central nervous system infection: radiological patterns
TRANSCRIPT
Central nervous system infection:Radiological patterns
RAD Magazine, 42, 494, 13-15
Dr Luke DixonSpR radiology
Dr Farah Alobeidi Consultant neuroradiologist
Department of neuroradiology, Charing Cross Hospital,Imperial College NHS Trust, London
Overview Infections of the central nervous system (CNS)can be highly debilitating and life threatening. Afavourable prognosis relies on rapid recognitionand early targeted treatment. Imaging plays apivotal role in diagnosis and in assessing treat-ment response. Unfortunately, the overlap of dis-ease patterns and radiological entities, togetherwith the evolution of CNS infections, for examplethe emergence of multi-drug resistance and HIV,often makes diagnosis difficult or delayed. Weaim to provide a pragmatic approach to adultCNS brain infections by reviewing common imag-ing patterns. Salient clinical and radiological fea-tures will be highlighted to differentiate fromnon-infectious disease mimics. Finally, we shallrecognise the particular difficulties of diagnosingand monitoring CNS infection in the immuno-compromised patient. ApproachCNS infections have considerable radiological overlap withnon-infectious disease. Correlation with patients’ demograph-ics, clinical presentation and other investigations is essential.CT is limited in diagnosis; its main role is to provide rapidassessment of emergency complications such as hydro-cephalus, raised intracranial pressure and haemorrhage.MRI is the primary study for detailed characterisation.Important sequences include: Fluid attenuated inversionrecovery (FLAIR), T2-weighted, T1-weighted post-gadoliniumand diffusion weighted imaging (DWI). We recommend clas-sifying the imaging pattern into two broad categories: 1) dif-fuse and 2) focal. Within these groups it is important todelineate involved anatomical compartments, for example,meninges versus parenchyma. Defining whether the diseaseis multifocal also matters, as this implies haematogenousspread as opposed to a single focus which may signify localspread. Finally, serial imaging is vital. The evolution ofimaging appearances not only helps to narrow differentialsbut follow-up imaging is essential to assess treatmentresponse.
Diffuse patternExtra-axialExtra-axial infections include meningitis and empyema. Itis vital to review the paranasal sinuses, mastoid air cells
and middle ear, as infection can spread from these sites.
MeningitisDiagnosis of meningitis is primarily based on clinical find-ings like fever and signs of meningism, plus laboratory tests,such as CSF analysis. Imaging is neither sensitive nor spe-cific for meningitis; its main role is to judge risk of hernia-tion from lumbar puncture and to assess complications suchas hydrocephalus, venous thrombosis and ischaemia. Thereare, however, MR imaging findings which support the diag-nosis. Abnormal subarachnoid hyper-intense signal can occuron FLAIR due to increased CSF protein, although this canbe artefactual or present in other conditions like subarach-noid haemorrhage.1 Restricted diffusion in the cerebral sulciis similarly not specific but is more prevalent in bacterialas opposed to viral meningitis.2 Abnormal enhancement ofthe pia occurs in about 50% of patients.3 Fine, linearenhancement along the sulci is typical in bacterial and viralmeningitis while thick, nodular enhancement in the basalcisterns is suggestive of tuberculosis (TB) or a non-infectiousaetiology such as sarcoidosis and carcinomatous meningitis.4
Basal TB leptomeningitis is associated with an obliterativeproximal intracranial arteriopathy, with infarcts mostcommonly in the basal ganglia and internal capsules(figure 1).5,6
EmpyemaAn empyema is a collection of pus in either the extraduralor subdural space. Causes include sinusitis, mastoiditis,meningitis and as a complication of surgery or trauma.7 Akinto extra-axial haematomas, extradural empyemas tend tobe lentiform versus subdural collections which are crescentic.In both there is enhancement of the surrounding capsule.In subdural empyema the subjacent parenchyma can showabnormal signal due to local oedema and ischaemia, this isless frequent in extradural empyema and belies the greaterrisks associated with a subdural empyema (15% mortality).8
