® wet to dry dressings

2. when purulence subsides, switch to normal saline wet to dry

C. antibiotics, may be useful as an adjunct to wound treatment initially, switch to oral antibiotics as early as possible, a duration of 10-14 days total is probably adequate if local wound care is being done

6. some prefer to close wound by primary intention³³, it is critical that there be no tension on the wound for healing to occur. Some close over an irrigation system or antibiotic beads. Retention sutures may be helpful³⁴

7. with large defects or when bone and/or dura becomes exposed, the use of a muscle flap (often performed by a plastic surgeon) is probably required³¹

8. CSF leakage requires exploration in the OR with watertight dural closure to prevent meningitis

16.4.2. Craniotomy infection

Also, see page 343 under meningitis, post-neurosurgical procedure.

C-reactive protein

Following uncomplicated craniotomy for microsurgery for brain tumors, C-reactive protein (CRP) peaked on post-op day (POD) 2 with a mean value of 32 ± 38 mg/l³⁵. Values declined from POD 3 through 5, reaching a mean of 6.7 ± 11 on POD 5. These values may be lower than with most post-op infections.

16.5. Osteomyelitis of the skull

The skull is normally very resistant to osteomyelitis, and hematogenous infection is rare. Most infections are due to contiguous spread (usually from an infected air sinus, occasionally from scalp abscess) or to penetrating trauma (including surgery and fetal scalp monitors³⁶). With longstanding infection, edema and swelling in the area may become visible (usually over the forehead, but also may occur over the mastoids), and is called “Pott puffy tumor”.

Staphylococcus is the most common organism, with S. aureus predominating, followed by S. epidermidis. In neonates, E. coli may be the infecting organism.

Imaging findings may include: bony resorption, periosteal reaction, contrast enhancement.

Treatment

Antibiotics alone are rarely curative. Treatment is usually surgical debridement of infected skull, biting off infected bone with rongeurs until a normal snapping sound replaces the more muted sound made by rongeuring infected bone. In the case of an infected craniotomy bone flap, the flap usually must be removed and the edges of the skull rongeured back to healthy bone. Closure of the scalp without cranioplasty is performed.

Surgery is followed by at least 6-12 weeks of antibiotics³⁷, usually IV for the first 1-2 weeks, then orally for the remainder. Until MRSA is ruled out, vancomycin + a 3rd generation cephalosporin are used. Once MRSA is ruled out, vancomycin may be changed to a penicillinase resistant synthetic penicillin (e.g. nafcillin). Most treatment failures occurred in patients treated with < 4 weeks of antibiotics following surgery.

Cranioplasty may be performed ≈ 6 mos post-op if there are no signs of infection,

16.6. Cerebral abscess

Key concepts:

• may arise from hematogenous spread, contiguous spread, or direct trauma

• risk factors: pulmonary abscess or AV fistulas, congenital cyanotic heart disease, immune compromise, chronic sinusitis/otitis, dental procedures

• symptoms are similar to any other mass lesions but tend to progress rapidly

• peripheral WBC may be normal or slightly ↑, CRP usually ↑

• organisms: Streptococcus is most common, up to 60% are polymicrobial

• imaging: usually round with thin enhancing ring on CT or MRI. T2WI → high signal lesion with thin rim of low intensity surrounded by hi signal (edema). Unlike with tumor, DWI often shows core of restricted diffusion (not reliable)

• treatment: IV antibiotics, needle drainage for some, excision infrequently (for fungal and resistant abscess)

EPIDEMIOLOGY

Approximately 1500-2500 cases per year in the U.S. Incidence is higher in developing countries. Male:female ratio is 1.5-3:1.

RISK FACTORS

Risk factors include: pulmonary abnormalities (infection, AV-fistulas…, see below), congenital cyanotic heart disease (see below), bacterial endocarditis, penetrating head trauma (see below), chronic sinusitis or otitis media, and AIDS.

VECTORS

Prior to 1980, the most common source of cerebral abscess was from contiguous spread. Now, hematogenous dissemination is the most common vector. In 10-60% no source can be identified³⁸.

HEMATOGENOUS SPREAD

Abscesses arising by this means are multiple in 10-50% of cases³⁹. No source can be found in up to 25% of cases. The chest is the most common origin:

• in adults: lung abscess (the most common), bronchiectasis and empyema

• in children: congenital cyanotic heart disease (CCHD) (estimated risk of abscess is 4-7%), especially tetralogy of Fallot. The increased Hct and low PO₂ provides an hypoxic environment suitable for abscess proliferation. Those with rightto-left (veno-atrial) shunts additionally lose the filtering effects of the lungs (the brain seems to be a preferential target for these infections over other organs). Streptococcal oral flora is frequent, and may follow dental procedures. Coexisting coagulation defects often further complicate management⁴⁰

• pulmonary arteriovenous fistulas: ≈ 50% of these patients have Osler-Weber-Rendu syndrome (AKA hereditary hemorrhagic telangiectasia), and in up to 5% of these patients a cerebral abscess will eventually develop

• bacterial endocarditis: only rarely gives rise to brain abscess⁴¹. More likely to be associated with acute endocarditis than with subacute form

• dental abscess

• GI infections: pelvic infections may gain access to the brain via Batson’s plexus

In patients with septic embolization, the risk of cerebral abscess formation is elevated in areas of previous infarction or ischemia⁴².

CONTIGUOUS SPREAD

1. from purulent sinusitis: spreads by local osteomyelitis or by phlebitis of emissary veins. Virtually always singular. Rare in infants because they lack aerated para-nasal and mastoid air cells. This route has become less common due to improved treatment of sinus disease

A. middle-ear and mastoid air sinus infections → temporal lobe and cerebellar abscess. The risk of developing a cerebral abscess in an adult with active chronic otitis media is ≈ 1/10,000 per year⁴³ (this risk appears low, but in a 30 year-old with active chronic otitis media the lifetime risk becomes ≈ 1 in 200)

B. ethmoidal and frontal sinusitis → frontal lobe abscess

C. sphenoid sinusitis: the least common location for sinusitis, but with a high incidence of intracranial complications due to venous extension to the adjacent cavernous sinus → temporal lobe

2. odontogenic → frontal lobe. Rare. Associated with a dental procedure in the past 4 weeks in most cases⁴⁴. May also spread hematogenously

FOLLOWING PENETRATING CRANIAL TRAUMA OR NEUROSURGICAL PROCEDURE

Post-neurosurgical: especially with traversal of an air sinus. The risk of abscess formation following civilian gunshot wounds to the brain is probably very low with the use of prophylactic antibiotics, except in cases with CSF leak not repaired surgically following traversal of an air sinus. An abscess following penetrating trauma cannot be treated by simple aspiration as with other abscesses, open surgical debridement to remove foreign matter and devitalized tissue is required. Abscess has been reported following use of intracranial pressure monitors and halo traction⁴⁵.

PATHOGENS

1. cultures from cerebral abscesses are sterile in up to 25% of cases

2. organisms recovered varies with the primary source of infection

3. in general: Streptococcus is the most frequent organism, 33-50% are anaerobic or microaerophilic. Multiple organisms may be cultured to varying degrees, usually in only 10-30% of cases, but can approach 60%³⁸, and usually includes anaerobes (Bacteroides sp. common)

4. when secondary to fronto-ethmoidal sinusitis: Strep. milleri and Strep. anginosus may be seen

5. from otitis media, mastoiditis, or lung abscess: usually multiple organisms, including anaerobic strep., Bacteroides, Enterobacteriaceae (Proteus)

6. post traumatic: usually due to S. aureus or Enterobacteriaceae

7. odontogenic (dental) source: may be associated with Actinomyces

8. following neurosurgical procedures: Staph. epidermidis and aureus may be seen

9. immunocompromised hosts including transplant patients (both bone marrow and solid organ) and AIDS: fungal infections are more common than otherwise would be seen. Organisms include:

A. Toxoplasma gondii: see page 365 and page 367

B. Nocardia asteroides: see page 356

C. Candida albicans

D. Listeria monocytogenes

E. mycobacterium

F. Aspergillus fumigatus often from a primary pulmonary infection

10. infants: Gram negatives are common because IgM antibodies don’t cross placenta

PRESENTATION

Symptoms: none are specific for abscess, and many are due to edema surrounding the lesion. Most are due to increased ICP (H/A, N/V, lethargy). Hemiparesis and seizures develop in 30-50% of cases. Papilledema is rare before 2 yrs of age. Symptoms tend to progress more rapidly than with neoplasms.

Newborns: patent sutures and poor ability of infant brain to ward off infection → cranial enlargement. Common: seizures, meningitis, irritability, increasing OFC, and failure to thrive. Some authors say most newborns with abscess are afebrile. Tend not to do well.

EVALUATION

BLOODWORK

Peripheral WBC: may be normal or only mildly elevated in 60-70% of cases (usually > 10,000).

Blood cultures: should be obtained when abscess is suspected, usually negative.

ESR: may be normal (especially in congenital cyanotic heart disease where polycythemia lowers the ESR).

C-reactive protein (CRP): infection anywhere in body (including brain abscess and dental abscess) can raise the CRP level. May also be elevated in noninfectious inflammatory conditions and brain tumor. Sensitivity for abscess is ≈ 90%, specificity is ≈ 77%⁴⁶. For normal values see page 387.

LUMBAR PUNCTURE (LP)

The role of LP is very dubious in abscess. Although LP is abnormal in > 90%, there is no characteristic finding diagnostic of abscess. The OP is usually increased, and the WBC count and protein may be elevated. The offending organism can rarely be identified from CSF obtained by LP (unless abscess ruptures into ventricles) with positive cultures in ≈ 6-22%⁴⁷. There is a risk of transtentorial herniation, especially with large lesions (see page 203 for discussion).

Σ	✖ Due to the risk involved and the low yield of useful information, avoid LP if not already done.

BRAIN IMAGING

CT: ring enhancing. Sensitivity ≈ 100%. For CT staging of abscess see below.

MRI: see Table 16-2 for findings. Enhanced T1WI → thin-walled ring enhancement surrounding low intensity central region (Figure 35-1, page 1214). Fluid-fluid levels may be seen. Occasionally gas producing organisms may cause pneumocephalus.

Diffusion MRI: DWI → bright, ADC → dark (restricted diffusion suggesting viscous fluid)⁴⁸ (see Figure 35-1, page 1214). Unlike most tumors which are dark on DWI (see Figure 35-2, page 1214). More reliable with pyogenic abscess, less reliable e.g. with fungal⁴⁹ or TB abscess).

MR-spectroscopy: amino acids and acetate or lactate are diagnostic for abscess.

Leukocyte scan with ^99mTc-HMPAO: patient’s own WBCs are tagged and reinjected. Close to 100% sensitivity and specificity (sensitivity will be reduced if patient is treated with steroids within 48 hrs prior to the scan)⁴⁶.

ADDITIONAL EVALUATION

CXR and chest CT (if indicated) to look for pulmonary source.

Cardiac echo (Doppler and/or echo with agitated saline injection (bubble study)): for suspected hematogenous spread, to look for patent foramen ovale or cardiac vegetations.

STAGING OF CEREBRAL ABSCESS

Table 16-1 shows the four well recognized histologic stages of cerebral abscess, and correlates this with the resistance to insertion of an aspirating needle at the time of surgery. It takes at least 2 weeks to progress through this maturation process, and steroids tend to prolong it.

Table 16-1 Histologic staging of cerebral abscess

Stage	Histologic characteristics (days shown are general estimates)	Resistance to aspirating needle
1	early cerebritis: (days 1-3) early infection & inflammation, poorly demarcated from surrounding brain, toxic changes in neurons, perivascular infiltrates	intermediate resistance
2	late cerebritis: (days 4-9) reticular matrix (collagen precursor) & developing necrotic center	no resistance
3	early capsule: (days 10-13) neovascularity, necrotic center, reticular network surrounds (less well developed along side facing ventricles)	no resistance
4	late capsule: (> day 14) collagen capsule*, necrotic center, gliosis around capsule	firm resistance, “pop” on entering

* abscess is ≈ the only process in the brain that leaves a collagen scar, all other scars are glial scars

CT staging

Late cerebritis (stage 2) has similar features to early capsule (stage 3) on routine contrast and non-contrast CT. There is some therapeutic importance in differentiating these two stages; the following aids in distinguishing⁵⁰:

• cerebritis: tends to be more ill-defined

A. ring-enhancement: usually appears by late cerebritis stage, usually thick

B. further diffusion of contrast into central lumen, and/or lack of decay of enhancement on delayed scan 30-60 min after contrast infusion

• capsule:

A. faint rim present on pre-contrast CT (necrotic center with edematous sur-rounding brain cause collagen capsule to be seen)

B. thin ring enhancement AND delayed scans → decay of enhancement

NB: Thin ring enhancement but lack of delayed decay correlates better with cerebritis

NB: Steroids reduce degree of contrast enhancement (especially in cerebritis)

MRI staging

Table 16-2 shows MRI findings in cerebral abscess. In the cerebritis stage, the margins are ill defined.

Table 16-2 MRI findings with cerebral abscess

Stage	T1WI	T2WI
cerebritis	hypointense	hi signal
capsular	lesion center → low signal, capsule → mildly hyperintense, perilesional edema → low signal	center → iso- or hyperintense, capsule → dark (collagen), perilesional edema → hi signal

TREATMENT

“There is no single best method for treating a brain abscess.” Treatment usually involves surgical drainage or excision, correction of the primary source, and long-term use of antibiotics (often IV x 6-8 weeks followed by oral route x 4-8 weeks).

SURGICAL VS. PURE MEDICAL MANAGEMENT

In a patient with suspected cerebral abscess, tissue should be obtained in almost every case to confirm diagnosis and to identify pathogens (preferably before antibiotics).

MEDICAL TREATMENT

In general, surgical drainage or excision is employed in the treatment. Purely medical treatment of early abscess (cerebritis stage)⁵¹, is controversial. NB: pathogens were cultured from well encapsulated abscesses despite adequate levels of appropriate antibiotics in 6 patients who failed medical therapy⁵². Failure may be due to poor blood supply and acidic conditions within the abscess (which may inactivate antibiotics in spite of concentrations exceeding the MIC).

Medical therapy alone is more successful if:

1. treatment begun in cerebritis stage (before complete encapsulation), even though many of these lesions subsequently go on to become encapsulated

2. small lesions: diameter of abscesses successfully treated with antibiotics alone were 0.8-2.5 cm (1.7 mean). Those that failed were 2-6 cm (4.2 mean). 3 cm is suggested as a cutoff⁵³, above this surgery should be included

3. duration of symptoms ≤ 2 wks (correlates with cerebritis stage)

4. patients show definite clinical improvement within the first week

Medical management alone considered if:

1. poor surgical candidate (NB: with local anesthesia, stereotactic biopsy can be done in almost any patient with normal blood clotting)

2. multiple abscesses, especially if small

3. abscess in poorly accessible location: e.g. brain stem⁵⁴

4. concomitant meningitis/ependymitis

SURGICAL TREATMENT

Indications for initial surgical treatment include:

1. significant mass effect exerted by lesion (on CT or MRI)

2. difficulty in diagnosis (especially in adults)

3. proximity to ventricle: indicates likelihood of intraventricular rupture which is associated with poor outcome^{40, 55}

4. evidence of significantly increased intracranial pressure

5. poor neurologic condition (patients responds only to pain, or does not even response to pain)

6. traumatic abscess associated with foreign material

7. fungal abscess

8. multiloculated abscess

9. follow-up CT/MRI scans cannot be obtained every 1-2 weeks

Surgical intervention in patient being treated medically:

Intervention if neurological deterioration, progression of abscess towards ventricles, or after 2 wks if the abscess is enlarged. Also considered if no decrease in size by 4 wks.

SPECIFIC MANAGEMENT

• obtain blood cultures (rarely helpful)

• initiate antibiotic therapy (preferably after biopsy specimen obtained), regardless of which mode of treatment (medical vs. surgical) is chosen (see below)

• LP: avoid in most cases of cerebral abscess (see page 352)

• anticonvulsants: indicated for seizures, prophylactic use is optional

• steroids: controversial. Reduces edema, but may impede therapy (see below)

ANTIBIOTICS

1. initial antibiotics of choice (when pathogen unknown, and especially if S. aureus suspected), make appropriate changes as sensitivities become available. If there is no history of trauma or neurosurgical procedure, then the risk of MRSA is low:

• vancomycin: covers MRSA. Adult: 1 gm IV q 12 hr. Peds: 15 mg/kg q 8 hr. Check peak & trough levels and adjust dose accordingly

PLUS

• a 3rd generation cephalosporin (e.g. cefotaxime (Claforan®))

PLUS

• one of the following

metronidazole (Flagyl®). Adult: 30 mg/kg/d total usually IV (divided q 12 hrs or q 6 hrs, not to exceed 4 gm/d). Peds: 10 mg/kg IV q 8 hrs

OR

chloramphenicol. Adult: 1 gm IV q 6 hr. Peds: 15-25 mg/kg IV q 6 hr OR

for post-traumatic abscess, use PO rifampin 9 mg/kg/d as 1 dose

2. if culture shows no staph (as is usual in non-traumatic abscess), change nafcillin to PCN G (high dose): adult: 5 M units IV q 6 hr; peds: 50,000-75,000 units/kg IV q 6 hr

3. if culture shows only strep, may use PCN G (high dose) alone

4. if cultures show staph that is not MRSA and the patient is not allergic to penicillin or nafcillin, substitute nafcillin for the vancomycin. Adult: 2 gm IV q 4 hrs. Peds: 25 mg/kg IV q 6 hrs

5. Cryptococcus neoformans, Aspergillus sp., Candida sp.:

A. amphotericin B: 0.5-1 mg/kg/day. Abelcet® (amphotericin B lipid complex) 5 mg/kg/d should be used when renal function is compromised

B. or liposomal amphotericin B: 3 mg/kg/day, increase to 15 mg/kg/d

6. in AIDS patients: Toxoplasma gondii is a common pathogen, and initial empiric treatment with sulfadiazine + pyrimethamine is often used (see page 366)

Duration of antibiotics

IV antibiotics for 6-8 wks (most commonly 6), may then D/C even if the CT abnormalities persist (neovascularity remains). NB: CT improvement may lag behind clinical improvement. Duration of treatment may be reduced if abscess and capsule entirely excised surgically. Oral antibiotics may be used following IV course. 5-20% of abscesses recur within 6 weeks of discontinuing antibiotics.

STEROIDS

Reduces edema, Decreases likelihood of fibrous encapsulation of abscess. May reduce penetration of antibiotics into abscess 53. Immune suppression may also be deleterious. Reserved for patients with clinical and imaging evidence of deterioration from marked mass effect, and duration of therapy should be minimized.

FOLLOW-UP IMAGING

If therapy is successful, imaging should show decrease in:

1. degree of ring enhancement

2. edema

3. mass effect

4. size of lesion: takes 1 to 4 wks (2.5 mean). 95% of lesions that will resolve with antibiotics alone decrease in size by 1 month

SURGICAL TREATMENT

Current options⁵⁶:

1. needle aspiration: the mainstay of surgical treatment. Especially well-suited for multiple or deep lesions (see below)

2. surgical excision: prevents recidivism. Shortens length of time on antibiotics. Recommended in traumatic abscess to debride foreign material (especially bone), and in fungal abscess because of relative antibiotic resistance (see below)

3. external drainage: controversial. Not frequently used

4. instillation of antibiotics directly into the abscess: has not been extremely efficacious, although it may be used as for refractory Aspergillus abscesses

NEEDLE ASPIRATION

If necessary, may be performed under local anesthesia. May be combined with irrigation with antibiotics or normal saline. Needs to be repeated in up to 70% of cases. May be the only surgical intervention required, but sometimes must be followed with excision (especially with multiloculated abscess). Stereotactic drainage may be ideal for deep lesions⁵⁷.

Performed through a trajectory chosen to:

1. minimize the path length through the brain

2. avoid traversing the ventricles or vital neural or vascular structures

3. avoid traversing infected structures outside the intracranial compartment (infected bone, paranasal sinuses, and scalp wounds)

4. in cases of multiples abscesses, target³⁹:

A. the largest lesion or the one causing the most symptoms

B. once the diagnosis of abscess is confirmed

1. any lesion ≥ 2.5 cm diameter

2. lesions causing significant mass effect

3. enlarging lesions

Cultures

Send aspirated material for the following:

1. stains

A. Gram stain

B. acid-fast stain (AFB stain) for Mycobacterium

C. modified acid-fast stain (for Nocardia, see below) looking for branching acid fast bacillus

D. special fungal stains (e.g., methenamine silver, mucicarmine)

2. culture

A. routine cultures: aerobic and anaerobic

B. fungal culture: this is not only helpful for identifying fungal infections, but since these cultures are kept for longer period and any growth that occurs will be further characterized, fastidious or indolent bacterial organisms may sometimes be identified

C. TB culture

EXCISION

Can only be performed during the “chronic” phase (late capsule stage). Abscess is removed as any well encapsulated tumor. The length of time on antibiotics can be shortened to ≈ 3 days in some cases following total excision of an accessible, mature abscess (e.g. located in pole of brain). Recommended for abscesses associated with foreign body and most Nocardia abscesses (see below). May also be needed necessary for: fungal abscess, multiloculated or resistant lesions.

