I . CerebrovasCular dIsease

1) Arterial Ischemic Stroke (AIS)

Pediatric AIS is less common and almost 50% of the pediatric AIS are idiopathic. Pediatric strokes can be classified as perinatal (between 28 weeks of gestation and 28 days of postnatal life) or childhood (between 30 days and 18 year of life) ( Figure 1) .

2) Sinus Venous Infarction (SVT)

SVT can occur due to infections, extrinsic compression of the venous sinus by intracranial mass, dehydration, trauma, and hypercoagable. Venous occlusion causes regional venous hypertension with breakdown of the blood brain barrier causing vasogenic edema. (Figure 2).

INTroduCTIoN

Diffusion-weighted magnetic resonance imaging (DWI) provides image contrast that is dependent on the molecular motion of water. This gets substantially altered by many CNS diseases . It has become a useful tool for probing tissue physiology at the cellular level. It enables detection of otherwise subtle abnormalities, narrows the differential diagnosis and provides additional relevant information when combined with routine MR imaging. As a result, DWI plays an important role in pediatric neuroimaging in better characterizing the disease process.

In this poster we will demonstrate the expanded clinical applications of DWI in a number of pediatric brain disorders.

PaTHoPHYsIoloGY

DWI provides a more direct way to assess the extent of tissue injury by measuring the apparent diffusion coefficient (ADC) of water within the imaged voxel. In the brain, factors contributing to the measured ADC include true random diffusion, tortuosity of the diffusion space, cytosolic streaming, exchange times between compartments and restriction by cell membranes.

ClINICal aPPlICaTIoNs

The practical applications of DWI are in identifying regions and patterns of abnormal DWI signal and further characterizing them to low or high ADC’s values. In this poster we will demonstrate various disease processes associated with bright DWI and variable ADC values.

II . dIsorders of alTeraTIoN IN auToreGulaTIoN

1) Status Epilepticus

It is a hypermetabolic state with imbalance in excitatory neurotransmitter and local hyperperfusion due to loss of autoregulation. Prolonged seizures can cause decreased diffusion. Cortical DWI hyperintensity that does not respect vascular boundaries with iso to mildly decreased ADC values are seen in the immediate post ictal period. (Figure 6)

Diffusion Weighted Imaging in Pediatric Neuroradiology

Figure 1. Neonatal Stroke. Axial (a) T2, (b) DWI and (c) ADC performed on day 2. There is loss of grey white matter differentiation in the left MCA territory. DWI there is a sharply marginated bright

lesion with low ADCs in a vascular distribution consistent with acute arterial ischemic infarct and associated cytotoxic edema.

Causes of Decreased ADC Values

1) Cytotoxic edema causing cellular swell-ing and decreased extracellular space e.g. arterial ischemic stroke

2) Spongiform /vacuole formation between the myelin lamellae and intramyelinic edema causing myelin compartmentalization e.g. prion disease.

3) High cellular density with overall reduction in extracellular space, e.g. PNET.

4) Increased viscosity e.g. abcesses, empyema.

Causes of Increased ADC Values

1) Vasogenic edema causing expansion of the extra cellular space e.g. PRES

2) Glial scarring or myelin loss e.g demyelinating diseases

Pallavi Sagar, M.D.; P. Ellen Grant, M.D.Massachusetts General Hospital, Boston, MA • Harvard Medical School, Boston, MA

Figure 3. Neonatal Profound hypoxic ischemic injury with central asphyxia pattern. Axial (a) T2 , (b) DWI and (c) ADC. Loss of the normal low T2 signal is noted in the posterior limb of the internal capsule and VL thalamus. Bright DWI signal and decreased ADCs are seen in these regions presumably due to cytotoxic edema.

Figure 4. Neonatal Hypoxic ischemic injury with peripheral partial asphyxia pattern. Axial (a) T2, (b)DWI and (c) ADC. Faint loss of grey white matter differentiation is noted in the posterior and parasagittal occipital lobes which can be easily overlooked. Diffuse bilateral hyperintense DWI signal with decreased ADCs are easily identified involving primarily the occipital cortex and white matter.