Although CT is often adequate for the diagnosis, restricteddiffusion on MR is a reliable finding that differentiates fromeffusions and chronic haematomas which are often insepa-rable on CT (figure 2).2,9
ParenchymalHerpes encephalitisHerpes simplex encephalitis (HSE) is the most common viralencephalitis.10 Patients present with fever, headache, seizuresand focal neurology.11 Untreated HSE has a high mortalityof 70% emphasising the need for prompt diagnosis and treat-ment.9 Imaging typically reveals bilateral, asymmetricinvolvement of the limbic system and insular. CT is oftennormal but can show ill-defined hypodensity and haemor-rhage. MRI is superior in showing the extent of inflamma-tion, best demonstrated by increased signal on FLAIR(figure 3). Associated haemorrhage manifests as foci ofT1-shortening and susceptibility on gradient echosequences.12 The presence of enhancement is variable.Restricted diffusion is an early, sensitive finding whichoccurs directly from local inflammation or secondary toseizure phenomenon.13,14
Imaging mimics include MCA infarcts, autoimmuneencephalitis and gliomas. HSE typically spares the basalganglia, which are commonly involved in MCA infarcts.Autoimmune encephalitis is often indistinguishable but isclassically more symmetrical and gliomas are usually moreindolent in presentation.9,15
RhomboencephalitisRhomboencephalitis is rare, life-threatening inflammationof the brainstem and cerebellum. The most common infec-tious cause is the bacteria Listeria monocytogenes. MRIshows ill-defined T2-hyperintensities, with variable restricteddiffusion. Heterogeneous parenchymal enhancement, whichextends along the cranial nerves, is sometimes present.16
Focal patternPyogenic abscessPyogenic abscesses evolve from cerebritis, a focus of infectedparenchyma. Cerebritis presents radiologically as an areaof swelling, with ill-defined T2-hyperintense signal, variableenhancement and restricted diffusion. As the infection coa-lesces an abscess sealed by a capsule forms. On CT thisappears as a defined, hypodense lesion with an enhancingcapsule. On MRI the cavity is typically T1-hypointense andT2-hyperintense and the capsule is T1-hyperintense andmarkedly T2-hypointense (figure 4).2,9 The appearance ofthe capsule is related to paramagnetic haemoglobin degra-dation products which can cause a ‘dual rim sign’ on SWI,characterised by an outer hypointense ring and a contrastinginner concentric hyperintense rim of granulation tissue. Thisfinding is specific for abscesses and can help differentiatefrom necrotic tumours.17 Abscesses also exhibit thin, smooth,ring-enhancement while tumours usually have thicker, morenodular enhancement. ‘Light bulb bright’ restricted diffusionhelps distinguish from tumours which are usually more vari-able on DWI.18,19 Finally, abscesses often grow towards theventricular system, hence the deepest portion of the cavitywall is the thinnest. They may therefore rupture, causingsecondary abscesses (Daughter cysts) or intraventricularextension and ventriculitis.7 The latter is associated withhigh mortality and is suggested by ventricular wall enhance-ment and intraventricular or ependymal restricted diffusion.9
TuberculosisSince the emergence of AIDS, multi-drug resistance andglobalisation there has been a surge in the incidence of TB.In addition to basal leptomeningitis, TB can also present ina parenchymal form as either a tuberculoma or abscess.Neurological symptoms relate to the mass effect of thelesion. Constitutional symptoms include fever, night sweatsand weight loss.
Tuberculomas are granulomas, which due to haematoge-nous spread classically occur at the grey-white matter junc-tion. Caseating granulomas have central T2-hypointensityand smooth ring enhancement whereas non-caseating gran-ulomas are T2-hypointense and solidly enhancing (figure1).20 Tuberculomas can develop into abscesses which, likepyogenic abscesses, exhibit central T2-hyperintensity andrestricted diffusion.2,9 Unlike pyogenic infections, TBabscesses tend to have thick, nodular capsules.
