Neurologic Infections

Transcription

1 neurology Board Review Manual Statement of Editorial Purpose The Hospital Physician Neurology Board Review Manual is a peer-reviewed study guide for residents and practicing physicians preparing for board examinations in neurology. Each manual reviews a topic essential to the current practice of neurology. PUBLISHING STAFF PRESIDENT, Group PUBLISHER Bruce M. White editorial director Debra Dreger EDITOR Tricia Faggioli, ELS assistant EDITOR Farrawh Charles executive vice president Barbara T. White executive director of operations Jean M. Gaul PRODUCTION Director Suzanne S. Banish PRODUCTION assistant Nadja V. Frist ADVERTISING/PROJECT director Patricia Payne Castle sales & marketing manager Deborah D. Chavis NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Psychiatry and Neurology. Neurologic Infections Editor: Alireza Atri, MD, PhD Instructor in Neurology, Harvard Medical School; Assistant in Neurology, Massachusetts General Hospital, Boston, MA; Associate Director, Center for Translational Cognitive Neuroscience, Geriatric Research Education and Clinical Center, VA Medical Center, Bedford, MA Associate Editor: Tracey A. Milligan, MD Instructor in Neurology, Harvard Medical School; Associate Neurologist, Brigham and Women s and Faulkner Hospitals, Boston, MA Contributors: Tracey A. Cho, MD, MA Instructor in Neurology, Harvard Medical School; Assistant in Neurology, Assistant Director, Neurology-Infectious Diseases Clinic, Massachusetts General Hospital, Boston, MA Nagagopal Venna, MD, MRCP Associate Professor of Neurology, Harvard Medical School; Director, Neurology and Neurology-Infectious Diseases Clinics, Massachusetts General Hospital, Boston, MA Table of Contents Introduction Acute Bacterial Meningitis Recurrent Aseptic Meningitis Viral Encephalitis Focal Brain Infection Infectious Myelitis References Cover Illustration by Kathryn K. Johnson Copyright 2008, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA ,. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment. Neurology Volume 12, Part 5

2 Neurology Board Review Manual Neurologic Infections Tracey A. Cho, MD, MA, and Nagagopal Venna, MD, MRCP INTRODUCTION Infections can affect every part of the nervous system, and presentations are diverse. The nervous system may be primarily involved, or neurologic symptoms can develop as a result of systemic infection. Except in cases of penetrating head trauma or neurosurgery, most infections gain access via other parts of the body. Common sources for brain and intraspinal abscesses include contiguous spread from dental infection, sinusitis, or osteomyelitis and hematogenous spread from infected heart valves or hardware. Meningitis may occur as a result of spread from pneumonia, sinusitis, or otitis media. The nature of neurologic infectious disease depends on both host factors and microbial tropism. An immunocompromised state (eg, HIV infection, posttransplantation, hematologic or autoimmune disorder, alcoholism, malnutrition, diabetes) may predispose to a broader array of infections as well as more severe manifestations of common infections. The extremes of age also cause relative immunocompromise and lead to different patterns of neurologic infection. Many infections have geographic patterns of distribution, and travel history is an essential part of the evaluation. In addition, certain seasonal and environmental exposures are associated with increased risk for specific infections and should be assessed in the proper context. For example, mosquito- and tick-borne diseases are more common in the late summer and early fall in locations where these vectors are more prevalent, intravenous (IV) drug use predisposes to intracranial and epidural abscess, and swimming in fresh water may expose patients to schistosomiasis and amoebae. Finally, certain microbes have a tropism for different parts of the nervous system. Bacterial meningitis in immunocompetent adults is most commonly due to pneumococcus or meningococcus, whereas the cause of intracranial abscesses tends to be polymicrobial, including anaerobes. Tuberculosis, syphilis, and borreliosis (Lyme disease) affect almost every part of the central nervous system (CNS). Herpes simplex virus type 1 (HSV-1) migrates to the trigeminal ganglion and spreads to the temporal and orbitofrontal brain parenchyma, while HSV-2 has a predilection for sacral dorsal root ganglia and may cause recurrent meningitis or lumbosacral radiculitis. Many neurologic infections are treatable, and knowledge of proper diagnostic and treatment approaches can lead to a good prognosis. With global travel and immigration on the rise, neurologists must be able to recognize and triage patients with diverse neurologic infections. By assessing for host factors and keeping in mind microbial tropism, the neurologist can narrow the possible infectious differential. Evidence for systemic involvement (clinical or based on diagnostic studies) can help secure a diagnosis when direct CNS detection is not possible. This manual approaches neurologic infections based on the neurologic localization. Although not meant to be a comprehensive review, several cases are presented to illustrate the approach to infections of the nervous system. Neurologic complications of HIV infection were addressed in a previous manual. 1 ACUTE BACTERIAL MENINGITIS CASE 1 PRESENTATION A 48-year-old man with no significant past medical history presents to the emergency department (ED) with recent-onset fever, headache, neck stiffness, and confusion. The patient was in his usual state of health until the day prior to presentation, when he developed right ear pain and drainage, followed by fevers, chills, and headache. During the night he began vomiting and became confused. In the ED, the patient is febrile (103 F), confused, and agitated, but he is awake and otherwise his examination is nonfocal. He complains of a stiff neck. Physical examination reveals no rash or signs of pulmonary consolidation. Otologic examination reveals purulent discharge from the right ear. Acute bacterial meningitis is suspected. What are common causes of acute bacterial meningitis? What is included in the differential diagnosis? This patient has the classic syndrome of acute bacterial meningitis, specifically fever, headache, neck stiffness, and mental status changes. Forty percent to 50% of patients Hospital Physician Board Review Manual