Table 16-3 Outcomes with cerebral abscess

mortality (CT era data)39, 58	0-10%
neurologic disability	45%
late focal or generalized seizures	27%
hemiparesis	29%

OUTCOME

In the pre-CT era, mortality ranged form 40-60%. With improvement in antibiotics, surgery, and the improved ability to diagnose and follow response with CT/MRI, mortality rate has been reduced to ≈ 10%, but morbidity remains high with permanent neurologic deficit or seizures in up to 50% of cases. Current outcomes are shown in Table 16-3. A worse prognosis is associated with poor neurologic function, intraventricular rupture of abscess, and almost 100% mortality with fungal abscesses in transplant recipients.

16.6.1. Some unusual organisms producing abscess

NOCARDIA

Nocardiosis is caused primarily by Nocardia asteroides (other Nocardia species such as N. brasiliensis are less common), a soil-born aerobic actinomycete (a bacteria, not a fungus) that is usually inoculated through the respiratory tract and produces a localized or disseminated infection. Hematogenous spread frequently results in cutaneous lesions and CNS involvement. Nocardia is responsible for 2% of all brain abscesses, the majority of these are N. asteroides.

Nocardiosis occurs primarily in patients with chronic debilitating illnesses including:

1. neoplasms: leukemia, lymphoma…

2. conditions requiring long-term corticosteroid treatment

3. Cushing’s disease

4. Paget’s disease of bone

5. AIDS

6. renal or cardiac organ transplant recipients

The diagnosis is suspected in high-risk patients presenting with soft-tissue abscesses and CNS lesions. CNS involvement occurs in about one-third and includes:

1. cerebral abscess: often multiloculated

2. meningitis

3. ventriculitis in patients with CSF shunt⁵⁹

4. epidural spinal cord compression from vertebral osteomyelitis⁶⁰

Diagnosis

Brain biopsy may not be needed in high-risk patients with confirmed nocardia infection in other sites⁵⁹, except possibly in AIDS patients where the risk of multiple organism infections or infection plus tumor (particularly lymphoma) is considerable.

Treatment

As for most abscesses, very small ones may be treated medically, lesions up to about 3 cm may undergo needle aspiration first, and larger lesions or those that grow despite medical therapy may require excision followed by antibiotics.

Medical treatment: Primary choice is trimethoprim-sulfamethoxazole (TMP-SMZ).

Rx: start with 15 mg/kg/d of TMP & 75 mg/kg/d of SMZ IV or PO divided in 2-4 doses. After 3-4 weeks, decrease to 10 mg/kg/d TMP in 2-4 doses PO. Check serum levels.

Alternatives: imipenem + amikacin. Also possibly effective: linezolid⁶¹.

Duration: because of risks of relapse or hematogenous spread, treatment is recommended for 3 months in immunocompetent hosts and 6 months for immunocompromised.

16.7. Subdural empyema

Referred to as subdural abscess prior to 194362. Subdural empyema (SDE) is a suppurative infection that forms in the subdural space, which has no anatomic barrier to spread⁶³ Antibiotic penetration into this space is poor. Distinguished from abscess which forms within brain substance, surrounded by tissue reaction with fibrin and collagen capsule formation. Hence, SDE tends to be more emergent.

SDE may be complicated by cerebral abscess (seen in 20-25% of imaging studies), cortical venous thrombosis with risk of venous infarction, or localized cerebritis.

EPIDEMIOLOGY

Less common than cerebral abscess (ratio of abscess:empyema is ≈ 5:1). Found in 32 cases in 10,000 autopsies. Male:female ratio is 3:1.

Location: 70-80% are over the convexity, 10-20% are parafalcine.

ETIOLOGIES

See Table 16-4. Most often occurs as a result of direct extension of local infection (rarely following septicemia). Spread of the infection to the intracranial compartment may occur through the valveless diploic veins, often with associated thrombophlebitis⁶⁶.

Chronic otitis media was the leading cause of SDE in the preantibiotic era, but has now been surpassed by paranasal sinus disease especially with frontal sinus involvement⁶⁴ (may also follow mastoid sinusitis). SDE is a rare but sometimes fatal complication of cranial traction devices^{64, 67}. Infection of preexisting subdural hematomas (both treated and un-treated, in infants and adults) have been reported⁶⁴.

Trauma includes compound skull fractures and penetrating injuries. Other etiologies include: osteomyelitis, pneumonia, unrelated infection in diabetics.

Table 16-4 Etiologies of SDE

Location	%
paranasal sinusitis (especially frontal)*	67-75
otitis (usually chronic otitis media)†	14
post surgical (neuro or ENT)	4
trauma	3
meningitis (more common in peds65)	2
congenital heart disease	2
misc. (including pulmonary suppuration)	4
undetermined	3

* more common in adults

^† no cases from otitis in a recent series⁶⁴

PRESENTATION

Neurologic findings are shown in Table 16-5. Symptoms are due to mass effect, inflammatory involvement of the brain and meninges, and thrombophlebitis of cerebral veins and/or venous sinuses. SDE should be suspected in the presence of meningismus + unilateral hemisphere dysfunction. Marked tenderness to percussion or pressure over affected air sinuses is common⁶³. Forehead or eye swelling (from emissary vein thrombosis) may occur.

Focal neurologic deficit and/or seizures usually occur late.

Table 16-5 Findings on presentation with SDE*

Finding	%
fever	95
H/A	86
meningismus (nuchal rigidity…)	83
hemiparesis	80
altered mental status	76
seizures	44
sinus tenderness, swelling or inflammation	42
nausea and/or vomiting	27
homonymous hemianopsia	18
speech difficulty	17
papilledema	9

* from a review of multiple articles⁶⁴

EVALUATION

• CT: IV contrast is usually helpful. CT may miss some cases (related to early generation scanners, failure to give IV contrast, poor scan quality…). If normal, repeat the CT at a later time or do an MRI if clinical suspicion persists. Findings: hypodense (but denser than CSF) crescentic or lenticular extracerebral lesion with dense enhancement of medial membrane; inward displacement of gray-white interface; ventricular distortion and effacement of basal cisterns are common findings⁶⁸

• MRI: low signal on T1WI, high signal on T2WI. Pial ependymal line: a non-specific MRI finding in CNS infection

• LP: ✖ potentially hazardous (risk of herniation). Organisms are usually present only in cases originating from meningitis. If no meningitis: moderate sterile pleocytosis (150-600 WBC/mm³) with PMNs predominating; glucose normal; opening pressure is usually high⁶³; protein is usually elevated (range: 75-150 mg/dl)

Table 16-6 Organisms in adult cases of SDE associated with sinusitis

aerobic streptococcus	30-50%
staphylococci	15-20%
microaerophilic and anaerobic strep	15-25%
aerobic Gram-negative rods	5-10%
other anaerobes	5-10%

Table 16-7 Organisms in SDE in childhood (age < 5 years)

Organisms are similar to meningitis for the same age group. Antibiotics choice is the same as for meningitis

ORGANISMS

The causative organism varies with the specific source of the infection. SDE associated with sinusitis is often caused by aerobic and anaerobic streptococci (see Table 16-6). Following trauma or neurosurgical procedures, staphylococci and Gram-negative species predominate. Sterile cultures occur in up to 40%. For SDE in peds, see Table 16-7.

TREATMENT

1. surgical drainage: indicated in most cases (nonsurgical management has been reported⁶⁹, but should only be considered with minimal neurologic involvement, limited extension and mass effect of SDE, and early favorable response to antibiotics) usually done relatively emergently

• early in the course, the pus tends to be more fluid and may be more amenable to burr hole drainage; later, loculations develop which may necessitate craniotomy

• there has been controversy over the optimal surgical treatment. Early studies indicated a better outcome with craniotomy. Recent studies show less difference

A. critically ill patients with localized SDE may be candidates for burr-hole drainage (usually inadequate if loculations are present). Repeat procedures may be needed, and up to 20% will later require a craniotomy

B. craniotomy: to debride and, if possible, drain. A wide craniotomy is often required because of septations. The dura appears white because of pus underneath. Open and wash out subdural space. Do not try to remove material adherent to cortex (may cause infarction)

2. antibiotics: similar to treatment for cerebral abscess

initially: a penicillin and a third-generation cephalosporin (e.g. cefotaxime)

metronidazole is added if there is a high suspicion of anaerobes

for post-op SDE: substitute vancomycin for PCN (switch vancomycin to a PCN if there is no staphylococcus)

modify antibiotics based on culture results

duration: usually 4-6 weeks

• anticonvulsants: usually used prophylactically, mandatory if seizures occur

OUTCOME

See Table 16-8. Neurologic deficits were present in 55% of patients at the time of discharge⁶⁴. Age ≥ 60 years, obtundation or coma at presentation, and SDE related to surgery or trauma carry a worse prognosis⁶⁴. Burr-hole drainage may be associated with a worse outcome than with craniotomy, but this may have been influenced by the poorer condition of these patients. Fatal cases may have associated venous infarction of the brain.

Table 16-8 Outcome with SDE

persistent seizures	34%
residual hemiparesis	17%
mortality	10-20%

16.8. Viral encephalitis

Encephalitides that come to the attention of the neurosurgeon usually cause imaging findings that may mimic mass lesions. Biopsy is helpful in some instances, and shunting for hydrocephalus may occasionally be needed. Those covered in this book:

1. herpes simplex encephalitis: see below

2. multifocal herpes varicella-zoster virus leukoencephalitis: see page 360

3. progressive multifocal leukoencephalopathy (PML): see page 364

16.8.1. Herpes simplex encephalitis

Key concepts:

• a hemorrhagic viral encephalitis with a predilection for temporal lobes

• definitive diagnosis requires brain biopsy

• optimal treatment: early administration of IV acyclovir

Herpes simplex encephalitis (HSE) AKA multifocal necrotizing encephalomyelitis, is caused by the herpes simplex virus (HSV) type I. It produces an acute, often (but not always) hemorrhagic, necrotizing encephalitis with edema. There is a predilection for the temporal and orbitofrontal lobes and limbic system.

EPIDEMIOLOGY⁷⁰

Estimated incidence of HSE: 1 in 750,000 to 1 million persons/yr. Equally distributed between male and females, in all races, in all ages (over 33% of cases occur in children 6 mos to 18 yrs), throughout the year.

PRESENTATION

Patients are often confused and disoriented at onset, and progress to coma within days. Adult presentations are shown in Table 16-9, and for pediatrics in Table 16-10. Other symptoms include headache.

Table 16-9 Adult presentation

altered consciousness	97%
fever	90%
seizures (usually focal onset)	67%
personality changes	71%
hemiparesis	33%

Table 16-10 Presentation in age < 10 yrs

irritability	altered mentation
malaise	seizure
disorientation	dysphasia
hemiparesis	fever
papilledema (except in age ≤ 2 yrs)

DIAGNOSTIC STUDIES

Diagnosis can often be made on the basis of history, CSF, and MRI. Treatment should be instituted rapidly without waiting for biopsy, before the onset of coma.

1. CSF: leukocytosis (mostly monos), RBCs 500-1000/mm³, (NB: 3% have no pleocytosis), protein rises markedly as disease progresses. HSV antibodies may appear in the CSF but takes at least ≈ 14 days and is thus not useful for early diagnosis

2. EEG: periodic lateralizing epileptiform discharges (PLEDs) (triphasic high-voltage discharges every few seconds) usually from the temporal lobe. EEG may vary rapidly over few days (unusual in conditions mimicking HSE)

3. CT: edema predominantly localized in temporal lobes (poorer prognosis once hemorrhagic lesions visible). In one review, 38% of initial CTs were normal⁷¹ (many were on early generation CT scanners or were done within 3 days of onset). Hemorrhages were apparent in only 12% of the initially abnormal CTs

4. MRI: more sensitive than CT⁷², demonstrates edema as high signal on T2WI, primarily within the temporal lobe, with some extension across sylvian fissure (“transsylvian sign”)⁷¹, especially suggestive of HSE if bilateral. Differentiate from MCA infarct (which may also span sylvian fissure) by typical arterial distribution of the latter. Enhancement doesn’t occur until the 2nd week

5. technetium brain scan: process localized to temporal lobes

6. brain biopsy: false negatives may occur⁷³

A. indications: reserved for questionable cases. May not be necessary in patients with fever, encephalopathy, compatible CSF findings, focal neuro findings (focal seizure, hemiparesis, or cranial nerve palsy), and supporting evidence of at least one of the following: focal EEG, CT, MRI or technetium brain scan abnormality

B. should be performed within ≤ 48 hrs of starting acyclovir (otherwise false negatives may occur)

C. anterior inferior temporal lobe is preferred site

1. the side chosen for biopsy is the one showing maximal involvement based on clinical information (e.g. localizing seizures), EEG and/or imaging studies⁷⁴

2. 10 x 10 x 5 mm deep specimen obtained from anterior portion of the inferior temporal gyrus with NO COAGULATION on specimen side (cut surface with #11 blade, then cauterize pial surface on non-specimen side)

3. 2nd specimen obtained from beneath surface specimen with fenestrated pituitary biopsy forceps

D. virus isolation is the most specific (100%) and sensitive (96-97%) test for HSE. Other findings (less accurate): perivascular cuffing, lymphocytic infiltration, hemorrhagic necrosis, neuronophagia, intranuclear inclusions (present in 50%)

E. if electron microscopy (EM) or immunohistofluorescence is available, 70% may be diagnosed within ≈ 3 hrs of biopsy

F. biopsy tissue handling

1. avoid macerating specimens for histology

2. tissue for EM: placed in glutaraldehyde

3. tissue for permanent histology: placed in formalin

4. tissue for culture:

a. handling: specimen is placed in sterile specimen container and sent directly to virology lab. If lab is closed, tissue may be:

i. placed in regular refrigerator for up to 24 hrs

ii. placed in –70° C freezer for indefinite time (virus remains viable for up to 5 yrs)

iii. DO NOT place in regular freezer (destroys virus)

b. cultures generally take at least 1 week to become positive

c. cultures checked for 3 weeks before being declared negative

G. biopsy results: of 432 brain biopsies meeting the above criteria, 45% had HSE, 22% had identifiable but non HSE pathology (e.g. vascular disease, other viral infection, adrenal leukodystrophy, bacterial infection…), and 33% remained without a diagnosis⁷⁵

TREATMENT

General supportive measures: to control elevated ICP from edema, includes: elevate HOB, mannitol, hyperventilation (dexamethasone unproven efficacy) (also see Treatment measures for elevated ICP, page 876). Phenytoin is used for seizure prophylaxis.

Antiviral medications

Ganciclovir is gaining favor over acyclovir.

acyclovir (Zovirax®)DRUG INFO

Rx Adult: 30 mg/kg/day, in divided q 8 hr doses in minimum volume of 100 ml IV fluid over 1 hr (caution: this fluid load may be hazardous, especially since cerebral edema is already usually problematic) for 14-21 days (some relapses have been reported after only 10 days of treatment).

Rx Children > 6 mos age: 500 mg/m² IV q 8 hrs x 10 days.

Rx Neonatal: 10 mg/kg IV q 8 hrs for 10 days.

vidarabine (Vira-A®)DRUG INFO

Outcome

Six month mortality following treatment with acyclovir was influenced by:

• age (6% under age 30, 36% over age 30)

• Glasgow coma score (GCS) at time of treatment initiation (25% for GCS ≤ 10, 0% for GCS > 10)

• duration of disease before therapy (0% for initiating therapy within 4 days, 35% if after 4 days)

16.8.2. Multifocal varicella-zoster leukoencephalitis

Caused by the herpes varicella-zoster virus (VZV) which is responsible for varicella (chickenpox), herpes zoster (HZ) (shingles), and post-herpetic neuralgia (see page 564). VZV is a herpesvirus that is distinct from the herpes simplex virus.

Symptomatic zoster-related encephalitis occurs in < 5% of immunocompromised patients (including AIDS patients) with cutaneous zoster⁷⁶. It typically follows cutaneous HZ by a short time (average: 9 days) although cases have been reported where many months have lapsed⁷⁷.

Manifestations include: altered level of consciousness, headache, photophobia, meningismus. Although focal neurologic deficits may occur, these are uncommon.

MRI may show multiple, discrete, round and oval lesions with minimal edema (best seen on T2WI) and minimal enhancement.

Unlike herpes simplex virus, VZV is difficult to isolate in culture. On brain biopsy, look for multiple discrete lesions within grey and white matter, with Cowdry type A intranuclear inclusion bodies in oligodendrocytes, astrocytes, and neurons, and a positive direct fluorescent antibody test directed against VZV.

There is a case report of VZV encephalitis treated with IV acyclovir⁷⁶.

16.9. Creutzfeldt-Jakob disease

Key concepts

• an invariably fatal encephalopathy characterized by rapidly progressive dementia, ataxia and myoclonus

• death usually occurs within 1 yr of onset of symptoms

• 3 forms: 1) transmissible (possibly via prions), 2) autosomal dominant inherited, 3) sporadic

• characteristic EEG finding: bilateral sharp wave (0.5-2 per second)

• pathology: status spongiosus without inflammatory response

Creutzfeldt-Jakob disease (CJD) is one of 4 known rare human diseases associated with transmissible spongiform encephalopathy agents, also called prions (proteinaceous infectious particles). Although sometimes also referred to as a “slow virus”, these agents contain no nucleic acids and are also resistant to processes that inactivate conventional viruses (see Table 16-12). Prions do not provoke an immune response. The protease-resistant protein associated with disease is designated PrP^res or PrP^Sc, and is an isoform of a naturally occurring protease-sensitive protein designated PrP^sen or PrP^C.

Annual incidence of CJD: 0.5-1.5 per million population⁷⁸. Over 200 people die of CJD in the U.S. each year. CJD occurs in 3 forms: transmissible, inherited and sporadic.

Acquired prion diseases: Natural route of infection is unknown and virulence appears low, with lack of significant dissemination by respiratory, enteric, or sexual contact. There is no increased incidence in spouses (only a single conjugal pair of cases has been verified), physicians or laboratory workers. There is no evidence of transplacental transmission. The only known cases of horizontal transmission of CJD have occurred iatrogenically (see below). Kuru has been transmitted via handling and ingestion of infected brains in ritualistic funereal cannibalism practiced among the Fore (pronounced: “foreay”) linguistic group in the eastern highlands of Papua, New Guinea⁷⁹, a practice which was generally abandoned in the 1950’s. Kuru is a subacute, uniformly fatal disease involving cerebellar degeneration (the word “kuru” means “to tremble” in the local language^{80 (p 6)}).

Most noniatrogenically transmitted cases of CJD occur in patients > 50 yrs old, and is rare in age < 30. The incubation period can range from months to decades. The onset of symptoms following direct inoculation is usually faster (common range: 16-28 mos), but still may be much longer (up to 30 years with corneal transplant⁸¹, and 4-21 yrs with hGH transmission).

Inherited CJD: 5-15% of cases of CJD occur in an autosomal dominant inheritance pattern with abnormalities in the amyloid gene⁸² on chromosome 20 with a penetrance of 0.5683. Since familial CJD is dominantly inherited, analysis for the PrP gene is not indicated unless there is a history of dementia in a first degree relative.

Sporadic CJD: In ≈ 90% of cases of CJD, no infectious or familial source can be identified⁸², and these cases are considered sporadic. 80% occur in persons 50-70 yrs old⁷⁸. Sporadic cases show no abnormality in the PrP gene.

New variant CJD: Cases of atypical CJD are well-recognized. A new variant of CJD (vCJD) was identified in 10 cases of unusually young individuals (median age at death: 29 yrs) during 1994-95 in the United Kingdom⁸⁴, and has been strongly linked to the 1980s epidemic of bovine spongiform encephalopathy (BSE), dubbed “mad cow” disease by the lay press. None of the vCJD patients had periodic spikes on EEG characteristic of classic CJD, the clinical course was atypical (having prominent psychiatric symptoms and early cerebellar ataxia, some-what similar to kuru), and brain plaques showed unusual features also reminiscent of amyloid plaques seen in kuru. A comparison of vCJD to sporadic CJD is shown in Table 16-11.

Table 16-11 Comparison of vCJD to sporadic CJD⁷⁸

Characteristic	vCJD	sporadic
mean age at onset (yr)	29	60
mean duration of disease (mo)	14	5
most consistent and prominent early signs	psychiatric abnormalities, sensory symptoms	dementia, myoclonus
cerebellar signs (%)	100	40
periodic complexes on EEG (%)	0	94
pathological changes	diffuse amyloid plaques	sparse plaques in 5-10%

Iatrogenic transmission of CJD

Described only in cases of direct contact with infected organs, tissues or surgical instruments. Has been reported with: corneal transplants^{81, 87}, intracerebral EEG electrodes sterilized with 70% alcohol and formaldehyde vapor after use on a CJD patient⁸⁸, operations in neurosurgical O.R.s after procedures on CJD patients, in recipients of pituitary-derived^A human growth hormone (hGH)⁸⁹, and dural graft with cadaveric dura mater (Lyodura®). Recommended sterilization procedures for suspected CJD tissues and contaminated materials appear in Table 16-12.