NeurocysticerosisNeurocysticerosis is caused by the pork tapeworm TaeniaSolium and is the most prevalent parasitic infection in theimmunocompetent patient.21,22 Parenchymal neurocysticerosishas four stages: 1) vesicular, 2) colloidal, 3) granular, and4) calcified-nodular.23 In the vesicular stage the parasiteresides quiescently in cavities. These appear as discrete cyst-like lesions with intrinsic T1-hyperintense dots, which rep-resent the scolex (head of the tapeworm). During thecolloidal stage the parasite dies causing disruption of thecyst and a resultant local inflammatory response, associatedwith incomplete ring-enhancement and surrounding oedema(figure 5).23 In the granular phase the cyst retracts, forminga ring or nodular enhancing granuloma with less surround-ing oedema. Calcification of the granuloma demarcates thenon-active calcified-nodular stage, characterised by punctatehigh density foci on CT and susceptibility on gradient echoor SWI. The presence of multiple cysts at different stagesof development is highly suggestive of neurocysticerosis.21-23
Infrequently, grape-like collections of cysts (racemose) canform in the subarachnoid space, these can rupture causingbasilar meningitis and vasculitis.24 Intraventricular cysticero-sis is difficult to detect and is often most conspicuous onFLAIR sequences. Occasionally ventricular cysts can causeobstructive hydrocephalus.25
ToxoplasmosisToxoplasmosis, caused by the protozoa Toxoplasma gondii,is the most common opportunistic infection in AIDS.26
Faecal-oral transmission from undercooked meat is the mainsource. Symptoms include fever, headache and altered con-sciousness. Neuroimaging shows ring-enhancing lesions withsurrounding oedema and a predilection for the basal gangliaand corticomedullary junction (figure 6). The ‘eccentric-target sign’ relates an asymmetric mural nodule and,although it only occurs in 30% of cases, has high specificitywhen present.27
Toxoplasmosis has overlapping imaging appearances withCNS lymphoma. Features that favour lymphoma includehyperattenuation on CT, subependymal spread, corpus cal-losum involvement and restricted diffusion on MR.28,29 If tox-oplasmosis is suspected, treatment is initiated after whichan interval decrease in lesion size is expected by two tothree weeks. If the lesion is unchanged or increased in sizethen lymphoma or an alternative diagnosis should be con-sidered. Advanced imaging is also useful. MR spectroscopytypically shows raised choline in lymphoma while lactateand lipid peaks are greater in toxoplasmosis.28-30 On perfusionimaging, lymphomas typically have elevated relative cerebralblood volume.31
CNS infection in the immunocompromised patientHIV in combination with advances in oncology, autoimmunedisease treatment and organ transplantation has resultedin a global increase in the number of immunocompromisedpatients. These patients are vulnerable to both atypicalopportunistic and common non-opportinistic infections which,due to variable immune responses, are often diverse inbehaviour and radiological pattern. Here we shall specificallyreview HIV-associated neurocognitive disorder (HAND), pro-gressive multifocal leukoencephalopathy (PML) and immunereconstitution syndrome (IRIS).
HIV-associated neurocognitive disorderHAND encompasses all neurocognitive diseases associatedwith direct HIV infection. HIV penetrates the CNS early ininfection and even with highly active anti-retroviral therapy(HAART) the CNS can act as a sanctuary for ongoing HIVreplication.32 Resultantly cognitive impairment is commondespite good virologic response to therapy. Severe HAND ischaracterised by subcortical dementia, with cognitive, behav-ioural and motor abnormalities. Imaging features includediffuse cerebral atrophy and symmetric T2-hyperintensityin the periventricular and deep white matter with noenhancement (figure 7). Symmetric involvement differenti-ates from PML which is typically asymmetric.9 Theseappearances are non-specific and include toxic and metabolicleukoencephalopathies, nevertheless if this image pattern ispresent the radiologist should always recommend testing forHIV.
Progressive multifocal leukoencephalopathyPML is a demyelinating disease caused by the opportunisticJC virus. HIV infection has the greatest risk of PML butthe disease has also emerged in many other immunocom-promised conditions. Recently, the therapeutic promise ofthe multiple sclerosis immunotherapy natalizumab has beentempered by the observed increased risk of PML.33,34 PML ischaracterised by progressive neurological decline and withouttreatment death usually occurs within months.