3 present with a majority of these classic symptoms, 95% will have at least 2, and nearly 99% will have at least 1. 2 In the absence of all 4 classic symptoms, the diagnosis is highly unlikely. Other manifestations of acute bacterial meningitis may include photophobia, seizure, focal neurologic symptoms, or coma. The classic signs of meningismus include nuchal rigidity and positive Kernig s or Brudzinski s sign. 3 The presence of a petechial rash or arthritis suggests meningococcal meningitis, whereas signs of pneumonia, otitis, or sinusitis may indicate streptococcal meningitis. Acute confusional state, stupor, and status epilepticus sometimes mask the usual signs of meningitis, and acute bacterial meningitis should be considered in the differential diagnosis of these syndromes. The differential diagnosis of acute meningitis includes nonbacterial infections (viral, fungal, tuberculous) and noninfectious causes such as subarachnoid hemorrhage, malignancy (carcinoma, lymphoma), use of certain drugs (eg, IV immunoglobulin [IVIG], trimethoprimsulfamethoxazole [TMP-SMX], nonsteroidal antiinflammatory drugs [NSAIDs]), and primary inflammatory diseases (eg, autoimmune disease). The presence of B symptoms (eg, weight loss, night sweats) or systemic symptoms (eg, polyarthralgias, sun-sensitive rash, sicca syndrome), or the use of implicated medications may suggest a nonbacterial process. Bacterial meningitis can be devastating. Patients become rapidly ill, with most presenting within the first 24 hours of symptoms. 4 The mortality rate of untreated bacterial meningitis is essentially 100%. Even with proper treatment, the mortality rate remains 20% to 25%. 2,5,6 Among those who survive, about 10% will have residual deficits such as sensorineural hearing loss, weakness, cognitive impairment, or cranial nerve palsy. 7 Because of the devastating morbidity and mortality, the underlying cause must be aggressively assessed and treated. Causative organisms vary by age and setting (community versus nosocomial), among other factors. In adults, Streptococcus pneumoniae is the leading cause of community-acquired bacterial meningitis, followed by Neisseria meningitidis (especially in young adults). Group B streptococcus is the leading cause in newborns, with Listeria monocytogenes playing a smaller but important role in the extremes of age. 2,5 Among causes of communityacquired bacterial meningitis, S. pneumoniae has the greatest morbidity and mortality. 2 In nosocomial bacterial meningitis, gram-negative bacilli are the most commonly identified cause, with streptococcal and staphylococcal species of skin flora also playing an important role. 6,8 What are next steps in the management of this patient? Suspected acute bacterial meningitis is a neurologic emergency. Once airway, breathing, and circulation are assessed and stabilized, blood should be drawn for Gram stain and culture. Lumbar puncture should be performed immediately, ideally before the initiation of antibiotics. However, in patients with focal neurologic symptoms, new-onset seizures, altered mental status, or immunocompromise, noncontrast computed tomography (CT) of the head should be obtained prior to lumbar puncture to evaluate for the presence of mass effect, which could lead to downward brain herniation with removal of cerebrospinal fluid (CSF). If CT cannot be performed immediately, empiric antibiotics should be initiated after blood cultures are drawn. 9 Blood cultures are positive in 50% to 75% of cases when obtained prior to the initiation of antibiotics. 2,7 CASE 1 CONTINUED Blood cultures are drawn. Laboratory testing reveals a white blood cell (WBC) count of 24,600 cells/μl (90% polymorphonuclear cells, 2% bands). The patient is started on ceftriaxone 2 g IV every 12 hours, vancomycin 1 g IV every 12 hours, and dexamethasone 10 mg IV every 6 hours. Noncontrast CT of the head suggests right mastoiditis. The patient is intubated due to agitation and undergoes a lumbar puncture. CSF analysis reveals cloudy CSF with a WBC count of 735 cells/μl (94% polymorphonuclear cells), glucose level of 18 mg/dl, and protein level of 550 mg/dl. CSF Gram stain reveals gram-positive diplococci in pairs and chains. What are common CSF findings in acute bacterial meningitis? Patients with acute bacterial meningitis typically have an elevated opening pressure in the range of 150 to 400 mm H 2 O, but values are wide-ranging. 5,10 CSF glucose is usually decreased (< 45 mg/dl), protein is elevated (> 500 mg/dl), and WBC count is markedly elevated (> 1000 cells/μl) with a polymorphonuclear predominance. 9 However, CSF results are variable, and many patients will not have a CSF profile that fits all of these parameters. CSF Gram stain has a variable sensitivity (50% 90%) but is essentially 100% specific. 2,7,10 CSF culture has a sensitivity of approximately 75%, with a small proportion of culture-negative CSF showing positive results on Gram stain. 4,6,7 The sensitivity of Gram stain and culture is significantly diminished if CSF is obtained after the initiation of antibiotics; in this case, other diagnostic tests may be helpful such as latex agglutination (antibodies to bacterial antigens cause clumping) or broad-based polymerase chain reaction (PCR), if available. 11,12 Neurology Volume 12, Part 5

4 What is the optimal treatment for acute bacterial meningitis? Empiric antibiotic regimens should include ceftriaxone 2 g IV every 12 hours, which has good CSF penetration and covers most community-acquired organisms, and vancomycin 1 g IV every 12 hours, which covers penicillin-resistant S. pneumoniae. Patients older than age 60 years or those who are immunocompromised should also receive ampicillin 2 g IV every 4 hours to cover for L. monocytogenes. For nosocomial infections or in immunocompromised patients, ceftazidime or cefepime 2 g IV every 8 hours should be substituted for ceftriaxone. 9 Antibiotics should be tailored to specific organisms once they are isolated. Much of the morbidity and mortality associated with acute bacterial meningitis is due to the marked inflammatory reaction and resultant complications, such as edema and infarction. Several studies have evaluated whether mitigating the inflammatory response with adjuvant corticosteroids would be beneficial in reducing morbidity or mortality. Although some debate remains, the results of a large, randomized, double-blind, placebocontrolled trial suggest a steroid benefit in patients with pneumococcal meningitis. 4 Thus, the Infectious Diseases Society of America recommends the use of adjuvant dexamethasone 0.15 mg/kg IV every 6 hours for 4 days in cases of suspected or proven meningitis due to S. pneumoniae. 9 Steroids should be initiated in conjunction with or just prior to antibiotic administration. For children, adjuvant corticosteroids should be given with or prior to antibiotics for suspected or proven Haemophilus influenzae type B meningitis, as it has been shown to reduce hearing loss. 13 There is currently no role for steroids in neonatal bacterial meningitis. 9,13 CASE 1 CONCLUSION Both CSF and blood cultures are positive for S. pneumoniae. The patient undergoes a right myringotomy, and culture of purulent discharge also grows S. pneumoniae. Antibiotics are narrowed to ceftriaxone 2 g IV every 12 hours. The patient completes 4 days of dexamethasone 10 mg IV every 6 hours. Due to difficulty weaning the patient from mechanical ventilation, he undergoes magnetic resonance imaging (MRI) of the brain, which reveals leptomeningeal and ventricular enhancement and a punctate left superior cerebellar lesion with restricted diffusion, suggestive of meningitis and ventriculitis with possible secondary vasculitic infarction. CT of the sinuses reveals a right temporal tegmen dehiscence. Upon being extubated on hospital day 4, the patient quickly improves, but he complains of hearing difficulty. Audiologic examination reveals bilateral hearing loss greater in the right ear than the left ear. A peripherally inserted central catheter line is placed, and the patient receives a total of 4 weeks of IV ceftriaxone for S. pneumoniae meningitis. Two months later, his hearing loss persists but he has otherwise recovered well and returned to work. What are the sequelae of acute bacterial meningitis? In 20% to 50% of cases, bacterial meningitis is complicated acutely by neurologic symptoms or signs, such as impaired mental status, coma, seizures, hearing loss and other cranial nerve deficits, increased intracranial pressure, and cerebral infarction due to arteritis or cortical thrombophlebitis. 4,6 Rarer complications are subdural and intraventricular loculated empyema and ventriculitis, which can underlie persisting fevers and persistent neurologic impairment despite antibiotic treatment. Even with proper treatment, patients may experience significant morbidity. However, a smaller percentage of these neurologic complications persist after effective treatment. 7 Certain features can help predict mortality and morbidity, including hypotension, altered mental status, and seizures at presentation. The risk of death or persistent deficit ranged in 1 study from 9% in patients with none of the aforementioned risk factors to 57% in those with 2 or 3 risk factors. The development of 1 or more of these features before initiation of antibiotics was also associated with a poor outcome. 7 RECURRENT ASEPTIC MENINGITIS CASE 2 PRESENTATION A 28-year-old woman with a history of hypothyroidism, anxiety, and genital herpes presents to the ED during the winter complaining of several days of severe headache, neck stiffness, photophobia, and malaise. A fever to 104 F and vomiting prompted her to seek medical attention. Physical examination reveals normal neurologic function and no genital lesions. Blood cultures are obtained, a lumbar puncture is performed, and broad-spectrum antibiotics and acyclovir are started for possible bacterial or viral meningitis. CSF analysis reveals normal glucose and protein, a WBC of 100 cells/μl with lymphocyte predominance, and a few red blood cells (RBCs) per μl. No organisms are seen on CSF Gram stain, and CSF and blood cultures are negative. What is the differential diagnosis of aseptic meningitis? Hospital Physician Board Review Manual

