infectiousmyelopathies - l.s. neurology diseases/infectious...myelopathy. vacuolar myelopathy is...

InfectiousMyelopathiesTracey A. Cho, MD; Henrikas Vaitkevicius, MD, MS

ABSTRACTPurpose of Review: Infections and secondary inflammatory changes play an im-portant role in spine pathology leading to myelopathy or myelitis. To achieve optimalclinical outcomes and accurate prognosis, physicians must promptly recognize thesedisorders. This review provides a contemporary overview of the major pathogensknown to cause myelopathic symptoms and focuses on unique clinical syndromesand signs to aid the differential diagnosis and further workup. This article will helpneurologists to consider infectious etiologies during the initial evaluation of patientswith myelopathic symptoms.Recent Findings: The spectrum of neurologic infectious diseases is ever evolvingbecause of immigration and travel, aggressive antibiotic use, vaccinations, andeffective antiretroviral therapies. One example of this is illustrated by the enter-oviruses. Poliovirus is an enterovirus that causes an acute flaccid paralysis but can beprevented by vaccination. A different enterovirus, enterovirus 71, is increasinglyreported as the etiologic agent of acute flaccid paralysis similar in presentation topoliomyelitis. This review recognizes the shifting spectrum of infections in immuno-compromised hosts, including patients with HIV in the era of effective antiretroviraltherapy. It outlines unique features of primary HIV complications as well as closelyassociated infections, such as tuberculosis, syphilis, and varicella-zoster virus. Finally,each section of this article outlines molecular and immunologic tools that arebecoming paramount for effective and rapid diagnosis of the pathogens.Summary: This article offers a basic review and definitions pertinent to myelopathicprocesses. Parainfectious, viral, bacterial, parasitic, and fungal infections are discussed.Each section offers clinical descriptions, pathophysiologic mechanisms, diagnosticstrategies, and an approach to treatment and prognosis. Clinical vignettes describeclinical presentations and imaging findings of prototype disorders leading tomyelopathy.

Continuum Lifelong Learning Neurol 2012;18(6):1351–1373.

INTRODUCTIONInfections are an important cause ofspinal cord dysfunction. In addition todirect neuronal invasion, many infec-tions have a predilection for stimulatingan inappropriate immune attack on thespinal cord. The clinical signs andsymptoms of spinal cord dysfunctionare caused by perturbation of afferentsensory nerves and efferent motor orautonomic pathways. Spinal cord dys-function of any etiologyVwhether focalor diffuse, because of intrinsic or extrin-sic pathologiesVis referred to as myel-opathy. Myelitis denotes the presence

of inflammation, and acute transversemyelitis is a more specific term refer-ring to an acute inflammatory processcausing a functional transection of thecord with motor and sensory dysfunc-tion below the level of the lesion. Someinfections preferentially involve anteriorhorn cells or motor roots, leading to asyndrome of acute flaccid paralysis.

History and physical examination ofthe patient with myelopathy are usedto localize the lesion to the root or specificlevel of the cord, which can guide imag-ing. The tempo of the illness, exposurehistory, and host immune status help to

Address correspondence toDr Tracey Cho, MGHNeurology, 55 Fruit St,Boston, MA 02114,[email protected].

Relationship Disclosure:Dr Cho serves as a neurologyconsultant and on a clinicalreview committee forOptumInsight/UnitedHealthGroup for a postmarketingsafety study. Dr Cho hasserved as a guest editor forSeminars in Neurology.Dr Vaitkevicius reportsno disclosure.

Unlabeled Use of Products/Investigational UseDisclosure: Drs Cho andVaitkevicius discuss theunlabeled, anecdotal useof IV immunoglobulin,cyclophosphamide, rituximab,and corticosteroids aspotential adjunct treatmentsfor infectious myelopathies.

* 2012, American Academyof Neurology.

1351Continuum Lifelong Learning Neurol 2012;18(6):1351–1373 www.aan.com/continuum

Review Article

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

narrow the differential diagnosis. Patientdemographic information is crucial forevaluating the risks for endemic infec-tions (Table 6-1). CSF is useful todifferentiate among viral, bacterial, par-asitic, fungal, or autoimmune etiolo-gies of the disease (Table 6-2). Timelyrecognition and diagnosis of infec-tious spinal cord disorders is critical forspecific treatment and prognosis. This re-view provides a general overview of theinfectious agents that cause prominentmyelopathic symptoms and includes

epidemiologic and clinical characteris-tics unique to each infectious agent.

PARAINFECTIOUS CAUSESAcute transverse myelitis is an inflamma-tory process resulting in demyelinationand neuronal injury with functionaltransection of the spinal cord. The gen-eral diagnostic approach to acute trans-versemyelitis is reviewed elsewhere.1 Asmany as 30% to 60% of cases of acutetransverse myelitis are preceded by a sys-temic infectious process or vaccination

KEY POINT

h Myelopathy refers tospinal cord dysfunction,and myelitis refers toinflammatory spinalcord dysfunction.

TABLE 6-1 Geographic Distribution of Select Infectious MyelopathyPathogens

Pathogen Endemic Region

Viruses

Human T-cell lymphotropicvirus

Japan, sub-Saharan Africa, Middle East, Caribbeanislands, and Central and South America

Poliovirus Sub-Saharan Africa, Middle East, andIndian subcontinent

Japanese encephalitis virus China, and South and Southeast Asia

Tick-borne encephalitis Europe, Russia, and China

Bacteria

Borrelia burgdorferiBannwarthmeningoradiculitis

Northern hemisphere: central Europe, UnitedStates (New England, Atlantic coast, northernMidwest, and Pacific Northwest)

Parasites

Gnathostoma spinigerum Southeast Asia (Cambodia, Laos, Myanmar,Indonesia, Philippines, and Malaysia)

Echinococcus granulosum(Hydatid)

Middle East, South America, New Zealand,and the Mediterranean coast

Taenia solium Central and South America, sub-SaharanAfrica, and South and Southeast Asia

Schistosoma mansoni Central and South America

S. mansoni andhaematobium

Sub-Saharan Africa

Fungi

Blastomyces dermatitidis Southern, Midwestern, and EasternUnited States

Coccidioides immitis Southwestern United States, Mexico,and Central and South America

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Infectious Myelopathies


and are referred to as parainfectiousacute transverse myelitis. The mecha-nism of parainfectious demyelination islikely due to activation of specific arms ofthe immune system through molecularmimicry, leading to generation of anti-bodies against pathogen proteins thatcross-react with host antigens presentwithin the spinal cord. Countless sys-temic infections have been implicatedin causing acute transversemyelitis.My-elopathy usually develops 2 to 4 weeksafter systemic infection or vaccination.The CSF profile in these disorders isvariable but usually reveals an elevationin protein concentration and pleocyto-sis with lymphocytic predominance.Oligoclonal bands may be present, andIgG index may be elevated. Diagnosisis usually confirmed by the presence ofpathogen-specific serology or antigensin CSF or serum (Case 6-1). Corticoste-roids are the mainstay of treatment. Re-fractory cases can be treated with IVimmunoglobulin (IVIg), cyclophospha-mide, or rituximab, but no controlledtrials have been done.

VIRAL CAUSESViral infection may cause a parainfec-tious neurologic injury or invade the

CNS and cause myelitis (Table 6-3). Afew virusesVvaricella-zoster virus (VZV),herpes simplex virus (HSV), rabies, andpolioVare capable of productive in-fection of neurons. Retroviruses (HIVand human T-cell lymphotropic virus)tend to cause subacute to chronic my-elitis. Herpes family viruses (HSV, VZV,cytomegalovirus [CMV], Epstein-Barrvirus [EBV]) and coxsackieviruses tendto cause white matter inflammation(transverse myelitis), while other enter-oviruses (poliovirus, enterovirus 71[EV71]) and flaviviruses (West Nilevirus, Japanese encephalitis virus, andtick-borne encephalitis virus) target an-terior horn cells (acute flaccid paralysis)(Table 6-4).

