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1172 SECTION 14: Neurology Central Nervous System and Spinal Infections Mary E. Tanski O. John Ma  CENTRAL NERVOUS SYSTEM INFECTIONS  BACTERIAL MENINGITIS INTRODUCTION AND EPIDEMIOLOGY Bacterial meningitis is a life-threatening emergency that affects about 1.2 millions individuals worldwide each year. 1 The incidence and major pathogens vary by region, country, age group, and immuniza tion status.2-4 For example, although meningococcal meningitis occurs worldwide in epidemic and sporadic form, the highest incidence is in the meningitis belt of sub-Saharan Africa, from Senegal to Ethiopia. 5 In the United States, the most common causes of bacterial meningitis are Streptococcus pneumoniae (58.0%), group B Streptococcus (18.1%), Neisseria meningitidis (13.9%), Haemophilus influenzae (6.7%), and Listeria monocytogenes (3.4%). 6 Escherichia coli in the neonatal population and Mycobacterium tuberculosis in immunocompromised hosts are also important considerations.7 PATHOPHYSIOLOGY Organisms enter the cerebrospinal fluid (CSF) either through hematogenous or direct contiguous spread. In hematogenous spread, bacteria colonize the upper airway and invade the bloodstream, gradually mak ing their way to the subarachnoid space. The subcapsular components of S. pneumoniae, H. influenzae type b, and N. meningitidis induce an inflammatory cascade, and leukocyte toxins cause cellular swelling and inflammation of the brain and meninges. 8 Blood–brain barrier permeability increases, allowing protein and water to enter and leading to vasogenic edema. CSF drainage is inhibited by reduced absorption of the arachnoid granules with resultant obstruction and hydrocephalus, and CSF is forced into the periventricular parenchyma, causing inter stitial edema. Disruption of cell membrane homeostasis causes cyto toxic edema. As the brain and meninges rest in a fixed-volume skull, this leads to an elevation in intracranial pressure. Vasculitis decreases cerebral blood flow and can cause ischemia and thrombosis. Addition ally, neurons are directly injured by free radicals from granulocytes and endothelial cells. In direct contiguous spread, organisms gain entry into the CSF from adjacent infections such as sinusitis, brain abscess, or otitis media. Organisms can also enter directly with penetrating traumatic injury, through congenital defects, or during neurosurgical procedures. In these cases, the organisms and their pathophysiologic effects vary. Important risk factors for bacterial meningitis are listed in Table 174-1. CLINICAL FEATURES The presentation of fever, headache, stiff neck, and altered mental status is commonly seen in patients with bacterial meningitis. Most patients have at least two of four of these symptoms, but their absence does not exclude meningitis. Headache is the most common symptom and is seen in more than 85% of patients. 9 Fever is the second most common symptom. Seizures and focal neurologic deficits are seen in 25% to 30% of patients.  HISTORY Assess historical data in order to elicit risk factors suggestive of certain pathogens. N. meningitidis is associated with close living quarters, such as in military barracks and college dormitories. Unvaccinated patients are at risk for H. influenzae. Consider L. monocytogenes in older adults and alcoholics. 10 Penetrating head trauma makes S. pneumoniae more likely.

tors suggestive of certain pathogens. N. meningitidis is associated with close living quarters, such as in military barracks and college dormitories. Unvaccinated patients are at risk for H. influenzae. Consider L. monocytogenes in older adults and alcoholics. 10 Penetrating head trauma makes S. pneumoniae more likely. Staphylococcus aureus , coagulase-negative staphylococci, and streptococci are commonly implicated organisms after craniotomy, whereas coagulase-negative staphylococci are commonly seen after ventriculoperitoneal shunt and spinal surgery. 4 Immunocompromised patients, such as those with human immunodeficiency virus, on chronic steroids, or with a history of splenectomy, are susceptible to meningitis with encapsulated organisms.  PHYSICAL EXAMINATION Evaluate for focal neurologic dysfunction such as hemiparesis, visual field deficits, or disordered eye movements. Increased intracranial pressure can cause papilledema or cranial nerve palsy especially involving cranial nerves 3, 4, 6, and 7. Assess for meningeal irritation with gentle neck flexion and extension, or Brudzinski sign (flexion of hips and knees in response to passive neck flexion) and Kernig sign (contraction of the hamstrings in response to knee extension while the hip is flexed). Examine the skin for cutaneous stigmata such as petechiae, splinter hemorrhages, and pustules. 11 Percuss the sinuses and examine the ears for signs of primary infection. DIAGNOSIS  LUMBAR PUNCTURE The diagnosis of meningitis is based on CSF results obtained by lumbar puncture (LP). Withhold LP if there is coagulopathy, as evidenced by thrombocytopenia or anticoagulant or antithrombotic use, until coagulopathy is corrected. In general, a platelet count ≤20,000/µL (and some prefer ≤50,000/µL) or INR ≥1.5 is a contraindication to performing an LP on an emergent basis. 12 The risk of bleeding complications such as epidural hematoma resulting from LP in the presence of anticoagulants, antiplatelet agents, and NSAIDs is not known, and risks and benefits of LP must be considered in such circumstances. 13,14 Send CSF for studies including Gram stain and culture, cell count with differential, glucose, and protein. 9 Typical CSF findings for bacterial, viral, fungal, and neo plastic meningitides are listed in Table 174-2, 15-18 but there is consider able overlap.  LABORATORY TESTING Bacterial meningitis is associated with an elevated opening pressure >170 mm H 2O, and WBCs are elevated greater than 1000/mm 3 with a neutrophilic predominance. CSF protein is often elevated above CHAPTER TABLE 174-1 Important Risk Factors for Bacterial Meningitis •   Acute or chronic otitis media •   Sinusitis •   Immunosuppression/splenectomy •   Alcoholism •   Pneumonia •   Diabetes mellitus •   Cerebrospinal fluid leak •   Pneumonia •   Endocarditis •   Neurosurgical procedure/head injury •   Indwelling neurosurgical device/cochlear implant •   Advanced age •   Malignancies •   Liver disease •   Unvaccinated to Haemophilus influenzae type b, Neisseria meningitidis, or Streptococcus pneumoniae Tintinalli_Sec14_p1101-1186.indd 1172 8/2/19 12:09 PM

