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Ростовский Государственный Медицинский Университет

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Thisdescriptor,“ring-enhancing,”comesupfrequentlyinneurology—wejustmentioneditin ourdiscussionoftoxoplasmosis(takealookagainattheMRIonpage219)—sowethought itdeservedashortparagraph.Whatdoesitmean?Aring-enhancinglesionisanabnormal radiographicfindingthatcanbeseenonacontrast-enhancedCTorMRIthatis characterizedbyaregionofhypo-orisodensity(onCT)orhypo-orisointensity(onMRI) surroundedbyarimofbrightlyenhancingcontrast.Thediagnosticdifferentialislong,but someofthemorecommonetiologiesinclude:

 Infections (bacterial or fungal abscess, tuberculoma, toxoplasmosis, neurocysticercosis) Neoplasticdisorders(CNSlymphoma,glioblastoma,metastasis)  Inflammatory disorders (sarcoid and a rare form of multiple sclerosis (MS) called tumefactiveMSthatappearslikeatumoronimaging) Vasculardisorders(subacuteinfarct,resolvinghematoma)

Theabilitytodifferentiateamongthesepotentialcausesreliesheavilyonclinicalcontext. However,furtherevaluation,withalumbarpunctureorbrainbiopsy,issometimesnecessary.

Neurosyphilis

Syphilis,causedbythespirocheteTreponemapalladum,hasexperiencedaresurgenceinrecentyears. Becausemostpatientsaretreatedearlyintheprimaryphasewhenthediseaseisstilllocalized,the neurologiccomplicationsofsyphilis,whichareassociatedwithuntreateddisease,areonlyrarely encountered.Nevertheless,neurosyphilishasnotvanishedfromthepopulation.Itisespeciallyprevalent intheHIV-positivepopulation.Becausethelong-termcomplicationsofneurosyphiliscanbedevastating andtreatmentwithpenicilliniscurative,thisisanotherdiagnosisyoudon’twanttomiss.

Theclinicalmanifestationsofneurosyphilisaretypicallydividedintoearly(occurringwithinmonths toafewyearsoftheinitialinfection)andlate(occuring10ormoreyearsaftertheinitialinfection) phases.

EarlyNeurosyphilis.Primarysyphilispresentsasapainlessgenitalulcer.Duringthesecondaryphaseof infection,thespirochete,ifuntreated,disseminatesthroughoutthebodycausingadiffuserashandcan seedmultipleorgans,includingthemeninges.

Meningeal involvement may remain asymptomatic or cause a variety ofsymptoms, ranging from thoseofatypicalacutemeningitistocranialnerveimpairmenttoseizures. Meningovascularinvolvementofthespinalcordandsometimesthebrainwithresultinginfarction (inessencethesearesmall strokes,andsymptomswill dependentirelyontheirlocation)isaless common manifestation of earlyneurosyphilis. Behavioral and personality changes, headache, and dizziness,likelyduetomildmeningitis,oftenprecedeandheraldactualinfarctionbydaystoweeks. Inat-riskpopulations,syphilisshouldbeconsideredasacauseoflarge-vesselstroke. Ocularsymptoms(lossofvisionorblurryvisionduemostoftentoposterioruveitisorpanuveitis) andoticsymptoms(hearingloss)canalsooccuratthisstage.

LateNeurosyphilis.Themanifestationsoflateneurosyphilisappearatleast10yearsandoftenseveral

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decadesafterinfection.Themajormanifestationsaregeneralparesis,tabesdorsalis,gummatous disease,andchronicmeningitis.Thesearerarelyseensincetheadventofmoderndiagnostictechniques

andantibiotictherapy.

 General paresis, aka syphilis dementia, is a gradual-onset dementia characterized by a constellation of symptoms that typically evolve 10 to 20 years after the initial infection. The mnemonicPARESISisusefulforrememberingthedomainsthatareaffected:

Personality(labile,paranoid,disinhibited)

Affect(flat,depressed,euphoric,manic)

Reflexes(hyperactivedeeptendonreflexes)

Eye(large,unequalpupilsthatreactslowlytolightandaccommodation;eventuallypatientsmaydevelop ArgyllRobertsonpupils[althoughthesearemorecommonlyseenwithtabesdorsalis],whicharesmall

andirregular,unreactivetolightbutabletoconstrictwithaccommodation)

Sensorium(delusions,illusions,hallucination)