5 Aseptic meningitis refers to a clinical syndrome of meningitis with CSF Gram stain and cultures that are negative for bacteria. Patients typically present with headache, fever, meningismus, and a CSF profile consisting of lymphocyte predominance. The differential diagnosis includes several infectious and noninfectious etiologies (Table 1). The most common identifiable causes of aseptic meningitis are viral pathogens, particularly enteroviruses, HSV-2, and varicella zoster virus (VZV). 14 More recently, HIV seroconversion has been found to be frequently associated with aseptic meningitis. 15 In addition to viruses, other infectious etiologies can include bacterial infections with a parameningeal focus (eg, otitis, mastoiditis, sinusitis), diseases caused by atypical bacteria (eg, tuberculosis, syphilis, Lyme disease, Rocky Mountain spotted fever), and, less commonly, fungal infection (eg, Cryptococcus, Coccidioides) and parasitic infection (eg, Angiostrongylus). Noninfectious causes include neoplastic diseases, especially large cell lymphoma and acute leukemia; inflammatory diseases, including sarcoidosis, systemic lupus erythematosus, (SLE), Sjögren s syndrome, and Behçet s disease; and use of NSAIDs, TMP-SMX, or IVIG. The history or physical examination may point toward a particular diagnosis. For instance, enteroviral illness and Lyme disease most commonly present in the late summer and early fall. Heavy NSAID use or treatment with TMP-SMX should raise suspicion for these etiologies. Rash may be associated with several etiologies, including enterovirus, VZV, Lyme disease, syphilis, Rocky Mountain spotted fever, SLE, and sarcoidosis. Genital vesicular eruptions may be seen in primary HSV-2, and recurrent oral and genital ulcers may suggest Behçet s disease. Cranial nerve deficits are more common with tuberculosis, sarcoidosis, syphilis, and Lyme disease. How is the CSF profile in aseptic meningitis different from that in bacterial meningitis? As opposed to the often low glucose level, markedly elevated protein level, and significant polymorphonuclear pleiocytosis in bacterial meningitis, CSF in aseptic meningitis typically shows a normal glucose level (45 80 mg/dl), normal to mildly elevated protein ( mg/dl), and a moderate lymphocytic pleiocytosis ( cells/μl). If aseptic meningitis is caused by HSV-2, VZV, mumps, or lymphocytic choriomeningitis virus, CSF glucose may sometimes be decreased. In general, a markedly low glucose level with lymphocytic pleiocytosis should raise suspicion for atypical bacteria, tuberculosis, or neoplasm as a cause. Early in the course of aseptic meningitis, there Table 1. Causes of Aseptic Meningitis Infectious Viral Enteroviruses Herpesviruses HIV LCMV Arboviruses Mumps Polioviruses Bacterial Partially treated pyogenic abscess Parameningeal focus Borreliosis Tuberculosis Syphilis Leptospirosis Fungal Cryptococcus Coccidioides Histoplasma Parasitic Angiostrongylus Toxoplasma Malaria Noninfectious Inflammatory Systemic lupus erythematosus Sarcoidosis Behçet s disease Rheumatoid arthritis Vogt-Koyanagi-Harada syndrome Malignant Carcinomatous Lymphomatous Leukemic CNS tumors and cysts Craniopharyngioma Epidermoid cyst Drugs NSAIDs Trimethoprimsulfamethoxazole Azathioprine Intravenous immunoglobulin CNS = central nervous system; LCMV = lymphocytic choriomeningitis virus; NSAIDs = nonsteroidal anti-inflammatory drugs. may be a polymorphonuclear predominance in CSF, but this changes over a period of days to a lymphocytic predominance. Viruses coxsackie, echovirus, mumps, West Nile, and Eastern equine in particular may be associated with a polymorphonuclear pattern. 16,17 By definition, CSF Gram stain and culture must be negative to make a diagnosis of aseptic meningitis. However, in partially treated bacterial meningitis, Gram stain and culture may also be negative and the CSF profile may be indistinguishable from aseptic meningitis. Despite attempts to differentiate pyogenic from aseptic meningitis on the basis of CSF patterns, patients should be treated empirically if there is any doubt. 18 CASE 2 CONTINUED Antibiotics are stopped and the patient is continued on acyclovir 10 mg/kg IV every 8 hours for 7 days. CSF HSV-2 PCR is positive. The patient s headache and other symptoms improve and she is discharged home. Three weeks later, she experiences a recurrence of similar but milder symptoms. A repeat lumbar puncture is performed, and CSF analysis reveals a similar pattern (normal protein and glucose, lymphocyte predominance). After 2 days of acyclovir 10 mg/kg IV every 8 hours, the patient s symptoms improve and she Neurology Volume 12, Part 5