a •   Endocarditis •   Neurosurgical procedure/head injury •   Indwelling neurosurgical device/cochlear implant •   Advanced age •   Malignancies •   Liver disease •   Unvaccinated to Haemophilus influenzae type b, Neisseria meningitidis, or Streptococcus pneumoniae Tintinalli_Sec14_p1101-1186.indd 1172 8/2/19 12:09 PM CHAPTER 174: Central Nervous System and Spinal Infections 1173 200 milligrams/dL, and glucose is often decreased below 40 milligrams/dL or the glucose serum–to–CSF ratio is <0.4. 15-17 Sterilization of the CSF is possible within 2 hours of initiating paren teral antibiotics in meningococcal and 6 hours in pneumococcal meningitis, highlighting the importance of timely LP . 19 Without antibiotics, Gram stain is positive in 60% to 80% of cases, but in patients treated with antibiotics, the Gram stain is positive in 7% to 41%. 17 CSF is positive in 80% to 90% of cases if analysis is performed before antibiotics are initi ated, although results are not available during the course of the ED stay. When bacterial meningitis is considered, never withhold empiric antibiotic therapy in order to collect the CSF sample. Rapid latex agglutination tests can be used to detect bacterial anti gens and improve bacterial identification. These tests are available for S. pneumoniae, group B streptococci, H. influenzae, E. coli, and N. meningitidis, but are associated with false-positive and false-negative results and limited sensitivity and specificity. Polymerase chain reaction testing is highly sensitive for organisms such as S. pneumoniae, N. meningitidis , group B streptococci, H. influenzae, L. monocytogenes, and M. tuberculosis but does not provide information on antimicrobial susceptibility. Serum procalcitonin, C-reactive protein, and CSF lactate concentrations have been studied as adjuncts to diagnosis of bacterial meningitis with negative CSF examinations, but are not a substitute for decision making in the treatment of an individual patient. 18,21 Recent studies suggest that serum procalcitonin may demonstrate a similar specificity to CSF markers of meningitis while offering a higher sensitivity, making it a useful adjunct for diagnosis. 22 If suspicion is great despite negative initial CSF results, admit for empiric antibiotic treatment and consider repeat LP .15  CT SCAN BEFORE LUMBAR PUNCTURE Perform the LP as soon as possible to secure the diagnosis of meningitis. Concern about the complication of cerebral herniation from LP has led to controversy in determining which patients require a CT scan of the brain prior to the procedure. Order a head CT prior to LP in patients with high-risk criteria for herniation (Table 174-3). Although a CT scan can help identify contraindications for an LP , a normal CT scan does not imply that there is no risk of herniation with LP if a patient exhibits clinical predictors of impending herniation such as deteriorating mental status, posturing, irregular respirations and pupillary changes, or seizures. TREATMENT After addressing airway, breathing, and circulation status, immediately initiate empiric antibiotic therapy if bacterial meningitis is clinically suspected. Never delay administration of empiric antibiotic therapy for neuroimaging or to perform LP , because antibiotic treatment takes precedence over definitive diagnosis. 8 Obtain blood cultures to assist in identification of the organism and to help guide inpatient therapy if it will not delay time to antibiotics. Base antibiotic selection on the clinical scenario including age, immunization status, living conditions, and past medical history. See Table 174-4 for general recommendations.

Obtain blood cultures to assist in identification of the organism and to help guide inpatient therapy if it will not delay time to antibiotics. Base antibiotic selection on the clinical scenario including age, immunization status, living conditions, and past medical history. See Table 174-4 for general recommendations.  EMPIRIC TREATMENT FOR PRESUMPTIVE BACTERIAL MENINGITIS The empiric antibiotic regimen for adults between 18 and 49 years of age is a third-generation cephalosporin, such as cefotaxime 2 grams IV or ceftriaxone 2 grams IV , plus vancomycin 15 to 20 milligrams/kg IV to achieve serum trough concentrations of 15 to 20 micrograms/mL, to cover the common pathogens S. pneumoniae and N. meningitidis . For adults 50 years and older or those who may be immunocompro mised, add ampicillin 2 grams IV to cover L. monocytogenes. 8 If patients have a severe allergy to penicillin, options include replacing ceftriaxone with meropenem or moxifloxacin and replacing ampicillin with trimethoprim-sulfamethoxazole. Add acyclovir 10 milligrams/kg IV if herpes simplex virus (HSV) encephalitis is suspected. 15 Use a third- or fourth-generation cephalosporin, such as ceftazidime or cefepime, plus TABLE 174-2 Cerebrospinal Fluid (CSF) Diagnostic Evaluation of Meningitis and Encephalitis Opening Pressure (<170 mm H 2O)* Color (clear) Gram Stain (negative) Cell Count (<5 WBC, 0 PMN) Glucose (>40 milligrams/dL) Protein (<50 milligrams/dL) Cytology (negative) Bacterial Elevated Cloudy, turbid Positive (60%–80% before antibiotic, 7%–41% after antibiotic) >1000–2000/mm 3 WBC, neutrophilic predominance, >80% PMN <40 milligrams/dL, CSF/blood glucose ratio <0.3–0.4 >200 milligrams/dL Negative Viral Normal Clear or bloody Negative <300/mm 3 WBC, lymphocytic predominance, <20% PMN Normal <200 milligrams/dL Negative Fungal Normal to elevated Clear or cloudy Negative <500/mm3 Normal to slightly low >200 milligrams/dL Negative Neoplastic Normal Clear or cloudy Negative <300/mm 3 Normal to slightly low >200 milligrams/dL Positive *Normal values and findings are in parentheses. Abbreviation: PMN = polymorphonuclear lymphocyte. TABLE 174-3 Criteria for Obtaining Head CT Before Lumbar Puncture 8,17,23 •   Altered mental status or deteriorating level of consciousness •   Focal neurologic deficit •   New-onset seizure •   Papilledema •   Immunocompromised state •   Malignancy •   History of focal CNS disease (stroke, focal infection, tumor) •   Concern for mass CNS lesion •   Age >60 y TABLE 174-4 Guidelines for Treatment of Meningitis Based on Patient CharacteristicsB Patient Characteristic Primary Empiric Therapy Presumed Bacteria Immunocompetent Cefotaxime 2 grams IV or ceftriaxone 2 grams IV, plus vancomycin 15–20 milligrams/kg IV If severe penicillin allergy, can replace ceftriaxone with meropenem 2 grams IV or moxifloxacin 400 milligrams IV S. pneumoniae and N. meningitidis Age >50 y Immunocompromised Cefotaxime 2 grams IV or ceftriaxone 2 grams IV, plus vancomycin 15–20 milligrams/kg IV PLUS ampicillin 2 grams IV If severe penicillin allergy, can replace ampicillin with trimethoprimsulfamethoxazole 15–20 milligrams/kg/d divided 4 times daily L. monocytogenes Tintinalli_Sec14_p1101-1186.indd 1173 8/2/19 12:09 PM