RetrovirusesHIV affects more than 34 million peopleworldwide and 1.2 million people in theUnited States. The virus gains access tothe CNS early during the illness byinfecting lymphocytes and microglia,which migrate across the blood-brainbarrier. HIV has not been found inneurons, but rather causes neuronalinsult through the toxicity of viral pro-teins and the chronic proinflammatorystate induced by local viral replication.2

KEY POINT

h Acute transversemyelitis is a focalfunctional transectionof the cord usuallycaused byparainfectiousdemyelination.

TABLE 6-2 Typical CSF Patterns in Infectious Myelopathy

Protein(mg/dL)

Glucose(mg/dL)

Nucleated Cells (cells/2L)[cell predominance]

Normal 15Y45 45Y85 G5

Pyogenic abscessa Increased Decreased Increased [neutrophilic]

Tuberculosis Increased Decreased Increased [lymphocytic]

Viral Increased Normal Increased [lymphocytic]b

Fungal Increased Decreased Increased [lymphocytic]C

Parasitic Increased Normal Increased [eosinophilic]

Parainfectious Increased Normal G500 [lymphocytic]a Lumbar puncture is not recommended in patients with epidural abscess as it has low yield andsignificant risks of introducing bacteria into CSF.

b West Nile virus and cytomegalovirus may cause neutrophilic pleocytosis.c Blastomyces and Aspergillus may cause neutrophilic pleocytosis.



Case 6-1A 19-year-old female college student developed 5 days of fevers, headache, nausea, andvomiting. She was brought to the emergency department after two episodes of syncopewith postural changes. She was found to have nuchal rigidity. CT of the brain wasunremarkable, and CSF demonstrated normal glucose concentration, elevated proteinconcentration (137 mg/dL), and pleocytosis (327 cells/2L) with lymphocytic predominance. Viralmeningitis was suspected, and supportive care was provided. Ten days after the onset ofsymptoms the patient developed urinary retention; multidirectional nystagmus was noted,followed shortly by right-sided numbness and diffuse weakness culminating in profoundencephalopathy. Neurologic examination within hours was significant for ocular bobbing andsevere flaccid quadriparesis. Mental status and weakness continued to worsen, and mechanicalventilation was required. MRI of the brain and spinal cord revealed diffuse expansion andintrinsic T2 signal hyperintensity of the spinal cord from the cervicomedullary junction to theconus (Figure 6-1). Serum studies were significant for IgM and IgG antibodies againstmycoplasma. CSF studies for infectious organisms, including mycoplasma antibodies and PCR,were negative. The patient was treated with azithromycin, levofloxacin, and high-dosecorticosteroids and ultimately received a course of IVIg. Later testing revealed an increase inmycoplasma IgG antibodies in convalescent serum. Despite initial lack of improvement, afterintense rehabilitation she recovered well enough to walk independently and return to school.

FIGURE 6-1 Mycoplasma-associated encephalomyelitis. Sagittal and axial T2-weighted MRI of cervicaland upper thoracic spinal cord demonstrate diffuse T2 signal changes (arrows)throughout the length of the cord focused predominantly around the central and ventralportions of the spinal cord. Diffuse cord edema is also seen.

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Early HIV infection has been asso-ciated with immune-mediated syn-dromes through immune dysregulation

even before the development of immu-nodeficiency. Like other viruses, it maycause an acute transverse myelitis

Comment. This case outlines some key features of parainfectious acute transversemyelitis. The syndrome begins with nonspecific infectious symptoms, including fever. Beforethe onset ofmyelopathic symptoms, the patient had an aseptic meningitis. The combination ofautonomic dysfunction, sensory dysfunction, and bilateral weakness suggests a functionaltransverse spinal cord lesion. The eye movement abnormalities and encephalopathy furthersuggest brain involvement, which is not unusual in parainfectious myelitis (technically, thiswould be considered acute disseminated encephalomyelitis). The lack of positive CSFmicrobiology studies is common. When available, specific antimicrobial treatments directedat identified infections should be instituted, along with corticosteroids, to reduce the durationof symptoms.

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TABLE 6-3 Classification and Features of Viral Causes of Myelopathy

Virus Genus/Family Features Target Cells Toxicity

HIV Lentivirus/Retroviridae

Enveloped,single-stranded(ss) RNA(+)

Lymphocytes,microglia,astrocytes

Parainflammatory,envelope glycoproteingp120, tat protein

Human T-celllymphotropic virus

Deltaretrovirus/Retroviridae

Enveloped,ssRNA(+)

Lymphocytes Parainflammatory, taxprotein, heterogeneousnuclear ribonucleoproteinA1

Polio

Coxsackieviruses

Echoviruses

Enterovirus 71

Enterovirus/Picornaviridae

Nonenveloped,ssRNA(+)

Neurons,astrocytes,glia

Translational inhibition

West Nile virus

Dengue

Yellow fever

Tick-borne encephalitis

Flavivirus/Flaviviridae

Enveloped,ssRNA(+)

Neurons,astrocytes

Parainflammatory,translational inhibition

Rabies Lyssavirus/Rhabdoviridae

Enveloped,ssRNA(-)

Neurons Translational toxicity,immune stimulating

Herpesvirus types 1and 2

Simplexvirus/Herpesviridae

Enveloped,double-stranded(ds) DNA

Neurons Parainflammatory

Varicella-zoster virus(Human herpesvirus[HHV] 3)

Varicellovirus/Herpesviridae

Enveloped,dsDNA

Neurons Vasculitis

Epstein-Barr virus(HHV-4)

Lymphocryptovirus/Herpesviridae

Enveloped,dsDNA

Lymphocytes Parainflammatory

Cytomegalovirus(HHV-5)

Cytomegalovirus/Herpesviridae

Enveloped,dsDNA

Monocytes,lymphocytes

Parainflammatory



responsive to steroids and combinationantiretroviral therapy during this stageof infection.3 As cellular immunitywanes below 200 CD4 cells/2L, patientsmay develop HIV-associated vacuolarmyelopathy. Vacuolar myelopathy ispathologically present in 20% to 50%of patients with AIDS, but only 10% to20% have clinical symptoms.

Patients with vacuolar myelopathypresent with a slowly progressive andtypically painlessmyelopathy, with lower-extremity weakness, gait difficulties,spasticity, mild paresthesia, and erectiledysfunction. Urinary urgency and incon-tinence are common later in the course.Examination reveals decreased vibrationsense and proprioception, hyperreflexia,and increased muscle tone. The lower-extremities are disproportionately af-

fected. Vacuolar myelopathy frequentlyco-occurs with HIV-related encephalop-athy and polyneuropathy, the latterof which may mitigate hyperreflexia.Vacuolar myelopathy is a diagnosis ofexclusion in patients who are HIV-positive and should be questioned ifthe presentation is acute, a spinal level orprominent pain is present, the upperextremities are prominently involved, orCSF is significantly inflammatory (whiteblood cell count greater than 20 cells/2L).Vacuolar myelopathy must be distin-guished from opportunistic infection,neoplasm, and cobalamin deficiency.

Imaging is frequently normal, but spi-nal cord atrophy and findings similar tosubacute combined degeneration havebeen reported. The pathologic changesalso resemble subacute combined degen-eration, with predominant involvementof the lateral and posterior thoracic cord.Microscopic findings include spongy vac-uolation ofmyelinwith lipid-ladenmacro-phages.4 The pathogenesis is unknown,and despite its similar pathologic features,vacuolar myelopathy does not respondto B12 supplementations or to combina-tion antiretroviral therapy, IVIg, or cor-ticosteroids. However, the incidence ofvacuolar myelopathy has decreased sig-nificantly since the introduction of ef-fective antiretroviral therapy.

Human T-cell lymphotropic virus(HTLV), another retrovirus, is the patho-logic agent of adult T-cell leukemia andHTLV-I associated myelopathy (HAM),also known as tropical spastic paraparesis(TSP).5 Approximately 20 million peopleare infected with HTLV-I, but only 4%will develop HAM/TSP. The virus istransmitted through exposure to bodyfluids.6 HTLV-I has a strong female pre-dominance, likely due to a highertransmission in male to female sexualencounters. The virus is endemic to Japan,sub-Saharan Africa, the Middle East,the Caribbean islands, and Central andSouth America.6

KEY POINTS

h Acute HIV may causeacute transverse myelitis.

h Chronic HIV causesvacuolar myelopathy.

h HIV vacuolarmyelopathy must bedistinguished fromopportunistic infection,neoplasm, andcobalamin deficiency.