Figure 7. Posterior reversible leukoencephalopathy. Axial (a) Flair, (b) DWI, (c) ADC and 3D TOF MRA. There is focal subcortical T2 hyperintensity involving the right occipital region (arrow). DWI shows increased subcortical ADCs values with regional narrowing of the right posterior cerebral artery on MRA. These findings are consistent with vasogenic edema and associated vasculopathy.

Figure 6. Status Epilepticus. Axial Flair (a & d), DWI (b & e) and ADC ( c & f ) few hours after seizure and follow up MR done 3 days later. There is subtle increased cortical signal in the right parieto-occipital region and pulvinar thalamus on the flair sequence. DWI and ADC map demonstrates bright DWI signal and normal to mildly reduced ADCs in the same regions. Follow up MR performed 3 days later demonstrates near complete resolution of the signal abnormalities suggesting a transient phenomenon of decreased diffusion due to a metabolic stress.

v. deMYelINaTING dIsorders

1) Multiple Sclerosis (MS)

MS is an inflammatory demyelinating process, which can be reversible due to reparative remyelination or become irreversible with tissue loss. Destruction of myelin sheath and axonal loss leads to expansion of extracellular space with a quantitative increase in water diffusion. Occasionally acute MS lesions may have decreased ADC values presumably due to more rapid demyelination. (Figure 17)

2) Acute disseminated encephalomyelitis (ADEM)

ADEM is also an inflammatory demyelinating disease that develops in close temporal relationship to a viral illness or vaccination. The neurologic picture of ADEM usually reflects a multifocal but often monophasic involvement. Mostly elevated ADC values in acute lesions are seen. Although decreased ADC values due to aggressive demyelination has also been reported. (Figure 18)

3) Wallerian degeneration

This is secondary degeneration of axons and myelin sheaths of the descending white matter tracts, due to cortical or subcortical injury. Cortical injury leads to cellular energy depletion of the cell bodies of neurons resulting in axonal swelling. This results in myelin fragmentation and vacuolization into ellipsoids and spheres causing decreased ADC values. This process occurs within 4 weeks of injury, during which conventional MRI is usually negative. (Figure 19)

vI. PedIaTrIC braIN TuMors

The most common pediatric brain tumors include PNET, ependymomas, astrocytomas and glioblastomas. DWI provides information about tumor cellularity and thereby helps in differentiation of different tumor subtypes. PNET are densely packed cellular tumors with decreased extracellular space and cause decreased diffusion in comparison to other tumors types. Evolving ADC changes with treatment may also provide valuable information about tumor response. (Figure 20)

vII. INfeCTIoNs

Bacterial meningitis is a clinical diagnosis and the use of MR is in identifying complications, such as arterial and venous infarcts secondary to septic arteritis and phlebitis. DWI is more sensitive in acute infections by demonstrating more lesions and its complications. In addition DWI is useful at detecting purulent debris in the ventricles, brain abscess and subdural empyemas. (Figure 21)

Figure 17. Multiple sclerosis. Axial (a) T2, (b) post contrast enhanced T1, (c) DWI and (d) ADC. There are multiple foci of T2 hyperintensites in the centrum semiovale, the largest lesion on the right with partial enhancement. DWI shows heterogenous increased signal and the ADC map demonstrates predominantly

increased diffusion, but also shows that the region with brightest DWI signal has decreased diffusion. The region of decreased ADC does not match the area of enhancement and may represent a subtype of active demyelination.

Figure 18. ADEM. Axial (a) T2, (b) Flair, (c) DWI and (d) ADC. There are multiple bilateral scattered foci of T2 and flair hyperintensities involving the subcortical white matter. On DWI, the lesions are bright, predominantly due to T2 shine through.

The ADC map shows signal heterogeneity with decreased ADC values around the periphery of the lesion possibly secondary to a subtype of active demyelination.

Figure 19. Neonatal Wallarian degeneration. Axial (a & b) DWI and (c & d) ADC map at the level of basal ganglia and brain stem is showing focal hyperintensities with decreased ADC values in the posterior limb of internal capsule and anterior

brain stem, on the left side along the course of corticospinal tract. This patient had a grade 4 intraparenchymal bleed with post hemorrhagic venous infarction involving the left periventricular region.