sed Cefotaxime 2 grams IV or ceftriaxone 2 grams IV, plus vancomycin 15–20 milligrams/kg IV PLUS ampicillin 2 grams IV If severe penicillin allergy, can replace ampicillin with trimethoprimsulfamethoxazole 15–20 milligrams/kg/d divided 4 times daily L. monocytogenes Tintinalli_Sec14_p1101-1186.indd 1173 8/2/19 12:09 PM 1174 SECTION 14: Neurology vancomycin for patients who have recently undergone a neurosurgical procedure.16 Initiate antibiotics as soon as possible in order to increase survival and reduce morbidity.3,9 Administration of dexamethasone to patients with presumptive pneumococcal meningitis before or with the first dose of antibiotics can reduce CSF inflammation, reduce the risk of morbidity and mortality in adults, and reduce hearing loss and other neurologic sequelae in chil dren. 10,24 The recommended dosage of dexamethasone is 10 milligrams IV every 6 hours for 3 days for adults.24 Current guidelines provide no recommendation for the most com mon ED situation, in which the first dose of empiric antibiotics is given before LP is performed or before results of LP are received. However, delayed initiation of antibiotic treatment in bacterial meningitis patients is associated with death or poor clinical outcomes. 25 Common sense suggests that dexamethasone could be administered just before, or concurrently with, empiric antibiotics to patients with strong suspicion for bacterial meningitis or to patients in whom grossly purulent CSF is obtained at the time of LP . One expert consensus panel opined that dexamethasone treatment can be administered up to 4 hours after initiation of antibiotic treatment. SPECIAL SITUATIONS  BACTERIAL MENINGITIS RESULTING FROM SINUSITIS OR OTITIS The prevalent use of antibiotics has decreased the frequency of suppu rative intracranial complications from sinusitis and otitis, but bacterial meningitis resulting from these diseases still occurs. The virulence of the affecting organism and host factors, such as immunocompromised state, influence spread to the CNS. In the ear, bacteria can spread through endolymphatic channels, bony erosions, or osteothrombophlebitis of small vessels. Thrombophlebitis of veins is a common mechanism by which bacteria disseminate from the sinuses; this may result in cavern ous sinus thrombosis or empyema. 26 CT imaging is very sensitive for sinusitis and permits earlier diagnosis with demonstration of air-fluid levels in the involved sinuses. CT is nonspecific, however, and should be interpreted with the clinical background in mind ( Figure 174-1). Infections are often polymicrobial. Initiate empiric antibiotic ther apy with fluoroquinolones, such as levofloxacin or moxifloxacin, or with a third-generation cephalosporin, such as ceftriaxone, plus metronidazole.  ADDITIONAL ADJUNCTIVE TREATMENT FOR BACTERIAL MENINGITIS Monitor patients with meningitis closely for complications or signs of clinical deterioration, especially evaluating their respiratory and neurologic status. Treat fever, and manage seizures with anticonvulsants. Avoid hypotonic fluids, and monitor serum sodium level serially to detect syndrome of inappropriate antidiuretic hormone or cerebral salt wasting. 9,24 Closely evaluate for signs of increased intracranial pressure and vasculopathy that may lead to brain ischemia. If signs of elevated intracranial pressure are detected, elevate the bed to 30 degrees, use 25% mannitol or hypertonic 3% saline for diuresis, and consider a trial of mild hyperventilation. Measurement of intracranial and systemic arterial pressure may be useful in severe cases to monitor cerebral perfusion pressure. Consider admission to the intensive care unit to ensure proper level of care.