TABLE 6-4 Viral Pathogensand CharacteristicMyelopathySyndromes

b Acute Flaccid ParalysisPicornavirusesPoliovirusCoxsackievirus A and BEchovirusesEnterovirus 71

FlavivirusesWest Nile virusJapanese encephalitis virusTick-borne encephalitis virus

RhabdovirusRabiesvirus

b Chronic Spastic ParalysisRetrovirusesHIVHuman T-cell lymphotropicvirus

b Mixed Transverse Myelitis+/– RadiculitisHerpesvirusesHerpes simplex virusVaricella-zoster virusCytomegalovirusEpstein-Barr virus




The pathophysiology of HAM/TSPis poorly understood. Some evidencesuggests virus-induced CD8+ T-cell me-diated neurotoxicity or inappropriateCNS immune attack through molecularmimicry.7 HAM/TSP has also been de-scribed as a two-phase disease consist-ing of an acute inflammatory phase anda chronic neurodegenerative phase.Pathologic examination reveals chronicinflammation, perivascular infiltrationwith macrophages, gliosis, and longtract degeneration.8

Most patients who develop HAM/TSPbecome symptomatic within 2 years ofthe infection, with an insidious onsetand slow progression of spastic lower-extremity weakness, prominent blad-der dysfunction (frequency and urgency,as well as retention), and constipation.Patients also report back pain and limbparesthesia. On physical examination,patients are typically spastic in the lowerextremities but have hyperactive reflexesthroughout, despite lack of significantweakness in the upper extremities.

Diagnosis is based on the appropriatedemographic and clinical scenario, withsupportive serologic studies. Peripheralatypical lymphocytes are characteristic.CSF usually demonstrates a mild lym-phocytic pleocytosis with slightly elevatedprotein concentration and presence ofoligoclonal bands. An ELISA is used forscreening, with confirmation byWesternblot. In addition, PCR in peripheralblood mononuclear cells allows for dis-tinction between HTLV-I and -II, as wellas quantification of proviral load forprognostic purposes. Early in the diseasecourse, imaging demonstrates focal T2prolongation predominantly in the lowercervical cord, occasionally with contrastenhancement, similar to lesions seen inmultiple sclerosis. The most commonMRI finding is cervical and thoracic cordatrophy. More than 50% of patients alsohave small intracranial white matter T2changes; in contrast tomultiple sclerosis,

however, periventricular and juxtacorti-cal regions are usually spared.9

HAM/TSP responds poorly to treat-ment, with no effective clinical trials todate. Based on the presumed patho-physiology and some similarities tomultiple sclerosis, most patients receivesteroids. Limited evidence suggests thatinterferon alpha, cyclosporine, or aza-thioprine may be effective, particularly inthe early phase of the disease. Somepatients have received antiretroviral ther-apy, with incomplete and temporaryeffectiveness. In the United States, infor-mation on clinical trials for HAM/TSPmay be found at http://clinicaltrials.gov/.

EnterovirusesEnteroviruses are ubiquitous RNAviruses in the Picornaviridae family. Theyare easily transmitted by direct contactbecause they reproduce in the upperrespiratory and gastrointestinal tracts.Most infections are asymptomatic, butthey can cause herpangina, pericarditis,myocarditis, conjunctivitis, and hand,foot, and mouth disease. Enterovirusesare themost common cause of viral men-ingitis but occasionally affect the brainor spinal cord parenchyma, character-istically as an acute flaccid paralysis.

Poliovirus is an enterovirus that causesacute flaccid paralysis through infectionof anterior horn cells. While largely erad-icated in developed countries throughvaccine campaigns, poliovirus is stillpresent in parts of sub-Saharan Africa,the Middle East, and the Indian subcon-tinent. Patients present with high fevers,meningismus, and muscle spasms fol-lowed by asymmetric, proximal morethan distal, flaccid paralysis evolvingover 48 hours. The lower extremitiestend to be involved more often, but abulbar form of the disease has also beendescribed. Older patients are morelikely to develop paralysis.

Postpolio syndrome has been de-scribed in patients with a remote history

KEY POINTS

h Human T-celllymphotropic viruscauses insidious spasticlower limb paresis.

h Enterovirusescharacteristicallymanifest in the spinalcord as acute flaccidparalysis.



http://clinicaltrials.gov/

of poliomyelitis whopresentwith a slowlyprogressive recrudescence of prior poliosymptoms. The pathophysiology of thissyndrome is highly debated and poorlyunderstood, with theories ranging fromdegeneration of large motor units toorthopedic alterations over time. Themost consistent risk factor is severityof initial disease. It remains unclearwhether postpolio syndrome is a uniqueentity or a consequence of aging in aneurologically and orthopedically im-paired individual.10

Nonpolio enteroviruses have sur-passed poliovirus as causes of infectiousflaccid paralysis throughout the worldin the postvaccine era. A recent reviewfrom India implicated group B cox-sackie viruses and echovirus 11 and 12as the most frequent strains isolatedfrom children with flaccid paralysis. Asurge of these infections occurs in latesummer and early fall, predominantlyaffecting children.11

Enterovirus 71 (EV71) is an emerg-ing pathogen in this family. It is asso-ciated with hand, foot, and mouthdisease, but it may also cause a severebrainstem encephalitis and flaccid para-lysis similar in presentation to polio-myelitis. Epidemics have been reportedthroughout the world, with the largestoutbreaks in the Asia-Pacific region.12

It is a highly contagious disease morecommon in children and presentingwith a characteristic mucocutaneousrash and fever. Neurologic symptomsusually develop rapidly 3 to 5 days afterthe onset of systemic disease. MRIcharacteristically reveals T2 hyperin-tense signal in the lower brainstemand deep cerebellar nuclei. Examplesof unilateral T2 changes over the an-terior cord as well as ventral rootenhancement have been published.13

CSF usually demonstrates a mild lym-phocytic pleocytosis (10 cells/2L to100 cells/2L). Fever exceeding 38.5-C(101.3-F) or lasting more than 3 days

is a risk factor for development of neu-rologic symptoms. No effective specifictreatment has been established forenteroviral myelitis, but IVIg has beenused with variable results. The antiviralmedication pleconaril, which has in vitroactivity against several enteroviruses, hasshown only modest effect against EV71and is not available for clinical use.14

FlavivirusesFlavivirus is a genus of RNA viruses thatincludes West Nile virus (WNV), denguevirus, yellow fever virus, Japanese ence-phalitis virus, tick-borne encephalitisvirus, and others.15 Most of these vi-ruses can cause encephalitis, but WNVin particular is associated with a flaccidpoliomyelitislike syndrome and iswidely distributed in the United States.Transmitted by a mosquito vector, WNVhas been reported in over 20,000 casessince the first documented case in theUnited States in 1999. Symptoms ofencephalitis are present in few (lessthan 1%) patients, and among thesefewer than 10% present with flaccidparalysis. However, WNV acute flaccidparalysis carries a mortality in the rangeof 50%.16 Patients present with feverand a nonpruritic generalized maculo-papular rash (19% to 50%). Myelitis de-velops over a period of 2 to 8 days andmay be unaccompanied by fever. Flac-cid paralysis is usually asymmetric andfrequently impairs respiratory and blad-der function. Examination may be com-plicated by encephalopathy but usuallydemonstrates hyporeflexia. The clinicalsyndrome and pathology are similar topoliomyelitis.17 Immunosuppression andage older than 50 years are associatedwith an increased risk for neurologicsymptoms in WNV-infected individuals,although WNV myelitis tends to occurat younger ages than encephalitis. Inaddition to stimulation of an inflamma-tory process, WNV directly infects neu-rons in the anterior horn, which