6 transitions to acyclovir 400 mg by mouth 3 times a day for 2 weeks. The patient has no symptoms for 1.5 years. However, during the summer, she once again develops headache, neck stiffness, and photophobia, accompanied by right arm and leg weakness. She presents to the ED, where a brain MRI is normal. Because she is afebrile, lumbar puncture is not performed. The patient gradually improves without specific treatment. She has no significant symptoms for several months but in the late winter develops severe headache, neck stiffness, and photophobia. Lumbar puncture at this time shows a lymphocytic pleiocytosis, and CSF HSV-2 PCR is again positive. What is the differential diagnosis for recurrent aseptic meningitis? Recurrent aseptic meningitis, also known as Mollaret s meningitis, is a rare disease characterized by multiple episodes of aseptic meningitis with spontaneous resolution. Time to recurrence is highly variable, from weeks to months or even years, as in the case patient. There is a female predominance; mean age of onset is 35 years Transient neurologic signs and symptoms (eg, seizures, hallucinations, diplopia, cranial nerve palsies, altered levels of consciousness) are present in up to 50% of patients. 22 The most commonly identified causative agent is HSV-2, which likely in part explains the predominance in young females, who have an increased incidence of HSV-2 due to sexual transmission A small number of cases are attributed to HSV-1. Presumably, HSV-2 lies dormant in sacral dorsal root ganglia and periodically reactivates, leaking into the CSF and causing inflammation. 22 Meningitis often occurs in the absence of a genital outbreak. Further differential of recurrent aseptic meningitis includes some of the same etiologies for aseptic meningitis, including drug-induced meningitis (NSAIDs, TMP- SMX, IVIG) and inflammatory diseases (sarcoidosis, SLE, Behçet s disease, and Vogt-Koyanagi-Harada syndrome). In addition, structural lesions such as epidermoid cysts or craniopharyngiomas may contribute by intermittently releasing debris that results in a chemical meningitis. 23,24 Recurrent bacterial meningitis may be due to a parameningeal focus or CSF leak. 25 As implied by the definition, the patient must return to normal between episodes (presumably with normalization of CSF). As opposed to recurrent meningitis, chronic meningitis is a syndrome of meningitis that lasts longer than 4 weeks and carries a distinct differential. Common infectious causes include tuberculosis, Lyme disease, syphilis, HIV, and cryptococcosis. Of note, HIV serology may be negative in the setting of meningitis associated with seroconversion; serum and CSF PCR can detect HIV RNA in this setting. Noninfectious causes are similar to those of recurrent meningitis and include neoplastic, drug-induced, and inflammatory processes. What is the work-up for recurrent aseptic meningitis? What is the most appropriate treatment? Patients presenting with signs and symptoms of recurrent meningitis should undergo a lumbar puncture as soon as possible. In the absence of focal neurologic deficits or altered mental status, neuroimaging may not be necessary prior to obtaining CSF. The typical CSF profile for recurrent aseptic meningitis includes a normal glucose (mean, 55 mg/dl), mildly elevated protein (mean, 122 mg/dl), and lymphocytic pleiocytosis (mean WBC count, 443 cells/μl with 86% lymphocytes). 22 Large, granular multilobulated atypical monocytes (Mollaret cells) may appear early in the course and are characteristic of recurrent aseptic meningitis; however, this finding is not specific. 21 Recognition of these cells is enhanced by alerting the cytology laboratory and examining the specimen within 24 hours of the onset of the illness. The gold standard for diagnosis is analysis of CSF for HSV DNA using PCR (both HSV-1 and HSV-2). 22 HSV culture and serum antibodies are not useful. Depending on clinical features, CSF studies may also include acid-fast bacterial smear and mycobacterial culture, Lyme antibody, cryptococcal antigen, VDRL, and HIV RNA by PCR. In the absence of an etiologic diagnosis based on CSF, structural lesions such as an epidermoid cyst or a parameningeal bacterial focus should be excluded with MRI of the brain and spine. Serologic markers of autoimmune disease may be useful when these diseases are suspected to play a role in recurrent meningitis. Because it is a rare disease, there are no controlled trials for the treatment of recurrent aseptic meningitis. Cases with mild symptoms may not require specific treatment, as these are usually self-limiting. In cases in which HSV is identified in CSF, the duration of symptoms may be shortened with oral antiviral treatment (valacyclovir or famciclovir). More severe cases with severe headache or prominent neurologic symptoms should be treated with acyclovir 10 mg/kg IV every 8 hours for 7 to 10 days. 22 For frequently recurring cases with documented HSV in the CSF or even in the absence of evidence of HSV, suppressive treatment with oral valacyclovir may lead to a decrease or resolution of the episodes. 26,27 Other anecdotal treatments have included indomethacin, colchicine, and steroids. 22,28 CASE 2 CONCLUSION The patient is treated with acyclovir 10 mg/kg IV every 8 hours for 3 days. Her symptoms Hospital Physician Board Review Manual

7 rapidly resolve, and she is transitioned to oral valacyclovir 500 mg daily. She improves but not completely to baseline. In late summer, she experiences another recurrence of severe headache, neck stiffness, photophobia, and nausea. She is hospitalized for pain management, but analgesics are of little benefit. Valacyclovir is increased to 1000 mg daily, and the patient goes several months without recurrence. VIRAL ENCEPHALITIS CASE 3 PRESENTATION A 53-year-old man with no significant past medical history presents to the ED in July with a temperature of 105 F and mild left arm weakness. A few days prior to presentation, the patient was seen by his primary care physician for malaise and fevers to 102 F. He had returned from a business trip to New Hampshire 7 days earlier. At that time, he was prescribed levofloxacin, but his symptoms progressed, with the interval development of myalgias and confusion. On examination in the ED, the patient demonstrates poor attention and impaired short-term memory. He has decreased spontaneous movement of the left upper extremity. Noncontrast CT of the head reveals prominence of the right medial temporal lobe but no obvious mass effect, hemorrhage, or infarction. Lumbar puncture is performed, and CSF analysis reveals a glucose level of 60 mg/dl, protein level of 164 mg/dl, WBC count of 455 cells/μl (5% polymorphonuclear cells, 78% lymphocytes, 9% monocytes), and RBC count of 68 cells/μl. CSF Gram stain and culture are negative. What is the differential diagnosis for this patient s clinical presentation? Based on the clinical presentation of fever, altered mental status, and focal neurologic symptoms, the patient most likely has infectious encephalitis. The CSF profile of lymphocytic predominance suggests that the cause is more likely viral than bacterial, and there is evidence of a meningitis as well. The leading cause of acute viral encephalitis in the Western world is HSV-1, 29 but it is a rare disease overall with an estimated incidence of 2 to 4 cases per million Many other viruses can infect the brain parenchyma (Table 2). Seasonal, geographic, and exposure history may give clues to certain pathogens. For instance, arboviruses cause encephalitis during seasons when mosquitoes are active. St. Louis encephalitis is active in North America, Venezuelan equine encephalitis is active Table 2. Differential Diagnosis for Acute Medial Temporal Lobe Lesions Mimicking Herpes Simplex Encephalitis Infectious Viral Murray Valley encephalitis Japanese B encephalitis West Nile encephalitis La Crosse encephalitis (especially in children) Varicella zoster encephalitis Human herpesvirus 6 (in immunocompromised patients) Progressive multifocal leukoencephalopathy (in immunocompromised patients) Bacterial Pyogenic abscess (especially from mastoiditis) Tuberculous abscess Listeria encephalitis (in immunocompromised patients) Neurosyphilis Noninfectious Immune mediated Acute disseminated encephalomyelitis Lupus encephalitis Steroid-responsive encephalitis with autoimmune thyroiditis (Hashimoto s encephalitis) Paraneoplastic limbic encephalitis Teratoma-associated NMDA-receptor antibody limbic encephalitis Voltage-gated potassium channel antibody limbic encephalitis Neoplastic Primary central nervous system lymphoma Gliomatosis cerebri Vascular Cerebral cortical vein thrombosis with hemorrhagic infarction of temporal lobe Metabolic Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes Epileptic Seizure-induced inflammatory changes NMDA = N-methyl D-aspartate. in South America, and rabies encephalitis is associated with exposure to a bite from an infected animal. There are several nonviral causes of infectious encephalitis as well as noninfectious imitators (Table 2). Acute disseminated encephalomyelitis (ADEM) is an important consideration, as a viral prodrome often precedes a presumed autoimmune reaction, which leads to parenchymal inflammation with subsequent focal or diffuse cerebral symptoms. HSV ENCEPHALITIS HSV may involve the CNS via different mechanisms. More than one third of the world s population is infected with HSV. 33 Primary infection typically occurs Neurology Volume 12, Part 5