30 degrees, use 25% mannitol or hypertonic 3% saline for diuresis, and consider a trial of mild hyperventilation. Measurement of intracranial and systemic arterial pressure may be useful in severe cases to monitor cerebral perfusion pressure. Consider admission to the intensive care unit to ensure proper level of care.  CHEMOPROPHYLAXIS FOR THOSE EXPOSED TO BACTERIAL MENINGITIS Bacterial meningitis is spread by droplets, and risk for developing bacterial meningitis after exposure is estimated to be 500 to 800 times higher than the general population. 16 Chemoprophylaxis can decrease transmission of N. meningitidis by 89% in close contacts. 11 Chemoprophylaxis is recommended for individuals who have been exposed to patients diagnosed with N. meningitidis and H. influenzae. 11 It is not recommended for patients diagnosed with pneumococcal meningitis. 16 Close contacts include housemates, individuals exposed to secretions (shared utensils or toothbrushes, kissing, mouth-to-mouth resuscita tion), and individuals who intubated the patient without a facemask. To be most effective, initiate chemoprophylaxis within 24 hours of contact. Risk of infection after a period of 2 weeks from exposure is considered rare, and prophylaxis is not recommended after this time period. Treatment options for high-risk contacts include rifampin 10 milligrams/kg to a maximum of 600 milligrams per dose every 12 hours for four doses, ciprofloxacin 500 milligrams orally once, or ceftriaxone 250 milligrams IM once. 11 Instruct all patients who receive chemoprophylaxis to seek FIGURE 174-1. Acute sinusitis with opacification of the maxillary sinus. [Reproduced with permission from Brunicardi FC, Andersen D, Billiar T, et al: Schwartz’s Principles of Surgery , 8th ed. New York, McGraw-Hill, Inc.] Tintinalli_Sec14_p1101-1186.indd 1174 8/2/19 12:09 PM

tients who receive chemoprophylaxis to seek FIGURE 174-1. Acute sinusitis with opacification of the maxillary sinus. [Reproduced with permission from Brunicardi FC, Andersen D, Billiar T, et al: Schwartz’s Principles of Surgery , 8th ed. New York, McGraw-Hill, Inc.] Tintinalli_Sec14_p1101-1186.indd 1174 8/2/19 12:09 PM CHAPTER 174: Central Nervous System and Spinal Infections 1175 medical attention immediately if they develop any symptoms of illness or meningitis. Admit all patients diagnosed with bacterial meningitis and those highly suspected of having meningitis to the hospital on droplet isolation.  VIRAL MENINGITIS INTRODUCTION Viral meningitis typically presents with subacute headache, fever, and findings of meningeal irritation, such as nuchal rigidity. Several viruses can cause viral meningitis, including nonpolio enteroviruses, HSV , varicellazoster virus, cytomegalovirus, adenovirus, and human immunodeficiency virus. Specific diagnosis depends on isolation of the virus or positive results on immunoassay of the CSF . Nonpolio enteroviruses (echovirus, coxsackievirus, and enterovirus) typically are seen in summer through fall and account for more than 90% of all cases of viral meningitis. LABORATORY TESTING Viral meningitis is associated with normal opening pressures and a negative Gram stain ( Table 174-2). WBCs are <300/mm 3 with a lym phocytic predominance, and usually less than 20% polymorphonuclear lymphocytes. 15 Protein is often slightly elevated, but not typically above 200 milligrams/dL, and CSF glucose is normal. The percentage of polymorphonuclear cells may be higher in early viral meningitis, and in some cases, glucose levels may be decreased. 15 Consider partially treated bacterial meningitis if a patient with symptoms consistent with meningitis had previously been treated with antibiotics and the LP suggests aseptic meningitis. Viral culture is insensitive, so if a viral etiology is suspected, send for molecular testing by polymerase chain reaction from the CSF . 4 Polymerase chain reaction testing is available for HSV , enterovirus, and other viral organisms. DISPOSITION AND FOLLOW-UP There can be overlap of CSF findings with early bacterial meningitis and partially treated bacterial meningitis, making the specific diagnosis for some cases of viral meningitis difficult in the ED. Although supportive care is the mainstay of treatment for viral meningitis, it is appropriate to admit the toxic-appearing patient to the hospital for empiric antibiotic therapy until culture results return in situations of diagnostic uncertainty. HSV-2 meningitis can cause necrotizing encephalitis and neurologic deficits. Admit patients with diagnosed or suspected HSV-2 meningitis after beginning treatment with acyclovir 10 milligrams/kg IV every 8 hours.  FUNGAL CNS INFECTIONS Over the past 30 years, the incidence of fungal CNS infections has been increasing, likely due to acquired immunodeficiency syndrome as well as an increase in patients on immunosuppressants due to stem cell and organ transplants. 28 The most common cause of fungal meningitis is Cryptococcus neoformans , followed by Coccidioides immitis , which can be seen in immunocompetent hosts as well as the immunocom promised.4,28 Aspergillus and Candida are most often discovered in immunocompromised hosts. Mucormycoses can be seen especially in diabetics from direct extension of sinus infection. LABORATORY TESTING The CSF analysis of fungal meningitis shows lymphocytic predomi nance, an elevated opening pressure, low glucose, and slightly increased protein (Table 174-2). 7,29 Significant elevations in opening pressure are often seen in cryptococcal meningitis. Gram stain is negative, and WBC is usually <500/mm 3.