KEY POINTS

h Enterovirus 71 and WestNile virus may causea poliomyelitislikesyndrome.

h West Nile virus maypresent with generalizedmaculopapular rashand may causeincontinence.




undergo necrosis and/or apoptosis. Inaddition to neuronal loss, pathologicexamination demonstrates glial nodulesand perivascular cuffing with mononu-clear cells. Patients frequently presentwith peripheral leukocytosis, thrombo-cytopenia, and mild elevations of liverenzymes and lipase. WNV is one of thefew viruses that may provoke a poly-morphonuclear or mononuclear pleo-cytosis (mean 200 cells/2L), as well aselevated protein and normal glucoseconcentrations. Viral levels are low inCSF, so diagnosis is usually made byserologic testing. CSF IgM, the mostsensitive and specific test, may persistfor 6 months. Spinal cord imaging istypically normal. Surprisingly, the se-verity of initial illness does not corre-late well with outcome, suggesting thatedema or reversible inflammation mayplay a role in the symptoms. Treatmentis supportive. Despite evidence from invitro and animal models for the effec-tiveness of ribavirin, interferon alpha,and IVIg (containing high titers of WNVantibody), these therapies have notbeen shown to be beneficial in humanstudies. Anecdotal reports of their use,along with corticosteroids, are availablewith varying results.16

Japanese encephalitis virus, a closelyrelated flavivirus to WNV, is an impor-tant cause of epidemic viral encephalitisin Asia (China, and South and SoutheastAsia). It predominantly affects childrenin endemic areas, but rare cases havebeen reported in travelers of all ages.Myelitis may occur but rarely in isola-tion from encephalitis. The clinicalsyndrome is similar to WNV with acuteflaccid paralysis. Diagnosis is made withCSF IgM but should be tested only inpatients from or travelers to endemicareas. Treatment is supportive. A vac-cine is available but has been anecdo-tally associated with transverse myelitisand other adverse side effects, so it isrecommended only for travelers to

endemic areas with particularly highrisk.18

Tick-borne encephalitis virus isanother flavivirus that causes encephali-tis and less commonly myelitis in CentralEurope, Russia, and China. Only fivecases were identified in the United Statesfrom 2000 to 2009, all with recent travelto endemic areas and four of the fivepatients recalling tick bites. Patients withmyelitis most commonly present withacute flaccid paralysis. CSF IgM is thediagnostic test of choice (availablethrough the Centers for Disease Controland Prevention). No specific treatment isused, and a vaccine is available in Europeand Canada but not the United States.

RabiesRabies virus is an RNA lyssavirus carriedin bats and other small animals indeveloped countries, while dogs remainthe largest reservoir worldwide. Over55,000 people die every year from rabies,mostly in developing countries, with afew cases reported each year in theUnited States.19 Although presentationsare variable, two forms of the diseaseare classic. About two-thirds of patientsexperience ‘‘furious’’ or encephaliticrabies. A prodrome of focal paresthesiaaround the site of inoculation is fol-lowed by focal weakness and pain;psychosis, hydrophobia, and aeropho-bia; and finally coma, autonomic insta-bility, and death. In about one-third ofcases, ‘‘paralytic’’ rabies occurs with a clin-ical presentation of acute flaccid para-lysis (resembling Guillain-Barre syndromeor poliomyelitis) but proceeds to ence-phalopathy and death. The exact path-ophysiologic mechanisms of neuronalcompromise remain unclear. Rabiesshould be considered in patients witha history of dog or animal bites indeveloping countries or bat exposuresin developed countries. PCR for virusin a skin biopsy from the nape of theneck is the most sensitive and specific

KEY POINTS

h The initial severity ofWest Nile virus infectiondoes not predictclinical outcome.

h Rabies should beconsidered in patientswith exposures toanimals, including bats.



diagnostic test, but a combination of se-rologic screening and virus amplificationin skin, saliva, and CSF is most reliable.Although no effective treatment is avail-able, diagnosis is important for ade-quate prophylaxis of family and healthcare workers as well as for a clear un-derstanding of prognosis.20

HerpesvirusesThe herpesviruses are a family of ubiq-uitous DNA viruses, including herpessimplex virus types 1 (HSV1) and 2(HSV2), VZV, EBV, and CMV. These vi-ruses share an ability to remain dor-mant in the peripheral nervous system,in sensory ganglia neurons or lympho-cytes and endothelial cells, for yearsafter primary infection. When associ-ated with spinal cord involvement,they tend to cause transverse myelitis.

HSV1 and HSV2 are closely relatedviruses, and both can causemyelitis. HSV1primarily enters the host through oralmucosa and is a less common cause ofmyelitis, occurring typically in children.HSV2 is transmitted through genitalmucosa; it is responsible for most HSV-related myelitis and occurs in adults.21

Primary HSV2 infection is usually asymp-tomatic, but the virus enters peripheralsensory nerves and is transported to thedorsal root ganglia, where it incorporatesinto the cell genome and may remainlatent for years. During reactivation, theviral particles are transported back to thesensory dermatome and may causeasymptomatic shedding of viral particlesand a vesicular rash. Rarely the reactiva-tion leads to inflammation in the dorsalroots and the neighboring spinal cord,causing radiculomyelitis (Elsberg syn-drome).22 Patients usually present withsubacute lower extremity weakness,which may ascend as the virus spreadsrostrally. Other common clinical fea-tures include numbness or tingling inlumbosacral dermatomes and urinaryretention. Patients often report lower

back pain. A more severe form of HSVmyelitis, acute necrotizing myelopathy,occurs in immunocompromised pa-tients.23 Neurologic examination revealsflaccid paraplegia with absent reflexes.Frequently no evidence of a systemicinflammatory response is present. CSFexamination usually demonstrates a mildlymphocytic pleocytosis (10 cells/2L to200 cells/2L) with elevated proteinconcentration, although acute necrotiz-ing myelitis may show a significantpolymorphonuclear pleocytosis.24 CSFPCR amplification of DNA is the main-stay of diagnosis. Imaging typicallydemonstrates enlargement of the spinalcord, T2 hyperintense signal, and con-trast enhancement of radicular roots andcord.25 Most patients are treated with 14days of IV acyclovir followed by oralacyclovir or valacyclovir until symptomsresolve or stabilize. The role of cortico-steroids is uncertain, but they shouldnot be given without concurrent anti-viral therapy.26 Outcomes are variable,but complete recovery is possible. In upto 20%of cases, themyelitis may recur.24

Primary VZV infection causes chick-enpox and then becomes latent in thesensory root ganglia. When it occurs,reactivation of the virus usually involvesa single dermatome and happens onlyonce during the lifetime of a host.Rarely, patients may develop myelora-diculitis during reactivation, usually inimmunosuppressed individuals. Patho-logic studies suggest that the viruscauses a necrotizing vasculitis with localdemyelination and neuronal inclu-sions.27 While zoster usually precedesmyelitis, cases have been reported with-out rash. Patients most often presentover days to weeks with progressive asym-metric paraparesis and sensory loss(pain and temperature more often thanvibration and position). CSF typicallydemonstrates a mononuclear pleocyto-sis and elevated protein concentration,although this pattern is also quite

KEY POINTS

h Elsberg syndrome is aform of radiculomyelitiscaused by reactivationof herpes simplexvirus type 2.

h Shingles may befollowed byvaricella-zostervirusYrelatedmyeloradiculitis.




Case 6-2A 55-year-old man with a history of advanced HIV and recurrent Burkitt lymphoma status postsystemicand intrathecal chemotherapy presented with 2 weeks of progressive but painless left and thenright lower-extremity weakness. He had not been adherent to antiretroviral therapy for the past6 months. On examination he was afebrile with profound distal more than proximal weakness inthe left lower extremity and mild weakness in the right lower extremity, normal sensation, and absentreflexes. Laboratory testing revealed a CD4 lymphocyte count cell count of 169 cells/2L (8.6%) andan HIV viral load of 56 copies/mL. MRI demonstrated intramedullary T2 hyperintense foci in the lowerthoracic spinal cord and conus medullaris with patchy contrast enhancement (Figure 6-2). CSF revealednormal glucose and protein, and a mild pleocytosis (68 cells/2L) with lymphocytic predominance.

