Prasad Hanagandi, Asim Bag, Lazaro do Amaral, Santanu Chakraborty Thanh Nguyen, Rafael Glikstein, John Woulfe, Gerard Jansen

1. The Ottawa Hospital, University of Ottawa, Canada2. University of Alabama at Birmingham, Birmingham, AL3. Medimagem &Hospital da Beneficência Portuguesa and Hospital São José- São Paulo ,Brazil

Acquired Focal and Diffuse White Matter Pathologies -A Practical approach to Radiologist's Dilemma. Role of Multimodality Imaging, Histopathology and Laboratory correlation

eEdE -29

No Disclosures

Purpose:

• In this education exhibit, we will describe• An image-based practical approach to acquired white

matter abnormalities in adults.

• A clinico-radiological algorithm demonstrating how to approach different white matter lesions in a day-to-day clinical practice.

• Examples of how to use this algorithm in some common and rare diseases.

Approach to the diagnosis:Ask yourself all these questions sequentially

• What is the clinical presentation?• Careful evaluation of T2-weighted images

is the key to the diagnosis:

– Is the lesion diffuse & confluent, non-discrete or discrete? if discrete, how many are they?

– Where is/are the lesion(s)?• Periventricular/pericallosal• Subcortical

– Is the adjacent cortex involved?

• Deep cerebral (in the centrum semiovale an in the corona radiata)

• Brain stem (Is it central or periphery?)• Cerebellum• Only callosal involvement??• Multidistributional

– Additional questions to ask:• Is it bilateral symmetrical?• Is temporal lobe white matter involved?

– Is it periventricular?– Is it anterior temporal lobe?

• Is there diffusion restriction?• Is it holo-lesional?• Is it at the periphery?

• Is there any enhancement?– Is it ring-like?– Is it incomplete ring?– Is it holo-lesional?

• No clue?– How is the perfusion?– How is the spectroscopy?

• Still no Clue??– What are the CSF findings?– What is the serum chemistry

• Still no clue???– Let’s consider for biopsy.

Approach to the diagnosis:Ask yourself all these questions sequentially

• What is the clinical presentation?• Careful evaluation of T2-weighted images is the

key to the diagnosis: Look for– Where is/are the lesion(s)?

• Periventricular/pericallosal• Subcortical

– Is the adjacent cortex involved?• Deep cerebral (in the centrum semiovale an in the

corona radiata)• Brain stem (Is it central or periphery?)• Cerebellum• Only callosal involvement??• Multidistributional

– Is the lesion diffuse or discrete? if discrete, how many are they?

– Additional questions to ask:• Is it bilateral symmetrical?• Is temporal lobe white matter involved?

– Is it periventricular?– Is it anterior temporal lobe?

• Is there diffusion restriction?

• Is it holo-lesional?• Is it at the periphery?

• Is there any enhancement?– Is it ring-like?– Is it incomplete ring?– Is it holo-lesional?

• No clue?– How is the perfusion?– How is the spectroscopy?

• Still no Clue??– What are the CSF findings?– What is the serum chemistry

• Still no clue???– Let’s consider for biopsy.

Clinico radiological algorithm

Diffuse confluent white matter disease

No neurologic symptoms

Small vessel disease

Prior radiation treatment

HIV encephalopathy

CADASIL

With neurologic symptoms

Asymmetric

Infectious1. HSV encephalitis

2. PML

White matter disease of systemic causes

Tumor1. Gliomatosis Cerebri

2. Lymphomatosis cerebri

Symmetric

CADASIL

White matter disease of systemic causes

Clinico-radiological algorithm

Diffuse white matter diseases of systemic

causes

Asymmetric

Infection

PML

HSV encephalitis

Metabolic 1. PRES

Bilateral symmetrical

Autoimmune 1. Hashimoto encephalitis

Metabolic disturbances

1. Hyperammonemia2. Hypoxic injury3. Hypoglycemia

Toxic leukoencphalopathy 1. Methotrexate encephalopathy

PRES: Posterior reversible encephalopathyPML: Progressive multifocal encephalopathy

Focal non-discreteLeukoencphalopathy

Subcortical

1. PRES2. Low grade glioma/cortical dysplasia3. Vasculitis4. ARIA, ABRA5. PML6. ADEM7. MELAS8. Cerebral vein thrombosis

Deep cerebral white matter

1. Small vessel disease2. Infarct3.PML4. Vasculitis5. Methotrexate encephalopathy6. Angiocentric lymphoma

Temporal lobe white matter

CADASIL

Periventricular

1. Small vessel disease2. MS3. CNS lymphoma

Mesodiencephalic junction

Behcet’s disease

Brainstem

1. Small Vessel disease2. Brainstem Glioma3. Central variant of PRES 4. Osmotic demyelination5. Rhombencephalitis6. NMO

Cerebellum

1. PML2. Cerebrotendinous xanthomatosis3. AV fistula

CADASIL: Cerebral autosomal dominant arteriopathy, subcortical infarct and leukoencephalopathy