MRI shows asymmetric, multifocal, T2-hyperintense whitematter lesions with characteristic involvement of the sub-cortical U-fibres (figure 7).35 The lesions do not typically
enhance and are not associated with mass effect. The pres-ence of restricted diffusion is a sign of active disease pro-gression.36
Immune reconstitution inflammatory syndromeIRIS can occur after commencing HAART in patients withHIV. It is characterised by dysregulated immune reactiva-tion stimulating an excessive inflammatory reaction to pre-existing infectious and non-infectious antigens.37 Infectiousantigens include PML and TB. Presentation usually occurssoon after starting HAART and is typified by paradoxicalclinical deterioration despite improving CD4 counts andreducing viral loads. Imaging appearances are highly vari-able and dependent on the associated antigen. PML-IRIS ischaracterised by multiple white matter lesions which, unlikeconventional PML, are associated with increased mass effectand atypical enhancement (figure 7). TB-IRIS is associatedwith increased leptomeningeal enhancement and largeenhancing tuberculomas.38 Inconstant imaging features makeit challenging to differentiate from other diseases like lym-phoma.
SummaryCNS infections are an expansive disease group with variedclinical and radiological presentations. Imaging is vital fora prompt diagnosis and early life saving treatment.Ultimately, CNS infections remain a challenge and are notalways ‘classical’ in their imaging presentation. Close cor-relation with clinical features and other investigations mustbe emphasised but infection should always be considered asa cause for a neurological presentation.
References1, Singer M B, Atlas S W, Drayer B P. Subarachnoid space disease:
Diagnosis with fluid-attenuated inversion recovery MR imaging and com-parison with gadolinium-enhanced spin-echo MR imaging blinded readerstudy. Radiology 1998;208(2):417e22.
2. Shih R Y, Koeller K K. Bacterial, fungal and parasitic infections of thecentral nervous system: Radiologic-pathologic correlation and historicalperspectives. Radiographics 2015;35 (4):1141-69.
3. Mohan S, Jain K K, Arabi M, Shah G V. Imaging of meningitis and ven-triculitis. Neuroimaging Clin N Am 2012;22(4):557-83.
4. Smirniotopoulos J G, Murphy F M, Rushing E J et al. Patterns of contrastenhancement in the brain and meninges. RadioGraphics 2007;27(2):525-51.
5. Gupta R K, Gupta S, Singh D et al. MR imaging and angiography intuberculous meningitis. Neuroradiology 1994;36(2):87-92.
6. Kalita J, Prasad S, Maurya P K et al. MR angiography in tuberculousmeningitis. Acta Radiol 2012;53(3):324-29.
7. Castillo M. Magnetic resonance imaging of meningitis and its complica-tions. Top Magn Reson Imaging 1994;6(1):53-58.
8. Karampekios S, Hesselink J. Cerebral infections. Eur Radiol2005;15(3):485e93.
9. Aiken A H. Central nervous system infection. Neuroimaging Clin N Am2010;20(4):557-80.
10. Whitley R J. Herpes simplex encephalitis: Adolescents and adults. AntiviralRes 2006;71:141-48.
11. Gennai S, Rallo A, Keil D et al. Elaboration of a clinical and paraclinicalscore to estimate the probability of herpes simplex virus encephalitis inpatients with febrile, acute neurologic impairment. Eur J Clin MicrobiolInfect Dis 2016; Mar 17.
12. Baskin H J, Hedlund G. Neuroimaging of herpesvirus infections in chil-dren. Pediatr Radiol 2007;37(10):949e63.
13. Heiner L, Demaerel P. Diffusion-weighted MR imaging findings in apatient with herpes simplex encephalitis. Eur J Radiol 2003;45(3):195-98.
14. Duckworth J L, Hawley J S, Riedy G et al. Magnetic resonance restricted
diffusion resolution correlates with clinical improvement and response totreatment in herpes simplex encephalitis. Neurocrit Care 2005;3:251e3.
15. Armangue T, Leypoldt F, Dalmau J. Auto-immune encephalitis as differ-ential diagnosis of infectious encephalitis. Current opinion in neurology.2014;27(3):361-68.
16. Alper G, Knepper L, Kanal E. MR findings in listerial rhombencephalitis.AJNR Am J Neuroradiol 1996;17:593-96.
17. Toh C H, Wei K C, Chang C N et al. Differentiation of pyogenic brainabscesses from necrotic glioblastomas with use of susceptibility-weightedimaging. AJNR Am J Neuroradiol 2012;33(8):1534-38.
18. Castillo M. Imaging brain abscesses with diffusion weighted and othersequences. AJNR Am J Neuroradiol 1999;20(7):1193e4.