CSF cytology was negative. CSF PCR was positive for VZV DNA, although CSF VZV IgG was negative.Despite treatment with IV acyclovir and corticosteroids, his examination worsened over thesubsequent 2 weeks, with left lower-extremity paralysis, profound right lower-extremity weakness,and development of urinary retention. He required intensive rehabilitation but had a significantimprovement, such that at 3-month follow-up he could ambulate with a walker, although he hadongoing urinary retention.

Comment. This is a challenging case that demonstrates the variability in clinical presentation ofinfections in immunocompromised hosts. The patient did not have shingles preceding his weakness,which is reported in a significant minority of patients with CNS VZV involvement. An asymmetricweakness progressing over weeks, as seen in this case, is typical for VZV. This case also demonstratesthe importance of a high index of suspicion for VZV and CSF evaluation by PCR as well as serology.

FIGURE 6-2 Varicella-zoster virus myeloradiculitis. A, B, D, Sagittal and axial T2-weighted and T1-weighted MRI withcontrast of the lumbar spine demonstrates T2 changes intrinsic to the lower spinal cord (arrowheads).C, Patchy enhancement of these intramedullary lesions as well as diffuse root enhancement are evident(arrows). Of note, evidence of severely distended bladder consistent with urinary retention is shown (arrowin panel A).



common in uncomplicated zoster.27,28

Anti-VZV IgM antibody assays in CSF aremore sensitive than PCR, although bothshould be tested, since PCR results aremore rapidly available.29 Imaging usu-ally shows asymmetric T2 hyperintenselesions in the spinal cord correspond-ing to the dermatome involved. Treat-ment based on case reports and expertopinion includes prolonged IV acyclo-vir and corticosteroids (Case 6-2).26

CMV is a ubiquitous virus capable ofinfecting neuronal and glial cells butrarely causes symptoms in normalhosts. In profoundly immunocompro-mised patients, particularly in HIVpatients with CD4 counts below 100cells/2L, CMV may cause a lumbosacralpolyradiculomyelitis characterized bysuperficial meningitis extending intonerve roots and the spinal cord, with focalnecrosis of the myelin.30 Less frequently,necrotizing myelitis may occur withoutradiculitis. Imaging typically demon-strates cord swelling and peripheralcontrast enhancement as well as spinalnerve root swelling, meningeal thicken-ing, and adherence of spinal roots tothe thecal sac. CSF examination revealspolymorphonuclear pleocytosis, andthe protein concentration is elevated,occasionally with a low glucose concen-tration. Experts recommend treatmentwith a combination of ganciclovir andfoscarnet, but prognosis is poor.

EBV is the causative agent of infectiousmononucleosis. Neurologic involvementusually occurs in children and youngadults at the time of primary infection,and less frequently in immunocompro-mised hosts, such as transplant patients,through reactivation. Neurologic syn-dromes associated with EBV infectioninclude aseptic meningitis, meningoen-cephalitis (especially cerebellitis), cranialand peripheral neuritis, Guillain-Barresyndrome, and myelitis.31 EBV does notinfect neurons, and the few pathologicstudies available suggest an immune-

mediated mechanism of injury ratherthan direct viral invasion.32 Patients withmyelitis usually present 2 to 3 weeksafter primary infection with flaccid weak-ness, a sensory level, and often radicul-opathy and urinary retention.26 CSFusually demonstrates a mononuclearpleocytosis with elevated protein andnormal glucose concentrations. Acuteand convalescent serologic testing canconfirm acute EBV infection, and de-tection of EBV DNA in CSF throughPCR is strong supportive evidence for apathogenic role in myelitis associatedwith primary infection. Imaging may de-monstrate T2 hyperintense cord signalabnormalities, contrast enhancement,and thickened nerve roots frequentlycoalesced in the posterior thecal sac.Although acyclovir inhibits viral replica-tion, it has little impact on the clinicalcourse of EBV infectious symptomatol-ogy. Most patients are treated with ste-roids, with relatively good outcomes.33

BACTERIAL CAUSESSyphilisSyphilis is caused by Treponema pal-lidum, a fragile, corkscrew-shaped spiro-chete. While antibiotics have dramaticallyaltered the incidence and course ofsyphilis, it continues to be a significantpathogen around the world, particularlyin patients with HIV coinfection. Neuro-syphilis has traditionally been dividedinto distinct syndromes with character-istic onset in the course of infection:asymptomatic, meningitic, meningovas-cular, general paresis, and tabes dorsa-lis. T. pallidum enters the CNS in asignificant proportion of patients(some have argued all) during theprimary and especially secondarystages, and may cause a relatively mildand often asymptomatic meningitis.34

As not all of these patients go on tosymptomatic stages, this is the mostcommon form of neurosyphilis in mod-ern times. The other syndromes are

KEY POINTS

h CSF antiYvaricella-zostervirus IgM serology ismore sensitive thanPCR in varicella-zostervirusYrelated CNSdisease.

h Treponema pallidumenters the CNS early inthe course of syphilis.




often grouped into meningovascular(meningitic and meningovascular) andparenchymatous (general paresis andtabes dorsalis) forms. While spinal cordinvolvement in the form of tabes dorsa-lis was historically the most commonmanifestation of neurosyphilis, in thepostantibiotic era its incidence has de-creased dramatically, with a relative risein the incidence of meningovascularforms. Meningovascular syphilis is char-acterized by chronic meningeal inflam-mation and endarteritis obliterans ofsmall vessels. Rarely meningovascularsyphilis may lead to cord infarction.35

Tabes dorsalis manifests with suba-cute to chronic onset of sensory ataxia,loss of vibration, loss of deep pain sen-sation, and lancinating pains. Physicalexamination usually demonstrateshyperreflexia, sensory ataxia, insensitiv-ity to deep pain, Charcot joints, andArgyll Robertson pupils.36 MRI demon-strates cord atrophy and nonenhancingT2 hyperintense signal abnormalitiesspanning the posterior aspect of thecord.37 Pathologic changes of tabes dor-salis are found predominantly in thedorsal roots and posterior columns belowthe midthoracic level, with lymphocyticinflammatory changes, astrocytic gliosis,and demyelination involving fasciculusgracilis and Lissauer tract.38 The precisepathophysiology remains unclear.

In addition to classical tabes dorsalisand cord infarction frommeningovascularsyphilis, T. pallidum may lead to severalother forms of myelopathy. Exceptionallyrare syphilitic spinal forms include hyper-trophic pachymeningitis, spinal cordgumma, anterior horn cell syndrome,and syringomyelia; and through indirectmechanisms, aortic aneurysm with sec-ondary anterior cord syndrome andCharcot deformations of vertebra withcord compression. In the current era,meningomyelitis is the most commonsyphilitic involvement of the spinalcord.39 It presents on average 6 years

after infection with progressive, at timesasymmetric, spastic paraparesis. Imag-ing characteristics are variable, rangingfrom central cord T2 hyperintensitywith gadolinium enhancement to moresuperficial pial enhancement with rever-sal of the typical T2 and T1 postcontrastsignal.39 Several case reports have notedrecovery clinically and radiographically,making this an important diagnosis toconsider and treat.40

Diagnosis is made by peripheralserology and CSF evaluation. Serologicscreening assays using nontreponemalantigens to detect antibodies found onthe membranes of T. pallidum, theVenereal Disease Research Laboratory(VDRL) and rapid plasma reagin (RPR)tests, are sensitive in early infection butmay become negative later in the dis-ease. A treponemal-specific test is per-formed for confirmation, and results willremain positive even in late disease. Thetreponema pallidum enzyme immuno-assay has become the preferred test inhigh-volume centers in the UnitedStates.41 If serum treponemal test resultsare negative, syphilis is excluded andother etiologies should be sought. Ifserum test results are positive, theconfirmation of neurosyphilis generallyrequires CSF examination. The CSF pro-file is mildly inflammatory. A positiveCSF VDRL confirms the diagnosis, but itssensitivity is low, so a negative test resultdoes not exclude the diagnosis. If CSFVDRL is negative but serologic evidencefor syphilis and a compatible clinicalsyndrome is present, CSF fluorescenttreponemal antibody absorption testingcan be used to confirm, as it is highlysensitive (but not specific).42

T. pallidum is exquisitely sensitiveto penicillin. However, during initiationof treatment, clinical symptoms mayworsen secondary to a sudden increasein pathogenic antigens due to lysis of thespirochetes (Jarisch-Herxheimer reac-tion). This is particularly important for

KEY POINTS

h T. pallidum can causeendarteritis obliterans ofsmall vessels, includingspinal vessels.

h Nontreponemalserologic tests forsyphilis, such asVenereal DiseaseResearch Laboratoryand rapid plasmareagin, may becomenegative in late stagesof syphilis.

h The Jarisch-Herxheimerreaction is a prototypeworsening of clinicalsymptoms withinitiation ofantimicrobial treatmentas spirochetes lyse andantigen levels rise.



syphilitic myelitis, which is often pre-emptively treated with corticosteroids.