Figure 20. Brain stem PNET. Axial (a) Post contrast T1, (b) DWI, (c) ADC and (d) targeted Multivoxel MR Spectroscopy at TE 135 ms. There is an expansile nonenhancing pontine mass that is DWI bright with isointense to slightly decreased ADCs suggesting a highly cellular tumor. A targeted

voxel from a Multivoxel MRS demonstrates elevated Cho/Cr ratio and a decreased NAA peak but not the classic marked Cho/Cr elevation, possibly due to volume averaging.

Figure 21. Neonatal Citrobacter Abscess. Axial (a) T2, (b) T1, (c) post contrast T1 and (d) DWI. There is bifrontal T2 prolongation, more prominent on the right side with central region of low T2 signal. Findings of white matter liquefaction are more

evident on T1 pre and post contrast images with debris layering in the posterior aspect of the cavities with peripheral rim enhancement. The debris shows bright DWI signal, which corresponded to decreased ADC (not shown) likely due to

a combination of viscous coagulative necrosis and possibly hypercellularity from polynucleated neutrophils in the pus. (Images courtesy of Charles Glasier, MD, UAMS, Little Rock, Arkansas)

Iv. ToXIC aNd MeTabolIC dIsorders

1) Methotrexate Neurotoxicity

Intrathecal or intravenous methotrexate can cross blood brain barrier and cause diffuse or multifocal white matter changes typically in the periventricular region. Alteration in myelin metabolism causing axonal swelling and intramyelinic edema has been proposed. In acute encephalopathy transient and reversible lesions with decreased diffusion can be observed. (Figure 9)

2) Heroin Induced Leukoencephalopathy

Inhaled or intravenous heroin vapor causes spongiform vacuolar degeneration of cerebral white matter. This results in DWI hyperintensity with reduced ADCs due to vacuolar white matter degeneration. (Figure 10)

3) Hypoglycemia

Excitotoxic brain damage can occur with severe hypoglycemia with a blood glucose concentration below 30mg/dl. Decrease diffusion with a posterior predominance involving the parieto-occipital lobes is typically observed, hypothesized secondary to excitotoxic neuronal injury from glutamate and aspartate on the NMDA receptors. (Figure 11)

4) Mitochondrial encephalopathy, lactic acidosis and stroke like syndromes (MELAS)

MELAS is a heterogeneous group of disorders affecting the CNS and skeletal muscles. This is caused by defect in mitochondrial respiratory chain leading to cellular energy depletion resulting in anaerobic glycolysis with lactate production. MRI shows signal change both in the grey and white matter in a nonvascular distribution. MRS usually demonstrate a lactate peak in the affected area. (Figure 12)

5) Kearns-Sayer Syndrome (KSS)

KSS is a rare mitochondrial deletion syndrome involving the muscle, eye and heart. MRI shows abnormal signal in the subcortical and periventricular white matter and deep grey nuclei (globus pallidus and caudate) with decreased diffusion that may persist for years probably due to spongiform change.( Figure 13)

6) Congenital muscle dystrophy with Merosin deficiency (CMD)

CMD involves CNS in form of white matter signal abnormalities. Merosin is a protein present in the basal lamina of the vessel walls and blood brain barrier, which links the extracellular matrix. Its deficiency causes vascular hyper permeability and deficient myelin leading to increased extracellular water with elevated ADC. (Figure 14)

7) Urea Cycle Defects

Disorders of urea cycle leads to hyperammonemia resulting in brain edema. There is often involvement of the bilateral cerebral cortex, subcortical white matter and deep grey nuclei. Decreased ADCs are seen with neonatal onset of disease and although similar to profound hypoxic ischemic brain injury, the pattern of basal ganglia involvement is different. (Figure 15)

8) Sulfite Oxidase Deficiency

Sulfite oxidase is a mitochondrial enzyme responsible for oxidation of sulfite to sulfate, which is an important step in metabolism of sulphur containing amino acids. The acute findings are of diffuse cerebral edema with rapid progression to cystic encephalomacia, cortical necrosis and extensive

cavitating necrosis. (Figure 16)

9) Leukodystrophies

Leukodystrophies are genetically determined metabolic diseases caused by enzyme deficiencies leading to biochemical abnormality which results in hypomyelination or dysmyelination, both of which can progress to demyelination. They are mostly characterized by myelin instability and destruction with increased extracellular water. However, decreased diffusion with low ADCs has been reported in a number of leukodystrophies such as Canavan’s disease, acute stages of adrenoleukodystrophy and in metachromatic leukodystrophy, probably due to ongoing inflammation and intramyelinic edema. The role of DWI is still evolving in this area.