A. there is no longer a risk of CJD with growth hormone in the U.S. since distribution of pituitary derived hGH was halted in 1985 and current hGH is obtained from recombinant DNA technology

Pathology

The typical form of CJD produces the classic histologic triad of neuronal loss, astrocytic proliferation, and cytoplasmic vacuoles in neurons and astrocytes (status spongiosus), all in the absence of an inflammatory response. There is a predilection for cerebral cortex and basal ganglia, but all parts of the CNS may be involved. In 5-10% of cases, these changes are accompanied by the deposition of amyloid plaques. Immunostaining for PrP^res is definitive.

Table 16-12 Operating room sterilization procedures for CJD⁸⁵

• Fully effective (recommended) procedures A. steam autoclaving for 1 hr at 132°C, or B. immersion in 1N sodium hydroxide (NaOH) for 1 hr at room temperature

• Partially effective procedures A. steam autoclaving at either 121° C or 132° C for 15-30 mins, or B. immersion in 1N NaOH for 15 mins, or lower concentrations (< 0.5N) for 1 hr at room temp, or C. immersion in sodium hypochlorite (household bleach) undiluted or up to 1:10 dilution (0.5%) for 1 hr86

• ✖ Ineffective procedures: boiling, UV or ionizing radiation, ethylene oxide, ethanol, formalin, beta-propiolactone, detergents, quaternary ammonium compounds, Lysol®, alcoholic iodine, acetone, potassium permanganate, routine autoclaving

Presentation

One third initially express vague feelings of fatigue, sleep disorders, or reduced appetite. Another third have neurologic symptoms including memory loss, confusion, or uncharacteristic behavior. The last third have focal signs including cerebellar ataxia, aphasia, visual deficits (including cortical blindness), or hemiparesis.

The typical course is inexorable, progression of dementia, often noticeably worse week by week, with subsequent rapid development of pyramidal tract findings (limb weakness and stiffness, pathologic reflexes), and late extrapyramidal findings (tremor, rigidity, dysarthria, bradykinesia) and myoclonus (often stimulus triggered). Clinical signs of sporadic CJD are shown in Table 16-13.

Supranuclear gaze palsy is an occasional finding, also usually late⁸³. In early stages, CJD may resemble Alzheimer’s disease (SDAT). 10% of cases present as ataxia without dementia or myoclonus. Cases with pre-dominant spinal cord findings may be initially mistaken for ALS.

Myoclonus subsides in the terminal phases, and akinetic mutism ensues.

Table 16-13 Major clinical signs in sporadic CJD⁷⁸

Sign	Freq (%)
cognitive deficits*	100
myoclonus	> 80
pyramidal tract signs	> 50
cerebellar signs	> 50
extrapyramidal signs	> 50
cortical visual deficits	> 20
abnormal extraocular movements	> 20
lower motor-neuron signs	< 20
vestibular dysfunction	< 20
seizures	< 20
sensory deficits	< 20
autonomic abnormalities	< 20

* dementia, psychiatric and behavioral abnormalities

DIAGNOSIS

The complete “diagnostic triad” (dementia, myoclonus and periodic EEG activity) may be absent in up to 25% of cases. Diagnostic criteria have been published⁹⁰ as shown in Table 16-14. No patients in their series with a diagnosis other than CJD fulfilled the criteria for clinically definite CJD. The most common condition other than CJD fulfilling the criteria for clinically probable CJD was SDAT (especially difficult to distinguish in the early stages). There is a CSF immunoassay for the 14-3-3 brain protein (see below).

Differential diagnosis

CSF examination to exclude infections such as tertiary syphilis or SSPE is recommended. Toxicity from bismuth, bromides and lithium must be ruledout. Myoclonus is usually more prominent early in toxic/metabolic disorders than in CJD, and seizures in CJD are usually late⁷⁸.

Diagnostic tests

• imaging: no characteristic CT or MR finding. These studies are frequently normal, but are essential to rule-out other conditions (e.g. herpes-simplex encephalitis, recent stroke…). Diffuse atrophy may be present, especially late. MRI may show increased intensity on T2WI in areas typically involved (basal ganglion, striatum) in up to 79% of cases (retrospectively)⁹¹. This is nonspecific but may help differentiate CJD from SDAT⁹²

• blood tests: serum assays for S-100 protein are so insensitive and nonspecific⁹³ that it can only be used as an diagnostic adjunct

• CSF:

A. routine labs: usually normal, although protein may occasionally be elevated

B. abnormal proteins:

1. abnormal proteins (130 & 131) have been identified in the CSF of patients with CJD⁹⁴, but the assay is technically difficult

2. proteins 130/131 were identified as the normal neuronal protein 14-3-3, and a relatively simple immunoassay for this was developed for use on as little as 50 μl of CSF⁹⁵. Detection of the 14-3-3 protein in the CSF has 96% sensitivity and specificity for CJD among patients with dementia. False positives may occur in other conditions involving extensive neuronal destruction including: acute CVA, herpes encephalitis, multi-infarct dementia, primary CNS lymphoma and rarely SDAT (most cases of SDAT test negative). Requires CSF (cannot be done on blood)

• EEG: characteristic finding of bilateral, symmetrical, periodic bi- or triphasic synchronous sharp-wave complexes, AKA periodic spikes, AKA pseudoperiodic sharp-wave complexes (0.5-2 per second) have ≈ 70% sensitivity and 86% specificity⁹⁶. They resemble PLEDs (see page 266), but are responsive to noxious stimulus (may be absent in familial CJD⁸³ and in the recent UK variant (see above))

• SPECT scan: may be abnormal in vCJD even when EEG is normal⁹⁷, however the findings are not specific for vCJD

• brain biopsy: see below

• tonsillar biopsy: patients with variant CJD (vCJD) may have detectable levels of variant type 4 of the abnormal prion protein (PrPSc) in their lymphoreticular system, which may be accessed by a 1 cm wedge-biopsy of one palatine tonsil (using careful aseptic precautions)⁹⁸

Brain biopsy

Due to lack of an effective treatment and the potential for iatrogenic infection in surgery, biopsy is reserved for cases where establishing the diagnosis is deemed important, or as part of a research study⁷⁴, or when diagnostic tests are equivocal and other potentially treatable etiologies are suspected.

Technique: to prevent aerosolization of the infectious agent, a manual saw is recommended over a power craniotome, and every effort should be made to avoid cutting the dura with the saw. Recommended decontamination procedures should be followed (see Table 16-12 and references). Specimens should be clearly labeled as being from suspected CJD patients to alert laboratory personnel to the hazard. Tissue should be fixed in a saturated 15% phenolized formalin (15 g of phenol per dl of 10% neutral buffered formalin with the undissolved phenol layering at the bottom of the solution)⁹⁹.

Treatment and prognosis

Given the lack of demonstrated infectivity (with tissues other than brain or CSF), isolation precautions such as gowns or masks are felt to be unnecessary⁷⁸.

There is no known treatment. The disease is rapidly progressive. Median survival is 5 months, and 80% of patients with sporadic CJD die within 1 year of diagnosis⁷⁸.

16.10. Neurologic manifestations of AIDS

TYPES OF NEUROLOGIC INVOLVEMENT

40-60% of all patients with acquired immunodeficiency syndrome (AIDS) will develop neurologic symptoms, with one third of these presenting initially with their neurologic complaint^{100, 101}. Only ≈ 5% of patients that die with AIDS have a normal brain on autopsy. One study found the CNS complications of AIDS shown in Table 16-15.

The most common conditions producing focal CNS lesions in AIDS¹⁰³:

1. toxoplasmosis

2. primary CNS lymphoma

3. progressive multifocal leukoencephalopathy (PML)

4. cryptococcal abscess

Manifestations of CNS toxoplasmosis

1. mass lesion (toxoplasmosis abscess): the most common lesion causing mass effect in AIDS patients (70-80% of cerebral mass lesions in AIDS¹⁰⁴) (see below for CT/MRI findings)

2. meningoencephalitis

3. encephalopathy

CNS toxoplasmosis occurs late in the course of HIV infection, usually when CD4 counts are < 200 cells/mm³.

Primary CNS lymphoma (PCNSL)

Occurs in ≈ 10% of patients with AIDS¹⁰⁵. PCNSL is associated with the Epstein-Barr virus (see page 673).

Table 16-15 CNS complications of AIDS (320 patients¹⁰⁰)

Complication	%
viral syndromes
subacute encephalitis*	17
atypical aseptic meningitis	6.5
herpes simplex encephalitis	2.8
progressive multifocal leukoencephalopathy (PML)	1.9†
viral myelitis	0.93
varicella zoster encephalitis	0.31
non-viral infections
Toxoplasma gondii	> 32
Cryptococcus neoformans	13
Candida albicans	1.9
coccidiomycosis	0.31
Treponema pallidum	0.62
atypical Mycobacteria	1.9
Mycobacterium tuberculosis	0.31
Aspergillus fumigatus	0.31
bacteria (E. coli)	0.31
neoplasms
primary CNS lymphoma	4.7
systemic lymphoma with CNS involvement	3.8
Kaposi’s sarcoma (including brain mets)	0.93
CVA (stroke)
infarct	1.6
intracerebral hemorrhage	1.2
miscellaneous/unknown	7.8

* CMV encephalitis occasionally occurs

^† more recent estimate¹⁰² of the incidence of PML in AIDS: 4%

Features of PML

1. caused by a ubiquitous polyomavirus (a subgroup of papova virus, small nonenveloped viruses with a closed circular double DNA-stranded genome) called “JC virus^A” (JCV). 60-80% of adults have antibodies to JCV¹⁰⁶

2. frequently manifests in patients with suppressed immune systems, including

A. AIDS: currently the most common underlying disease associated with PML

B. prior to AIDS, the most common associated diseases were chronic lymphocytic leukemia & lymphoma

C. allograft recipients: due to immunosuppression¹⁰⁷

D. chronic steroid therapy

E. PML also occurs with other malignancies, and with autoimmune disorders (e.g. SLE)

3. pathologic findings: focal myelin loss (demyelination, affects white matter) with sparing of axon cylinders, surrounded by enlarged astrocytes and bizarre oligodendroglial cells with eosinophilic intranuclear inclusion bodies. EM can detect the virus. Sometimes occurs in brainstem and cerebellum

4. clinical findings: mental status changes, blindness, aphasia, progressive cranial nerve, motor, or sensory deficits and ultimately coma. Seizures are rare

5. imaging findings: see below

6. clinical course: usually rapidly progressive to death within a few months, occasionally longer survival occurs inexplicably¹⁰⁸. There is no effective treatment. Some promise initially with anti-retroviral therapy¹⁰⁹

7. definitive diagnosis requires brain biopsy (sensitivity: 40-96%) although it is infrequently employed. JCV has been isolated from brain and urine. Polymerase chain reaction (PCR) of JCV DNA from CSF has been reported, and is specific but not sensitive for PML

A. named after the initials of the patient in whom it was first discovered, not to be confused with Jakob-Creutzfeldt (a prion disease) nor with Jamestown Canyon virus (also confusingly called JC virus, (a single-stranded RNA virus that occasionally causes encephalitis in humans)

Primary effects of AIDS infection

Neurologic involvement with infection with the Human Immunodeficiency Virus (HIV) (aside from opportunistic infection and tumors caused by the immunodeficient state) includes:

1. AIDS encephalopathy: the most common neurologic involvement, occurs in ≈ 66% of patients with AIDS involving the CNS

2. AIDS dementia AKA HIV dementia complex

3. aseptic meningitis

4. cranial neuropathies: including “Bell’s palsy” (occasionally bilateral)

5. AIDS related myelopathy: vacuolization of spinal cord (see Myelopathy, page 1185)

6. peripheral neuropathies

Neurosyphilis

1. AIDS patients can develop neurosyphilis as little as 4 mos from infection¹¹⁰ (unlike the 15-20 yrs usually required in non-immunocompromised patients)

2. neurosyphilis can develop in spite of what would otherwise be adequate treatment for early syphilis with benzathine PCN^{110, 111}

3. the CDC recommends treating patients having symptomatic or asymptomatic neurosyphilis for at least 10 days with probenecid 500 mg PO QID plus either aqueous crystalline PCN-G, 2-4-million units IV q 4 hrs (total of 12-24-million units/d), or aqueous procaine PCN-G 2.4-million units IM q d. This 10 day regimen should be followed by benzathine PCN 2.4-million units IM q week x 3 weeks. Benzathine PCN is NOT recommended initially¹¹²

NEURORADIOLOGIC FINDINGS IN AIDS

A series of 200 consecutive AIDS patients¹¹³ with neurologic symptoms followed to biopsy, autopsy, or for 2 yrs showed the following on initial CT:

• 81 patients (40%) had initially normal CT, only 5% of which went on to develop progression of neurologic abnormalities or developed CT abnormalities

• 75 patients (38%) showed only diffuse cerebral atrophy; 5 of these subsequently developed focal CT findings shown to be Toxoplasma gondii infection

• 44 patients (22%) had ≥ 1 focal lesion

See Table 16-16 for a comparison of neuroradiologic findings in toxoplasmosis, PCNSL and PML.

CT/MRI findings in toxoplasma abscess

1. most common findings: large area (low density on CT) with mild to moderate edema, ring enhancement with IV contrast in 68% compatible with abscess (of those that did not ring enhance, many showed hypodense areas with less mass effect with slight enhancement adjacent to lesion), well circumscribed margins¹¹⁴

2. most commonly located in basal ganglia, are also often subcortical

3. often multiple (typically > 5 lesions¹¹⁵) and bilateral

4. usually with little to moderate mass effect¹⁰³ (in BG, may compress third ventricle and sylvian aqueduct causing obstructive hydrocephalus)

5. most patients with toxoplasmosis had evidence of cerebral atrophy

CT/MRI findings in PML (see Table 16-16)

Note: the appearance of PML may differ in AIDS patients from non-AIDS patients.

1. CT: diffuse areas of low density. MRI: high intensity on T2WI

2. normally involves only white matter (spares cortex), however in AIDS patients gray matter involvement has been reported

3. no enhancement (on either CT or MRI), unlike most toxoplasmosis lesions

4. no mass effect

5. no edema

6. lesions may be solitary on 36% of CTs and on 13% of MRIs

7. borders are usually more ill-defined than in toxoplasmosis¹¹⁴

CT/MRI findings in primary CNS lymphoma (PCNSL) (see Table 16-16)

NB: the appearance of PCNSL may differ in AIDS patients from non-AIDS patients.

1. multiple lesions with mild mass effect and edema that tend to ring-enhance on CT, or appear as areas of hypointensity surrounding central area of high intensity (target lesion) targets onT2WI MRI (unlike non-AIDS cases which tend to enhance homogeneously¹¹⁶)

2. there is a greater tendency to multicentricity in AIDS patients than in the nonimmunosuppressed population¹¹⁷

Imaging recommendations

MR with gadolinium is recommended as the initial screening procedure of choice for AIDS patients with CNS symptoms (lower false negative rate than CT¹⁰³).

MANAGEMENT OF INTRACEREBRAL LESIONS

Neurosurgical consultation is often requested for biopsy in an AIDS patient with questionable lesion(s). The diagnostic dilemma is usually for low density lesions on CT, and in the United States is primarily between the following:

• toxoplasmosis: treated with pyrimethamine and sulfadiazine (see below)

• PML: no proven effective treatment (antiretroviral therapy may help¹⁰⁹)

• CNS lymphoma: usually treated with RTX (see CNS lymphoma, page 672)

• TB: tends to be unlikely except in Haitian population

• note: cryptococcus is more common than PML or lymphoma, but usually manifests as cryptococcal meningitis (and not as a ring enhancing lesion) (see page 374)

RECOMMENDATIONS

PML can usually be identified radiographically. However, radiographic imaging alone cannot reliably differentiate toxoplasmosis from lymphoma or from some other concurrent conditions (patients with toxoplasmosis may have other simultaneous diseases). Therefore, the following recommendations are made:

1. obtain baseline toxoplasmosis titer on all known AIDS patients (NB: 50% of the general population have been infected by toxo and have positive titer by age 6 years, 80-90% will be positive by middle adulthood). The chances of toxo are higher with serum antibodies > 1:16115 (most are > 1:256)

2. multiple enhancing lesions with basal ganglion involvement in a patient whose toxo titer changes from negative to positive have a high probability of being toxo

3. primary CNS lymphoma (PCNSL)

A. with single lesions, lymphoma is more likely than toxo

B. if possibility of PCNSL is strong

1. consider LP (contraindicated in presence of mass effect)

a. high volume LP for cytology: PCNSL can be diagnosed in ≈ 10-25% of cases using ≈ 10 ml of CSF (see page 674 for more details)

b. or send CSF for polymerase chain reaction (PCR) amplification of viral DNA of Epstein-Barr virus or JC-virus¹¹⁸ (the agents responsible for AIDS-related PCNSL and PML, respectively)

2. some recommend early biopsy^A to identify PCNSL cases to avoid delaying RTX for 3 weeks while assessing response to antibiotics¹⁰³

4. in patient with possible toxoplasmosis (i.e. positive toxo titer and CT findings not atypical for toxo) even if other conditions have not been excluded:

A. empirically start: pyrimethamine (Daraprim®) (200 mg loading dose, then 75-100 mg/d), sulfadiazine (75 mg/kg PO loading dose, then 25 mg/kg q 6 hrs), folic acid (5-40 mg/d, usually 10 mg with each dose of pyrimethamine)

B. if sulfa allergy develops (which commonly occurs), change sulfadiazine to clindamicin 400-600 mg PO or 600 mg IV q 6 hrs

C. alternatives for complete intolerance:

1. spiramycin (Rovamycine®) 3-4 gms/d (peds: 50-100 mg/kg/d x 3-4 wks)

2. atovaquone

D. there should be a clinical and radiographic response within 2-3 weeks¹¹⁹

E. if response is good, reduce dosage after 6-12 weeks to 50% of the above doses and maintain for life

F. if these drugs are continued, it should be possible to maintain control for remainder of patient’s life (cure is not generally possible)

G. if no response to therapy after 3 weeks (some recommend 7-10 days¹²⁰), then consider biopsy^A

5. perform biopsy in the following settings:

A. in patient with a negative toxo titer (note: patients occasionally have negative titer because of anergy)

B. accessible lesion(s) atypical for toxo (i.e. non-enhancing, sparing basal ganglia, periventricular location)

C. in the presence of extraneural infections or malignancies that may involve the CNS

D. lesion that could be either lymphoma or toxo (e.g. single lesion, see 3. A.)

E. in patients who have lesions not inconsistent with toxo but fail to respond to appropriate anti-toxo medications in the recommended time (see above)

F. the role of biopsy for non-enhancing lesions is less well defined as the diagnosis does not influence therapy (most are PML or biopsies are non-diagnostic), it may be useful only for prognostic purposes¹²⁰

G. note: the risk of open biopsy in AIDS patients may be higher than nonimmunocompromised patients. Stereotactic biopsy may be especially well suited, with up to 96% efficacy, fairly low morbidity (major risk: significant hemorrhage, ≈ 8% incidence) and low mortality^{121, 122}

6. stereotactic biopsy guidelines:

A. if multiple lesions are present, choose the most accessible lesion in the least eloquent brain area, or the lesion not responding to treatment

B. biopsy the center of non-enhancing lesions, or the enhancing portion of ring-enhancing lesions

C. recommended studies on biopsy: histology; immunoperoxidase stain for Toxoplasma gondii; stains for TB and fungus; culture for TB, fungi, pyogens

A. instead of biopsy, a few centers advocate empiric radiation treatment (for possible lymphoma)

PROGNOSIS

Patients with CNS toxo have a median survival of 446 days, which is similar to that with PML but longer than AIDS-related PCNSL¹¹⁵. Patients with CNS lymphoma in AIDS survive on average a shorter time than similarly treated CNS lymphoma in nonimmunosuppressed patients (3 months vs. 13.5 mos). Median survival is < 1 month with no treatment. CNS lymphoma in AIDS tends to occur late in the disease, and patients often die of unrelated causes (e.g. Pneumocystis carinii pneumonia)¹²⁰.

16.11. Lyme disease - neurologic manifestations

Lyme disease (LD) is a complex multisystem disease caused by various species of Borrelia spirochetes (in North America: Borrelia burgdorferi) transmitted to humans by the Ixodes scapularis or pacificusticks (the American dog tick is not involved). It was first recognized in Lyme, Connecticut in 1975, and is now the most common arthropod-borne infection in the U.S.¹²³.

CLINICAL FINDINGS

There are 3 clinical stages which can overlap or occur separately.

Stage 1 (early localized disease, erythema migrans and flu-like illness)

Systemic signs of infection usually begin with a flu-like illness within days to weeks of infection, symptoms include: fever, chills, malaise, fatigue or lethargy, backache, headache, arthralgia, and myalgia. Regional or generalized lymphadenopathy may occur.

The hallmark of LD is erythema chronicum migrans (ECM) (classically a “bullseye rash”) which begins 3-30 days after the tick bite, and occurs in 60-75% of patients. ECM usually begins in the thigh, inguinal region, or axilla, and consists of an expanding macular rash with bright red borders and central clearing and induration that usually fades without scarring in 3-4 weeks. Within 30 days of the tick bite, spirochetes may be demonstrated in acellular spinal fluid.