ORATORY TESTING The CSF analysis of fungal meningitis shows lymphocytic predomi nance, an elevated opening pressure, low glucose, and slightly increased protein (Table 174-2). 7,29 Significant elevations in opening pressure are often seen in cryptococcal meningitis. Gram stain is negative, and WBC is usually <500/mm 3. Consider fungal testing especially for immuno compromised patients in whom fungal etiologies are suspected, includ ing India ink staining and serum cryptococcal antigen testing, cytology, and histopathology. 7 Send CSF for Borrelia antibodies in patients with suspected Lyme disease and for acid-fast stain and culture for suspected mycobacteria in tuberculous meningitis. Patients often have a prolonged symptom course. Use fungal stain and culture for diagnosis if a fungal etiology is suspected, and look for elevated opening pressure during LP . Consider CT or MRI to search for intracranial complications such as granulomas or abscesses. TREATMENT Treatment for fungal infections is dependent on diagnosis through LP . Liposomal amphotericin B is the agent of choice in cryptococcal meningitis. Use fluconazole or itraconazole for C. immitis. Treat Candida meningitis with liposomal amphotericin B often combined with flucytosine.  VIRAL ENCEPHALITIS Viral CNS infections can also cause viral encephalitis, which is an infection and inflammation of the brain parenchyma. 4 Viral encephalitis is clinically distinguished from viral meningitis with presence of neuro logic findings such as altered level of consciousness, focal weakness, or seizures, although the two often coexist. The causes of viral encephalitis vary year to year and across geo graphical locations, with an incidence of 3.5 to 7.5 per 100,000 people. Immune status, exposure to insects or animals, and travel history play a key role in determining the etiology. An underlying cause, however, is found in only about a third of cases. 29 HSV accounts for 40% to 50% of cases where a cause is determined. 30 HSV-1 is responsible for most cases of HSV encephalitis; HSV-2 frequently causes aseptic meningitis but is not usually associated with development of encephalitis. 30 Other viral pathologic agents in North America include Epstein-Barr virus, cytomegalovirus, and rabies. Common arboviral encephalitides include La Crosse encephalitis, St. Louis equine encephalitis, Western equine encephalitis, and West Nile virus. PATHOPHYSIOLOGY Immunocompromised patients such as those with organ or stem cell transplants are susceptible to new or reactivated infections with HSV and varicella-zoster virus. Impaired immune status also plays a role in cyto megalovirus encephalitis. The arboviruses are transmitted by mosquitoes and ticks. Rabies is transferred by the bite of an infected animal and leads to severe encephalitis and a very high mortality rate. 4 Common to all is preliminary viral invasion of the host at a site where replication takes place that is outside the CNS. Most viruses then reach the nervous sys tem hematogenously during viremia. However, at least three important viruses—rabies, HSV , and herpes zoster virus—reach the spinal cord and eventually the brain by traveling backward within axons from a distal site, where they gain access to nerve endings. Once in the brain, disruption of neural cell functions by the virus and by the effects of the host’s inflammatory responses ensues. Gray matter is predominantly affected, resulting in cognitive and psychiatric signs, lethargy, and seizures. CLINICAL FEATURES Consider encephalitis in patients exhibiting behavioral changes, new psychiatric symptoms, cognitive deficits, or seizures. 29 The triad of headache, fever, and altered mental status may be seen but is not invariably present.

ected, resulting in cognitive and psychiatric signs, lethargy, and seizures. CLINICAL FEATURES Consider encephalitis in patients exhibiting behavioral changes, new psychiatric symptoms, cognitive deficits, or seizures. 29 The triad of headache, fever, and altered mental status may be seen but is not invariably present. Rash or skin vesicles suggest herpes zoster, and skin vesicle culture may be useful for diagnosis. Lymphadenopathy or splenomegaly points to Epstein-Barr virus, which can be picked up on serologic test ing. New onset of psychiatric symptoms and behavioral changes may be attributable to HSV . MRI, electroencephalogram, and polymerase chain reaction of the CSR could assist in making the diagnosis.  PHYSICAL EXAMINATION Examine for signs of meningeal irritation and increased intracranial pressure and for neurologic findings that reflect the areas of involve ment. Carefully assess mental status and cognition. Encephalitis may Tintinalli_Sec14_p1101-1186.indd 1175 8/2/19 12:09 PM

ld assist in making the diagnosis.  PHYSICAL EXAMINATION Examine for signs of meningeal irritation and increased intracranial pressure and for neurologic findings that reflect the areas of involve ment. Carefully assess mental status and cognition. Encephalitis may Tintinalli_Sec14_p1101-1186.indd 1175 8/2/19 12:09 PM 1176 SECTION 14: Neurology show regional tropism. HSV involves limbic structures of the temporal and frontal lobes with prominent psychiatric features, memory distur bance, and aphasia. Some arboviruses predominantly affect the basal ganglia, causing choreoathetosis and parkinsonian movements. Involvement of the brainstem nuclei that control swallowing leads to the hydrophobic choking response characteristic of rabies encephalitis. DIAGNOSIS Neuroimaging studies such as MRI or CT and electroencephalography are important in ruling out mass occupying lesions and making the diagnosis of encephalitis. MRI is more sensitive than CT. Obtain an MRI to help exclude lesions such as brain abscesses, and examine for findings suggestive of HSV encephalitis, such as involvement of the gray matter in the medial temporal and inferior frontal lobes (Figure 174-2). Electroencephalogram findings are generally nonspecific but can be useful in cases such as HSV encephalitis where an almost pathognomonic picture of periodic, asymmetric sharp waves is seen in the setting of acute febrile encephalopathy. 29 LP is the most useful diagnostic procedure in the ED, and CSF should be sent for Gram stain and culture, cell count with differential, glucose, and protein. Viral polymerase chain reaction can be helpful in detecting viral pathogens and has a 95% sensitivity and specificity for HSV . 9,32 CSF findings are similar to those in viral meningitis, with a lymphocytic pleocytosis, modestly elevated protein, and normal glucose. Consider bacterial meningitis in the differential diagnosis when fever and meningeal symptoms predominate. A late-summer encephalopathy suggests the possibility of arbovirus encephalitis, and an animal bite for which no antirabies treatment was administered has relevance for rabies. Suspect subarachnoid hemorrhage with acute onset of severe headache as the presenting sign. Lyme disease, tuberculosis, and fungal and neoplastic meningitis are in the differential diagnosis in less fulmi nant cases. If focal neurologic signs are present, consider brain abscess, empyema, or cavernous sinus thrombosis as possible causes. TREATMENT The antiviral of choice for HSV encephalitis is high-dose acyclovir at 10 milligrams/kg per dose IV every 8 hours. 10,30 Initiate treatment as soon as possible because the prognosis of HSV encephalitis is correlated with neurologic condition at the time antivirals are initiated. Treat varicellazoster virus with acyclovir, 10 to 15 milligrams/kg per dose IV every 8 hours. Patients with herpes zoster virus encephalitis may also benefit from acyclovir therapy. Treat patients with cytomegalovirus encephalitis with ganciclovir, 5 milligrams/kg per dose IV every 12 hours. 31 There are no known treatments for arbovirus encephalitis; consider initiating treatment with acyclovir empirically until a CSF diagnosis is made. 10 Rabies encephalitis is rare but neurologically devastating, and once symptomatic, it is usually fatal. DISPOSITION AND FOLLOW-UP Prognosis of viral encephalitides depends on the causative virus and host factors. Older adults and those who are immunocompromised are more likely to have an adverse outcome. Admit patients with encepha litis to the hospital. Patients may require intensive care unit care if they have signs of altered mental status or coma.