8 in children and involves the oropharyngeal mucosa. The virus reaches the trigeminal ganglion through retrograde axonal transport, where colonization is established. The virus may cause encephalitis by extension from the olfactory tract or trigeminal ganglion into the parenchyma (primary infection) or through viral reactivation in the trigeminal ganglion with subsequent spread into the parenchyma of the temporal and frontal lobes, often unilaterally (most commonly in middle-aged and older adults). 29,33 What are the typical clinical manifestations of HSV encephalitis? How is HSV encephalitis diagnosed? Signs and symptoms of HSV encephalitis are related to the infection s predilection for the inferior frontal and medial temporal lobes. The disease typically presents with the acute or subacute onset (< 1 wk) of fever and some combination of altered mental status/behavioral changes, headache, focal seizure activity, aphasia, or hemiparesis. 29,32,33 A prodrome of upper respiratory or gastrointestinal symptoms is reported in 30% to 60% of cases. 34 Untreated HSV encephalitis has a mortality rate in excess of 70%, with only 2.5% of untreated patients returning to baseline after the disease course. 32 All patients presenting with fever and mental status or other neurologic changes warrant emergent neuroimaging and lumbar puncture. In HSV encephalitis, CSF typically reveals elevated opening pressure, normal glucose, mildly elevated protein (mean, 100 mg/dl), a lymphocytic pleiocytosis (mean, 100 cells/µl), and at times a mild elevation in RBCs. Although a mild elevation in RBCs is a classic finding in HSV encephalitis due to hemorrhagic necrosis, this is neither sensitive nor specific. 29,32 34 Neuroimaging studies typically show abnormalities in the inferior frontal and medial temporal lobes, often in an asymmetric pattern. Although CT may show hypodense or hemorrhagic lesions, these findings typically occur later in the course and even then have only a 50% sensitivity. 35 MRI is much more sensitive than CT, especially early in the course. Data suggest that up to 85% of cases will have an abnormal MRI, so a normal MRI should raise suspicion for an alternative diagnosis. 29,36 Typical early findings on T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI include hyperintense lesions in medial temporal and inferior frontal structures; contrast enhancement is common later in the disease course and may be accompanied by small hemorrhages. 36 The electroencephalogram (EEG) is abnormal in 80% of cases of HSV encephalitis, with classic findings of intermittent high amplitude slow waves over the affected temporal lobes, at times with periodic lateralized epileptiform discharges The presence of these findings in association with clinical and CSF parameters consistent with viral encephalitis is highly suggestive of HSV encephalitis but lacks specificity. 32 Prior to PCR-based tests for the presence of HSV DNA in CSF, brain biopsy was the gold standard for diagnosis. However, brain biopsy is now reserved for difficult or unusual clinical presentations. Classic findings of viral encephalitis on brain biopsy include lymphocytic perivascular cuffing, glial nodules or stars, and lymphocytic infiltration accompanied by regions of necrosis. In HSV encephalitis, virus may be cultured from brain tissue or identified by immunohistochemistry. The current gold standard for diagnosis is CSF PCR for HSV DNA, with a sensitivity and specificity exceeding 95% PCR is typically positive early in the disease course and persists for 2 to 4 weeks, although degrading more rapidly with treatment, making false-negative results more likely if CSF is obtained several hours to days after initiation of acyclovir. Due to the delay in obtaining PCR results, patients with suspected HSV encephalitis are typically started on treatment pending PCR results. CASE 3 CONCLUSION MRI of the brain reveals medial temporal and inferior frontal T2 hyperintensity and enhancement, which are more pronounced on the right than the left side (Figure 1). CSF PCR is sent for HSV DNA, and blood is sent for West Nile and Eastern equine encephalitis serology. The patient is started on broadspectrum antibiotics, acyclovir 10 mg/kg IV every 8 hours, and phenytoin for seizure prophylaxis. On hospital day 2, the patient is intubated due to hypoventilation felt to be caused by oversedation and encephalopathy. An EEG reveals generalized slowing throughout with rare spikes arising predominantly from the left frontocentral regions and periods of frontal intermittent rhythmic activity. CSF PCR is ultimately positive for HSV DNA. The patient completes a 21-day course of acyclovir 10 mg/kg IV every 8 hours; however, his course is complicated by seizures and respiratory failure, requiring prolonged sedation and intubation. Ultimately, his seizures are controlled on 2 antiepileptic drugs (AEDs), and his respiratory status improves. Two years later, the patient has no obvious residual neurologic deficits but continues to require 2 AEDs to control seizures. What is the optimal treatment for HSV encephalitis? What is the long-term prognosis? Given the high morbidity and mortality associated with untreated HSV encephalitis, appropriate early treatment is essential. Based on 2 randomized, double-blind, Hospital Physician Board Review Manual

9 placebo-controlled trials of acyclovir versus vidarabine (previously the best available treatment), the optimal treatment consists of acyclovir 10 mg/kg IV every 8 hours for 21 days. 30,43 Because of the small but potential risk of a false-negative result on CSF PCR, acyclovir should be continued in cases with strong clinical suspicion, even if PCR results are negative. Patients should receive adequate hydration to minimize crystallization of acyclovir in the urine, which can be nephrotoxic; patients with renal failure require dose adjustment. Measures should be taken to address seizure prevention, respiratory support, and nutrition. Even with prompt diagnosis and proper treatment, the mortality rate for HSV encephalitis remains high at 20% to 30%. 30,43 Similarly, HSV encephalitis is associated with a high morbidity at 6 months, as measured by the ability to return to normal functioning (38% 56% return to normal). 30,43 Long-term residual deficits may include subtle cognitive dysfunction, short-term memory deficits, and behavioral changes such as Kluver-Bucy syndrome. 44,45 In addition, some patients may require life-long AED treatment. FOCAL BRAIN INFECTION CASE 4 PRESENTATION A 41-year-old woman who emigrated from Colombia 20 years ago presents to the neurology clinic for evaluation of sensory symptoms in her left arm for the past 7 to 10 years, which have worsened over the previous several months. The patient describes a sensation of numbness that starts in her left third finger and, over a span of minutes, radiates upward to involve her whole arm. The episodes have become more frequent, occurring every 2 to 3 weeks. She recently began to lose strength in her left hand during these events. The patient also recently had an unwitnessed episode of loss of consciousness while watching television. She awoke feeling tired and confused but did not seek medical attention. She additionally reports continuous, intense headaches, at times accompanied by dizziness and nausea. Review of systems is negative for fever, rash, night sweats, weight loss, or head trauma. There is no family history of migraine or seizures. General medical and neurologic examinations are unremarkable. Noncontrast CT of the head shows a solitary calcification in the right primary sensory cortex, and MRI confirms a solitary T1-hypointense, rimenhancing lesion in the right sensory cortex (Figure 2). Routine EEG and electromyography/nerve conduction A B Figure 1. Herpes simplex encephalitis. (A) Fluid-attenuated inversion recovery magnetic resonance image (MRI) showing right anterior temporal and inferior posterior frontal T2-weighted hyperintensity; (B) gradient echo sequence showing susceptibility artifact within the lesion, indicative of hemorrhage; and (C) T1-weighted postcontrast axial MRI showing patchy leptomeningeal enhancement. studies are unrevealing. Serologic testing for neurocysticercosis (NCC) is negative. What is the differential diagnosis for rim-enhancing mass lesions in the brain? How are causes of solitary brain lesions distinguished? Parenchymal mass lesions with rim enhancement may be caused by infection (pyogenic abscess, tuberculoma, NCC, syphilitic gumma, toxoplasmosis, aspergilloma), neoplasm (primary tumors such as glioma and lymphoma, metastases), or inflammatory demyelination (tumefactive multiple sclerosis, ADEM). 46 Among infectious causes, pyogenic bacteria are the most frequently isolated agent in immunocompetent patients. NCC is the most common cause of cerebral abscess in patients from endemic areas (eg, parts of Latin America, Africa, and South Asia). Toxoplasmosis and aspergilloma are rare in immunocompetent hosts, and syphilitic gummas are rare and usually arise from meningeal involvement. 47 Clinical and radiographic characteristics may suggest the appropriate diagnosis. Tuberculomas may present in C Neurology Volume 12, Part 5