Stage 2 (early disseminated disease)

Several weeks to months after infection, untreated patients develop more serious organ involvement. Cardiac and neurologic involvement may occur. Manifestations include:

1. cardiac: occurs in 8%. Conduction defects (usually A-V block, generally brief and mild) and myopericarditis

2. ocular: panophthalmitis, ischemic optic atrophy, and interstitial keratitis occur rarely

3. neurologic: occurs in 10-15% of patients with stage 2 disease

A. the clinical triad of neurologic manifestations of Lyme disease is¹²⁴:

• cranial neuritis (especially that mimicking Bell’s palsy: Lyme disease is the most common cause of bilateral “Bell’s palsy” (facial diplegia) in endemic areas)

• meningitis

• radiculopathy

B. other possible neurologic involvement includes: encephalitis, myelitis, peripheral neuritis

Neurologic findings are frequently migratory, and ≈ 60% of patients have multiple neurologic findings simultaneously. In Europe, Bannwarth’s syndrome (chronic lymphocytic meningitis, peripheral neuropathy, and radiculopathy) is the most common manifestation, and primarily affects the peripheral nervous system¹²⁵. Neurologic symptoms usually resolve gradually.

Stage 3 (late disease)

Arthritis and chronic neurologic syndromes may occur in this stage. Arthralgias are common in stage 1, but true arthritis usually does not begin for months to years after infection, and is seen in ≈ 60% of cases¹²⁶. When arthritis occurs, it may affect the knee (89%), hip (9%), shoulder (9%), ankle (7%) and/or elbow (2%)¹²⁷. Neurologic involvement includes¹²⁸:

1. encephalopathy^A

2. encephalomyelitis^A

3. peripheral neuropathy^A

4. ataxia

5. dementia

6. sleep disorder

7. neuropsychiatric disease and fatigue syndromes

A. these conditions are chronic, and their manifestation may be subtle

DIAGNOSIS

There is no test indicative of active infection. The spirochete is difficult to culture from infected humans. Diagnosis is easy if a history of travel to endemic areas, tick bite, and ECM are identified. Table 16-17shows the CDC criteria for diagnosis.

Serology

It takes 7-10 days from initial infection to develop antibodies to B. burgdorferi, but it takes ≈ 2-3 wks before antibodies can reliably be detected in un-treated patients (antibiotics can reduce the immune response)¹³⁰. If the first serum test is negative, it should be repeated in 4-6 weeks if the clinical suspicion of LD is strong (seroconversion from negative to positive is supportive of B. burgdorferi infection). False positives can occur with other borrelial and treponemal infections (e.g. syphilis, however, VDRL test will differentiate the two).

Enzyme-linked immunosorbent assay (ELISA) detects IgM or IgG. Antibodies to B. burgdorferi is the usual test method. IgM is elevated acutely, and IgG gradually rises and is elevated in almost all patients at 4-6 weeks and is usually highest in patients with arthritis¹²³. Western blot may help identify false-positive ELISA results (more sensitive and specific than ELISA, however, results may vary between labs). Amplification of B. burgdorferi DNA by polymerase chain reaction (PCR) yields a more very sensitive test that may have significant false positives, and can be positive even if the DNA is from dead organisms.

Table 16-17 CDC criteria for diagnosis of Lyme disease¹²⁹

In endemic area: • erythema chronicum migrans (ECM) • antibody titer ≥ 1:256 by IFA* and involvement of ≥ 1 organ system†

In non-endemic area: • ECM with antibody titer ≥ 1:256 • ECM with involvement of ≥ 2 organ systems† • antibody titer ≥ 1:256 by IFA* and involvement of ≥ 1 organ system

* IFA = immunofluorescence antibody

^† either musculoskeletal, neurologic or cardiac

CSF

Elevated CSF IgG antibody titer to B. burgdorferi may occur with neurologic involvement¹³¹. CSF findings in late disease are usually compatible with aseptic meningitis. Oligoclonal bands and increased ratio of IgG to albumin may occur¹³².

TREATMENT^{128, 133, 134}

Antibiotic therapy is more effective early in the illness.

16.12. Parasitic infections of the CNS

Many parasitic infections may involve the central nervous system. Immunosuppression (including HIV) increases the susceptibility¹³⁵. CNS parasitic infections include (those that potentially involve neurosurgical intervention have a dagger (^†):

1. cysticercosis^†: see Neurocysticercosis below

2. toxoplasmosis^†: may occur as a congenital TORCH infection, or in the adult usually with AIDS (see Neurologic manifestations of AIDS, page 364). Toxoplasma gondii is an obligate intracellular protozoan that is ubiquitous but does not cause clinical infection except in immunocompromised hosts. Histologic features: necrosis containing 2-3 nm tachyzoites (cysts)

3. echinococcus^†: see page 373

4. amebiasis^†: ≈ exclusively Naegleria fowleri (see page 375)

5. schistosomiasis

6. malaria

7. African trypanosomiasis

^† parasitic infections with a dagger are those that are more likely to come to neurosurgical attention

16.12.1. Neurocysticercosis

Key concepts:

• intracranial encystment of larva of Taenia solium (pork tapeworm)

• the most common parasitic infection of the CNS

• neurological symptoms: seizures or progressive intracranial hypertension

• occurs from ingesting the parasite’s eggs, not from eating infested meat

• characteristic imaging finding: low density cysts with eccentric punctate high density (the scolex = tapeworm head). Hydrocephalus is common

• medical treatment: all patients get steroids. Start antihelmintic drugs (praziquantel or albendazole) when no signs of intracranial hypertension

• biopsy sometimes needed for diagnosis. Surgery: may be required for spinal, intraventricular or subarachnoid cysts (more refractory to medical therapy) or for giant cysts (> 50 mm) when intracranial hypertension persists despite steroids

Cysticercosis is the most common parasitic infection involving the CNS¹³⁶ and is the most common cause of acquired epilepsy in low-income countries¹³⁷. It is caused by Cysticercus cellulosae, the larval stage of the pork tapeworm Taenia solium, which has a marked predilection for neural tissue. Cysticercosis is endemic in areas of Mexico, Eastern Europe, Asia, Central and South America, and Africa. The incidence of neurocysticercosis (encystment of larva in the brain) may reach 4% in some areas¹³⁸. The incubation period varies from months to decades, but 83% of cases show symptoms within 7 years of exposure.

LIFE CYCLE OF T. SOLIUM

There are 3 stages to the life cycle: larva, embryo (or oncosphere) and adult. T. solium can infect man in two different ways: as the adult worm or as the larva.

Infection with the adult worm (taeniasis - a parasitic infection)

Human intestinal tapeworm infection (taeniasis) results from eating undercooked infested (measly) pork. The encysted larvae are released in the small bowel and can then mature within the intestine into an adult over about 2 months. The scolex (head) of the segmented adult worm attaches by means of four suckers and two rows of hooklets to the wall of the small intestine where the worm absorbs food directly through its cuticle. Man is the only known definitive host for the adult tapeworm, for which the GI tract is the sole habitat. Proglottids (mature segments, each containing reproductive organs) produce eggs which are liberally excreted along with gravid proglottid segments in the feces.

Infection with the larva

The disease cysticercosis occurs when animals or humans become an intermediate host for the larval stage by ingesting viable eggs produced by the proglottid. The most common routes of ingestion of viable eggs are:

1. food (usually vegetables) or water contaminated with human feces containing eggs or gravid proglottids (this is the means whereby pigs acquire the disease)

2. fecal-oral autoinoculation in an individual harboring the adult form of the tape-worm due to lack of good sanitary habits or facilities

3. autoinfection by reverse peristalsis of gravid proglottids from the intestine into the stomach (unproven theoretical possibility)

In the duodenum of man and pig, the shell of the ova dissolves and the thusly hatched embryos (oncospheres) burrow through the small bowel wall to enter the lymphatics or systemic circulation and gain access to:

• brain: involved in 60-92% of cases of cysticercosis. Latency from ingestion of eggs to symptomatic neurocysticercosis: 2-5 years¹³⁹

• skeletal muscle

• eye: immunologically privileged, like brain

• subcutaneous tissue

• heart

Once in the tissue of the intermediary host, embryos develop a cyst wall in ≈ 2 months (immature cyst) which matures in ≈ 4 months to a larva. Larval cysts are usually rapidly eliminated by the immune system. Many larvae die naturally within 5-7 yrs or with cysticidal therapy producing an inflammatory reaction with collapse of the cyst (granular nodular stage), these sometimes calcify (nodular calcified stage). In pigs, the larva lie dormant in the muscle, “waiting” to be eaten after which the cycle repeats.

TYPES OF NEUROLOGIC INVOLVEMENT

Spinal cord and peripheral nerves involvement is rare.

Giant cysts: definition: cyst with diameter > 50 mm¹⁴⁰.

Two types of cysts tend to develop in the brain¹⁴¹:

1. cysticercus cellulosae: regular, round or oval thin-walled cyst, ranging in size from ≈ 3 to 20 mm tending to form in the parenchyma or narrow subarachnoid spaces. This cyst contains a scolex (head), is usually static, and produces only mild inflammation during the active phase

2. cysticercus racemosus: larger (4-12 cm), grows actively producing grape-like clusters in the basal subarachnoid spaces and produces intense inflammation. There are no larvae in these cysts. These cysts usually degenerate in 2-5 years, in which the capsule thickens and the clear cyst contents are replace by a whitish gel which undergoes calcium deposition with concomitant shrinkage of the cyst

Location of the cysts tends to fall into 1 of 4 groups:

1. meningeal: found in 27-56% of cases with neural involvement. Cysts are adherent or free-floating and are located either in:

dorsolateral subarachnoid space: usually C. cellulosae type, causing minimal symptoms

basal subarachnoid space: usually the expanding C. racemosus form producing arachnoiditis and fibrosis comprising a chronic meningitis with hypoglycorrhachia. Can obstruct foramina of Luschka and Magendie producing hydrocephalus, or can cause entrapment of basal cisterns → cranial neuropathies (including visual disturbance). Extremely high mortality with this form

2. parenchymal: found in 30-63%; focal or generalized seizures occurs in ≈ 50% of cases (up to 92% in some series)

3. ventricular: found in 12-18%, possibly gaining access via the choroid plexus. Pedunculated or free floating cysts occur, can block CSF flow and cause hydrocephalus with intermittent intracranial hypertension (Brun syndrome). There may be adjacent ependymal enhancement (ependymitis)

4. mixed lesions: found in ≈ 23%

CLINICAL

Presentation: seizures, signs of elevated ICP, focal deficits related to the location of the cyst, and altered mental status are the most common findings. Increased ICP may be due to hydrocephalus or to giant cysts. Symptoms may also be produced by the immunologic reaction to the infestation (cysticercotic encephalitis). Cranial nerve palsies can occur with basal arachnoiditis. Subcutaneous nodules may sometimes be felt.

DIAGNOSIS

Diagnosis is usually made by imaging studies and confirmatory serologic tests.

LABORATORY EVALUATION

Mild peripheral eosinophilia can occur, but is inconsistent and thus unreliable.

CSF may be normal. Eosinophils are seen in 12-60% of cases and suggests parasitic infection. Protein may be elevated.

Stool: less than 33% of cases have T. solium ova in the stool.

Serology

Most centers use enzyme-linked immunoelectrotransfer blot (EIBT) against glycoprotein antigens (western blot) which is ≈ 100% specific and 98% sensitive¹⁴², although sensitivity is less (70%) in cases with a solitary cyst¹⁴³. May be used on serum or CSF. EIBT has effectively superseded ELISA where titer is considered significant at 1:64 in serum, and 1:8 in the CSF; checking for titer exceeding these thresholds in the serum produces a test that is more sensitive and in the CSF is more specific for cysticercosis. False negative rates are higher in cases without meningitis.

RADIOGRAPHIC EVALUATION

Soft-tissue x-rays may show calcifications in subcutaneous nodules, and in thigh and shoulder muscles.

Skull x-rays show calcifications in 13-15% of cases with neurocysticercosis. May be single or multiple. Usually circular or oval in shape.

CT

The following findings on brain CT have been described (modified^{141, 144}):

1. ring enhancing cysts of various sizes representing living cysticerci. Little inflammatory response (edema) occurs as long as larva is alive. Characteristic finding: small (< 2.5 cm) low density cysts with eccentric punctate high density that may represent the scolex

2. low density with ring enhancement seen as an intermediate stage between living cyst and calcified remnant representing intermediate stage in granuloma formation. Resultant inflammatory reaction can cause edema, and basal arachnoiditis in cysts located in basal subarachnoid space. Often ring enhancing

3. intraparenchymal punctate calcifications (granuloma) sometimes with, but usually without surrounding enhancement, seen with dead parasites

4. hydrocephalus. Sometimes with intraventricular cysts which may be isointense with CSF on plain CT¹⁴⁵ and may require contrast CT ventriculography¹⁴⁶ or MRI to be demonstrated

MRI

Early findings: nonenhancing cystic structure(s) with eccentric T1WI hyperintensity (scolex) with no inflammatory response. Lesions may be seen in parenchyma, ventricle, and subarachnoid space. The cyst collapses in later stages of parasitic evolution, with initial edema that gradually resolves with time.

TREATMENT

Combination of:

1. antihelmintic medication: antiparasitic and/or cysticidal regimens

2. antiepileptics: to treat seizures, which may sometimes be medically refractory

3. steroids (see below)

4. surgery:

A. surgical resection of lesions when appropriate

B. ventricular CSF diversionary procedures

Steroids

Corticosteroids should be used in all patients. May temporarily relieve symptoms, and may help decrease edema that tends to occur initially during treatment with anti-helmintic drugs. If possible, start 2-3 d before antihelmintics (e.g. dexamethasone 8 mg q 8 hours¹⁴⁰), on day 3 decrease to 4 mg q 8 hours, on day 6 change to prednisone 0.4 mg/kg per day divided TID. Taper steroids after antihelmintics are discontinued. In patients with symptoms of intracranial hypertension: antihelmintic treatment is started after symptoms subside (usually after 3 doses). ✖ Any cysticercocidal drug may cause irreversible damage when used to treat ocular or spinal cysts, even with corticosteroid use.

Antiepileptics

Seizures usually respond to a single AED. However, the risk of seizures may be lifelong. Risk factors for recurrent seizures: calcified brain lesions, multiple seizures, multiple brain cysts¹⁴⁷.

Antihelmintic drugs

Praziquantel (Biltricide®) is an antihelmintic with activity against all known species of schistosomas. Several regimens have been published:

• 50 mg/kg/d divided in 3 doses (same dose for pediatrics) for 15 days (doses of 100 mg/kg/d have been recommended¹⁴⁰ because steroids reduce serum concentration by 50%¹⁴⁸). Produces a significant reduction in symptoms and in number of cysts seen on CT¹³⁶

• 10-100 mg/kg/d x 3-21 days

• high dose single day regimen: 25-30 mg/kg q 2 hrs x 3 doses

• for intestinal infestation: single oral dose of 5-10 mg/kg

Albendazole (Zentel®) 15 mg/kg per day divided in 2-3 doses, taken with a fatty meal to enhance absorption (same dose for pediatrics), may be given for 3 months^{149, 150}, can be stopped sooner if imaging shows resolution¹⁴⁰. More parasiticidal than praziquantel and may have fewer side effects.

Niclosamide (Niclocide® and others) may be given orally to treat adult tapeworms in the GI tract. Rx 1 gm (2 tablets) chewed PO, repeated in 1 hour (total = 2 gm).

Intraventricular disease: There is no consensus on the efficacy of medical treatment for intraventricular cysts^{140, 151, 152}.

Surgery

Surgery may sometimes be necessary to establish the diagnosis. Stereotactic biopsy may be well suited for some cases, especially with deep lesions.

CSF diversion is necessary for patients with symptomatic hydrocephalus, although tubing may become obstructed by granulomatous inflammatory debris¹⁵³.

Surgery may be indicated for spinal cysts¹³⁸ and for intraventricular cysts which may be less responsive to medical therapy. The latter may sometimes be dealt with using stereotactic techniques and/or endoscopic instrumentation¹⁴⁶, however, shunting and antihelmintics may suffice¹⁵². Surgery may also be needed for giant cysts when intracranial hypertension does not respond to steroids¹⁴⁰. Antihelmintics may be required even after complete surgical removal because of possibility of relapse¹⁴⁰.

Follow-up

CT or MRI scan every 6 months until lesions disappear or calcify¹⁴⁰.

Contacts

Both patients with cysticercosis and their personal contacts should be screened for tapeworm infection since a single dose of niclosamide or praziquantel will eliminate the tapeworm¹⁵⁴. Close contacts of persons with tapeworms should have screening by medical history and serologic testing for cysticercosis; if suggestive of cysticercosis a neurologic exam and CT or MRI should be done.

16.12.2. Echinococcosis

AKA hydatid (cyst) disease. Caused by encysted larvae of the dog tapeworm Echinococcus granulosa in endemic areas (Uruguay, Australia, New Zealand…). The dog is the primary definitive host of the adult worm. Intermediate hosts for the larval stage include sheep and man. Ova are excreted in dog feces and contaminate herbage eaten by sheep. After ingestion, the embryos hatch and the parasite burrows through the duodenal wall to gain hematogenous access to multiple organs (liver, lungs, heart, bone, brain). Dogs eat these infested organs and the parasite enters the intestine where it remains.

Man is infected either by eating food contaminated with ova, or by direct contact with infected dogs. CNS involvement occurs in only ≈ 3%. Produces cerebral cysts that are confined to the white matter. Primary cysts are usually solitary, secondary cysts (e.g. from embolization from cardiac cysts that rupture or from iatrogenic rupture of cerebral cysts) are usually multiple. The CT density of the cyst is similar to CSF, it does not enhance (although rim enhancement may occur if there is an inflammatory reaction), and there is little surrounding edema. It contains germinating parasitic particles called “hydatid sand” containing ≈ 400,000 scoleces/ml. The cyst enlarges slowly (rates of ≈ 1 cm per year are quoted, but this is variable and may be higher in children), and usually does not present until quite large with findings of increased ICP, seizures, or focal deficit. Patients often have eosinophilia and may have positive serologic tests for hydatid disease.

Treatment

Treatment is surgical removal of the intact cyst. Every effort must be made to avoid rupturing these cysts during removal, or else the scoleces may contaminate the adjacent tissues with possible recurrence of multiple cysts or allergic reaction. May use adjunctive medical treatment with albendazole (Zentel®) 400 mg PO BID (pediatric dose: 15 mg/kg/d) x 28 days, taken with a fatty meal, repeated as necessary¹⁵⁰.

The Dowling technique is recommended¹⁵⁵:

1. the head is positioned so that the cyst points straight up towards the ceiling when the OR table is 30° head up

2. drilling burr holes and performing craniotomy must be done very carefully to avoid rupturing the cyst or tearing the dura which is thin and under tension

3. do not coagulate with anything but low-power bipolar (to avoid cyst rupture)

4. open the dura circumferentially away from the dome of the cyst as it may be adherent to the dura

5. keep the surface of the cyst moist to prevent desiccation and rupture

6. open the thinned overlying cortex gently, separating it from the cyst with irrigation and cottonoids. The cortical opening need only be ≈ 3/4 the cyst diameter but no less

7. insert a soft rubber catheter between the cyst and the brain, and gently irrigate with saline as the head of the OR table is slowly lowered 45° while the surgeon supports the adjacent cortex with his/her fingers

8. continue irrigating more saline and float the cyst out and into a saline filled receptacle

9. if the cyst is ruptured during the procedure, immediately place a sucker in the cyst to aspirate the contents, remove the capsule, and wash the cavity with saline for 5 minutes. Change instruments and gloves. Placing 10% formalin soaked cottonoids on the cavity for a few minutes is controversial^{156 (p 3750)}

16.13. Fungal infections of the CNS

Most are medically treated conditions that do not require neurosurgical intervention. They tend to present either with chronic meningitis or brain abscess. Some of the more common ones or those of particular relevance to neurosurgery include:

1. cryptococcosis: see below

A. cryptococcal meningitis

B. cryptococcoma (mucinous pseudocyst): rare

2. candidiasis: the most common fungal infection of the CNS, but rarely diagnosed before autopsy. Very rare in healthy individuals. Most are C. albicans

A. candidal meningitis: the most common CNS infection (see page 345 for Rx)

B. parenchymal infection: candida brain abscesses are rare

C. following ventricular shunt placement: almost all fungal VP shunt infections are due to Candida spp.¹⁶ (see page 346)

3. aspergillosis: may be associated with cerebral abscess in organ transplant patients (see page 351)

4. coccidiomycosis: caused by the dimorphic fungus Coccidioides immitis. Endemic in southwestern U.S., Mexico, and Central America. Usually presents as meningitis, with rare reports of parenchymal lesions¹⁵⁷

5. mucormycosis (phycomycosis): usually occurs in diabetics (see page 836)

CRYPTOCOCCAL INVOLVEMENT OF THE CNS

CNS involvement is diagnosed more frequently in living patients than any other fungal disease. Occurs in healthy or immunocompromised patients. In HIV, Cryptococcus neoformans is the typical agent.