ARIA: amyloid related imaging abnormalityABRA: Amyloid beta related angiitisADEM: Acute disseminated encphalomyelitisMELAS: Mitochondrial enchalopathy,lactic acidosis, stroke-like syndromeMS: Multiple sclerosisNMO: Neuromyelitis optica

Subcortical nonfluent white

matter abnormalities

Hypertensive emergencyImmunomodulator/cancer

chemotherapyPRES

History of seizureNo enhancement

No diffusion restriction

±Focal mass effect Low grade glioma

No mass effect±

Radiation band towards ventricle

Cortical dysplasia± H/O connective tissue

disorder±enhancement±Hemorrhage

± diffusion restrictionVessel lumen irregularity

Vasculitis

Age >45-50History of amyloid modifying drugs

Micro- macrohemorrhage± enhancement

± diffusion restriction

ARIAABRA

H/O Immune deficiencyNO mass effect

Diffusion restriction at the advancing edgeNO enhancement

PML

Prodromal historyLesions at other locations,

particularly art basal ganglia± Enhancement

±Diffusion restriction ADEM

Multiple episodes of focal neurologic deficits

Family history in the mother ‘s sideDiffusion restriction

Increased lactate peak

MELAS

FLAIR signal and T1 hyperintensity in the

Adjacent cortical vein± diffusion restriction

Cortical vein thrombosis

Focal non-discrete deep cerebral white matter lesion

Asymptomatic Small vessel disease

Acute onsetHolo-lesional Diffusion restriction

Infarct

H/O Methotrexate therapySubacute onset

Holo-lesional diffusion restrictionMethotrexate encephalopathy

H/O immunodeficiencySub acute onset

Diffusion restriction at the margin PML

H/O autoimmune disease (lupus, Sjogren etc. )

HeadacheVessel wall irregularity on

angiogram

Vasculitis

Subacute onsetDiffusion restriction

Nodular/Perivascular pattern of enhancement

Angiocentric LymphomaGranulomatous vasculitis

Non discrete brainstem white matter lesions

Central ponsNO symptoms

Small vessel disease

Central pons, sparing peripheryH/O Hyponatremia or alcoholism

± Diffusion restrictionOsmotic demylaination syndrome

Involvement of the midbrain± involvement of thalamus

No overt mass effectNo enhancement

Behcet disease

Diffuse brainstem enlargement with increased FLAIR signal

Acute presentation Hypertensive urgencyImmune modulator/chemotherapy

LupusCentral variant of PRES

Subacute presentation1. Brainstem glioma

2. Rhombencephalitis

Involvement of the floor of the 4th ventricle

(Area prostrema)NMO

Discrete white matter lesion

Subcortical

1. Small vessel disease2. MS3. Metastasis4. Ganglioglioma/DNET

Deep cerebral

1. Small Vessel disease2. Lacunar infarct3. MS4. Border zone infarct

Callosal

1. MS2. Reversible splenial abnormality3. Susac syndrome4. Marchiafav-Bignami syndrome

Periventricular/pericallosal1. Small vessel disease2. MS3. Lacunar infarct

Brain stem MS

Cerebellum MS

Examples

Case: 1.65 Year normotensive male presenting with headache and subacute onset (Over several days) visual field deficits.

Image Analysis:Pattern: Patchy non-discreteLocation: SubcorticalNumber: Multifocal Diffusion restriction: No

Associated Clues: 1. Microhemorrhage2. No appreciable

enhancement

Pertinent negative clues:NO sinus thrombosisNO arterial OcllusionLow perfusion

H and E stain and Beta Amyloid stain confirm the diagnosis of Amyloid Angiopathy

Diagnosis: Amyloid Angiopathy

Case analysis:– Older patient, subacute etiology, no

hypertensive urgency– Subcortical non-discrete lesions– Microhemorrhages– No diffusion restriction– No enhancement

Case 2:24 Year female presenting with multiple episodes of headache seizures and right sided weakness.

T1W , FLAIR and T2W images depict confluent area of T2-FLAIR signal abnormality in the left posterior frontal and parietal shite matter with no significant mass effect.

T2W coronal, FLAIR sagittal images depict similar white matter changes.Multiple punctate foci of microhemorrhage are noted on the GRE sequence. Focal leptomeningeal and perivascular space enhancement is noted on the post gadolinium axial image.

MR spectroscopy reveals Decreased peak heights of all metabolites.