10 A B C D Figure 2. Neurocysticercosis. (A) Noncontrast computed tomography scan and (B) magnetic resonance image (MRI) gradient echo hypointense artifact showing solitary calcified lesion in the right postcentral cortex. MRI with (C) T1 hypointense and (D) T1-weighted postcontrast rim-enhancing lesion in the right postcentral cortex. the setting of prior pulmonary disease, but latent infection should be assessed with a tuberculin test. Patients should be assessed for immunocompromise, including review of medications and HIV serology, as this will broaden the differential. Although history and physical examination can give clues to a diagnosis, neuroimaging is essential for distinguishing brain lesions. CT should be performed with contrast to assess for rim enhancement or other patterns. MRI is more useful than CT for brain abscess and likewise should be done with contrast enhancement. 48 In particular, diffusion-weighted MRI may be useful to distinguish abscesses (which have central restricted diffusion due to increased viscosity) from neoplastic processes. 49,50 Ultimately, without systemic signs of a source, neuroimaging may be unable to distinguish between etiologies, and brain biopsy must be performed for definitive diagnosis. In cases in which biopsy is not possible due to untenable risks, empiric treatment for more than 1 process may be necessary. PYOGENIC BRAIN ABSCESS Solitary pyogenic abscess usually occurs as a result of direct extension from dental, ethmoid, or otic sources, and careful history and examination should be directed toward infections in these sites. 51 Neurosurgical procedures and penetrating head trauma may likewise lead to solitary abscess by direct extension. By contrast, multifocal abscesses typically result from hematogenous spread of systemic infection. 52,53 These metastatic abscesses often form in the distribution of the middle cerebral artery at the junction of gray and white matter. 54 Patients with pyogenic brain abscess may present with headache, neck stiffness, altered mental status, or seizures depending on the size or location of the lesions. 51 Fever occurs in only 50% of patients; focal neurologic deficits are found in 50%, usually days to weeks after onset of systemic symptoms. 55 Patients with headache and focal neurologic signs or seizures should undergo brain imaging with contrast. As previously noted, MRI is more useful for distinguishing brain abscess from other causes of mass lesions. While blood cultures may reveal a pathogen in 15% of cases, lumbar puncture rarely yields a diagnosis and may be dangerous if there is significant mass effect. 52 For both diagnosis and treatment, biopsy and aspiration are often necessary. Infectious causes vary with the source of primary infection. Streptococcus is the most common pathogen in cases of direct spread from dental, sinus, or ear infection. Staphylococcus is more common with neurosurgical or penetrating head wounds. Anaerobic bacterial coinfection is common with all pyogenic abscesses. Prior to isolation of a causative organism, patients with proven or suspected pyogenic abscess should be treated empirically with vancomycin (methicillin-resistant Staphylococcus and Streptococcus), ceftriaxone (Streptococcus and gram-negative bacteria), and metronidazole (anaerobic species). Postsurgical patients should receive ceftazidime in place of ceftriaxone. The prognosis for properly treated pyogenic brain abscess is fair, with a mortality rate varying from 8% to 25% and neurologic sequelae present in 30% of survivors. 51,55,56 NEUROCYSTICERCOSIS NCC is caused by brain infection by larvae of the parasite Taenia solium, or pork tapeworm. NCC is endemic in Latin America, sub-saharan Africa, South Asia, Indonesia, and China; however, due to immigration and travel, NCC may be found throughout the United States. Taenia may infect humans as an adult tapeworm (via ingestion of pork contaminated with cysticerci) or in larval form (via fecal-oral transmission of eggs shed by human carriers of adult tapeworm). Once ingested, eggs reach the gut, enter submucosal blood and lymphatic vessels, and travel to the brain, eyes, muscle, and 10 Hospital Physician Board Review Manual

11 subcutaneous tissue. 57 Cysticerci may lodge throughout the CNS, including brain parenchyma, subarachnoid space, ventricles, or spinal cord. Parenchymal involvement is most common, with the cortex and basal ganglia most frequently affected. 58 How does NCC usually present? How is NCC diagnosed? Although a majority of infections are asymptomatic, NCC is a major cause of morbidity in endemic areas. 59,60 Once lodged in the brain, cysticerci pass through several stages with different clinical and radiographic manifestations. In the vesicular stage, host immune tolerance prevents significant inflammation, and the larvae survive within a fluid-filled cyst (typically 8 10 mm) with a thin surrounding membrane. In the transitional (colloidal or granular-nodular) stage, larvae begin to degenerate, with surrounding parenchymal inflammation. This is the stage with the highest risk of clinical manifestations, most commonly seizure. In the calcific stage, the cysts either involute or are replaced by a calcified nodule, which may serve as a focus for chronic seizures. 57 Thus, clinical manifestations of NCC typically appear 3 to 5 years after infection but can occur as many as 30 years later. Seizures (focal and generalized) constitute the most common and often the only clinical manifestation of NCC. In endemic countries, NCC is the leading cause of adult-onset epilepsy. Patients may also present with severe headaches. If infection involves the ventricles or subarachnoid space, patients may present with symptoms and signs of intracranial hypertension. Physical examination is typically normal, although focal signs related to cortical lesions may be detected. Routine laboratory testing, including serum chemistries, complete blood count, and liver function tests, is typically normal. Most patients with NCC have no viable intestinal organisms, and therefore stool inspection for ova and parasites is usually negative. Diagnosis is often based on results of neuroimaging. On noncontrast CT of the head, viable cysts will be hypodense, whereas calcified lesions will be hyperdense. MRI of viable larvae may reveal the characteristic scolex within the cyst but usually shows no evidence of edema on contrast enhancement. 61,62 T2-weighted or FLAIR MRI will show areas of hyperintensity with rim enhancement in transitional (degrading) lesions and areas of hypointensity within calcified lesions. Gradient echo sequences will reveal susceptibility artifact in calcified lesions. Classically, multiple lesions will be present in the cortex and basal ganglia. In certain populations, including patients in India and immigrants to the United States, patients with NCC often present with solitary lesions, which makes the diagnosis more difficult. 63,64 Noncontrast CT of thigh muscle can sometimes suggest the diagnosis of NCC by demonstrating cystic calcification. 65 Serologic testing for antibodies to T. solium may be useful, particularly in cases with 2 or more lesions. Enzymelinked immunoelectrotransfer blot assay is currently the test of choice for detecting antibodies. 65 Antibodies to T. solium may also be found in CSF, but analysis of CSF is less sensitive than serologic testing. Of note, in patients from endemic areas, the presence of antibody does not necessarily designate active infection. However, a negative result on serologic testing should raise suspicion for an alternative diagnosis unless the clinical presentation and imaging findings are compatible with NCC. However, in patients with solitary lesions, serology is insensitive. 66 Although ocular involvement occurs in a small percentage of patients with NCC, ophthalmologic examination may confirm the diagnosis by identifying parasites in the subretinal space and should be performed prior to initiating treatment for brain lesions to avoid inflammatory damage to the eye if steroids are not given concurrently. In the absence of brain biopsy or extraneural evidence of NCC, definitive diagnosis may be difficult, especially with solitary lesions. Criteria have been expanded for the diagnosis of NCC based on objective clinical, imaging, immunologic, and epidemiologic data. 58 An important point is that spontaneous resolution of a solitary enhancing cortical lesion is a characteristic of NCC but is rare in other infectious or malignant etiologies. CASE 4 CONTINUED Given the patient s country of origin and the consistent and stable radiographic finding, she is diagnosed with possible NCC with a solitary calcified lesion. She is started on gabapentin 300 mg at night, and her symptoms gradually improve. For 3 years, the patient has no significant symptoms. During a trip back to Colombia, she again develops headaches and an almost constant pain in the left hand and arm extending to the axilla. Repeat MRI reveals a new small, enhancing lesion in the left centrum semiovale with minimal surrounding edema (Figure 3). Repeat EEG is normal. What is the optimal treatment for NCC? Treatment of NCC consists of antihelminthic medications, AEDs, corticosteroids, and, rarely, neurosurgery. The treatment regimen depends on the location, severity, and chronicity of infection. For single calcified lesions detected incidentally, no treatment is necessary. 67,68 Controversy continues for other treatment indications, Neurology Volume 12, Part 5 11