1. cryptococcoma (mucinous pseudocyst): a parenchymal collection which occurs almost exclusively in AIDS patients. Much less common than cryptococcal meningitis. No enhancement of the lesion or the meninges. Usually 3-10 mm in diameter and are frequently located in the basal ganglia (due to spread by small perforating vessels)

2. cryptococcal meningitis:

A. occurs in 4-6% of patients with AIDS¹⁵⁸. Typical symptoms: fever, malaise and H/A¹⁵⁹. Meningeal signs (nuchal rigidity, photophobia…) occur in only ≈ 25%. Encephalopathic symptoms (lethargy, altered mentation…) usually from increased ICP occur in a minority

B. can also occur without AIDS: gatti variety can infect the brain of immuno-competent hosts¹⁶⁰

C. may be associated with increased ICP (with or without hydrocephalus on CT/MRI), decreased visual acuity, and/or cranial nerve deficits. Dilation of Virchow-Robbins spaces may be seen on imaging; on MRI the signal is similar to CSF on T1WI & T2WI but will be higher signal on FLAIR

D. late deterioration in the absence of documented infection may respond to decadron 4 mg q 6 hrs transitioned to prednisone 25 mg p.o. q d¹⁶¹

Diagnosis

LP: should be done at the time of diagnosis, with OP measured in the lateral decubitus position¹⁶². CSF cryptococcal antigen titer is invariably high with cryptococcal meningitis or meningoencepahlitis. OP is usually elevated, and is > 20 cm H₂O in up to 75%.

Serum cryptococcal Ag: almost always elevated with CNS involvement¹⁶².

Management

2009 CDC guidelines for CNS cryptoccal infection in HIV-infected adolescents/adults¹⁶²:

1. antifungal agents: the recommended initial standard treatment¹⁶² is amphotericin B deoxycholate (Amphocin®) 0.7 mg/kg IV q d, plus fluconazole (an oral triazole) 100 mg/kg po q d in 4 divided doses

2. patients with clinical signs of increased ICP (confusion, blurred vision, papilledema, LE clonus…) should have LP to measure ICP

3. management of intracranial hypertension (ICHT) (OP ≥ 25 cm H₂O) with or without hydrocephalus:^A

A. daily LPs: drain enough CSF to reduce ICP by 50% (typically 20-30 ml)¹⁶⁴

B. daily LPs may be suspended when pressures are normal for several consecutive days

C. lumbar drain: occasionally needed for extremely high OPs (> 40 cm H₂O) when frequent LPs are required to or fail to control symptoms¹⁶³

D. CSF shunt: considered when daily LPs are no longer tolerated or when signs and symptoms of ICHT are not being relieved (neither dissemination of infection through the distal shunt nor creation of a nidus of infection refractory to medical therapy has been described¹⁶⁵). Options:

1. lumboperitoneal shunt

2. VP or VA shunt^{166, 167}

4. antifungal treatment is continued for ≥ 2 weeks if renal function is normal^B

5. after 2 weeks of treatment, repeat the LP to look for clearance of the organism from the CSF. Positive CSF cultures after 2 weeks of treatment are predictive of future relapse and are associated with worse outcome

6. treatment failures: defined as lack of clinical improvement after 2 weeks of appropriate therapy including management of ICHT, or relapse after an initial response, defined as either a positive CSF culture and/or rising CSF cryptococcal Ag titer with a compatible clinical picture. Management:

A. optimal management has not been defined

B. trials with alternative antifungals (e.g flucytosine) or higher doses of fluconazole

7. maintenance therapy (secondary prophylaxis): HIV patients who have completed 10 weeks of treatment should be maintained on fluconazole 200 mg q d until immune reconstitution occurs, otherwise lifetime treatment is indicated¹⁶²

8. the risk of recurrence is low for patient who remain asymptomatic after a complete course of therapy and have sustained increase (> 6 months) of CD4+ counts to ≥ 200 cells/μL. Some experts perform an LP to document negative CSF culture and antigen before stopping maintenance therapy

A. corticosteroids, acetazolamide and mannitol have not been shown to be effective¹⁶³

B. most immunocompetent patients will be successfully treated with 6 weeks of therapy¹⁶³

16.14. Amebic infections of CNS

Naegleria fowleri: the only ameba known to cause CNS infection in humans → primary amebic meningoencephalitis (PAM): diffuse encephalitis with hemorrhagic necrosis and prurulent meningitis involving brain and spinal cord. Rare (only 95 cases in the U.S. as of 2002, and ≈ 200 cases worldwide as of 2004). Typically occurs ≤ 5 days of exposure, usually from diving in warm freshwater. The ameba gains entry to the CNS by invading nasal olfactory mucosa.

Associated cerebral edema may cause increased ICP and, ultimately, herniation. Fatal in ≈ 95% usually within 1 week.

CSF: cloudy and often hemorrhagic, ↑ leukocytes, ↑ protein, normal or ↓ glucose, Gram stain negative (no bacteria or fungi), wet prep → motile trophozoites (may be confused with WBCs).

Treatment

Drug of choice: amphotericin B (lipid preparations (Abelcet®) achieve higher MICs than other amphotericin preparations). Miconazole may be synergistic.

Surgical intervention: ventriculostomy with CSF drainage may be indicated when findings are suggestive of increased ICP. In one survivor, surgical drainage of a brain abscess was performed in addition to treatment with a 6-week course of amphotericin B, rifampicin, and chloramphenicol.

16.15. Spine infections

Spine infections may be divided into the following major categories:

1. vertebral osteomyelitis (spondylitis): see page 380

A. pyogenic

B. nonpyogenic, granulomatous

1. tuberculous spondylitis

2. brucellosis

3. aspergillosis

4. blastomycosis

5. coccidiomycosis

6. infection with Candida tropicalis

2. discitis: see page 383, usually associated with vertebral osteomyelitis (spondylodiscitis) see page 380

A. spontaneous

B. post-operative/post-procedure

3. spinal epidural abscess (see below)

4. spinal subdural empyema

5. meningitis

6. spinal cord abscess

MRI experience suggests that patients with infectious spondylitis will develop an associated epidural abscess if untreated, and that epidural empyema is unusual in the absence of vertebral osteomyelitis¹⁶⁸. Thus, the discovery of one of these conditions should prompt a search for the other.

16.15.1. Spinal epidural abscess

Key concepts:

• should be considered in a patient with back pain, fever, and spine tenderness

• major risk factors: diabetes, IV drug abuse, chronic renal failure, alcoholism

• may produce progressive myelopathy, sometimes with precipitous deterioration

• fever, sweats or rigors are common, but normal WBC and temperature can occur

• classical presentation of a skin boil (furuncle) occurs in only ≈ 15%

• treatment: controversial. Many patients improve with antibiotics alone. Early surgery is advocated by some even if no neuro deficit because of risk of precipitous deterioration

EPIDEMIOLOGY

Incidence: 0.2-1.2 per 10,000 hospital admissions annually¹⁶⁹, possibly on the rise¹⁷⁰. Average age: 57.5 ± 16.6 years¹⁷¹.

Thoracic level is the most common site (≈ 50%), followed by lumbar (35%) then cervical (15%)¹⁷¹. 82% were posterior to the cord, and 18% anterior in one series¹⁶⁹. SEA may span from 1 to 13 levels¹⁷².

Spinal epidural abscess (SEA) is often associated with vertebral osteomyelitis (in one series of 40 cases, osteomyelitis occurred in all cases of anterior SEA, in 85% of circumferential SEA, and no cases of posterior SEA) and intervertebral discitis.

CO-MORBID CONDITIONS

Chronic diseases associated with compromised immunity were identified in 65% of 40 cases¹⁷³. Associated conditions included diabetes mellitus (32%), IV drug abuse (18%), chronic renal failure (12%), alcoholism (10%), and the following in only 1 or 2 patients: cancer, recurrent UTI, Pott’s disease, and positivity for HIV. Chronic steroid use and recent spinal procedure or trauma (e.g. GSW) are also risk factors¹⁷². Also, skin infection.

CLINICAL FEATURES

Usually presents with excruciating pain localized over spine, tender to percussion. Radicular symptoms follow with subsequent distal cord findings, often beginning with bowel/bladder disturbance, abdominal distension, weakness progressing to para- and quadriplegia. Average time is 3 days from back pain to root symptoms; 4.5 days from root pain to weakness; 24 hrs from weakness to paraplegia.

Fever, sweats or rigors are common, but are not always present¹⁷².

A furuncle may be identified in 15%.

Patients may be encephalopathic. This may range from mild to severe and may further delay diagnosis. Meningismus with a positive Kernig’s sign may occur.

Patients with post-operative SEA may demonstrate surprisingly few signs or symptoms (including lack of leukocytosis, lack of fever) aside from local pain¹⁷⁴.

Pathophysiology of spinal cord dysfunction

Although some cord symptoms may be due to mechanical compression (including that due to vertebral body collapse), this is not always found¹⁷⁵. A vascular mechanism has also been postulated, and various combinations of arterial and venous pathology have been described¹⁶⁹ (one autopsy series showed little arterial compromise, but did show venous compression and thrombosis, thrombophlebitis of epidural veins, and venous infarction and edema of the spinal cord¹⁷⁶). Occasionally, there may be infection of the spinal cord itself, possibly by extension through the meninges.

Differential diagnosis

SEA should be considered in any patient with backache, fever, and spine tenderness¹⁷⁷. Also see Differential diagnosis, Myelopathy on page 1185.

Differential diagnosis

1. meningitis

2. acute transverse myelitis (paralysis is usually more rapid, radiographic studies are normal)

3. intervertebral disc herniation

4. spinal cord tumors

5. post-op SEA may appear similar to pseudomeningocele¹⁷⁴

SOURCE SITE OF INFECTION

• hematogenous spread is the most common source (26-50% of cases) either to the epidural space or to the vertebra with extension to epidural space. Reported foci include:

A. skin infections (most common): furuncle may be found in 15% of cases

B. parenteral injections, especially with IV drug abuse¹⁷⁸

C. bacterial endocarditis

D. UTI

E. respiratory infection (including otitis media, sinusitis, or pneumonia)

F. pharyngeal or dental abscess

• direct extension from:

A. decubitus ulcer

B. psoas abscess: see below

C. penetrating trauma, including: abdominal wounds, neck wounds, GSW

D. pharyngeal infections

E. mediastinitis

F. pyelonephritis with perinephric abscess

• following spinal procedures (3 of 8 of these patients had readily identified perioperative infections of periodonta, UTI, or AV-fistula¹⁷³)

A. open procedures: especially lumbar discectomy (incidence¹⁷⁴ ≈ 0.67%)

B. closed procedures: e.g. epidural catheter insertion for spinal epidural anesthesia^179-181, lumbar puncture¹⁸²…

• a history of recent back trauma is common (in up to 30%)

• no source can be identified in up to 50% of patients in some series¹⁸³

Psoas abscess

1. psoas muscle:

A. one of 2 heads of the iliopsoas muscle (the other head is iliacus)

B. origin: inner surface of ilium, base of sacrum, and transverse processes, vertebral bodies (VB) and intervertebral discs of spinal column starting from the inferior margin of T12 VB, extending to the upper part of L5 VB. Insertion: lesser trochanter of the femur. Psoas is the primary hip flexor

C. innervation: branches of L2-4 nerve roots proximal to the formation of the femoral nerve

D. susceptibility to infection

1. rich vascular supply makes it vulnerable to hematogenous spread

2. proximity to structures that may be a source of infection: sigmoid colon, jejunum, vermiform appendix, ureters, aorta, renal pelvis, pancreas, iliac lymph nodes and spine

2. may be primary (no identifiable underlying disease) or secondary in which it may be associated with one of the conditions shown in Table 16-18

3. risk factors: IV drug abuse, HIV/AIDS, age > 65 years, DM, immunosuppression, renal failure

4. physical findings: signs of iliopsoas inflammation include:

A. active: pain on flexing the hip against resistance

B. passive: with the patient lying on the unaffected side, hyperextension of the affected hip stretches the psoas muscle and produces pain

5. diagnostic tests:

A. routine infection work-up: WBC (often elevated), blood cultures, U/A + C&S (pyuria may be seen)

B. AP abdominal x-ray: psoas shadow may be obliterated

C. CT: sensitivity is 80-100% (MRI is not better)¹⁸⁵. Enlargement of psoas muscle on affected side best seen inside iliac wing

6. treatment often includes drainage of the psoas abscess either surgically or percutaneously with CT-guidance

7. mortality rates with psoas abscess: 2.4% with primary, 19% with secondary¹⁸⁶

Table 16-18 Conditions associated with secondary psoas abscess¹⁸⁴

Organ system	Condition
gastrointestinal	diverticulitis, appendicitis, Crohn’s disease, colorectal cancer
genitourinary	UTI, cancer
musculoskeletal infections	vertebral osteomyelitis, infectious sacroiliitis, septic arthritis
other	endocarditis, femoral artery catheterization, infected abdominal aortic aneurysm graft, hepatocellular Ca, intrauterine contraceptive device, trauma, sepsis, dialysis (peritoneal or long-term hemodialysis)

ORGANISMS

Operative cultures are most useful in identifying the responsible organism, these cultures may be negative (possibly more common in patients previously on antibiotics) and in these cases blood cultures may be positive. No organism may be identified in 29-50% of cases.

1. Staph. aureus: the most common organism (cultured in > 50%) possibly due to its propensity to form abscesses, its ubiquity, and its ability to infect normal and immunocompromised hosts (these facts help explain why many SEA arise from skin foci)

2. aerobic & anaerobic streptococcus: second most common

3. E.coli

4. Pseudomonas aeruginosa

5. Diplococcus pneumoniae

6. Serratia marcescens

7. Enterobacter

8. chronic infections:

A. TB is the most common of these, and although it has become less wide-spread in the U.S. it is still responsible for 25% of cases of SEA¹⁸⁷, it is usually associated with vertebral osteomyelitis (Pott’s disease) (see Tuberculous vertebral osteomyelitis, page 381)

B. fungal: cryptococcosis, aspergillosis, brucellosis

C. parasitic: Echinococcus

9. multiple organisms in ≈ 10%

10. anaerobes cultured in ≈ 8%

LABORATORY TESTS

CBC: leukocytosis common in acute group (average WBC = 16,700/mm³), but usually normal in chronic (ave. WBC = 9,800/mm³)¹⁶⁹.

ESR elevated in most⁷⁰, usually > 30¹⁷³.

LP: performed cautiously in suspected cases at a level distant to the clinically suspected site (C1-2 puncture may be needed to do myelogram) with constant aspiration while approaching thecal sac to detect pus (danger of transmitting infection to subarachnoid space); if pus is encountered, stop advancing, send the fluid for culture, and abort the procedure. CSF protein & WBC usually elevated; glucose normal (indicative of parameningeal infection). 5 of 19 cases grew organisms identical to abscess.

Blood cultures: may be helpful in identifying organism in some cases.

Anergy battery: (e.g. mumps and Candida) to assess immune system.

RADIOGRAPHIC STUDIES

Plain films: Usually normal unless there is osteomyelitis of adjacent vertebral bodies (more common in infections anterior to dura). Look for lytic lesions, demineralization, and scalloping of endplates (may take 4-6 weeks after onset of infection).

MRI: Imaging study of choice. Differentiates other conditions (especially transverse myelitis or spinal cord infarction) better than myelo/CT, and doesn’t require LP.

Typical findings: T1WI → hypo- or isointense epidural mass, vertebral osteomyelitis shows up as reduced signal in bone. T2WI → high intensity epidural mass that often enhances with gadolinium (3 patterns of enhancement: 1) dense homogeneous, 2) inhomogeneous with scattered areas of sparse or no uptake, and 3) thin peripheral enhancement¹⁸⁸) but may show minimal enhancement in the acute stage when comprised primarily of pus with little granulation tissue. Vertebral osteomyelitis shows up as increased signal in bone, associated discitis produces increased signal in disc and loss of intranuclear cleft. Unenhanced MRI may miss some SEA¹⁸⁹, gadopentetate dimeglumine enhancement may slightly increase sensitivity¹⁹⁰.

Myelogram: Usually shows findings of extradural compression (e.g. “paintbrush appearance” when complete block is present). In the event of complete block, C1-2 puncture is needed to delineate upper extent (unless post-myelographic CT shows dye above the lesion). See cautions above regarding LP.

CT scan: Intraspinal gas has been described on plain CT¹⁹¹. Post-myelographic CT is more sensitive.

TREATMENT

Controversial. Some advocate early surgical evacuation combined with antibiotics as the treatment of choice. Argument: although there are reports of management with antibiotics alone^192-194 ± immobilization¹⁶⁸, rapid and irreversible deterioration has occurred even in patients treated with appropriate antibiotics who were initially neurologically intact^{171, 173}. 86% of those who deteriorated were initially treated it with antibiotics alone¹⁷². Therefore it is recommended that nonsurgical management be reserved for the following patients (reference¹⁹² modified¹⁷²):

1. those with prohibitive operative risk factors

2. involvement of an extensive length of the spinal canal

3. complete paralysis for > 3 days

Surgery

Goals are establishing diagnosis and causative organism, drainage of pus and debridement of granulation tissue, and bony stabilization if necessary. Most SEA are posterior to dura and are approached with extensive laminectomy. For posteriorly located SEA and no evidence of vertebral osteomyelitis, instability will usually not follow simple laminectomy and appropriate postoperative antibiotics¹⁸³. Closure is performed with limited wire sutures. Post-op drainage is not necessary in cases with only granulation tissue and no pus. For recurrent infections, reoperation and post-op suction-irrigation may be needed¹⁹⁵.

Patients with vertebral osteomyelitis may develop instability after laminectomy alone¹⁹⁶ especially if significant bony destruction is present. Thus for anterior SEA, usually with osteomyelitis (especially Pott’s disease), a posterolateral extracavitary approach is utilized whenever possible (to avoid transabdominal or transthoracic approach in these debilitated patients) with removal of devitalized bone usually followed by posterior instrumentation and fusion. Strut grafting with autologous bone (rib or fibula) can be done acutely in Pott’s disease with little risk of graft infection. With purulent osteomyelitis, metal hardware is not contraindicated but bone grafting risks continuation of infection.

Specific antibiotics

If organism and source unknown, S. aureus most likely. Empiric antibiotics:

1. 3rd generation cephalosporin, e.g. cefotaxime (Claforan®)

PLUS

2. vancomycin: until methicillin resistant S. aureus (MRSA) can be ruled out. Once MRSA is ruled out switch to synthetic penicillin (e.g. nafcillin or oxacillin)

PLUS

3. rifampin PO

Modify antibiotics based on culture results or knowledge of source (e.g. IV drug abusers have a higher incidence of Gram-negative organisms).

Duration of treatment

For SEA, 3-4 weeks of IV antibiotics followed by 4 weeks of oral antibiotics usually suffices. 6-8 weeks of IV antibiotics are suggested if there is documented concomitant vertebral osteomyelitis¹⁹⁷ (although some argue that osteomyelitis is present pathologically in most cases even if not demonstrated radiographically, and therefore there should be no treatment difference between these groups¹⁹⁸). Serial ESRs may also guide duration (failure to reduce suggests residual infection¹⁷⁰). Immobilization for at least 6 weeks during antibiotic therapy is recommended.

OUTCOME

Fatal in 4-31%¹⁹⁹ (the higher end of the range tends to be in older patients and in those paralyzed before surgery¹⁷³). Patients with severe neurologic deficit rarely improve, even with surgical intervention within 6-12 hrs of onset of paralysis, although a few series have shown a chance for some recovery with treatment within 36 hrs of paralysis^{177, 198}. Reversal of paralysis of caudal spinal cord segments if present for more than a few hours is rare (exception: Pott’s disease has 50% return). Mortality is usually due to original focus of infection or as a complication of residual paraplegia (e.g. pulmonary embolism).

16.15.2. Vertebral osteomyelitis

Key concepts:

• presentation and risk factors similar to spinal epidural abscess (see page 376)

• percutaneous needle biopsy for C&S and to rule-out tumor. Can be done by neurosurgeon or interventional radiologist

• treatment: most cases can be managed nonsurgically with long-term antibiotics

• surgery is considered for instability, and infrequently for severe resistance to Abx

For differential diagnosis, see Destructive lesions of the spine, page 1232. Often associated with discitis, which may be grouped together under the term spondylodiscitis. VO has features similar to spinal epidural abscess (SEA)(see page 376).

Vertebral body collapse and kyphotic deformity may occur with possible retropulsion of necrotic bone and disc fragments, compressing the spinal cord or cauda equina.

EPIDEMIOLOGY

Vertebral osteomyelitis (VO) comprises 2-4% of all cases of osteomyelitis²⁰⁰. Incidence is 1:250,000 in general population. Incidence appears to be rising. Male:female ratio is 2:1. Incidence increases with age, most patients are > 50 years old. The lumbar spine is the most common site, followed by thoracic, cervical and sacrum²⁰¹. Thoracic VO may → empyema.