osis of viral encephalitides depends on the causative virus and host factors. Older adults and those who are immunocompromised are more likely to have an adverse outcome. Admit patients with encepha litis to the hospital. Patients may require intensive care unit care if they have signs of altered mental status or coma.  BRAIN ABSCESS INTRODUCTION A brain abscess begins as a focal area of cerebritis, which develops into a central pus-filled cavity ringed by a layer of granulation tissue and an outer fibrous capsule in a period of about 14 days. 33 It is surrounded by edematous brain tissue infiltrated with inflammatory cells. A brain abscess is a pathologic response typical of a relatively competent immune system against a bacterial invader. Focal brain infections from other organisms, such as granulomas due to tuber culosis, necrotic lesions of toxoplasmosis in immunocompromised patients, or cystic lesions of cysticercosis, are not abscesses in the pathologic sense. PATHOPHYSIOLOGY Organisms reach the brain hematogenously, from direct contiguous infection, or by direct seeding by neurosurgery or penetrating trauma. Hematogenous spread accounts for 15% to 30% of cases, direct spread from infection accounts for 25% to 50%, and trauma or surgery for 8% to 20%, while the route is unknown in 15% to 20% of cases. 33,34 Direct spread usually results in an isolated brain abscess, whereas hematog enous seeding results in multiple abscesses. Investigate for the source of the brain abscess in order to determine the likely bacterial etiology and to treat the source itself. Otogenic brain abscesses are often caused by gram-negative rods and are located adjacent to the temporal lobe or cerebellum. Sinogenic or odontogenic abscesses are often caused by anaerobic and microaerophilic streptococci and are commonly located in the frontal lobes. Abscesses formed from hematogenous spread are usually polymicrobial, with anaerobic and microaerophilic streptococci commonly represented. Direct implanta tion or traumatic injuries yield staphylococci, with gram-negative rods also seen in cases related to neurologic surgery. CLINICAL FEATURES  HISTORY Presenting features of brain abscess are nonspecific, and patients gen erally appear nontoxic. Headache is the most common feature, with fever as a close second. Although most patients present with one or more findings of headache, fever, altered mental status, focal neurologic symptoms, seizures, or balance changes, the classic triad of headache, fever, and focal neurologic deficit is present in <25% of all patients. 33,34 The nonspecific presentation contributes to both severity and outcome of brain abscesses because diagnosis and treatment are often delayed. Symptoms reflect the infectious and neurologic (focal and mass effect producing) aspects of the disease and are often present for 1 to 8 weeks. The presentation may be dominated by the origin of the infection (e.g., ear or sinus pain). Seizure occurs in 25% to 34% of patients. FIGURE 174-2. Fluid-attenuated inversion recovery hyperintensity in the left temporal lobe and left insula ( arrow) suggests the diagnosis of herpes encephalitis. [Photo contributed by Elizabeth Yutan, Department of Radiology, Oregon Health & Science University.] Tintinalli_Sec14_p1101-1186.indd 1176 8/2/19 12:09 PM

s. FIGURE 174-2. Fluid-attenuated inversion recovery hyperintensity in the left temporal lobe and left insula ( arrow) suggests the diagnosis of herpes encephalitis. [Photo contributed by Elizabeth Yutan, Department of Radiology, Oregon Health & Science University.] Tintinalli_Sec14_p1101-1186.indd 1176 8/2/19 12:09 PM CHAPTER 174: Central Nervous System and Spinal Infections 1177  PHYSICAL EXAMINATION Examine for focal neurologic signs that demonstrate the site of the lesion. Focal signs are present in approximately 60% of patients. 9,37 Assess for potential sites of origin, which may raise suspicion of brain abscess when the presentation is otherwise nonspecific in a patient with subacute headache and lethargy. DIAGNOSIS Neuroimaging is essential to the diagnosis of brain abscess and is one instance where a contrast-enhanced head CT scan is preferred over a noncontrast study in the ED. A noncontrast CT scan may only show a hypodense low-attenuation abnormality with mass effect, but later in the course, may show a peripheral ring. 33 A head CT with IV contrast shows one or several thin, smooth rings of enhancement surrounding a low-density central area and surrounded by edema (Figure 174-3). MRI usually demonstrates a ring whether or not gadolinium enhancement is used. Both CT and MRI are highly sensitive; CT is often more readily available in the ED. Avoid LP if clinical suspicion is high or focal neu rologic deficits are present to prevent potential herniation in the case of increased intracranial pressure. If possible, obtain cultures of blood and other sites of infection to guide future management. The differential diagnosis is broad because of the nonspecific symp toms of brain abscess. A sudden onset with focal features may suggest cerebrovascular disease. Prominent fever, stiff neck, and altered mental status may suggest meningitis or encephalitis. A protracted course with features of increased intracranial pressure may suggest neoplasm. Brain neoplasm, subacute brain hemorrhage, and other focal brain infections, such as toxoplasmosis, may mimic the imaging findings of brain abscess.  TREATMENT Early combination empiric antibiotic therapy is important (Table 174-5). A multidisciplinary approach with neurosurgery and infectious disease consultations will help guide treatment selection. Aminoglycosides, macrolides, and first-generation cephalosporins are not effective treat ment for brain abscess. Treatment with steroids is controversial. DISPOSITION AND FOLLOW-UP Neurosurgery involvement is paramount in treatment and management decisions. Patients with small abscesses <2.5 cm, with a Glasgow coma score >12, and who have an etiology that is known may be treated with IV antibiotics alone. 38 Aspiration may be done by the neurosurgical team to elucidate the causative organism. Total excision is less necessary with improved imaging, although it is performed in the setting of increased intracranial pressure or after failed medical management or aspiration.  SPINAL INFECTIONS  EPIDURAL ABSCESS INTRODUCTION AND EPIDEMIOLOGY Spinal epidural abscess is a collection of pyogenic material that accumulates in the epidural space between the dura and vertebral periosteum and often leads to devastating neurologic outcomes. 39,40 The incidence of spinal epidural abscess has doubled in the past two decades, largely attributed to factors such as an increasing proportion of immunocompromised patients, more prevalent IV drug use, an increasing number of spinal procedures, and improved imaging modalities for detection. 41,42 Despite improvement in diagnosis and treatment, mortality remains high at 2% to 20%. 39 S. aureus is the most commonly involved bacteria and is FIGURE 174-3. Ring-enhancing brain abscess with surrounding edema (arrow).