Intellect(impairedmemory,judgment,andinsight)

Speech(slurred)

Tabesdorsalis will notusuallydevelopuntilatleast20 yearsafterinfection.Involvementofthe posterior(akadorsal)columnsofthespinalcordandthedorsalrootganglia(tabesdorsalisroughly translates from Latin as “dorsal decay”) results in gradual sensory loss in the lower extremities, hyporeflexia,andlightning-likelancinatingpainsoftheface,trunk,and/orextremities.Theloss of painandproprioceptioncan lead to jointdestruction (Charcotjoints) andtraumatic ulcers. Other manifestationsoftabesdorsalisincludesensory ataxia,bladderdysfunction,gastrointestinalupset, andpupillaryabnormalities,includingArgyllRobertsonpupils. Gummas are a type of granulomatous lesion that develop in the brain or spinal cord late in the courseoftertiarysyphilis.Theypresentlikemasslesions(seepage390). Chronicmeningitiscanalsooccurandisthoughttobethecauseofthedementiaseenwithgeneral paresis.

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Immunostainingdemonstratesnumerousspirochetes.(ReprintedfromRubinR,StrayerDS.Rubin’s Pathology:ClinicopathologicFoundationsofMedicine.5thed.LippincottWilliams&Wilkins;2008.)

Diagnosis.Acombinationofthefollowingthreeitemsestablishesthediagnosisofneurosyphilis:

1. clinicalsymptoms,

2. apositiveCSFserology—thetestusedmostoftenistheVDRL,5and

3. anelevatedCSFcellcountorprotein.

However,notallpatientswithneurosyphiliswillmeetallthreecriteria;that’swhereclinicaljudgment comesin.Patientswithapositivebloodserology,whetheranonspecifictest(e.g.,VDRLorRPR)or specifictreponemaltest(e.g.,FTA-ABS),plusanyoftheabovecriteria,warrantseriousconsideration forthediagnosisofneurosyphilis.

Patientswithneurologic,ocular,orotalgicsymptomsconsistentwithsyphilisshouldundergolumbar punctureeveniftheirsyphilishistoryisuncertainandtheresultsofserologictestingarenotconfirmatory.

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Inaddition,somepatientshaveasymptomaticneurosyphilis.Thesepatientshaveevidenceofprimary orsecondarysyphilisbutwithoutanyneurologicsignsorsymptoms.Guidelinesvary,butalumbar puncturemaystillberecommendedifthesepatientsareathighriskforneurosyphilis,thatis,iftheyare HIVpositive,haveahighRPRtiterandalow(<350/µL)CD4+Tcellcount,andhavenotbeentreated withantiretroviraltherapy.ApositiveCSFVDRLconfirmsthediagnosis.EvenwithoutapositiveCSF VDRL,anelevatedCSFwhitecellcountand/orproteinisconsistentwithneurosyphilis,althoughitcan alsobecausedbyHIVitself.Mostguidelinesrecommendtreatingthesepatientsasthoughtheyhave neurosyphilis.

Treatment.Syphilisinanyphaseisresponsivetopenicillin;resistancetopenicillinhasnotbeena problem.Unlikepatientswithprimarysyphilis,whichcanbetreatedwithasingleintramuscular(IM) injection,patientswithneurosyphilisshouldreceivea10-to14-daycourseofeitherIVorIMpenicillin. Penicillin-allergicpatientsshouldbedesensitizedtopenicillinifpossible;ifnot,ceftriaxoneisan alternativeoption.

ThesuccessoftherapyisjudgedbothbyclinicalimprovementandbynormalizationofCSF abnormalities.Followingthecourseoftreatment,patientsshouldhavearepeatCSFanalysisperformed every3to6months.Failureofthecellcounttodecreaseby6monthsoroftheCSFVDRLtodeclineat least4-foldby1yearareindicationsforrepeattreatment.

LymeDisease:NeurologicManifestations

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LymeisspreadthroughthebiteofinfectedIxodesticks.Thesesameseedshowsrelativesize.(Reprinted fromEnglebergNC,DiRitaVJ,DermodyTS.Schaechter’sMechanismsofMicrobialDisease.5thed. WoltersKluwerHealth/LippincottWilliams&Wilkins;2012.)