19. Reddy J S, Mishra A M, Behari S et al. The role of diffusion-weightedimaging in the differential diagnosis of intracranial cystic mass lesions:A report of 147 lesions. Surg Neurol 2006;66(3):246e50.
20. Bernaerts A, Vanhoenacker F M, Parizel P M et al. Tuberculosis of thecentral nervous system: Overview of neuroradiological findings. Eur Radiol2003;13(8):1876e90.
21. Castillo M. Imaging of neurocysticercosis. Semin Roentgenol2004;39(4):465e73.
22. Garcia H H, Del Brutto O H. Imaging findings in neurocysticercosis. ActaTrop 2003;87(1):71e8.
23. Noujaim S E, Rossi M D, Rao S K et al. CT and MR imaging of neuro-cysticercosis. AJR Am J Roentgenol 1999;173(6):1485-90.
24. Kimura-Hayama E T, Higuera J A, Corona-Cedillo R et al.Neurocysticercosis: Radiologic-pathologic correlation. RadioGraphics2010;30(6):1705-19.
25. Rangel-Guerra R A, Herrera J, Elizondo G et al. Neurocysticercosis. ArchNeurol 1988;45(5):492.
26. Smith A B, Smirniotopoulos J G, Rushing E J. From the archives of theAFIP: Central nervous system infections associated with human immun-odeficiency virus infection. Radiologic-pathologic correlation. Radiographics2008;28(7):2033e58.
27. Ramsey R G, Gean A D. Neuroimaging of AIDS. I. Central nervous systemtoxoplasmosis. Neuroimaging Clin N Am 1997;7(2):171-86.
28. Koeller K K, Smirniotopoulos J G, Jones R V. Primary central nervoussystem lymphoma: Radiologic-pathologic correlation. RadioGraphics1997;17(6):1497-526.
29. Camacho D L, Smith J K, Castillo M. Differentiation of toxoplasmosisand lymphoma in AIDS patients by using apparent diffusion coefficients.AJNR Am J Neuroradiol 2003;24(4):633-37.
30. Batra A, Tripathi R P, Gorthi S P. Magnetic resonance evaluation of cere-bral toxoplasmosis in patients with the acquired immunodeficiency syn-drome. Acta Radiol 2004;45(2):212e21.
31. Ernst T M, Chang L, Witt M D et al. Cerebral toxoplasmosis and lym-phoma in AIDS: Perfusion MR imaging experience in 13 patients.Radiology 1998;208(3):663e9.
32. Saylor D, Dickens A M, Sacktor N et al. JC1 HIV-associated neurocognitivedisorder – pathogenesis and prospects for treatment. Nat Rev Neurol2016;12(4):234-48.
33. Kleinschmidt-DeMasters B K, Tyler K L. Progressive multifocal leuko-encephalopathy complicating treatment with natalizumab and interferonbeta-1a for multiple sclerosis. N Engl J Med 2005;353(4):369-74.
34. Yousry T A, Major E O, Ryschkewitsch C et al. Evaluation of patientstreated with natalizumab for progressive multifocal leukoencephalopathy.N Engl J Med 2006;354(9):924-33.
35. Shah R, Bag A K, Chapman P R, Curé J K. Imaging manifestations ofprogressive multifocal leukoencephalopathy. Clin Radiol 2010;65(6):431-39.
36. Küker W, Mader I, Nägele T et al. Progressive multifocal leukoencephalopa-thy: Value of diffusion-weighted and contrast-enhanced magnetic resonanceimaging for diagnosis and treatment control. Eur J Neurol 2006;13(8):819-26.
37. Post M J, Thurnher M M, Clifford D B et al. CNS-immune reconstitutioninflammatory syndrome in the setting of HIV infection, part 1: Overviewand discussion of progressive multifocal leukoencephalopathy-immunereconstitution inflammatory syndrome and cryptococcal-immune reconsti-tution inflammatory syndrome. AJNR Am J Neuroradiol 2013;34(7):1297-307.
38. Post M J, Thurnher M M, Clifford D B et al. CNS-immune reconstitutioninflammatory syndrome in the setting of HIV infection, part 2: Discussionof neuro-immune reconstitution inflammatory syndrome with and withoutother pathogens. AJNR Am J Neuroradiol 2013;34(7):1308-18.