Lyme DiseaseBorrelia is another genus of spirochetesthat frequently affects the nervoussystem. Borrelia burgdorferi is trans-mitted to humans by the Ixodes tick spe-cies and is endemic to North America,Europe, and Asia. Early infection is usu-ally associated with erythema migrans.The classic triad of early neurologicinvolvement includes peripheral facialpalsy, aseptic meningitis, and painfulradiculitis. Transverse myelitis is a raremanifestation of early Lyme disease, usu-ally as a segmental lesion at the level ofa painful radiculitis (ie, Bannwarthsyndrome). More commonly reportedin Europe, it constitutes a small (4% inone series) proportion of early neuro-logic Lyme involvement.43 A morechronic and progressive myelopathyin late Lyme disease has also beendescribed in Europe. In the UnitedSates, transverse myelitis is restrictedto case reports and generally occurs inearly disseminated disease.44

Lyme disease should be suspectedin the patient with a history of a tickbite who has traveled to or resides inan endemic area, and especially in thepatient with a history or the presenceof the typical erythema migrans lesion.By the time of neurologic involve-ment, serologic evidence of infectionwill be present in almost all cases. Inthe United States, an ELISA is used forscreening and a Western blot forconfirmation. PCR has not been vali-dated in CSF and is not useful in mostcases. CSF evaluation typically demon-strates lymphocytic pleocytosis, ele-vated protein concentration, normalglucose concentration, and increasedIgG index. An increased CSF to serumratio of Lyme-specific immunoglobulinis highly supportive of CNS Lymedisease. Imaging of the spine is usually

normal but may demonstrate a seg-mental T2-weighted cord lesion atthe level of meningeal and radicularroot enhancement.44,45 For transversemyelitis associated with Bannwarthmeningoradiculitis, IV ceftriaxone isthe agent of choice, usually given for14 to 28 days with a short course oforal or IV corticosteroids.46

TuberculosisMycobacterium tuberculosis (TB) is aslow-growing aerobic organism thatmay cause chronic infection of theCNS. The World Health Organizationreported 8.8 million cases and 1.1million deaths attributed to TB in2010. CNS TB, primarily in the form oftuberculous meningitis, accounts for1% of TB cases and 6% of extrapulmo-nary TB. In developed countries, TBusually presents as reactivation in adultimmigrants from endemic countries. Inthe CNS, this usually takes the form ofmeningitis from the rupture of ameningeal focus into the subarachnoidspace. In developing countries, otherCNS complications, such as parenchymaltuberculoma or spinal arachnoiditis, mayoccur as part of primary dissemination inchildren and young adults. Risk factorsfor CNS involvement include malnutri-tion, immunosuppression, and extremesof age. HIV coinfection does not appearto alter the clinical course of CNS TB indeveloped countries, but patients in de-veloping countries with HIV show lessinflammation on CSF and imaging stud-ies and have less favorable response totreatment.47 Notably, fewer than half ofpatients with CNS TB have pulmonarysymptoms at presentation.

The most common cause of myelop-athy in patients with TB is vertebral bodyinfection, or Pott disease. Spreadingthrough the vertebral venous system, itinvolves predominantly anterior seg-ments of thoracic and lumbar spine,leading to collapse of these vertebral

KEY POINTS

h The classic triad ofneuroborreliosis includesperipheral facial nervepalsies, asepticmeningitis, andpainful radiculitis.

h Most patients with CNStuberculosis have nopulmonary symptoms atthe time of neurologicmanifestation.




bodies with secondary spinal root andcord injury. Most patients with this syn-drome present with back pain, leg weak-ness, and a gibbus deformity.

TB less commonly leads to intra-medullary or intradural extramedullarytuberculomas, granulomatous myelora-diculitis, spinal artery vasculitis withcord infarct, or acute disseminatedencephalomyelitis.48,49 These forms ofTB typically occur in association withmeningitis but may present with onlymyelopathic symptoms. Epidural orintramedullary tuberculomas usuallypresent with subacute myelopathicsymptoms, depending on the specificlocation of the space-occupying gran-uloma. In granulomatousmyeloradiculitis,TB enters the CNS through the hema-togenous route and then spreads withinthe CNS via the subarachnoid space. Pa-tients usually experience a subacute (1to 2 month) prodrome followed by arelatively rapid culmination of symp-toms, including radicular pain, paresthe-sia, flaccid weakness with extensor plantarresponses, and bladder dysfunction.50

CSF typically reveals moderate lym-phocytic pleocytosis, low glucose con-centration, and at times markedly highprotein concentrations indicating spinalblock. CSF acid-fast stains and culturesare positive in up to 80% of TB men-ingitis with optimal sampling and pro-cessing, but the sensitivity for spinalinvolvement in the absence of menin-gitis is not well established. Tuberculinskin test results may be positive in only40% of these patients.51 MRI in Pottdisease reveals T1 hypointensity withT2 hyperintensity with contrast en-hancement, progressing to vertebralbody collapse and cord compression.Tuberculomas show contrast-enhanc-ing T1 hypointense rings with high T2signal centrally. In granulomatous mye-loradiculitis, MRI may reveal contrastenhancement and thickening of themeninges and spinal roots. Pathology is

characterized by granulomatous inflam-mation with thick exudates engulfingthe meninges and nerve roots. In somecases, spinal involvement may lead tosyringomyelia. Blood vessels may alsobe directly involved by the necrotizinggranulomas or a vasculitic process in-duced by the local proinflammatory cy-tokine milieu.

Treatment of spinal TB is similar tothat for TB meningitis, namely a four-drug regimen for 2 months followedby 7 to 10 months of isoniazid andrifampin. In patients who are ambula-tory at diagnosis (primarily vertebraldisease with pain), medical therapyhas been shown to be equally effectiveto combined medical and surgicaltherapy.52 However, with neurologiccompromise, instability of vertebralbodies, or failure of medical therapy,adjunctive surgery is often necessary.Depending on the duration, location,and spinal level, patients have varyingoutcomes with lumbar involvement show-ing more improvement than thoracic.

Pyogenic BacteriaMyelopathy may occur with pyogenicinfection through different pathogenicmechanisms. Vertebral osteomyelitismay lead to structural spine collapse orextension of the infection into the epidu-ral space causing an epidural abscess.Rarely, an intramedullary abscess mayoccur from primary hematogenousseeding.53

Pyogenic infections of the spine havean incidence of 2.4 per 100,000 popu-lation. Of these,myelopathic or radicularsigns develop in about 30%.54 Epiduralabscess in the setting of osteomyelitis isusually caused by hematogenous spreadof the pathogen to the vertebra duringperiods of bacteremia. Alternatively,bacteria may spread from local soft tis-sues, viscera, or surgical instrumenta-tion. Direct seeding of the epidural spaceusually involves the posterior epidural

KEY POINTS

h Tuberculosis maycause necrotizinggranulomatousvasculitis, includingspinal vessels.

h Pyogenic infectionsusually seed the anteriorepidural space via directextension from boneand soft-tissue foci,and the posteriorepidural space viahematogenousdissemination.



space, while infections related to osteo-myelitis or soft-tissue infections usuallyinvolve the anterior epidural space.55

Themost important risk factors for epi-dural abscess include diabetes mellitus,alcohol abuse, traumaor instrumentation,skin infection, and a history of IV druguse. The thoracic region is most fre-quently involved.56 Patients usuallypresent with focal back pain over thesite of infection, usually associated withmuscle spasms. Fever is present in fewerthan half of the patients.54 Epiduralabscesses are most frequently caused bygram-positive organisms with Staphylo-coccus aureus isolated in over 70% andStreptococcus species isolated in 7% ofcases.56 The most frequent gram-nega-tive organisms identified are Escherichiacoli and Pseudomonas aeruginosa.