LikeTreponemapallidum,Borreliaburgdorferi,thecauseofLymedisease,isaspirochete.Similarto syphilis,whentheprimaryinfectiongoesuntreated,theorganismcandisseminatetootherorgans.Other thantheskinandjoints,thenervoussystemisthemostcommonlyaffectedorgansystem.Reminiscentof neurosyphilis,nervoussysteminvolvementinLymediseasecanpresentinseveralways.

 Central nervous system involvement. Meningeal seeding presents like a typical aseptic meningitis. Symptoms includefever, headache,neck stiffness,andphotophobia. IfCSFanalysis is performed, itwillshow mild pleocytosis, moderate elevationinprotein,andnormal glucose.Far lesscommonly,patientscandevelopsignsandsymptomsofencephalopathyorencephalomyelitis, withbrainandspinalcordinvolvement.However,mostpatientswithLymediseasewhocomplainof headache,mild cognitive impairment, or memory deficits probablydo nothaveactualinfectionof theCNS;rather,justaswithothernonspecificsymptomssuchasfeverandfatigue,thesepatientsare probablyexperiencingsymptomsthatfrequentlyaccompanyanyinflammatoryprocess. Peripheralnervoussysteminvolvementis common.Anycranial nervecanbe affected,but most often it is the seventh cranial nerve that is involved, producing a facial palsy. Inendemic areas, patientswithfacialpalsyshouldbetestedforLymedisease.Mostcasesareunilateral,butbilateral involvementdoesoccur.Otherperipheralnervescanbeaffectedaswell.Radiculoneuritistypically presentswithpain, oftenaccompanied bysensory or motor findingsandhyporeflexia;the clinical picturecanmimictypicalmechanicalradiculopathies(seeChapter11)suchassciatica.

ThediagnosisofnervoussystemLymediseaserequiresclinicalevidenceofneurologicinvolvement alongwithapotentialtickexposureandapositivebloodserology.CSFanalysisistypicallynot

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performedinpatientswithperipheralnerveinvolvementormildnonspecificsymptoms,butitis recommendedinpatientswithmeningitisifonlytoruleoutothermorethreateningpathogens.TheCSF willusually,butnotalways,testpositiveforLymeantibodies.Aswithneurosyphilis,thesensitivityof PCRtestingistoolowtobeuseful.

AllpatientswithconfirmedLymediseaseshouldbetreated.Oraldoxycyclineremainsthedrugof choiceevenforpatientswithneurologicinvolvement,withtheexceptionofthoserarepatientswith encephalitis;theyrequiretreatmentwithIVceftriaxone.

Box8.6Post-LymeSyndrome

SomepatientswhohavebeentreatedappropriatelyforLymediseasecontinuetoexperience nonspecificsymptomsthatmayhaveaneurologicflavor—headache,generalizedweakness, andimpairedcognitivefunction.Thesepatientsaresufferingandtheirsymptomsshouldbe takenseriously,butthereisnoevidencethattheyhaveongoinginfection.Thecauseoftheir symptomsisnotcurrentlyunderstood.Additionalantibiotictherapywillnotbehelpful.

COVID-19:NeurologicManifestations

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Thebynowall-too-familiarpictureoftheSARS-CoV-2virus.

TheneurologicmanifestationsofCOVID-19,thediseaseassociatedwiththeSARS-CoV-2virus,are,like everythingassociatedwiththispathogen,proteantosaytheleast.Itiseasiesttogroupthemintoseveral categories:

Secondary manifestations of the underlying disease, such as headache and dizziness (just as one mightseewithanyfebrileillness) Encephalopathy/encephalitis.Manypatientspresentwithalteredmentalstatus,butitremainsunclear if this is the result of true CNS infection (encephalitis) or is simply secondary to the effects of systemicinfectionandconsequentmetabolic derangements(encephalopathy). Nonspecific but very realanddebilitatingcognitivesymptomsmaypersistformanymonthsinsomepatients. Anincreasedriskofbothischemicandhemorrhagicstroke,eveninyoungpatients.Thisappearsto reflect the hypercoagulable state associated with the excess inflammatory response that is responsibleforsomanyoftheseverecomplicationsofthedisease. Peripheral and cranial nerve involvement, including, in many patients with COVID-19, a loss of tasteandsmell Skeletalmuscledamage,whichcanleadtorhabdomyolysis

AFewOtherCNSInfectionstoKnowAbout

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Neurocysticercosis

Neurocysticercosis(NCC)iscausedbythelarvalstageoftheporktapeworm,Taeniasolium.NCCisthe mostcommonparasiticdiseaseofthecentralnervoussystemandthemostcommoncauseofacquired epilepsyintheworld.ItisendemicinLatinAmerica,Asia,Africa,andIndia.