12 A Figure 3. Neurocysticercosis. (A) T1-weighted postcontrast magnetic resonance images demonstrating a small enhancing lesion in the left centrum semiovale with surrounding hyperintensity on fluid-attenuated inversion recovery (B). primarily over the benefits versus dangers of antihelminthic treatment in patients with multiple cysts. Based on a randomized controlled trial and a meta-analysis, cysticidal medications (ie, albendazole, praziquantel) appear to be beneficial in reducing enhancing lesions and in reducing the frequency of generalized seizures in patients with viable cysticerci. 69,70 Because it has better CNS penetration and more effective cyst destruction and does not interact with AEDs, albendazole is the preferred agent at a usual dose of 10 mg/kg divided twice daily for 15 days. 71 Due to the risk of worsening inflammation as cysts rapidly degenerate, corticosteroids should be given concomitantly with cysticidal medication. For patients with more than 50 cysts or with subarachnoid or ventricular involvement, antihelminthic medication may be contraindicated due to the profound inflammation that can result. These patients should be treated for increased intracranial pressure or edema prior to initiation of antihelminthics. AEDs are often continued for 1 year and then tapered as tolerated. For patients with single lesions, the prognosis for seizure-free survival is excellent. 72 In general, patients with resolving parenchymal lesions have a good prognosis for recovery free of seizures. 73 CASE 4 CONCLUSION Repeat NCC serology is positive. Because the patient s MRI shows a likely degenerating cyst, no cysticidal treatment is given. She is changed from gabapentin to levetiracetam 500 mg twice daily with resolution of her symptoms. INFECTIOUS MYELITIS CASE 5 PRESENTATION B A 29-year-old man from central Brazil with no past medical history presents to the ED in late November with lower extremity weakness and numbness. He was in his usual state of good health until early November, when he developed lower back pain. Over a few days, the pain became more severe, and he developed numbness on the sole of his right foot, which spread up his right leg; a similar pattern then began in his left foot. He also has weakness in both feet and his lower legs, as well as a clumsy gait. In addition, he reports a recent onset of urinary retention. Further history reveals that the patient immigrated to the United States almost 7 years ago and has not returned to Brazil. Family history reveals that his mother had spinal schistosomiasis. On examination, the patient has mild weakness in his distal lower extremities; absent reflexes in the patella and ankle bilaterally; and decreased sensation in all modalities, but more so in the right than the left lower extremity and in the perianal region, with allodynia to light touch over the same areas. What is the differential for cauda equina syndrome? Cauda equina syndrome consists of low back pain, saddle anesthesia, bowel and/or bladder dysfunction, and lower extremity weakness and sensory loss. It is caused by damage to the lower lumbar and sacral nerve roots and is often associated with and may be hard to distinguish from conus medullaris syndrome, in which the lower spinal cord is primarily affected. In the case patient, the loss of reflexes in the lower extremities and the lack of sensory dissociation (pain and temperature versus proprioception and vibration) suggest cauda equina syndrome. Cauda equina syndrome is most commonly due to trauma, disk herniation, infection, or malignancy. Less common etiologies include tethered cord, sarcoidosis, or dural arteriovenous fistula. In cases of subacute onset, infection and malignancy are most likely. Infectious causes of myelopathy and polyradiculopathy include bacterial abscess, tuberculosis, HSV-2 (Elsberg syndrome), cytomegalovirus (CMV; polyradiculitis), meningovascular syphilis, human T-lymphotropic virus-1 (HTLV-1), Lyme disease, and schistosomiasis. Clinical and demographic information can sometimes clue to the etiology. Pyogenic epidural abscesses are more common in the thoracic region but can occur anywhere along the spinal cord. Pain is often early and prominent, and fever occurs in a minority of patients. Tuberculosis may cause a spinal meningoradiculitis, usually in the setting of basal brain meningitis. The thoracic region of the spine is most commonly affected. HSV-2 may reactivate from dorsal root ganglia to cause a radiculomyelopathy in patients with prior genital lesions. CMV may cause a lumbosacral polyradiculitis, typically in severely immunocompromised hosts. Meningovascular 12 Hospital Physician Board Review Manual