Erythrocyte sedimentation rate orC-reactive protein is elevated in almost100% of patients. Blood cultures are pos-itive in about 60%of patients. Rapid spineimaging is critical. MRI is the modality ofchoice, but CT may be better for charac-terizing bony involvement. Lumbar punc-ture is relatively contraindicated becauseit has low yield and poses a risk of intro-ducing bacteria into the CSF.55

The treatment of choice for epiduralabscess is emergent drainage and pro-longed antibiotics. Medical therapyalone is considered only in patients withlongitudinally extensive epidural in-volvement, or in critically ill patients.Even with proper treatment, mortality is10% to 23%. The severity of neurologicdeficits at the time of surgery is thestrongest predictor of mortality. A delayin surgical treatment by more than 12hours after development of neurologicdeficits leads to no or minimal recoveryof neurologic deficits (Case 6-3).55

PARASITIC CAUSESSchistosomiasisSchistosoma is a genus of the trem-atode parasite (fluke) that commonly

causes myelopathy or encephalopathyamong infected hosts. It is endemic tomost tropical regions of the world, andover 200 million people are infected,although the species that typically causeneurologic disease are concentrated inCentral and South America (Schisto-soma mansoni) and sub-Saharan Africa(S. mansoni and Schistosoma haema-tobium).57 Fresh water snails serve asintermediate hosts and higher verte-brates as definitive hosts. Cercariae(larvae) released from snails penetratethe skin of vertebrates, and through he-matogenous and lymphatic spread settlein the portal circulation. Schistosomamate in the liver before migrating tothe mesenteric and vesicular veins,where females release eggs by the hun-dreds each day, leading to excretion instool (S. mansoni) and urine (S. hae-matobium). Retrograde migration ofeggs from the portal venous systemthrough the valveless pelvic and epi-dural venous plexus leads to deposi-tion around CNS tissue and generationof a granulomatous inflammatory re-sponse (arterial dissemination has alsobeen described).

Most reported cases of spinal cordschistosomiasis are caused by S. man-soni, usually in adolescents and youngadults. Patients present with subacutelower back pain radiating to the lowerlimbs, followed by weakness, derma-tomal sensory abnormalities, andbowel and bladder dysfunction.58 Thelower cord (especially T11-L1) and caudaequina are most commonly affected, butcervical and thoracic cord involvementoccurs. Physical examination reveals var-iable degrees of myelopathy and/or ra-diculopathy. Most patients have noextra CNS symptoms at time of onset.

MRI usually shows cord enlarge-ment, intramedullary T2-weightedhyperintense signal within the lowerthoracolumbar cord or conusmedullaris/cauda equina, and heterogeneous

KEY POINTS

h Most patients withpyogenic epiduralabscesses are notfebrile.

h Erythrocytesedimentation rateor C-reactive protein areelevated in almost allpatients with pyogenicepidural abscess.

h Epidural abscess is asurgical emergency withover 20% mortality.

h Schistosomiasis is themost common parasiticcause of myelopathyworldwide.

h Schistosoma mansonieggs are usually foundin stool and those ofSchistosomahaematobium in urine.

h Schistosomiasis-relatedmyelopathy is caused bychronic inflammationdirected at the eggs ofthe organism.




contrast enhancement of the cord orroots. Diagnosis is based on three fea-tures: (1) a lower spinal cord or caudaequina lesion, (2) evidence of schisto-somal infection (ova in stool or urine,

rectal biopsy, or serologic), and (3)exclusion of other causes.59 Microbiol-ogy expertise should be sought whenconsidering the diagnosis for optimiza-tion of sampling and processing, and

Case 6-3A 77-year-old previously healthy man presented with low-grade fevers, chest pain, back pain, andlower-extremity numbness. While trying to move a boulder in his yard 1 week earlier, he developedchest pain that evolved into rib pain over 2 days. He presented to the emergency department, wherechest x-rays and ECG were unremarkable. He was treated with cephalexin for a cellulitis of his finger.He noted unsteadiness on his feet the next day and then developed lower-extremity numbness,prompting a return to the emergency department. His temperature was 37.8-C (100-F). He wasfound to have thoracic spine tenderness and over the next 3 days developed bilateral lower-extremityweakness and urinary retention. Laboratory studies were significant for an elevated erythrocytesedimentation rate and white blood cell count differential with a leftward shift. MRI demonstratedan epidural fluid collection and evidence of osteomyelitis at T7-8 (Figure 6-3). He was taken urgentlyto the operating room for decompression, and intraoperative cultures grew S. aureus. Bloodcultures and transthoracic echocardiogram results were negative. He completed a prolonged course ofIV antibiotics, and his symptoms improved gradually although 2 years later he had residual gait

unsteadiness.Comment.

This casedemonstratesambiguoussymptoms inan initiallywell-appearingpatient whorapidlydeteriorated andhad to be rushedto the operatingroom. Cliniciansshould maintaina high index ofsuspicion forepidural abscessin patients withatypical backpain, especiallywith an elevatederythrocytesedimentationrate or C-reactiveprotein. Patients

usually present with pain and radicular symptoms and are likely to have no fever. Invasion of theanterior epidural compartment usually indicates a neighboring osteomyelitis or soft-tissue infectionas in this case. Staphylococcus is the most likely pathogen, as demonstrated here. Lumbar punctureis relatively contraindicated. Treatment almost always involves surgery in addition to prolongedantibiotics.

FIGURE 6-3 Epidural abscess. Sagittal (A) and axial (C) T2-weighted and sagittal T1-weighted(B) MRI with contrast of the thoracic and lumbar spine demonstrate focal T2changes in the bone and disk that vividly enhance, consistent with osteomyelitis.

B, Focus of enhancing fluid collection (arrowheads) surrounding the cord and exerting masseffect (thin arrow in panel C). The posterior fluid collection demonstrates significant cephalicextension. C, A large enhancing mass within the paraspinal muscle consistent with anabscess (thick arrow).



even then only 50% of patients will havepositive parasitology in stool. Blood orCSF eosinophilia is characteristic butmay be absent. Peripheral serology(ELISA, indirect hemagglutination, or im-munofluorescence) may be particularlyuseful for establishing exposure in trav-elers but has little utility in patients fromendemic areas because of high sero-prevalence. Serologic tests in CSF aremore specific. Identification of parasiteantigens in peripheral plasma or CSFusing monoclonal antibodies or PCRshow promise as more specific testsbut are not widely available.60 Tissuebiopsy remains the gold standard fordiagnosis but is avoided in CNS diseasebecause of morbidity.