Thecysticercosislifecycleresultsin3phasesofdisease:(1)theinitial(orviable)phaseisusually asymptomatic;(2)thedegeneratingphaseissymptomaticowingtoaninducedinflammatoryresponse;and (3)thenonviablephase,inwhichthecysticerciresolveandcalcify.IntraparenchymalNCCisthemost commonform,characterizedbyoneormorecystswithinthebrainparenchyma.Symptomsvarybasedon cystlocation,butseizuresarethemostcommonpresentation.Feverisoftenabsent.Extraparenchymal formsincludeintraventricular,subarachnoid,ocular,andspinaldisease.Thediagnosisisbasedon clinicalsymptoms,epidemiologicexposure,andconsistentneuroimagingfindings.

ScansfromdifferentpatientswithNCC,showingthedifferentstagesofthedisease:(A)theviablestage onFLAIRMRI,withasinglenonenhancingcyst;(B)thedegenerating(i.e.,enhancing)stageon postcontrastMRI,withasingleenhancingcystsurroundedbysignificantedema;and(C)thenonviable (i.e.,calcified)stageonCT,withseveralscatteredcalcifiedcysts.(CourtesyofJonathanHoward.)

Initialtreatmentshouldbefocusedonthemanagementofelevatedintracranialpressure,theresultof diffuseedemacausedbyahighcystburden(steroidsarefirst-linetherapy),andseizurecontrol. Antiparasitictherapywithalbendazoleandpraziquantelisindicatedforpatientswithviableor degeneratingcystsonimaging,butshouldbeavoidedinthosewithahighcystburdenbecauseofthe dangerofworseningtheinflammation.

Leprosy

Leprosywasforthousandsofyearsbelievedtobe,invariousforms,ahereditarydisease,acurse,ora punishmentfromGod.We’velearnedafewthingsovertheyearsandnowknowthatthediseaseiscaused byMycobacteriumleprae,anacid-fastbacillusthatwasidentifiedinthe1870sbyDr.GerhardHenrik ArmauerHansen(leprosyisalsoknownasHansendisease).Despiteeverythingwenowunderstand aboutleprosy,andinpartbecauseofthedramaticallyreducedprevalenceofthediseaseoverthepast severaldecades(mostcliniciansintheUnitedStateswillneverseeasinglecase),itremainsafearedand largelymisunderstoodillness.Leprosyisrarelylife-threatening.Itisnothighlycontagious,andtreatment

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iseffective.

Today,themajorityofcasesoccurindevelopingcountries.Riskfactorsincludeolderage,prolonged closecontactwithaffectedpatients,andexposuretowildarmadillos(themechanismoftransmission fromarmadillotohumanisunclear,butarmadillosinthesouthernUnitedStatescomprisealarge reservoirofM.leprae).Puttingasidearmadillos,transmissioninmostcasesisthoughttooccurvia respiratorysecretions.Cutaneouslesionsandperipheralnervedamagearethemajorclinical manifestations;Mycobacteriumlepraegrowsbestincoolertemperatures,henceitspredilectionforthe skinandsuperficialnerves.

Anarmadillo.Itisunclearifthisonecarriesleprosy.

Therearenumeroustypesofleprosy,buttwoinparticularareimportanttoknow.Thetuberculoidform ofthediseaseislimitedtohypopigmentedskinlesionsthatareassociatedwithtenderenlargednerves andpredominantlysensorynervedamage,whichcausesareasofdecreasedsensationtypicallyinand aroundtheskinlesions.Thelepromatousformofthedisease,amorediffuseformthat’sseenmostoften inimmunocompromisedpatients,characteristicallycausesmorewidespreadcutaneouslesionswithmore extensivesensorylossthatcanresultinseverebodyanddigitaldeformities.Motorneuropathies,body hairloss(predominantlyaffectingtheeyebrowsandeyelashes),andcollapseofthenasalseptumcanalso occur.

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Lepromatousleprosycancausethelossofeyebrowsandeyelashesaswellasnasalseptalperforation andcollapse.(ReprintedfromGargSJ.Uveitis.2nded.WoltersKluwer;2018.)

Thediagnosisisbasedpredominantlyonclinicalfindings;skinbiopsyandtissuePCRtestingcanhelp

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