13 syphilis may affect the spinal cord, and patients present with sudden onset of bowel or bladder dysfunction, weakness, and/or sensory disturbance. HTLV-1 causes tropical spastic paraparesis and is transmitted through sexual contact, blood transfusion, or sharing of needles for IV drug use or from mother to child. HTLV-1 associated myelopathy usually progresses slowly but steadily over 1 to 2 years and then stabilizes. Lyme disease may affect the spinal nerve roots in early disseminated disease, often in association with a meningitis or cranial neuritis. Patients often present with pain and motor and sensory changes in a radicular pattern during the late summer and early fall in endemic areas. SPINAL EPIDURAL ABSCESS Spinal epidural abscess is a rare but important cause of myelopathy, with an incidence of 1 case per 100,000 person-years in the normal population and up to 20 cases per 100,000 person-years in hospitalized patients. 74,75 Because the dura is not adherent to bone in the posterior and lateral aspects of the spinal canal, pyogenic spinal epidural abscess is much more common than intracranial epidural infection. The thoracic and lumbar regions are most often affected, usually over a span of 3 to 5 segments. 76,77 Infection typically reaches the epidural space by direct extension from the skin or vertebral disk or body; spinal procedures or prolonged indwelling catheters for pain control increase the risk. Hematogenous seeding also occurs, particularly in the setting of IV drug use. Most patients with spinal epidural abscess have predisposing risk factors, including diabetes, alcoholism, HIV infection, local or systemic infection, trauma, tattoos, acupuncture, and local spinal injections. 74,78 The most common pathogen is Staphylococcus aureus, which causes about two thirds of cases. 76,77,79 Patients classically present with fever, spinal pain, and neurologic symptoms and signs, but they rarely exhibit all 3 features simultaneously. 80 Back pain is usually followed by myelopathy, which may progress rapidly. Although epidural abscess is a rare cause of back pain, the diagnosis should be considered in patients with fever, risk factors, or progressive neurologic deficits. Laboratory evaluation usually reveals an elevated erythrocyte sedimentation rate. 80,81 MRI is the diagnostic modality of choice, due to its high sensitivity early in the course and its ability to distinguish other causes of back pain and myelopathy. 82 While blood cultures will reveal a pathogen in up to 62% of cases, aspiration and drainage is the preferred diagnostic and treatment option. Lumbar puncture rarely yields a diagnosis. 77 Empiric antibiotic regimens should include vancomycin 1 g every 12 hours (to cover Staphylococcus, including methicillin-resistant strains), ceftazidime 2 g every 12 hours (to cover gram-negative rods), and metronidazole 500 mg every 6 hours (to cover anaerobes). Once a microbe is isolated, antibiotics should be tailored accordingly; treatment is typically for at least 6 weeks. 78 Early treatment with surgical drainage and appropriate antibiotics is crucial, as paralysis is often irreversible. 74,77 SCHISTOSOMIASIS Schistosomiasis is caused by parasitic blood flukes and is estimated to affect more than 200 million people worldwide. 83 Among the major species, Schistosoma mansoni is endemic to South America, the Caribbean, sub-saharan Africa, and the Middle East; S. japonicum is isolated to Asia; and S. haematobium is prevalent in Africa and the Arabian peninsula. 84 The parasites are acquired by exposure to fresh water (eg, swimming), so travelers to endemic areas may also be affected Cercarial larvae penetrate the skin and, after becoming schistosomulae, migrate into blood vessels and then into arterial circulation, eventually reaching the liver, where they mature into adults over several weeks. Each species has a tropism within the human host: S. mansoni goes to colonic mesenteric venules, S. japonicum to small intestine mesenteric venules, and S. haematobium to the venous plexus of the bladder. 84,87,88 The worms survive several years, with the female worms releasing eggs, which can travel to other sites and are eventually secreted in urine and feces. Clinical disease occurs when the eggs generate an immune response in the tissues where they have migrated, which can occur over many years. 89,90 As the symptoms are related to high parasite load, patients from endemic areas tend to have more clinical manifestations as compared with travelers. The peak age of disease burden is 15 to 20 years. 88,91 What are the neurologic complications of schistosomiasis? Serious neurologic complications can develop in patients with schistosomiasis, even in those with mild infection. There are 2 main clinical syndromes: spinal schistosomiasis, more commonly associated with S. mansoni and S. haematobium, and localized cerebral or cerebellar schistosomiasis, frequently associated with S. japonicum. Infection of the spinal cord by S. mansoni and S. haematobium can lead to transverse myelitis. Patients with spinal schistosomiasis present with acute to subacute lower extremity pain, weakness, and bowel and bladder dysfunction. The incubation time from infection to neurologic symptoms is variable, with estimates ranging from a few months to several years. 92 In cerebellar schistosomiasis, infection can lead to increased intracranial pressure and Neurology Volume 12, Part 5 13

14 A C Figure 4. Spinal schistosomiasis. (A) Sagittal T2-weighted magnetic resonance image (MRI) showing intramedullary signal change in the conus and lower thoracic cord. (B) Sagittal MRI and (C) axial T1- weighted postcontrast MRI showing patchy, asymmetric enhancement in the conus. subsequent development of focal neurologic symptoms and seizures. In addition to these neurologic complications, many other organs can be affected, including the 84, 88 intestines, liver, bladder, and lungs. CASE 5 CONTINUED T2-weighted MRI of the spine reveals hyperintensity and expansion in the spinal cord extending from the conus superiorly to the T9 level, with enhancement of the inferior spinal cord, conus medullaris, and cauda equina nerve roots (Figure 4). The patient undergoes a lumbar puncture, and CSF analysis reveals a glucose level of 59 mg/dl, protein level of 114 mg/dl, and WBC count of 28 cells/μl (1% polymorphonuclear cells, 94% lymphocytes, 4% monocytes, 1% eosinophils). CSF PCR is negative for VZV, CMV, Epstein-Barr virus, HSV, enterovirus, and antibodies to Borrelia and Mycoplasma. Acid-fast bacterial smear, mycobacterial culture, and VDRL are also negative. Serologic testing for B antischistosomal antibiotics is performed at an outside laboratory, with results pending. Serum HIV serology is negative. A tuberculin test is positive but chest radiograph is normal. During admission, the patient develops sensory gait ataxia. How is spinal schistosomiasis diagnosed and treated? Spinal schistosomiasis causes transverse myelitis and a granulomatous inflammation of the conus medullaris and cauda equina. Thus, MRI will characteristically show T2 hyperintensity and enlargement within the thoracolumbar cord, with patchy nodular enhancement of the conus and cauda equina. 87,90,93,94 Routine laboratory testing is often nonspecific. Peripheral eosinophilia may be present early in the infection but is often not present at the time of neurologic presentation. 95 Indirect evidence of schistosomiasis may be found with abnormal liver function tests (mildly elevated alkaline phosphatase and γ-glutamyl transferase) or hematuria. Likewise, ultrasonography of the liver or bladder may reveal abnormalities. 96 Examination of urine and stool samples may reveal ova, but the sensitivity depends on the severity of infection. Serologic tests for antibodies to Schistosoma species are relatively sensitive and specific but are not standardized. 97,98 However, serologic tests cannot distinguish between active and prior infection. As results of serologic tests take several weeks, treatment should not be withheld in patients with typical MRI findings and endemic exposure. Based on this patient s emigration from an endemic area and characteristic MRI findings, a presumptive diagnosis of spinal schistosomiasis should be given. All patients with schistosomiasis should undergo treatment with praziquantel 40 mg/kg in one or divided doses. 99,100 Corticosteroids should be given in conjunction with treatment to prevent worsening inflammation from parasite lysis as well as address the underlying granulomatous inflammatory mechanism of spinal cord disease. 101 The duration of steroid treatment is not well established, but at least several weeks of treatment is recommended. 102,103 As MRI does not always correlate with clinical response to treatment, the decision to continue steroids is based on clinical status. Most patients improve significantly, especially if treatment is initiated within 30 days of symptom onset. 103 CASE 5 CONCLUSION Prior to initiating treatment for suspected spinal schistosomiasis, the patient undergoes an ophthalmologic examination to exclude ocular involvement. He is started on dexamethasone 6 mg twice daily and receives praziquantel 1500 mg twice daily for 1 day. Due to 14 Hospital Physician Board Review Manual