Treatment includes praziquantel (var-ious dosing regimens have been usedwithout randomized trials to define clearguidelines), which does not destroyeggs but stops egg production; and con-current corticosteroids to reduce theinflammatory response and edema, usu-ally with a several-month taper. Rarely,surgery for decompression may be nec-essary with fulminant or medically re-fractory cases. Clinical and radiographicrecovery occurs in most patients treatedearly (Case 6-4).58,61

Other ParasitesOther parasites are rare causes of myel-opathy. Toxoplasma gondii is a ubiq-uitous intracellular protozoan that mostoften causes asymptomatic infection,but reactivation of dormant cysts cancause disease in immunocompromisedpatients. The most frequent manifesta-tion is multifocal cerebral mass lesionsin patients with advanced HIV, but sim-ilar lesions may occasionally be found inthe spinal cord, typically with concur-rent brain involvement. Diagnosis isusually made in patients with HIV withcerebral and spinal cord inflammatorymass lesions, positive peripheral IgGserology (sensitive but not specific), pos-

itive CSF toxoplasma PCR (specific butnot sensitive), and response to treat-ment. The organism is exquisitely sensi-tive to a combination of pyrimethamine(supplemented by folinic acid) and sul-fadiazine or clindamycin.62

Neurocysticercosis is caused by thecystic larval form of the cestode Taeniasolium, which is endemic in Central andSouth America, sub-Saharan Africa, andSouth and Southeast Asia. Neurologicdisease is common but usually involvesthe brain parenchyma, ventricles, or cere-bral subarachnoid space. Only 1.2% to5.8% of neurocysticercosis cases involvethe spinal cord, predominantly in thesubarachnoid space but rarely as intra-medullary cysts, which can mimic neo-plasm. The subarachnoid cysts mostlikely migrate from the basilar cisterns,and up to 75% of cases occur in patientswith known intracranial neurocysticer-cosis.63 The cysts are initially mobile,but when degeneration begins they be-come fixed anywhere along the length ofthe thecal sac.64 Diagnosis is based ondemographics and imaging, with sup-portive serology. CSF typically showshigh protein concentration and eosino-philia. Spinal cysts are treated with acombination of albendazole and corti-costeroids, sometimes requiring surgeryfor decompression or hydrocephalus.63

Hydatid disease is a cystic infectioncaused by the cestode Echinococcus.Most CNS hydatid disease occurs in thebrain as a result of the species Echino-coccus granulosum, which is endemicto the Middle East, South America, NewZealand, and the Mediterranean. Spinalinvolvement is rare and may affect thevertebra, extradural or paraspinal struc-tures, or intradural extramedullaryspace, with only a few intramedullarycysts reported in the literature.65 Can-ines are definitive hosts for the tape-worms, and humans are infected via thefecal-oral route. Once ingested, theeggs hatch and form oncosphere larvae,

KEY POINTS

h In schistosomiasis, bloodand CSF eosinophilia isclassic but not universal.

h Response to treatmentis part of diagnosticcriteria fortoxoplasmosis.

h Neurocysticercosissometimes invades thesubarachnoid space butrarely involves the spine.




which migrate across the intestinal walland form hydatid cysts in the liver andother tissues, including the CNS. Thesecysts may grow extremely large, and

pathology is caused by a combinationof mass effect, bony destruction, andhost inflammatory response. MRI revealscharacteristic cysts causing mass effect

Case 6-4A 29-year-old man from Brazil presented to a local emergency department after 3 weeks of worseninglower back pain radiating to his bilateral knees. The pain was moderately responsive to nonsteroidalanti-inflammatory medication but worsened over the week prior to presentation, and he developedright-leg numbness and weakness. On the day of presentation he developed urinary retention andbowel incontinence. On examination he had full strength, decreased sensation to light touch andpinprick in a saddle distribution as well as distal lower extremities, and reduced reflexes in thelower but not upper extremities. Hematologic studies and liver function tests were normal. MRI ofthe spine showed patchy enhancement of the lower spinal cord and cauda equina (Figure 6-4).CSF studies were significant for elevated protein (114 mg/dL), normal glucose, and mild pleocytosis(28 cells/2L) with lymphocytic predominance and increased eosinophils. Stool screening for ova andparasites was negative. He was treated with ivermectin, praziquantel, and high-dose corticosteroids.

Serology wasultimately positivefor IgG againstschistosomalantigens (resultsobtained 2 weeksafter presentation).He regained boweland bladderfunction. He hadtemporaryworsening whencorticosteroidswere tapered after1 month buttolerated a longertaper with onlymild residual distallower-extremityparesthesia.

Comment.This caseillustrates astereotypicpresentation ofschistosomiasis,

which should be ruled out in any patient from endemic regions with subacute back pain accompaniedby sensory deficits and weakness. Most of the patients are young, and the pain initially responds wellto nonsteroidal anti-inflammatory drugs, as was seen in this case. The symptoms arise from theinflammatory response to the parasite eggs, which tend to migrate to the lower cord via the venoussystem. Cauda equina symptoms and these imaging findings are typical for this infection. The patient’sCSF had elevated eosinophils, which should increase the index of suspicion for parasitic infections.As described above, most of these patients do well on combination therapy against the parasite andcorticosteroids to mitigate the inflammatory response to the eggs.

FIGURE 6-4 Schistosomal lumbosacral myeloradiculitis. A, C, Sagittal and axial T2-weightedand T1-weighted MRI with contrast of the thoracic and lumbar spinedemonstrates diffuse intramedullary T2 cord changes (arrows). B, Contrast

studies demonstrate clustering and largely peripheral nodular enhancement of the lowerspinal cord including conus (arrowheads). D, Thick nodular root enhancement within caudaequina is shown (arrowheads).



on the cord, and serologic testing is alsoavailable. Treatment includes surgicaldecompression and albendazole, butrecurrence is the norm.66

Gnathostoma spinigerum is anematode endemic to Southeast Asiatransmitted to humans via undercookedinfested fish, reptiles, or poultry. Larvaemay invade spinal roots, causing severeradicular pain, and then travel rostrally,causing radiculomyelitis through directmechanical disruption of tissues as wellas the inflammatory response to itssecretions. Diagnosis is made by historyof endemic exposure, biopsy of skinlesions, eosinophilic CSF profile, andserologic testing. Treatment usually in-cludes surgical resection of the larvaefollowed by albendazole or ivermectin.67

Angiostrongylus cantonensis is anothernematode that is a common cause ofeosinophilic meningitis, but an extremelyrare cause of myelitis in endemic areas(Southeast Asia, Pacific Basin, andCaribbean).68

FUNGAL CAUSESFungal infections of the CNS are usuallyassociated with some degree of immuneincompetence. Fungal CNS syndromesvary with the type of pathogen and im-mune state. Molds (most commonlyAspergillus) tend to cause focal CNS dis-ease in mildly immunosuppressed pa-tients, with vascular invasion leading tothrombosis and hemorrhage in patientswith more profound immunocompro-mise. Yeasts (most commonly crypto-coccus) cause a chronic basal meningitisand granuloma formation. While CNSinvolvement typically manifests as men-ingitis or brain lesions, spinal cord dis-ease occurs in the form of epiduralabscess, chronic arachnoiditis, intra-medullary granuloma, frank myelitis, orvasculitiswith cord infarction.69 Most casesare related to regional spine invasionfrom vertebral osteomyelitis. Table 6-5lists specific pathogens. Fungal causesof transverse myelitis are extremelyrare.

KEY POINTS

h Gnathostoma causesinjury via directdestruction of tissueas larvae migrate.

h Aspergillus invadesblood vessels andcauses thrombosisand hemorrhages.

TABLE 6-5 Fungal Causes of Myelopathy

Fungus Pathology Clinical Clues Diagnosis Treatment

Cryptococcusneoformans

Granulomatousmeningitis andmyeloradiculitis

Ubiquitous,encephalopathy, highCSF opening pressure

CSF India ink stain,CSF antigen

Amphotericin B +flucytosine, thenfluconazole; shunt

Coccidioidesimmitis

Osteomyelitis Southwest United States,Latin America; pulmonarysymptoms; spares disks

CSF antibodies Fluconazole;voriconazole,intrathecalamphotericinB (second-linealternatives)

Blastomycesdermatitidisa

Granulomatousosteomyelitis

North America;pulmonary symptoms;fistula formation

CSF culture Surgery andamphotericinB, followed byazole

Aspergillusspecies

Focal vascularinvasion andhemorrhages

Ubiquitous, exposure tosteroids, pulmonarysymptoms

Non-CNS histology orculture, serum or CSFgalactomannan, serum"-D-glucan

Voriconazole;amphotericin B

a This is a rare cause; other rare fungal causes of osteomyelitis include Candida and Histoplasma capsulatum.




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