Risk factors

1. IV drug abuse²⁰²

2. diabetes mellitus: susceptible to unusual bacterial infections and even fungal osteomyelitis

3. hemodialysis: a diagnostic challenge since radiographic changes of osteomyelitis can occur even in the absence of infection (see Destructive lesions of the spine, page 1232)

4. immunosuppression

A. AIDS

B. chronic corticosteroid use

C. ethanol abuse

5. infectious endocarditis

6. following spinal surgery or invasive diagnostic or therapeutic procedures

7. may occur in elderly patients with no other identifiable risk factors²⁰³

Complications that may accrue

1. spinal epidural abscess

2. subdural abscess

3. meningitis

4. bony instability

5. progressive neurologic impairment

6. unique to cervical spine involvement: pharyngeal abscess

7. unique to thoracic spine involvement: mediastinitis

CLINICAL

Signs/symptoms: localized pain (90%), fever (52%, with fever spikes and chills being rare), weight loss, paraspinal muscle spasm, radicular symptoms (50-93%) or myelopathy. VO sometimes produces few systemic effects (e.g. WBC and/or ESR may be normal). ≈ 17% of patients with VO have neurologic symptoms. The risk of paralysis may be higher in the older patient, in cervical VO (vs. thoracic or lumbar), in those with DM or rheumatoid arthritis, and in those with VO due to S. aureus¹⁹⁶. Neurologic findings are uncommon initially, which may delay the diagnosis²⁰⁴. Sensory involvement is less common than motor and long-tract signs because compression is primarily anterior.

PATHOGENESIS

Source of infection

Sources of spontaneous VO: UTI (the most common), respiratory tract, soft-tissues (e.g. skin boils, IV drug abuse…), dental flora, blunt trauma to the spine. In 37% of cases a source is never identified²⁰⁵.

Potential routes of spread

Three main routes (arterial, venous, and direct extension):

1. hematogenous: hematogenously disseminated spondylodiscitis in adults usually involves bone initially, and once infection is established in the subchondral space, spread is to the adjacent disc and thence to the next VB²⁰⁶

A. arterial

B. via spinal epidural venous plexus (Batson’s plexus²⁰⁷)

2. direct extension (e.g. following surgery/LP, trauma, or local infection)

Organisms

1. Staphylococcus aureus is the most common pathogen (> 50%) as in SEA

2. E. coli is a distant second

3. organisms associated with some primary infection sites²⁰⁸:

A. IV drug abusers: Pseudomonas aeruginosa is common

B. urinary tract infections: E. coli & Proteus spp. are common

C. respiratory tract infections: Streptococcus pneumoniae

D. alcohol abuse: Klebsiella pneumoniae

E. endocarditis:

1. acute endocarditis: Staph. aureus

2. subacute endocarditis: Streptococcus spp.

4. tuberculous VO: Mycobacterium tuberculosis (see below)

5. unusual organisms include: nocardia (see page 356)

6. Mycobacterium avium complex (M. Avium and M. intracellulare) (MAC) can cause pulmonary disease in nonimmunocompromised patients (usually elderly or on chronic steroids), but can cause VO similar to TB²⁰⁹ as part of disseminated disease which usually occurs in HIV patients

7. rarely (< 2.5%) pyogenic infections are polymicrobial

Tuberculous vertebral osteomyelitis: AKA tuberculous spondylitis, AKA Pott’s disease. More common in third world countries. Typically symptomatic for many months. Usually affects more than one level. The most common levels involved are the lower thoracic and upper lumbar levels. Has a predilection for the vertebral body, sparing the posterior elements. Psoas abscess is common (the psoas major muscle attaches to the bodies and intervertebral discs from T12-L5). Sclerosis of the involved vertebral body may occur. Definitive diagnosis requires the identification of acid fast bacilli on culture or Gram stain of biopsy material (may be done percutaneously).

Neurologic deficit develops in 10-47% of patients²¹⁰, and may be due to medullary and radicular inflammation in most cases. The infection itself rarely extends into the spinal canal²¹¹, however, epidural granulation tissue or fibrosis or a kyphotic bony deformity may cause cord compression²¹⁰.

The role of surgical debridement and fusion with TB is controversial, and good results may be obtained with either medical treatment or surgery. Surgery may be more appropriate when definite cord compression is documented or for complications such as abscess or sinus formation²¹².

DIAGNOSTIC TESTS

Laboratories

WBC: elevated in only ≈35% (rarely > 12,000), associated with poor prognosis.

ESR: elevated in almost all. Usually > 40 mm/hr. Mean: 85.

CRP: may be more sensitive than ESR, and may tend to normalize more quickly with appropriate treatment²¹³. For normal values see page 387.

Cultures/biopsy

Culture: blood (positive in ≈ 50%), urine and any focal suppurative process.

Needle biopsy with cultures: can usually be done percutaneously via transpedicular approach with CT or fluoroscopic guidance. May be helpful even if blood cultures are positive (different organisms retrieved in 15%²¹⁴) an attempt at direct culture from the involved site should be made. Ideally, cultures should be done before antibiotics are started. The yield of needle biopsy cultures ranges from 60-90%. Open biopsy is more sensitive, but morbidity is higher.

IMAGING

A comparison of sensitivities and specificities of various imaging modalities is shown in Table 16-19. NB: MRI and CT may be negative if done too early in the course.

MRI: T1WI → confluent low signal in vertebral bodies and intervertebral disc space. T2WI → increased intensity of involved VBs and disc space²¹⁵. Contrast: enhancement of VB and disc, also look for paraspinal and epidural mass.

Plain x-ray: changes take from 2-8 weeks from the onset of infection to develop. Earliest changes are loss of cortical endplate margins and loss of disc space height.

Bone scan: three phase bone scan (see page 140) has reasonably good sensitivity and specificity. Gallium scan (see page 141) has better accuracy, findings include increased uptake in the 2 adjacent VBs with loss of intervening disc²¹⁶. Indium-111 labeled WBC scan: low sensitivity for vertebral osteomyelitis.

WORK-UP

In patients with suspected vertebral osteomyelitis (VO) (see text above for details):

1. clinical: history of IV drug abuse, DM, skin boil

2. physical exam: R/O radiculopathy & myelopathy, point tenderness over spine

3. diagnostic tests:

A. bloodwork: WBC, ESR (a normal ESR is almost incompatible with VO), blood cultures

B. imaging: MRI without and with contrast. Bone scan is used when suspicion is high and MRI is contraindicated

C. percutaneous needle biopsy with cultures: usually by radiologist. Cultures should include: fungal, aerobic and anaerobic bacterial, and TB

Table 16-20 Candidates for non-surgical treatment in pyogenic spontaneous spondylodiscitis²⁰⁸

• organism identified • antibiotic sensitivity • single disc space involvement with little VB involvement • minimal or no neurologic deficit • minimal or no spinal instability

TREATMENT

90% of cases can be managed non-surgically with antibiotics and immobilization. Characteristics of potential candidates for non-surgical treatment are listed in Table 16-20. Must also take into account level(s) involved and patient’s condition.

In cases with high suspicion for VO, antibiotics may be started as soon as biopsy has been performed (some treat even earlier). For details of antimicrobials, see Treatment, page 379 (under spinal epidural abscess).

Improvement on imaging can lag behind clinical response and ESR/CRP.

Indications for neurosurgical^A intervention:

1. progression of disease despite adequate best-case antibiotic therapy

2. spinal instability

3. spinal epidural abscess: see page 376

4. chronic infection refractory to medical management

For patients not being treated surgically:

1. percutaneous biopsy to obtain ID & sensitivity of organism

2. antibiotics:

A. IV antibiotics for at least 6 weeks^B (longer, e.g. 12 weeks, if ESR not normalizing or if extensive bone involvement and paravertebral infection)

B. followed by 6-8 weeks of oral agents²⁰⁸

3. pain medication as appropriate for pain

4. TLSO brace: to reduce pain (due to movement at involved site) and to reduce stress on weakened bone until healing

5. check upright films in the TLSO to verify stability in the brace

6. follow-up at approximately 8 and 12 weeks with x-rays in brace, then consider discontinuing brace if infection and pain are under control

Surgical treatment

Decompression of neural elements, removal of inflammatory tissue and infected bone to decrease bioburden. Use of instrumented fusion is not contraindicated even for pyogenic infections. Use of bone morphogenic protein (rhBMP-2) in 14 patients undergoing circumferential fusion for refractory infections did not produce complications²¹⁷.

16.15.3. Discitis

An uncommon primary infection of the nucleus pulposus. May start in cartilaginous endplate and spread to disc and vertebral body (VB). Can occur following a number of procedures (see Epidemiology, page 386) or may be “spontaneous” (the latter being more common). Often a benign, self-limited disease. Similar to vertebral osteomyelitis, except osteomyelitis primarily involves the VB and spreads secondarily to the disc space. Features and management common to spontaneous and postoperative discitis are discussed in the “general” section below, followed by sections describing characteristics unique to each (see Spontaneous discitis, page 386 or Postoperative discitison page 386).

Many radiographic features of spondylodiscitis and tumor (metastatic and primary) are similar, but tumors rarely involve the disc space, whereas most infections begin in, or before too long, involve the disc space (for more details, see Differentiating factors, page 1233).

DISCITIS IN GENERAL

CLINICAL

1. symptoms:

A. pain (the primary symptom)

1. local pain, moderate to severe, exacerbated by virtually any motion of the spine, usually well localized to the level of involvement

2. radiating to abdomen²¹⁸, hip, leg, scrotum, groin, or perineum

3. radicular symptoms: in 50%²¹⁹ to 93%²²⁰ depending on the series

B. fever and chills (only 30-50% are febrile)

2. signs:

A. tenderness

B. paravertebral muscle spasm

C. limitation of movement

A. intervention by a general surgeon may be indicated for empyema, psoas abscess…

B. the rate of treatment failure is increased when IV antibiotics are given for < 4 weeks²⁰⁸

WORK-UP (SEE TEXT FOR DETAILS)

1. MRI: also evaluates for epidural spread

2. blood tests

A. WBC

B. ESR & CRP

C. blood cultures

3. echocardiogram: rule-out endocarditis or valvular vegetations

4. percutaneous needle biopsy

RADIOGRAPHIC EVALUATION

A characteristic radiographic finding that helps distinguish infection from meta-static disease is that destruction of the disc space is highly suggestive of infection, whereas in general, tumor does not cross the disc space (see Differentiating factors, page 1233).

PLAIN X-RAYS

Usually not helpful for early diagnosis. Sequence of changes on plain films:

• earliest changes: interspace narrowing with some demineralization of the VB. Not seen < 2-4 wks following onset of clinical symptoms, nor later than 8 wks

• sclerosis (eburnation) of adjacent cortical margins with increased density of adjacent areas of VB representing new bone formation, starting 4-12 weeks following onset of clinical symptoms

• irregularity of the adjacent vertebral endplates, with sparing of the pedicles (except for tuberculosis, which may involve the pedicles)

• in 50% of cases, the infection remains confined to the disc space, in the other 50% it spreads to adjacent VB

• a late finding is widening (ballooning) of the disc space with erosion of the VB

• circumferential bone formation may lead to exuberant spur formation between VBs 6-8 months into course of illness

• spontaneous fusion of the VB may occur

MRI

Demonstrates involvement of disc space and of VBs. MRI can R/O paravertebral or epidural spinal abscess but is poor in assessing bony fusion. As sensitive as radionuclide bone scan. Characteristic finding: decreased signal from the disc and adjacent portion of VBs on T1WI, and increased signal from these structures on T2WI. Characteristic findings may occur 3-5 days after onset of symptoms. MRI also rules-out other causes of postop pain (epidural abscess, recurrent/residual disc herniation…).

The triad of gadolinium enhancement shown in Table 16-21 is strongly suggestive of discitis (some asymptomatic patients may have some of these findings, but they rarely have all)²²¹.

Table 16-21 Gadolinium enhancement in discitis

Location of gadolinium enhancement	Number (out of 15 patients without discitis)	Number (out of 7 patients with discitis)
1. vertebral bone marrow	1	7
2. disc space	3	5
3. posterior annulus fibrosus	13	7

CT

May also R/O paravertebral or epidural spinal abscess, and is better for assessing bony fusion. With the addition of water soluble intrathecal contrast, also assesses the spinal canal for compromise.

Diagnostic criteria

Three basic changes on CT²²² (if all 3 are present, pathognomonic for discitis; if only the 1st 2 are present, then only 87% specific for discitis):

1. endplate fragmentation

2. paravertebral soft-tissue swelling with obliteration of fat planes

3. paravertebral abscess

SPINE POLYTOMOGRAMS

For postoperative discitis (POD): performed through level of previous discectomy. Otherwise, center tomograms on painful level.

SCINTIGRAMS

Very sensitive for discitis and vertebral osteomyelitis (85% sensitivity), but may be negative in up to 85% of patients with Pott’s disease. Uses either technetium-99 (abnormal as early as 7 days following onset of clinical symptoms) or gallium-67 (abnormal within 14 days). A positive scan shows focal increased uptake in adjacent endplates, and may be differentiated from osteomyelitis which will involve only one endplate. A positive scan is not specific for infection, and may also occur with neoplasms, fractures, and degenerative changes.

LABORATORY STUDIES

ESR: In non-immunocompromised patients, ESR will be elevated in almost all cases with an average of 60 mm/hr (although it can rarely occur, a normal ESR should call the diagnosis into question). Interpreting ESR may be more problematic in post-op discitis (see page 387). ESR may be useful to follow as an indicator of response to treatment.

C-reactive protein: See C-reactive protein on page 387.

WBC: Peripheral WBC is often normal, and rarely is elevated above 12,000.

PPD: Applied to help R/O Pott’s disease (see Tuberculous vertebral osteomyelitis, page 381), may be negative in 14% of cases²²³.

Cultures: An attempt should be made to obtain direct cultures from the involved disc space. These may be obtained percutaneously with CT or other radiographic guidance (reported up to 60% positive culture rate; if available, a nucleotome provides a higher yield than e.g. Craig needle biopsy), or from intraoperative specimen (NB: surgery for open biopsy alone is usually not indicated). Staining for TB must be done in all cases.

Blood cultures may be positive in ≈ 50% of cases, and are helpful in guiding choice of antimicrobial agent when positive.

PATHOGENS

Staphylococcus aureus is the most common organism when direct cultures are obtained, followed by S. albus and S. epidermidis (S. epidermidis is the most common pathogen in POD). Gram negative organisms may also be found, including E. coli and Proteus species. Enteric flora in post-op discitis may due to undetected breach of the anterior longitudinal ligament with bowel perforation.

Pseudomonas aeruginosa may be more common in IV drug abusers.

H. flu is common in juvenile discitis (see below).

Tuberculous spondylitis (Pott’s disease) may also occur.

TREATMENT

Outcome is generally good, and antibiotics together with immobilization are adequate treatment in ≈ 75% of cases. Occasionally surgery is required. Also see Management, page 387 under postoperative discitis for other aspects of management.

IMMOBILIZATION

Probably does not affect final outcome, but generally affords earlier pain relief, and may allow return to activity at an earlier time.

Most patients are started on strict bed rest, and are fitted for a plastic-type body jacket in which they are allowed to ambulate, and in which they remain for 6-8 weeks on the average. Alternative forms of immobilization include spica cast (provides better immobilization) and a corset-type brace.

ANTIBIOTICS

Current thinking is that most patients should receive antibiotics, guided by the results of the direct cultures when positive. In the 40-50% of cases where no organism is isolated, broad spectrum antibiotics should be used.

Two alternative treatment plans suggested:

1. treat with IV antibiotics for an arbitrary period of time, usually ≈ 4-6 weeks, followed with oral antibiotics for an additional 4-6 weeks

2. treat with IV antibiotics until the ESR normalizes, then change to PO

SURGERY

Required in only ≈ 25% of cases. Debridement may be done through the previous laminectomy site. However, if there has been significant bone loss and instability, then an anterior discectomy and fusion through a retroperitoneal approach may be required.

Surgery is reserved for:

1. situations where the diagnosis is uncertain, especially when neoplasm is a strong consideration (CT guided needle biopsy may help here)

2. decompression of neural structures, especially with associated spinal epidural abscess or compression by reactive granulation tissue. Ascending numbness, weakness, or onset of neurogenic bladder herald cauda equina syndrome

3. drainage of associated abscess, especially septated abscesses that might be recalcitrant to CT guided percutaneous needling

4. rarely, to fuse an unstable spine. Poorly endorsed in the face of active infection, especially since most go on to spontaneous fusion

Approaches

1. anterior discectomy and corpectomy removes the offending infected tissue, with strut graft using iliac crest (or, in the thoracic region, a posterolateral approach, with the strut made from the resected rib if large enough)

2. posterior laminectomy may be adequate for emergent decompression, but does not allow access to the site of pathology in cervical or thoracic regions

SPONTANEOUS DISCITIS

No recent history of surgery or instrumentation. Higher incidence of neurologic deficits and radiculopathy than with postoperative discitis (POD).

Two distinct types:

1. juvenile: more common; age usually < 20 yrs (see below)

2. adult: usually occurs in susceptible patients (diabetics, IV drug abusers)

JUVENILE DISCITIS

Age usually < 20 yrs, with a peak between 2-3 years. Probably due to the presence of primordial feeding arteries that nourish the nucleus pulposus and which involute at ≈ 20-30 yrs age. Lumbar spine is more commonly involved than thoracic or cervical. Common presentation: refusal to walk or stand progressing to refusal to sit in young children. Back pain is most common in children > 9 yrs age. Low grade fever may be present. ESR is usually 2-3 xnormal. WBC is sometimes elevated. H. flu is a more commonly seen pathogen in this group.

In most cases, there is complete resolution in 9-22 weeks without recurrence in long-term follow-up studies^{210 (p 365-71)}. Surgery is reserved for the rare case that progresses in spite of antibiotics, for spinal instability, or for recurrent cases.

Most authors reserve antibiotics for patients with^{210 (p 365-71)}:

1. positive cultures (blood cultures or biopsy cultures)

2. elevated WBC count, constitutional symptoms, or high fever

3. poor response to rest or immobilization

4. neurologic sequelae (very rare)

Antibiotics should be given for a total of 4-6 weeks. Start with IV antibiotics, and when clinical symptoms improve convert to PO for the remainder of therapy.

POSTOPERATIVE DISCITIS

Unless otherwise specified, the following is based on a series of 27 post-op cases identified retrospectively at Duke²²⁴.

EPIDEMIOLOGY

Incidence after lumbar discectomy²²⁵: 0.2-4% (realistic estimate is probably at the lower end of this range). May also occur after LP, myelogram, cervical laminectomy, lumbar sympathectomy, chemonucleolysis²²⁶, discography (see page 436), fusions and other procedures. Very rare after ACDF. Risk factors include: advanced age, obesity, immuno-suppression, systemic infection at the time of surgery.

PATHOPHYSIOLOGY

There is some controversy as to whether some cases of post-op discitis are not infectious²²⁷, an autoimmune process has been implicated in some of these so-called “avascular” or “chemical” or “aseptic” discitis cases. These cases are less common than infectious ones. ESR and CRP abnormalities may be less pronounced in these patients, and biopsy of the disc space fails to grow organisms or show signs of infection (infiltrates of lymphocytes or PMNS) on microscopy²²⁷.

In septic cases, various mechanisms for infection have been proposed: direct inoculation at the time of surgery, infection following aseptic necrosis of disc material…

CLINICAL

1. interval from operation to onset of symptoms: 3 days to 8 mos (most commonly 1-4 wks post-op, usually after an initial period of pain relief and recovery from surgery). 80% present by 3 wks

2. symptoms:

A. moderate to (usually) severe back pain at the site of operation was the most common symptom, exacerbated by virtually any motion of the spine, often accompanied by paraspinal muscle spasms. Back pain is usually out of pro-portion to the findings

B. fever (> 38° C in 9 patients; literature reports only 30-50% are febrile) and chills

C. pain radiating to hip, leg, scrotum, groin, abdomen or perineum (true sciatica is uncommon)

3. signs: all had paravertebral muscle spasm and limited range of motion of the spine. 13 were virtually immobilized by pain. Point tenderness over infected spine occurred in 9, expressible pus in 2 (literature reports 0-8%). No new neurologic deficits were noted. Only 10-12% have associated wound infection²¹⁹

4. lab findings:

• ESR: 26/27 had ESR > 20 mm/hr (60 = ave.; > 40 in 17 patients; > 100 in 5 patients; the single patient < 20 was on steroids). ESR increases after un-complicated discectomy, peaking at 2-5 days, and can fluctuate for 3-6 weeks before normalizing²²⁸. A n elevated ESR that never decreases after surgery is a strong indicator of discitis. NB: ESR in anemic patients is un-reliable and no reference range can be established (use CRP in these cases)

• C-reactive protein (CRP)²²⁸: an acute phase protein synthesized by hepatocytes that because of rapid decomposition may be a more specific indicator of post-op infection than ESR. Values vary from lab to lab, but CRP is normally not detectable in the blood (i.e. < 0.6 mg/dL = 6 mg/L). After uncomplicated discectomy (i.e. in the absence of discitis), CRP peaks ≈ 2-3 days post-op (to 4.6 ± 2.1 mg/dL after lumbar microdiscectomy, 9.2 ± 4.7 after conventional lumbar discectomy, 7.0 ± 2.3 after anterior lumbar fusion, and 17.3 ± 3.9 after PLIF), and returns to normal between 5-14 days post op

• WBC: elevated > 10,000 in only 8/27 (prevalence in literature: 18-30%)

RADIOGRAPHIC EVALUATION

Also, see Radiographic evaluation, page 384 under Discitis in general.