Lumen

Adventitia

Media

Internal elastic lamina

H & E stain reveals thickening of the tunica media with inflammatory changes surrounding the adventia representing features of Primary CNS angiitis

Diagnosis:Primary CNS Angiitis

• Case analysis– Young female patient (Unlikely to be ABRA)– Non discrete subcortical white matter lesion– Absence of other lesions (unlikely to be ADEM)– Presence of microhemorrhage– Leptomeningeal enhancement– Lack of choline peak (Unlikely to be tumor or acute

demyelination

Case 3.63 Year male presenting with subacute onset seizures and left sided weakness.

T2W and FLAIR images depict confluent area of hyperintense signal abnormality in the right frontal subcortical white matter with minimal mass effect and Diffusion restriction. Nodular and linear enhancement is predominantly centered around the perivascular spaces on the post gadolinium images.

H & E stain shows diffuse sheet of lymphocytes encasing the vessel ( arrows) .CD20 immunostaining positive for lymphoma.

Diagnosis:Angiocentric Lymphoma

Vessel lumen

lymphocytes

CD20 immunostaining positive for lymphoma

• Case Analysis– Subacute onset– Deep cerebral non-discrete white matter disease– No significant mass effect– Nodular and perivascular enhancement– Diffusion restriction

Case 4:65 Year male presenting with subacute onset of altered level of consciousness and seizures.

T2W and FLAIR images depict confluent area of hyperintense signal abnormality in both cerebral hemispheres with nodular and linear enhancement on the post gadolinium images. Diffusion restriction is predominantly noted in the central deep white matter.

DiagnosisIntravascular Lymphoma

H & E stain showing sludging of the vessel lumen by lymphocytes (arrow) . CD45 immunostaining positive for lymphoma (arrow).

• Case analysis– Subacute onset– White matter lesions are non discrete, multiple,

involves subcortical, deep cerebral and periventricular white matter.

– Positive diffusion restriction– Perivascular enhancement

Case 5. 51 Year female HIV Positive and low CD4 count presenting with seizures and abnormal behavior

T2W and FLAIR images depict confluent areas of hyperintense signal abnormality in both cerebral hemispheres extending into the parieto-occipital subcortical and deep white matter. Diffusion restriction is noted along the periphery of these lesions with no enhancement on the post gadolinium images. Generalized Volume loss is noted . Diffusion restriction ,lack of mass effect and no enhancement are the key features.

H & E stain showing enlarged oligodendrocyte infected with PML virus (arrow). PML virus probe stain demonstarting the viral inclsuion bodies within the infected oligodendrocyte (arrow).

Diagnosis:PML

• Case analysis– Immunodeficiency patient– Diffuse and confluent white matter

lesions– Absence of mass effect– Absence of enhancement– Diffusion restriction at the advancing

edge

Case 6. 46 Year male presenting with left sided weakness and facial paresthesia.

T2W and FLAIR images depict confluent hyperintense signal abnormality in the right posterior frontal and parietal subcortical white matter. Please note the mainted morphology of the adjacent cortex. Incomplete ring enhancement is noted with peripheral diffusion restriction . MR spectroscopy shows elevated choline peak and reduced NAA.

LFB stain (Luxol fast blue stain) demonstrates the myelin pallor corresponding to the demyelinating zone and the area of transition with normal myelin staining( arrow) Myelin pallor Normal Myelin

Zone of transition Diagnosis:

Tumefactive MS

• Case analysis– Focal discrete subcortical lesion– Maintained morphology of the adjacent cortex– “Open- ring” or “C” type enhancement with the open

end facing the the gray matter (Key finding)– Peripheral diffusion restriction – High choline peak, low NAA peak

Case 7. 52 Year male presenting with seizures.

T2W and FLAIR images demonstrate confluent areas of infiltrative pattern of hyperintense signal abnormality predominantly involving the right temporal lobe and insular cortex with extension across the midline. Focal diffusion restriction is noted in the right anterior putamen. There is minimal mass effect with effacement of cortical sulci. However there is no midline shift.

Intense enhancement with elevated rCBV is noted in the right anterior putamen focus on perfusion study. Rest of the infiltrative white matter changes do not exhibit any obvious enhancement.

Ki-67 proliferation marker showing high proliferation index.

Diagnosis:Gliomatosis cerebri

• Case analysis– Older patient– Diffuse confluent involvement of >3 brain lobes

associated with mass effect (Key finding)– Focal area of enhancement with increased rCBV (Key

finding)

Conclusion

• Pattern recognition of the T2 abnormality is the key to successful diagnosis of the white matter lesions– Remember the clinical presentation– Assess lesion morphology– Assess lesion(s) distribution– Look for suggestive clues from

• Post contrast imaging• Diffusion imaging• Perfusion imaging• Spectroscopy• Angiography

– If no clue: look for appropriate CSF and blood tests– If still no clue: Suggest biopsy