use, an increasing number of spinal procedures, and improved imaging modalities for detection. 41,42 Despite improvement in diagnosis and treatment, mortality remains high at 2% to 20%. 39 S. aureus is the most commonly involved bacteria and is FIGURE 174-3. Ring-enhancing brain abscess with surrounding edema (arrow). [Photo contributed by David Peterson, Department of Radiology, Oregon Health & Science University.] TABLE 174-5 Guidelines for Empiric Treatment of Brain Abscess Based on Presumed Source Presumed Source Primary Empiric Therapy Alternative Therapy Otogenic Cefotaxime 2 grams IV every 4–6 h or ceftriaxone 2 grams IV every 12 h PLUS metronidazole 500 milligrams IV every 8 h Piperacillin/tazobactam 4.5 grams IV every 6 h Odontogenic Penicillin G 4 million units IV every 4 h Ceftriaxone 2 grams IV every 12 h PLUS metronidazole 500 milligrams IV every 6 h Sinogenic Cefotaxime 2 grams IV every 6 h or ceftriaxone 2 grams IV every 12 h PLUS metronidazole 500 milligrams IV every 8 h No recommendation Penetrating trauma Cefotaxime 2 grams IV every 6 h or ceftriaxone 2 grams IV every 12 h PLUS metronidazole 500 milligrams IV every 8 h ± rifampin 10 milligrams/kg every 24 h No recommendation After neurosurgical procedure Vancomycin loading dose 25–30 milligrams/kg IV loading dose or linezolid 600 milligrams IV every 12 h PLUS ceftazidime 2 grams IV every 8 h ± rifampin 10 milligrams/kg every 24 h Can substitute linezolid 600 milligrams IV every 12 h instead of vancomycin. Can substitute meropenem 2 grams IV every 8 h OR piperacillin/tazobactam 4.5 grams IV every 6 h OR cefepime 2 grams IV every 8 h for ceftazidime. Unknown source Cefotaxime 2 grams IV every 6 h PLUS metronidazole 500 milligrams IV every 6 h No recommendation Note: See also http://www.hopkins-abxguide.org. Tintinalli_Sec14_p1101-1186.indd 1177 8/2/19 12:09 PM

ry 8 h OR piperacillin/tazobactam 4.5 grams IV every 6 h OR cefepime 2 grams IV every 8 h for ceftazidime. Unknown source Cefotaxime 2 grams IV every 6 h PLUS metronidazole 500 milligrams IV every 6 h No recommendation Note: See also http://www.hopkins-abxguide.org. Tintinalli_Sec14_p1101-1186.indd 1177 8/2/19 12:09 PM 1178 SECTION 14: Neurology responsible for 70% of cases, with a higher proportion of methicillinresistant S. aureus seen in patients with implantable devices. 39,42 Other pathogens include Staphylococcus epidermidis , streptococcal species, and gram-negative bacilli, which is especially prevalent in IV drug users. Mycobacteria and fungi causing spinal epidural abscess are rare. Tuberculosis spinal epidural abscess, also known as Pott’s disease, is seen in areas where tuberculosis remains endemic and in the immuno compromised population. PATHOPHYSIOLOGY Spinal epidural abscess can arise from hematogenous spread through blood circulation with soft tissue, urine, and respiratory infections contributing in the majority of cases. In general, hematogenously spread epidural abscesses are more likely to be found in the posterior epidural space. 42 Less commonly, spinal epidural abscesses are caused by direct extension from infected adjacent tissue, such as vertebral spondylodiscitis or vertebral osteomyelitis, which occurs when areas of slow blood flow in the vertebral body end plates are occluded by venous or arterial septic emboli, causing osteonecrosis. 44 Direct extension typically infects the anterior portion of the spinal column. 39,45 Fifteen to 22% of spinal epidural abscesses are caused iatrogenically from neurosurgical procedures, including percutaneous diagnostic and therapeutic techniques. 42 Trauma contributes to a small proportion of spinal epidural abscesses, with the remainder of cases without an identifiable source. 41,42 Most spinal epidural abscesses affect the thoracic and lumbar spine, where the epidural space is wider with a larger venous plexus. The cer vical spine is affected only 5% to 20% of the time, although morbidity and neurologic devastation are much greater than in thoracic or lumbar locations. Mechanisms for spinal cord neurologic sequelae are uncertain and are thought to be from a combination of direct compression from the abscess itself, ischemia due to compression of spinal veins and arteries, and septic thrombophlebitis. CLINICAL FEATURES Back pain is the most common presenting complaint and is seen in the majority of cases. Fever is another common symptom, followed by the presence of a neurologic deficit. However, the classic triad of back pain, fever, and neurologic symptoms is seen in a minority of patients (8% to 37%). 39,42 Typically, patients with spinal epidural abscess progress through four stages in a period ranging from hours to days. Stage 1 consists of back pain, fever, and localized spinal tenderness. Stage 2 is composed of spinal irritation, including radicular pain, hyperreflexia, and nuchal rigidity. Stage 3 involves the bowel and bladder, with symp toms of fecal or urinary incontinence, as well as focal neurologic deficits such as motor weakness. Finally, in stage 4, paralysis ensues. 39,42 Patients with tuberculosis as an etiology may also endorse night sweats and weight loss. HISTORY Screen any patient presenting with back pain, fever, or neurologic complaint for spinal epidural abscess. Patients may have a history of chronic back pain or may offer a mechanism of mild trauma, which can distract from a diagnosis of spinal epidural abscess. Similarly, neck pain or stiffness is often thought to be meningitis or encephalitis, causing cervical spinal epidural abscess to be overlooked.