In postoperative discitis (POD), the average time from surgery to changes on plain x-ray is 3 mos (range: 1-8 mos). Changes are detectable earlier on polytomograms (3 wks to 2 mos). Average time from first change to spinal fusion: 2 yrs.

PATHOGENS

See Table 16-22. Most studies report S. aureus as the most commonly identified organism, accounting for ≈ 60% of positive cultures²²⁵, followed by other staph species. Also reported: Gram-negative organisms (including E. coli), Strep viridans, Streptococcus species anaerobes, TB and fungi.

Blood cultures were positive in 2 of 6 (both S. aureus).

For culture techniques, see below.

Table 16-22 Culture results (14 patients, Craig needle biopsy)

Organism	No. of patients
Staphylococcus epidermidis	4
S. aureus	3
No growth	7

MANAGEMENT

1. admitting labs (in addition to routine): ESR, C-reactive protein, CBC, blood cultures

2. analgesics + muscle relaxants (e.g. diazepam (Valium®) 10 mg PO TID)

3. antibiotics:

• IV antibiotics for 1-6 wks (or until ESR decreases), then PO for 1-6 mos (typically 6 weeks)

• most start with anti-staphylococcal antibiotics (initial empiric therapy: vancomycin + PO rifampin) and a broad spectrum antibiotic (e.g. Cefizox), modify based on sensitivities if positive cultures are obtained

4. activity restriction (one of the following used, usually until significant pain relief):

• spinal immobilization with spica cast or plastic body jacket

• strict bed rest

• activity with corset

5. some authors recommend steroid therapy initially to assist pain relief

6. cultures: performed if radiographs suspicious, usually performed utilizing percutaneous CT-guided technique

A. sites

1. disc aspiration if evidence of disc space involvement

2. needling of paraspinal mass if present

B. send cultures for the following:

1. stains

a. Gram stain

b. fungal stain

c. AFB stain

2. culture

a. routine cultures: aerobic and anaerobic

b. fungal culture: this is not only helpful for fungus, but since these cultures are kept for longer period and any growth that occurs will be further characterized, fastidious or indolent bacterial organisms may sometimes be identified

c. TB culture

7. 3 patients in Duke series underwent anterior discectomy and fusion after unsuccessful medical therapy

OUTCOME

9 patients developed bony bridging in 12-18 mos; 10 developed bony fusion in 18-24 mos.

All patients eventually become pain free (or significantly improve). This is not the case in all series, where some report 60% were pain free at F/U, others found slight back pain in most patients, and yet others report severe chronic LBP in 75%²²⁵. 67-88% return to their previous work, and 12-25% received disability pension; these numbers are similar to the outcome from disc surgery in general.

No difference in outcome was found for the various activity restrictions specified, except for earlier pain relief with first two types listed above.

16.16. References

1. Gaskill S J, Marlin A E: Vancomycin: Its effect on intracranial pressure. Pediatr Neurosurg 18 (3): Pediatr Neurosurg: 139-43, 1992.

2. Linezolid (Zyvox). Med Letter 42: 45-6, 2000.

3. Kaiser A B: Antimicrobial prophylaxis in surgery. N Engl J Med 315: 1129-38, 1986.

4. Frame P T, Watanakunakorn C, McLaurin R L: Penetration of nafcillin, methcillin, and cefazolin into human brain tissue. Neurosurgery 12: 142-7, 1983.

5. Kernodle D S, Classen D C, Burke J P, et al.: Failure of cephalosporins to prevent staphylococcal aureus surgical wound infections. JAMA 263: 961-6, 1990.

6. Barker F G: Efficacy of prophylactic antibiotics for craniotomy: A meta-analysis. Neurosurgery 35: 484-92, 1994.

7. Young R F, Lawner P M: Perioperative antibiotic prophylaxis for prevention of postoperative neurosurgical infection. J Neurosurg 66: 701-5, 1987.

8. Baltas I, Tsoulfa S, Sakellariou P, et al.: Posttraumatic meningitis: Bacteriology, hydrocephalus, and outcome. Neurosurgery 35: 422-7, 1994.

9. Eljamel M S M, Foy P M: Post-traumatic CSF fistulae, the case for surgical repair. Br J Neurosurg 4: 479-83, 1990.

10. Lewin W: Cerebrospinal fluid rhinorrhea in closed head injuries. Clin Neurosurg 12: 237-52, 1966.

11. Horwitz N H, Levy C S: Comment on Baltas I, et al.: Posttraumatic meningitis: Bacteriology, hydrocephalus, and outcome. Neurosurgery 35: 426, 1994.

12. Yogev R: Cerebrospinal fluid shunt infections: A personal view. Pediatr Infect Dis 4: 113-8, 1985.

13. Ammirati M, Raimondi A: Cerebrospinal fluid shunt infections in children: A study of the relationship between the etiology of the hydrocephalus, age at the time of shunt placement, and infection. Childs Nerv Syst 3: 106-9, 1987.

14. McLone D, Czyzewski D, Raimondi A, et al.: Central nervous system infection as a limiting factor in the intelligence of children with myelomeningocele. Pediatrics 70: 338-42, 1982.

15. Amacher A L, Wellington J: Infantile hydrocephalus: Long-term results of surgical therapy. Childs Brain 11: 217-29, 1984.

16. Sanchez-Portocarrero J, Martin-Rabadan P, Saldana C J, et al.: Candida cerebrospinal fluid shunt infection. Report of two new cases and review of the literature. Diagn Microbiol Infect Dis 20: 33-40, 1994.

17. Nguyen M H, Yu V L: Meningitis caused by Candida species: An emerging problem in neurosurgical patients. Clin Infect Dis 21: 323-7, 1995.

18. Geers T A, Gordon S M: Clinical significance of Candida species isolated from cerebrospinal fluid following neurosurgery. Clin Infect Dis 28: 1139-47, 1999.

19. O’Brien M, Parent A, Davis B: Management of ventricular shunt infections. Childs Brain 5: 304-9, 1979.

20. Wald S L, McLaurin R L: Shunt-associated glomerulonephritis. Neurosurgery 3: 146-50, 1978.

21. Section of Pediatric Neurosurgery of the American Association of Neurological Surgeons, (ed.) Pediatric neurosurgery. 1st ed., Grune and Stratton, New York, 1982.

22. Frame P T, McLaurin R L: Treatment of CSF shunt infections with intrashunt plus oral antibiotic therapy. J Neurosurg 60: 354-60, 1984.

23. James H E, Walsh J W, Wilson H D, et al.: Prospective randomized study of therapy in cerebrospinal fluid shunt infection. Neurosurgery 7: 459-63, 1980.

24. Steinbok P, Cochrane D D, Kestle J R W: The significance of bacteriologically positive ventriculoperitoneal shunt components in the absence of other signs of shunt infection. J Neurosurg 84: 617-23, 1996.

25. Tumialan L M, Lin F, Gupta S K: Spontaneous bacterial peritonitis causing serratia marcescens and proteus mirabilis ventriculoperitoneal shunt infection. Case report. J Neurosurg 105 (2): 320-4, 2006.

26. Vinchon M, Baroncini M, Laurent T, et al.: Bowel perforation caused by peritoneal shunt catheters: Diagnosis and treatment. Neurosurgery 58: ONS76-82; discussion ONS76-82, 2006.

27. Gaskill S J, Marlin A E: Spontaneous bacterial peritonitis in patients with ventriculoperitoneal shunts. Pediatr Neurosurg 26 (3): 115-9, 1997.

28. Rush D S, Walsh J W, Belin R P, et al.: Ventricular sepsis and abdominally related complications in children with cerebrospinal fluid shunts. Surgery 97: 420-7, 1985.

29. Bayston R: Epidemiology, diagnosis, treatment, and prevention of cerebrospinal fluid shunt infections. Neurosurg Clin N Am 12 (4): 703-8, viii, 2001.

30. Salomao J F, Leibinger R D: Abdominal pseudocysts complicating CSF shunting in infants and children. Report of 18 cases. Pediatr Neurosurg 31 (5): 274-8, 1999.

31. Shektman A, Granick M S, Solomon M P, et al.: Management of infected laminectomy wounds. Neurosurgery 35: 307-9, 1994.

32. Kurz A, Sessler D I, Lenhardt R: Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. N Engl J Med 334: 1209-15, 1996.

33. Dernbach P D, Gomez H, Hahn J: Primary closure of infected spinal wounds. Neurosurgery 26: 707-9, 1990.

34. Ebersold M J: Comment on Shektman A, et al.: Primary closure of infected spinal wounds. Neurosurgery 35: 309, 1994.

35. Mirzayan M J, Gharabaghi A, Samii M, et al.: Response of C-reactive protein after craniotomy for microsurgery of intracranial tumors. Neurosurgery 60 (4): 621-5; discussion 625, 2007.

36. Listinsky J L, Wood B P, Ekholm S E: Parietal osteomyelitis and epidural abscess: A delayed complication of fetal monitoring. Pediatr Radiol 16: 150-1, 1986.

37. Bullitt E, Lehman R A W: Osteomyelitis of the skull. Surg Neurol 11: 163-6, 1979.

38. Calfee D P, Wispelwey B: Brain abscess. Semin Neurol 20 (3): 353-60, 2000.

39. Mamelak A N, Mampalam T J, Obana W G, et al.: Improved management of multiple brain abscesses: A combined surgical and medical approach. Neurosurgery 36: 76-86, 1995.

40. Takeshita M, Kagawa M, Yato S, et al.: Current treatment of brain abscess in patients with congenital cyanotic heart disease. Neurosurgery 41: 1270-9, 1997.

41. Kanter M C, Hart R G: Neurologic complications of infective endocarditis. Neurology 41: 1015-20, 1991.

42. Garvey G: Current concepts of bacterial infections of the central nervous system: Bacterial meningitis and bacterial brain abscess. J Neurosurg 59: 735-44, 1983.

43. Nunez D A, Browning G G: Risks of developing an otogenic intracranial abscess. J Laryngol Otol 104: 468-72, 1990.

44. Hollin S A, Hayashi H, Gross S W: Intracranial abscesses of odontogenic origin. Oral Surg 23: 277-93, 1967.

45. Williams F H, Nelms D K, McGaharan K M: Brain abscess: A rare complication of halo usage. Arch Phys Med Rehabil 73: 490-2, 1992.

46. Grimstad I A, Hirschberg H, Rootwelt K: ^99mTchexamethylpropyleneamine oxime leukocyte scintigraphy and c-reactive protein levels in the differential diagnosis of brain abscesses. J Neurosurg 77: 732-6, 1992.

47. Fritz D P, Nelson P B: Brain abscess. In Central nervous system infectious diseases and therapy, Roos K L, (ed.). Marcel Dekker, New York, 1997: pp 481-98.

48. Desprechins B, Stadnik T, Koerts G, et al.: Use of diffusion-weighted MR imaging in differential diagnosis between intracerebral necrotic tumors and cerebral abscesses. AJNR Am J Neuroradiol 20 (7): 1252-7, 1999.

49. Mueller-Mang C, Castillo M, Mang T G, et al.: Fungal versus bacterial brain abscesses: Is diffusion-weighted MR imaging a useful tool in the differential diagnosis? Neuroradiology 49 (8): 651-7, 2007.

50. Britt R H, Enzmann D R: Clinical stages of human brain abscesses on serial CT scans after contrast infusion. J Neurosurg 59: 972-89, 1983.

51. Heineman H S, Braude A I, Osterholm J L: Intracranial suppurative disease. JAMA 218: 1542-7, 1971.

52. Black P, Graybill J R, Charache P: Penetration of brain abscess by systemically administered antibiotics. J Neurosurg 38: 705-9, 1973.

53. Rosenblum M L, Hoff J T, Norman D, et al.: Non-operative treatment of brain abscesses in selected high-risk patients. J Neurosurg 52: 217-25, 1980.

54. Ruelle A, Zerbi D, Zuccarello M, et al.: Brain stem abscess treated successfully by medical therapy. Neurosurgery 28: 742-6, 1991.

55. Zeidman S M, Geisler F H, Olivi A: Intraventricular rupture of a purulent brain abscess: Case report. Neurosurgery 36: 189-93, 1995.

56. Stephanov S: Surgical treatment of brain abscess. Neurosurgery 22: 724-30, 1988.

57. Hollander D, Villemure J-G, Leblanc R: Thalamic abscess: A stereotactically treatable lesion. Appl Neurophysiol 50: 168-71, 1987.

58. Rosenblum M L, Hoff J T, Norman D, et al.: Decreased mortality from brain abscesses since advent of CT. J Neurosurg 49: 658-68, 1978.

59. Byrne E, Brophy B P, Pettett L V: Nocardia cerebral abscess: New concepts in diagnosis, management, and prognosis. J Neurol Neurosurg Psychiatry 42: 1038-45, 1979.

60. Awad I, Bay J W, Petersen J M: Nocardial osteomyelitis of the spine with epidural spinal cord compression - a case report. Neurosurgery 15: 254-6, 1984.

61. Moylett E H, Pacheco S E, Brown-Elliott B A, et al.: Clinical experience with linezolid for the treatment of nocardia infection. Clin Infect Dis 36 (3): 313-8, 2003.

62. Stephanov S, Sidani A H: Intracranial subdural empyema and its management. A review of the literature with comment. Swiss Surg 8 (4): 159-63, 2002.

63. Kubik C S, Adams R D: Subdural empyema. Brain 66: 18-42, 1943.

64. Dill S R, Cobbs C G, McDonald C K: Subdural empyema: Analysis of 32 cases and review. Clin Inf Dis 20: 372-86, 1995.

65. Jacobson P L, Farmer T W: Subdural empyema complicating meningitis in infants: Improved prognosis. Neurology 31: 190-3, 1981.

66. Maniglia A J, Goodwin W J, Arnold J E, et al.: Intracranial abscess secondary to nasal, sinus, and orbital infections in adults and children. Arch Otolaryngol Head Neck Surg 115: 1424-9, 1989.

67. Garfin S R, Botte M J, Triggs K J, et al.: Subdural abscess associated with halo-pin traction. J Bone Joint Surg 70A: 1338-40, 1988.

68. Weisberg L: Subdural empyema: Clinical and computed tomographic correlations. Arch Neurol 43: 497-500, 1986.

69. Mauser H W, Ravijst R A P, Elderson A, et al.: Non-surgical treatment of subdural empyema: Case report. J Neurosurg 63: 128-30, 1985.

70. Wilkins R H, Rengachary S S, (eds.): Neurosurgery. McGraw-Hill, New York, 1985.

71. Neils E W, Lukin R, Tomsick T A, et al.: Magnetic resonance imaging and computerized tomography scanning of herpes simplex encephalitis. J Neurosurg 67: 592-4, 1987.

72. Schroth G, Gawehn J, Thron A, et al.: The early diagnosis of herpes simplex encephalitis by MRI. Neurology 37: 179-83, 1987.

73. Whitley R J, Soong S-J, Dolin R, et al.: Adenosine arabinoside therapy of biopsy-proved herpes simplex encephalitis: National institute of allergy and infectious diseases collaborative antiviral study. N Engl J Med 297: 289-94, 1977.

74. Schlitt M J, Morawetz R B, Bonnin J M, et al.: Brain biopsy for encephalitis. Clin Neurosurg 33: 591-602, 1986.

75. Whitley R J, Cobbs C G, Alford C A, et al.: Diseases that mimic herpes simplex encephalitis: Diagnosis, presentation, and outcome. JAMA 262: 234-9, 1989.

76. Carmack M A, Twiss J, Enzmann D R, et al.: Multifocal leukoencephalitis caused by varicella-zoster virus in a child with leukemia: Successful treatment with acyclovir. Pediatr Infect Dis J 12: 402-6, 1993.

77. Horten B, Price R W, Jiminez D: Multifocal varicella-zoster virus leukoencephalitis temporally remote from herpes zoster. Ann Neurol 9: 251-66, 1981.

78. Johnson R T, Gibbs C J: Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies. N Engl J Med 339: 1994-2004, 1998.

79. Gajdusek D C: Unconventional viruses and the origin and disappearance of kuru. Science 197: 943-60, 1977.

80. Klitzman R: The trembling mountain. A personal account of kuru, cannibals, and mad cow disease. Plenum Trade, New York, 1998.

81. Heckmann J G, Lang C J G, Petruch F, et al.: Transmission of Creutzfeldt-Jakob disease via a corneal transplant. J Neurol Neurosurg Psychiatry 63: 388-90, 1997.

82. Hsiao K, Pruisner S B: Inherited human prion diseases. Neurology 40: 1820-7, 1990.

83. Bertoni J M, Brown P, Goldfarb L G, et al.: Familial Creutzfeldt-Jakob disease (codon 200 mutation) with supranuclear palsy. JAMA 268: 2413-5, 1992.

84. Will R G, Zeidler J W, Cousens S N, et al.: A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347: 921-5, 1996.

85. Rosenberg R N, White C L, Brown P, et al.: Precautions in handling tissues, fluids and other contaminated materials from patients with documented or suspected Creutzfeldt-Jakob disease. Ann Neurol12: 75-7, 1986.

86. Brown P, Gibbs C J, Amyx J L, et al.: Chemical disinfection of Creutzfeldt-Jakob virus. N Engl J Med 306: 1279-82, 1982.

87. Duffy P, Wolf J, Collins G, et al.: Possible person to person transmission of Creutzfeldt-Jakob disease. N Engl J Med 290: 692-3, 1974.

88. Bernoulli C, Siegfried J, Baumgartner G, et al.: Danger of accidental person-to-person transmission of Creutzfeldt-Jakob disease by surgery. Lancet 1: 478-9, 1977.

89. Fradkin J E, Schonberger L B, Mills J L, et al.: Creutzfeldt-Jakob disease in pituitary growth hormone recipients in the United States. JAMA 265: 880-4, 1991.

90. Brown P, Cathala F, Castaigne P, et al.: Creutzfeldt-Jakob disease: Clinical analysis of a consecutive series of 230 neuropathologically verified cases. Ann Neurol 20: 597-602, 1986.

91. Finkenstaedt M, Szudra A, Zerr I, et al.: MR imaging of Creutzfeldt-Jakob disease. Radiology 199: 793-8, 1996.

92. Gertz H-J, Henkes H, Cervos-Navarro J: Creutzfeldt-Jakob disease: Correlation of MRI and neuropathologic findings. Neurology 38: 1481-2, 1988.

93. Otto M, Wiltfang J, Schutz E, et al.: Diagnosis of Creutzfeldt-Jakob disease by measurement of s100 protein in serum: Prospective case-control study. Br Med J 316: 577-82, 1998.

94. Harrington M G, Merril C R, Asher D M, et al.: Abnormal proteins in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. N Engl J Med 315: 279-83, 1986.

95. Hsich G, Kenney K, Gibbs C J, et al.: The 14-3-3 brain protein in cerebrospinal fluid as a marker for transmissible spongiform encephaloptahies. N Engl J Med 335: 924-30, 1996.

96. Steinhoff B J, Räcker S, Herrendorf G, et al.: Accuracy and reliability of periodic sharp wave complexes in Creutzfeldt-Jakob disease. Arch Neurol 53: 162-6, 1996.

97. de Silva R, Patterson J, Hadley D, et al.: Single photon emission computed tomography in the identification of new variant Creutzfeldt-Jakob disease: Case reports. Br Med J 316: 593-4, 1998.

98. Hill A F, Butterworth R J, Joiner S, et al.: Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 353: 183-9, 1999.

99. Brumbach R A: Routine use of phenolized formalin in fixation of autopsy brain tissue to reduce risk of inadvertent transmission of Creutzfeldt-Jakob disease. N Engl J Med 319: 654, 1988.

100. Levy R M, Bredesen D E, Rosenblum M L: Neurological manifestations of the acquired immunodeficiency syndrome (AIDS): Experience at ucsf and review of the literature. J Neurosurg 62: 475-95, 1985.

101. Simpson D M, Tagliati M: Neurologic manifestations of HIV infection. Ann Intern Med 121: 769-85, 1994.

102. Berger J R, Kaszovitz B, Post J D, et al.: Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection: A review of the literature with a report of sixteen cases. Ann Intern Med 107: 78-87, 1987.

103. Ciricillo S F, Rosenblum M L: Use of CT and MR imaging to distinguish intracranial lesions and to define the need for biopsy in AIDS patients. J Neurosurg 73: 720-24, 1990.

104. Chaisson R E, Griffin D E: Progressive multifocal leukoencephalopathy in AIDS. JAMA 364: 79-82, 1990.

105. Jean W C, Hall W A: Management of cranial and spinal infections. Contemp Neurosurg 20 (9): 1-10, 1998.

106. Demeter L M: JC, BK, and other polyomaviruses; progressive multifocal leukoencephalopathy. In Mandell, Douglas and Bennett principles and practice of infectious diseases, Mandell G L and Bennett J E, (eds.). Churchill Livingstone, New York, 4th edition ed., 1995, Vol. 2: pp 1400-6.