Figure 9. Methotrexate toxicity. Axial (a) T2 and (b) DWI. There is faint T2 hyperintensity in the left posterior centrum semiovale. DWI is more sensitive in demonstrating increased signal in this region and an additional lesion on the right side presumably due to intramyelinic edema which can be reversible.

Figure 10. Heroin induced encephalopathy. Axial (a) T2, (b) DWI and (c) ADC. There is T2 prolongation in the centrum semiovale bilaterally. DWI shows bright DWI signal and reduced ADCs presumably due to spongiform degeneration of the white matter with intramyelinic edema that is known to occur in this disorder.

Figure 11. Neonatal hypoglycemia. Axial (a) T2, (b) DWI and (c) ADC. There is subtle loss of grey white matter differentiation posteriorly. Bright DWI signal and decreased ADC values are noted in the bioccipital cortex and subcortical white matter.

Figure 12. MELAS. Axial (a) Flair, (b) DWI (c) ADC and (d) Single voxel MR spectroscopy at TE 135 ms on the abnormality. A transient lesion in a patient with MELAS presenting with seizures. Note the involvement of the crest of the gyrus of the right frontal lobe on Flair, with corresponding bright DWI and isointense cortical ADCs in addition there is elevated subcortical ADCs. Targeted MR Spectroscopy identified lactate. (arrow)

Figure 13. Kearns Sayer syndrome. Axial (a ) Flair, (b & c) DWI and (d) ADC. Symmetric increased T2 and DWI signal is noted in the deep white matter and globus pallidus. The corresponding ADC values are isoin-tense to slightly decreased. These findings remained unchanged over years. The cause of bright T2 signal and isointense to decreased ADCs is unknown, yet suggests that the increased fluid is not in the extracel-lular space.

Figure 14. Merosin deficient congenital muscular disorder. Axial (a) T1, (b) T2, (c) DWI and (d) ADC. There is bilateral diffuse decreased T1 and increased T2 signal in the white matter sparing the corpus callosum and internal capsule. The areas of white matter involvement correspond to decreased DWI signal and increased ADC values, presumably due to increased extracellular water.

Figure 15. Neonatal Urea cycle defect. Axial (a) T2, (b) DWI and (c) ADC. There is subtle stripe of increased T2 signal coursing through the lentiform nucleus bilaterally. These findings are more conspicuous on DWI with increased DWI signal and low ADCs. In addition, decreased diffusion is noted extending to the caudate and in the VL thalamus, presumably due to cytotoxic edema.

Figure 16. Neonatal Sulfite oxidase deficiency. Axial (a) T2, (b) DWI, (c) ADC on day 4 and (d) follow up T2 after 4 months. There is subtle loss of grey white matter differentiation posteriorly. On DWI there is extensive signal increase and on ADC marked signal decrease involving the cortex and subcortical white matter diffusely. Similar but less marked findings are also noted in the bilateral basal ganglia and portions of the thalamus likely secondary to cytotoxic edema. On followup imaging, there is marked volume loss of the white matter, basal ganglia and to a lesser extent thalami. In addition diffuse ulegyria is noted. The subdural collections are secondary to the marked interval volume loss.