Figure 1Tuberculosis. 25-year-old woman increased confusion. (A) Axial T2W and (B)T1W post-gadolinium images demonstrate a small tuberculoma with central T2-hypointensity and a smooth ring of enhancement. (C) Axial T1W post-gadolinium image of the same patient shows marked, thick, nodular basal cistern enhancement reflecting severe leptomeningitis. (D) Axial DWI demon-strates bilateral areas of restricted diffusion in both basal ganglia, consistentwith secondary infarcts. (E) A year later after poor treatment compliance axialT1W post-gadolinium and axial T2W. Note the temporal horn dilation. (F) Image demonstrates numerous basal tuberculomas. (G) Coronal CTA imageof same patient demonstrates severe attenuation of the intracranial arteries inkeeping with obliterative arteriopathy.
Figure 2Subdural empyema. 30-year-old woman headache two weeks after surgical exci-sion of glioma. (A) Axial T2W image demonstrates a small left subdural effusionday one after surgery. (B) Axial CT on re-presentation two weeks later, noteslight interval increase in depth of left subdural collection. (C) Axial DWI showsdiffusion restriction in the subdural collection confirming empyema. (D) AxialT1W post-gadolinium demonstrates marked enhancement of the meninges surrounding the collection.
A
A B C D
B C D
E F G
Figure 3HSV encephalitis. 37-year-old woman with fevers and seizures. (A) Axial T2Wimages show asymmetric hyperintense signal and swelling in the right tempo-ral and frontal lobes, insula and hypothalamus. (B) Axial T1W post-gadoliniumshows ill-defined enhancement of the hypothalamus and frontal lobe. (C) AxialDWI and ADC maps demonstrate restricted diffusion in the right temporal andfrontal lobes. (D) Subsequent CT six days after initial MRI shows newparenchymal haemorrhage in the right temporal lobe.
Figure 4Pyogenic abscess. 42-year-old man with meningism and right hemiparesis. (A) Axial T2W image demonstrates an abscess in the left corona radiata whichhas a hyperintense cavity with a hypointense capsule. There is surroundinghyperintense signal reflecting oedema. (B) Axial T1W post-gadolinium showssmooth, thin enhancement of the abscess capsule. (C) Axial DWI demonstratesintra-cavity restricted diffusion. (D) Coronal T1W post-gadolinium shows theabscess growing towards the lateral ventricle, note the capsule is thinnest atthis point.
A
C D
B
A B C D
Figure 5Neurocysticerosis. Colloidal neurocysticerosis. (A) Axial T2W demonstrates ahyperintense cyst in the left corona radiata with surrounding oedema (B) T1Wpost-gadolinium images of the same patient, shows associated ring enhance-ment. Note a separate non-enhancing lesion in the left posterior parietal lobe in keeping with vesicular neurocysticerosis. (C) Sagittal T1W demonstratesintrinsic T1-shortening in the posterior parietal lobe lesion in keeping with ascolex. (D) Axial CT demonstrates several punctate calcifications reflecting calcified-nodular neurocysticerosis. (E) Axial FLAIR images of different patientshows a grape-like cluster of cysts closely related to the left lateral ventricle inkeeping with rare ‘racemose’ form.
Figure 6Toxoplasmosis. 42-year-old man, increased confusion. (A) Axial T2W shows aheterogeneous irregular lesion in the left basal ganglia with surroundingoedema and associated mass effect. (B) T1W post-gadolinium images demon-strates irregular ring enhancement.
A
D E
B C
A B
Figure 7CNS infection in the immunocompromised. (A) Progressive multifocal leuko-encephalopathy. Axial T2W images demonstrate multifocal, asymmetrical whitematter lesions. (B) T1W post-gadolinium image of the same patient shows noassociated enhancement. (C) HIV-associated neurocognitive disorder. Axial T2Wimage demonstrates diffuse cerebral atrophy and symmetric T2-hyperintensitiesin the periventricular and deep white matter. (D) Immune reconstitutioninflammatory syndrome. Axial T2W demonstrates nodular hyperintensities inthe left middle cerebellar peduncle initially thought to be PML. (E) Axial T1Wpost-gadolinium image of the same patient shows associated contrast enhance-ment atypical for PML and suggestive of PML-IRIS.
A
C D E
B