107. Krupp L B, Lipton R B, Swerdlow M L, et al.: Progressive multifocal leukoencephalopathy: Clinical and radiographic features. Ann Neurol 17: 344-9, 1985.

108. Berger J R, Mucke L: Prolonged survival and partial recovery in AIDS-associated progressive multifocal leukoencephalopathy. Neurology 38: 1060-5, 1988.

109. Elliot B, Aromin I, Gold R, et al.: 2.5 year remission of AIDS-associated progressive multifocal leukoencephalopathy with combined antiretroviral therapy. Lancet 349: 850, 1997.

110. Johns D R, Tierney M, Felenstein D: Alterations in the natural history of neurosyphilis by concurrent infection with the human immunodeficiency virus. N Engl J Med 316: 1569-92, 1987.

111. Lukehart S A, Hook E W, Baker-Zander S A, et al.: Invasion of the central nervous system by treponema pallidum: Implications for diagnosis and treatment. Ann Int Med 109: 855-62, 1988.

112. Centers for Disease Control: Recommendations for diagnosing and treating syphilis in HIV-infected patients. MMWR 37: 600-2, 1988.

113. Levy R M, Rosenbloom S, Perrett L V: Neuroradiologic findings in AIDS: A review of 200 cases. AJNR 7: 833-9, 1986.

114. Jarvik J G, Hesselink J R, Kennedy C, et al.: Acquired immunodeficiency syndrome: Magnetic resonance patterns of brain involvement with pathologic correlation. Arch Neurol 45: 731-6, 1988.

115. Sadler M, Brink N S, Gazzard B G: Management of intracerebral lesions in patients with HIV: A retrospective study with discussion of diagnostic problems. Q J Med 91: 205-17, 1998.

116. Schwaighofer B W, Hesselink J R, Press G A, et al.: Primary intracranial CNS lymphoma: MR manifestations. AJNR 10: 725-9, 1989.

117. So Y T, Beckstead J H, Davis R L: Primary central nervous system lymphoma in acquired immune deficiency syndrome: A clinical and pathological study. Ann Neurol 20: 566-72, 1986.

118. Cinque P, Brytting M, Vago L, et al.: Epstein-Barr virus DNA in cerebrospinal fluid from patients with AIDS-related primary lymphoma of the central nervous system. Lancet 342: 398-401, 1991.

119. Cohn J A, Meeking M C, Cohen W, et al.: Evaluation of the policy of empiric treatment of suspected toxoplasma encephalitis in patients with the acquired immunodeficiency syndrome. Am J Med 86: 521-7, 1989.

120. Chappell E T, Guthrie B L, Orenstein J: The role of stereotactic biopsy in the management of HIV-related focal brain lesions. Neurosurgery 30: 825-9, 1992.

121. Levy R M, Russell E, Yungbluth M, et al.: The efficacy of image-guided stereotactis brain biopsy in neurologically symptomatic acquired immunodeficiency syndrome patients. Neurosurgery 30: 186-90, 1992.

122. Nicolato A, Gerosa M, Piovan E, et al.: Computerized tomography and magnetic resonance guided stereotactic brain biopsy in nonimmunocompromised and AIDS patients. Surg Neurol 48: 267-77, 1997.

123. Nocton J J, Steere A C: Lyme disease. Adv Int Med 40: 69-117, 1995.

124. Pachner A R, Steere A C: The triad of neurologic manifestations of Lyme disease: Meningitis, cranial neuritis, and radiculoneuritis. Neurology 35: 47-53, 1985.

125. Pachner A R, Duray P, Steere: Central nervous system manifestations of Lyme disease. Arch Neurol 46: 790-5, 1990.

126. Steere A C, Schoen R T, Taylor E: The clinical evolution of Lyme arthritis. Ann Intern Med 107: 735-31, 1987.

127. Centers for Disease Control: Lyme disease - Connecticut. MMWR 37: 1-3, 1988.

128. Sigal L H: Lyme disease overdiagnosis: Cause and cure. Hosp Pract 31: 13-5, 1996 (editorial).

129. Weinstein A, Bujak D I: Lyme disease: A review of its clinical features. NY State J Med. 1989, pp 566-71.

130. Magnarelli L A: Current status of laboratory diagnosis for Lyme disease. Am J Med 98 (S4A): 10-2S, 1995.

131. Wilkse B, Scheirz G, Preac-Mursic V, et al.: Intrathecal production of specific antibodies against borrelia burgdorferi in patients with lymphocytic meningoradiculitis (Bannwarth’s syndrome). J Infect Dis 153: 304-14, 1986.

132. Henriksson A, Link H, Cruz M, et al.: Immunoglobulin abnormalities in cerebrospinal fluid and blood over the course of lymphocytic meningoradiculitis (Bannwarth’s syndrome). Ann Neurol 20: 337-45, 1986.

133. Treatment of Lyme disease. Med Letter 30: 65-6, 1988.

134. Steere A C: Lyme disease. N Engl J Med 321: 586-96, 1989.

135. Walker M, Kublin J G, Zunt J R: Parasitic central nervous system infections in immunocompromised hosts: Malaria, microsporidiosis, leishmaniasis, and african trypanosomiasis. Clin Infect Dis 42 (1): 115-25, 2006.

136. Sotelo J, Escobedo F, Rodriguez-Carbaja, et al.: Therapy of parenchymal brain cysticercosis with praziquantel. N Engl J Med 310: 1001-7, 1984.

137. Garcia H H, Gonzales A E, Evans C A W, et al.: Taenia solium cysticersosis. Lancet 362: 547-56, 2003.

138. Sotelo J, Guerrero V, Rubio F: Neurocysticercosis: A new classification based on active and inactive forms. Arch Intern Med 145: 442-5, 1985.

139. Garcia H H, Del Brutto O H, for The Cysticercosis Working Group in Peru: Neurocysticercosis: Updated concepts about an old disease. Lancet Neurology 4: 653-61, 2005.

140. Proano J V, Madrazo I, Avelar F, et al.: Medical treatment for neurocysticercosis characterized by giant subarachnoid cysts. N Engl J Med 345 (12): 879-85, 2001.

141. Leblanc R, Knowles K F, Melanson D, et al.: Neurocysticercosis: Surgical and medical management with praziquantel. Neurosurgery 18: 419-27, 1986.

142. Wilson M, Bryan R T, Fried J A, et al.: Clinical evaluation of the cysticercosis enzyme-linked immunoelectrotransfer blot in patients with neurocysticercosis. J Infect Dis 164: 1007-9, 1991.

143. Prabhakaran V, Rajshekhar V, Murrell K, et al.: Taenia solium metacestode glycoproteins as diagnostic antigens for solitary cysticercus granuloma in Indian patients. Trans R Soc Trop Med Hyg 98: 478-84, 2004.

144. Enzman D R: Cysticercosis. In Imaging of infections and inflammations of the central nervous system: Computed tomography, ultrasound, and nuclear magnetic resonance. Raven Press, New York, 1984: pp 103-22.

145. Madrazo I, Renteria J A G, Paredes G, et al.: Diagnosis of intraventricular and cisternal cysticercosis by computerized tomography with positive intraventricular contract medium. J Neurosurg 55: 947-51, 1981.

146. Apuzzo M L J, Dobkin W R, Zee C-S, et al.: Surgical considerations in treatment of intraventricular cysticercosis: An analysis of 45 cases. J Neurosurg 60: 400-7, 1984.

147. Del Brutto O H: Prognostic factors for seizure recurrence after withdrawal of entiepileptic drugs in patients with neurocysticercosis. Neurology 44: 1706-9, 1994.

148. Jung H, Hurtado M, Sanchez M, et al.: Plasma and CSF levels of albendazole and praziquantel in patients with neurocysticercosis. Clin Neuropharmacol 13 (6): 559-64, 1990.

149. Sotelo J, Penagos P, Escobedo F, et al.: Short course of albendazole therapy for neurocysticercosis. Arch Neurol 45: 1130-3, 1988.

150. Drugs for parasitic infections. Med Letter 37: 99-108, 1995.

151. Colli B O, Carlotti C G, Machado H R, et al.: Treatment of patients with intraventricular cysticercosis. Contemp Neurosurg 21 (21): 1-7, 1999.

152. Bandres J C, White A C, Jr., Samo T, et al.: Extra-parenchymal neurocysticercosis: Report of five cases and review of management. Clin Infect Dis 15 (5): 799-811, 1992.

153. McCormick G F, Zee C-S, Heiden J: Cysticercosis cerebri. Arch Neurol 39: 534-9, 1982.

154. Centers for Disease Control: Locally acquired neurocysticercosis. MMWR 41: 1-4, 1992.

155. Carrea R, Dowling E, Guevara J A: Surgical treatment of hydatid cysts of the central nervous system in the pediatric age (Dowling’s technique). Childs Brain 1: 4-21, 1975.

156. Youmans J R, (ed.) Neurological surgery. 3rd ed., W. B. Saunders, Philadelphia, 1990.

157. Mendel E, Milefchik E N, Ahmadi J, et al.: Coccidioidomycotic brain abscess: Case report. J Neurosurg 80: 140-2, 1994.

158. Chuck S L, Sande M A: Infections with cryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl J Med 321: 794-9, 1989.

159. Aberg J, Powderly W G: Cryptococcosis. In AIDS therapy, Dolin R, Masur H, and Saag M S, (eds.). Churcill Livingstone, New York, 2002: pp 498-510.

160. Lan S, Chang W, Lu C, et al.: Cerebral infarction in chronic meningitis: A comparison of tuberculous meningitis and cryptococcal meningitis. Q J Med 94: 247-53, 2001.

161. Lane M, McBride J, Archer J: Steroid responsive late deterioration in cryptococcus neoformans variety gattii meningitis. Neurology 63: 713-4, 2004.

162. Kaplan J E, Benson C, Holmes K H, et al.: Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents. MMWR Recomm Rep 58 (RR-4): MMWR Recomm Rep: 1-207; quiz CE1-4, 2009.

163. Saag M S, Graybill R J, Larsen R A, et al.: Practice guidelines for the management of crytpococcal disease. Clin Infect Dis 30: Clin Infect Dis: 710-8, 2000.

164. Fessler R D, Sobel J, Guyot L, et al.: Management of elevated intracranial pressure in patients with Cryptococcal meningitis. J Acquir Immune Defic Syndr Hum Retrovirol 17 (2): J Acquir Immune Defic Syndr Hum Retrovirol: 137-42, 1998.

165. Park M K, Hospenthal D R, Bennett J E: Treatment of hydrocephalus secondary to cryptococcal meningitis by use of shunting. Clin Infect Dis 28 (3): 629-33, 1999.

166. Bach M C, Tally P W, Godofsky E W: Use of cerebrospinal fluid shunts in patients having acquired immunodeficiency syndrome with cryptococcal meningitis and uncontrollable intracranial hypertension. J Neurosurg 41: 1280-3, 1997.

167. Liliang P C, Liang C L, Chang W N, et al.: Use of ventriculoperitoneal shunts to treat uncontrollable intracranial hypertension in patients who have cryptococcal meningitis without hydrocephalus. Clin Infect Dis 34 (12): E64-8, 2002.

168. Cahill D W: Infections of the spine. Contemp Neurosurg 15: 1-8, 1993.

169. Baker A S, Ojemann R G, Swartz M N, et al.: Spinal epidural abscess. N Engl J Med 293: 463-8, 1975.

170. Nussbaum E S, Rigamonti D, Standiford H, et al.: Spinal epidural abscess: A report of 40 cases and review. Surg Neurol 38: 225-31, 1992.

171. Danner R L, Hartman B J: Update of spinal epidural abscess: 35 cases and review of the literature. Rev Infect Dis 9: 265-74, 1987.

172. Curry W T, Jr., Hoh B L, Amin-Hanjani S, et al.: Spinal epidural abscess: Clinical presentation, management, and outcome. Surg Neurol 63 (4): 364-71; discussion 371, 2005.

173. Hlavin M L, Kaminski H J, Ross J S, et al.: Spinal epidural abscess: A ten-year perspective. Neurosurgery 27: 177-84, 1990.

174. Spiegelmann R, Findler G, Faibel M, et al.: Postoperative spinal epidural empyema: Clinical and computed tomography features. Spine 16: 1146-9, 1991.

175. Browder J, Meyers R: Pyogenic infections of the spinal epidural space. Surgery 10: 296-308, 1941.

176. Russell N A, Vaughan R, Morley T P: Spinal epidural infection. Can J Neurol Sci 6: 325-8, 1979.

177. Heusner A P: Nontuberculous spinal epidural infections. N Engl J Med 239: 845-54, 1948.

178. Koppel B S, Tuchman A J, Mangiardi J R, et al.: Epidural spinal infection in intravenous drug abusers. Arch Neurol 45: 1331-7, 1988.

179. Abdel-Magid R A, Kotb H I M: Spinal epidural abscess after spinal anesthesia: A favorable outcome. Neurosurgery 27: 310-1, 1990.

180. Loarie D J, Fairley H B: Epidural abscess following spinal anesthesia. Anesth Analg 57: 351-3, 1978.

181. Strong W E: Epidural abscess associated with epidural catheterization: A rare event? Report of two cases with markedly delayed presentation. Anesthesiology 74: 943-6, 1991.

182. Bergman I, Wald E R, Meyer J D, et al.: Epidural abscess and vertebral osteomyelitis following serial lumbar punctures. Pediatrics 72: 476-80, 1983.

183. Rea G L, McGregor J M, Miller C A, et al.: Surgical treatment of the spontaneous spinal epidural abscess. Surg Neurol 37: 274-9, 1992.

184. Riyad N Y M, Sallam A, Nur A: Pyogenic psoas abscess: Discussion of its epidemiology, etiology, bacteriology, diagnosis, treatment and prognosis - case report. Kuwait Medical Journal 35: 44-7, 2003.

185. Taiwo B: Psoas abscess: A primer for the internist. South Med J 94 (1): 2-5, 2001.

186. Gruenwald I, Abrahamson J, Cohen O: Psoas abscess: Case report and review of the literature. J Urol 147 (6): 1624-6, 1992.

187. Kaufman D M, Kaplan J G, Litman N: Infectious agents in spinal epidural abscesses. Neurology 30: 844-50, 1980.

188. Post M J D, Sze G, Quencer R M, et al.: Gadolinium-enhanced MR in spinal infection. J Comput Assist Tomogr 14: 721-9, 1990.

189. Post M J D, Quencer R M, Montalvo B M, et al.: Spinal infection: Evaluation with MR imaging and intraoperative ultrasound. Radiology 169: 765-71, 1988.

190. Sandhu F S, Dillon W P: Spinal epidural abscess: Evaluation with contrast-enhanced MR imaging. AJNR 158: 1087-93, 1991.

191. Kirzner H, Oh Y K, Lee S H: Intraspinal air: A CT finding of epidural abscess. AJR 151: 1217-8, 1988.

192. Leys D, Lesoin F, Viaud C, et al.: Decreased morbidity from acute bacterial spinal epidural abscess using computed tomography and nonsurgical treatment in selected patients. Ann Neurol 17: 350-5, 1985.

193. Mampalam T J, Rosegay H, Andrews B T, et al.: Nonoperative treatment of spinal epidural infections. J Neurosurg 71: 208-10, 1989.

194. Hanigan W C, Asner N G, Elwood P W: Magnetic resonance imaging and the nonoperative treatment of spinal epidural abscess. Surg Neurol 34: 408-13, 1990.

195. Garrido E, Rosenwasser R H: Experience with the suction-irrigation technique in the management of spinal epidural infection. Neurosurgery 12: 678-9, 1983.

196. Eismont F J, Bohlman H H, Soni P L, et al.: Pyogenic and fungal vertebral osteomyelitis with paralysis. J Bone Joint Surg 65A: 19-29, 1983.

197. Verner E F, Musher D M: Spinal epidural abscess. Med Clin North Am 69: 375-84, 1985.

198. Curling O D, Gower D J, McWhorter J M: Changing concepts in spinal epidural abscess: A report of 29 cases. Neurosurgery 27: 185-92, 1990.

199. Pereira C E, Lynch J C: Spinal epidural abscess: An analysis of 24 cases. Surg Neurol 63: S26-9, 2005.

200. Schmorl G, Junghanns H: The human spine in health and disease. Grune & Stratton, New York, 1971.

201. Waldvogel F A, Vasey H: Osteomyelitis: The past decade. N Engl J Med 303: 360-70, 1980.

202. Holzman R S, Bishko R: Osteomyelitis in heroin addicts. Ann Intern Med 75: 693-6, 1971.

203. Cahill D W, Love L C, Rechtine G R: Pyogenic osteomyelitis of the spine in the elderly. J Neurosurg 74: 878-86, 1991.

204. Burke D R, Brant-Zawadzki M B: CT of pyogenic spine infection. Neuroradiology 27: 131-7, 1985.

205. Sapico F L, Montgomerie J Z: Pyogenic vertebral osteomyelitis: Report of nine cases and review of the literature. Rev Infect Dis 1: 754-76, 1979.

206. Skaf G S, Fehlings M G, Bouclaous C H: Medical and surgical management of pyogenic and nonpyogenic spondylodiscitis: Part I. Contemp Neurosurg 26 (19): 1-5, 2004.

207. Batson O V: The function of the vertebral veins and their role in the spread of metastases. Ann Surg 112: 138, 1940.

208. Skaf G S, Fehlings M G, Bouclaous C H: Medical and surgical management of pyogenic and nonpyogenic spondylodiscitis: Part II. Contemp Neurosurg 26 (20): 1-5, 2004.

209. Weiner B K, Love T W, Fraser R D: Mycobacterium avium intracellulare: Vertebral osteomyelitis. J Spinal Disord 11 (1): J Spinal Disord: 89-91, 1998.

210. Rothman R H, Simeone F A, (eds.): The spine. 3rd ed., W.B. Saunders, Philadelphia, 1992.

211. Kinnier W S A: Tuberculosis of the skull and spine. In Neurology. Edward Arnold, London, 1940, Vol. 1: pp 575-83.

212. Medical Research Council Working Party on Tuberculosis of the Spine: Controlled trial of short-course regimens of chemotherapy in the ambulatory treatment of spinal tuberculosis: Results at three years of a study in korea. J Bone Joint Surg 75B: 240-8, 1993.

213. Rath S A, Nelf U, Schneider O, et al.: Neurosurgical management of thoracic and lumbar vertebral osteomyelitis and discitis in adults: A review of 43 consecutive surgically treated patients. Neurosurgery 38: 926-33, 1996.

214. Patzakis M J, Rao S, Wilkins J, et al.: Analysis of 61 cases of vertebral osteomyelitis. Clin Orthop 264: 178-83, 1991.

215. Modic M T, Feiglin D H, Piraino D W, et al.: Vertebral osteomyelitis: Assessment using MR. Radiology 157: 157-66, 1985.

216. Hadjipavlou A G, Cesani-Vazquez F, Villaneuva-Meyer J, et al.: The effectiveness of gallium citrate Ga 67 radionuclide imaging in vertebral osteomyelitis revisited. Am J Orthop 27 (3): 179-83, 1998.

217. Allen R T, Lee Y P, Stimson E, et al.: Bone morphogenetic protein-2 (BMP-2) in the treatment of pyogenic vertebral osteomyelitis. Spine 32 (26): 2996-3006, 2007.

218. Sullivan C R, Symmonds R E: Disk infections and abdominal pain. JAMA 188: 655-8, 1964.

219. Malik G M, McCormick P: Management of spine and intervertebral disc space infection. Contemp Neurosurg 10: 1-6, 1988.

220. Kemp H B S, Jackson J W, Jeremiah J D, et al.: Pyogenic infections occurring primarily in intervertebral discs. J Bone Joint Surg 55B: 698-714, 1973.

221. Boden S D, Davis D O, Dina T S, et al.: Postoperative diskitis: Distinguishing early MR imaging findings from normal postoperative disk space changes. Radiology 184: 765-71, 1992.

222. Kopecky K K, Gilmor R L, Scott J A, et al.: Pitfalls of CT in diagnosis of discitis. Neuroradiology 27: 57-66, 1985.

223. Lifeso R M, Weaver P, Harder E H: Tuberculous spondylitis in adults. J Bone Joint Surg 67A: 1405-13, 1985.

224. Rawlings C E, Wilkins R H, Gallis H A, et al.: Postoperative intervertebral disc space infection. Neurosurgery 13: 371-6, 1983.

225. Iversen E, Nielsen V A H, Hansen L G: Prognosis in postoperative discitis. A retrospective study of 111 cases. Acta Orthop Scand 63: 305-9, 1992.

226. Deeb Z L, Schimel S, Daffner R H, et al.: Intervertebral disk-space infection after chymopapain injection. AJNR 6: 55-8, 1985.

227. Fouquet B, Goupille P, Jattiot F, et al.: Discitis after lumbar disc surgery. Features of “aseptic” and “septic” forms. Spine 17: 356-8, 1992.

228. Thelander U, Larsson S: Quantitation of c-reactive protein levels and erythrocyte sedimentation rate after spinal surgery. Spine 17: 400-4, 1992.