CoNClusIoNs

DWI with accompanying ADC map provides additional useful information to the standard imaging sequences. Pathophysiological mechanisms resulting in both baseline normal ADC values and changes with disease processes are not well understood and therefore caution should be used when prognosticating the outcome of regions with abnormal ADC.

refereNCes

Lovblad KO, Schneider J, Ruoss K, Steinlin M, Fusch C, Schroth G: Isotropic apparent diffusion coefficient mapping of postnatal cerebral development. Neuroradiology 45:400-403, 2003

Lynch JK, Hirtz DG, DeVeber G, Nelson KB: Report of the National Institute of Neurological Disorders and Stroke workshop on perinatal and childhood stroke. Pediatrics 109:116-123, 2002

Grant PE, Yu D: Acute injury to the immature brain with hypoxia +/- hypoperfusionMagn Reson Imaging Clin N Am In Press, 2005

Kim JA, Chung JI, Yoon PH, Kim DI, Chung TS, Kim EJ, et al: Transient MR signal changes in patients with generalized tonicoclonic seizure or status epilepticus: periictal diffusion-weighted imaging. AJNR Am J Neuroradiol 22:1149-1160, 2001

Majoie CB, Akkerman EM, Blank C, Barth PG, Poll-The BT, den Heeten GJ: Mitochondrial encephalomyopathy: comparison of conventional MR imaging with diffusion-weighted and diffusion tensor imaging: case report.

III . TrauMa

1) Diffuse Axonal Injury (DAI)

DAI refers to traumatic white matter injury induced by sudden acceleration-deceleration, rotational and shearing forces leading to axonal stretching, disruption and eventual separation of nerve fibres. DWI is more sensitive and shows variable diffusion. Decreased ADC values are due to axotomy with formation of traction balls and elevated ADC values are secondary to vasogenic edema. (Figure 8)

Posterior Reversible Encephalopathy Syndrome (PRES)

PRES occurs with seizures, hypertension and uremic encephalopathy due to impaired autoregulation with vasodilatation leading to vasogenic edema. It is characterized by transient posterior cortical and subcortical lesions of increased T2 signal with increased or rarely decreased ADC values. (Figure 7)

Figure 8. Diffuse axonal injury. Axial (a & d) Flair, (b & e) DWI and (c & f ) ADC. A right frontal-parietal contusion results in increased signal in the cortex and subcortical white matter on FLAIR and predominately increased ADC values (arrows). Additional subtle hazy increased FLAIR signal is seen in the right greater than left centrum semiovale and splenium with associated increased DWI signal and decreased ADC values due to axonal shear injury. Only mild volume loss was present in these regions on follow-up.

3) Global Hypoxia and Hypoperfusion

Perinatal Hypoxic Ischemic Brain Injury

Hypoxic ischemic brain injury results from a combination of global cerebral hypoxia and hypoperfusion. Two patterns have been described. Partial asphyxia or peripheral pattern with bilateral white matter injury and a profound or central pattern with corticospinal tract, VL thalamus, and perirolandic involvement. Conventional imaging may be negative until 3-7 days after the insult. DWI provides a means of earlier detection of injury especially in the first hours after the insult (Figures 3 and 4).

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Figure 2. Neonatal Deep Vein thrombosis. Axial (a) T2, (b) Susceptibility, (c) DWI, (d) ADC. There is extensive thrombosis of the internal cerebral veins with edema of the basal ganglia. There is diffuse diffusion signal abnormality of the white matter with a combination of vasogenic (arrowhead) and cytotoxic edema (arrows) due to venous hypertension.

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Figure 5. Cardiopulmonary arrest in a 10 year old. Axial (a & d) T2 , (b & e) DWI and (c &f ) ADC within 12 hours of injury and follow-up MR 2 days . The T2 is falsely negative. On DWI there are bright foci involving the posterior putamina and VL thalamus that correspond to foci of decreased ADCs consistent with cytotoxic edema. After 2 days there is interval progression to involve the bilateral basal ganglia, thalami and posterior occipital lobe consistent with delayed cytotoxic edema. The child succumbed to diffuse cerebral injury within 4 days.

Hypoxic Ischemic Injury in the Young Child

Most of the hypoxic or anoxic injuries in young child are a result of choking or near drowning. The initial DWI hyperintensities start in the posterior lentiform nucleus and VL thalamus and can progress over time. Imaging studies performed on the 3-4 day after insult best correlate with clinical outcome. Therefore if the initial imaging in the first 1-2 days is negative, repeat imaging is warranted to convincingly rule out hypoxic brain injury. ( Figure 5)

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