inal epidural abscess. Patients may have a history of chronic back pain or may offer a mechanism of mild trauma, which can distract from a diagnosis of spinal epidural abscess. Similarly, neck pain or stiffness is often thought to be meningitis or encephalitis, causing cervical spinal epidural abscess to be overlooked. Carefully search for back pain red flags in the patient’s history, including immunocompromised states and immunosuppressant medications. Elicit a history of recent systemic illness or infection. Inquire about travel and history of tuberculosis. Ask about any current or former IV drug use, which can make patients higher risk for spinal epidural abscess development from Pseudomonas species. Solicit information about prior spinal surgeries or procedures, including LPs, epidurals, spinal injections, or epidural anesthesia. Ask about any changes in bowel or bladder habits, specifically episodes of bladder fullness or urinary or fecal incontinence. 42,48 PHYSICAL EXAMINATION Perform a thorough physical examination starting with a general assessment of sources of infection. Palpate the spine, searching for tenderness to palpation, especially in the midline, which may sug gest spinal epidural abscess. Complete a full neurologic examination, including sensory dermatome testing and motor evaluation including ambulation. Check reflexes for hyper- or areflexia. Evaluate for symp toms of cauda equina syndrome. Perform a rectal examination looking for decreased rectal tone, which has a sensitivity of 60% to 80%, and an evaluation of perianal sensation for saddle anesthesia, which has a sensitivity of 75%. DIAGNOSIS Diagnosis is delayed in many patients with spinal epidural abscess due to nonspecific presenting symptoms and the rarity of diagnosis. Send blood for laboratory studies including blood culture, CBC, erythrocyte sedimentation rate, and C-reactive protein. Leukocytosis is seen in only 60% to 78% of patients and is not sensitive or specific enough for a diagnosis of spinal epidural abscess. 42 Erythrocyte sedimentation rate is much more sensitive and, in one study, was elevated in 110 of 117 patients diagnosed with spinal epidural abscess. 42 C-reactive protein has the advantage of rising faster than erythrocyte sedimentation rate and returns to normal sooner as well, but some labs have a delay in resulting C-reactive protein. Do not withhold further diagnostics and treatment pending C-reactive protein. 42 Blood cultures are positive in up to 60% of cases and may be helpful for inpatient teams. 42 Do not perform LP if there is suspicion for spinal abscess. CSF culture is positive less than a quarter of the time, and LP poses the risk of traversing an abscess and causing meningitis or a subdural infection. MRI with gadolinium is the gold standard imaging study for the diagnosis of spinal epidural abscess and has a sensitivity and specificity greater than 90%. 45 If MRI is not available, consider emergent transfer to an appropriate referral center. In patients with contraindications to MRI, CT with myelography can be useful to localize epidural compression but is limited in its ability to distinguish abscess from other compressive lesions. 42 Plain radiographs are not sensitive or specific for diagnosis of spinal epidural abscess.45 TREATMENT Once diagnosis has been established, prompt treatment is essential to reduce morbidity and enhance survival. Immediate consultation with a spine surgeon is paramount, and if a spine surgeon is not available, transfer to a referral center. 42 Neurologic outcome is correlated with degree of neurologic deficit prior to treatment.

gnosis has been established, prompt treatment is essential to reduce morbidity and enhance survival. Immediate consultation with a spine surgeon is paramount, and if a spine surgeon is not available, transfer to a referral center. 42 Neurologic outcome is correlated with degree of neurologic deficit prior to treatment. There are no conclusive data regarding surgery versus conservative antibiotic therapy, and practices vary considerably from immediate operative therapy to conservative IV antibiotic therapy. 45 Patients with neurologic deficits usually require evacuation of the abscess with decompressive laminectomy, debridement, and long-term IV antibiotics, and some studies have shown improved outcomes with emergent surgery. 41 Patients who are neurologically intact or who have had neurologic deficits for >72 hours may be candidates for conservative treatment or CT-guided aspiration depending on the spinal surgeon’s practice, with the understanding that if they develop neurologic deficits or decompensate, immediate surgical therapy is likely required. Start empiric antibiotic therapy if there will be an unavoidable delay for surgery or if the patient exhibits neurologic dysfunction or signs of sepsis. Appropriate empiric antibiotics can include a combination of Tintinalli_Sec14_p1101-1186.indd 1178 8/2/19 12:09 PM