INTRODUCTION

In addition to ultrasound, fetal magnetic resonance imag-ing (MRI) is a fast and available imaging technique allow-ing characterization of the fetal brain. In particular, thehigh resolution T2 weighted imaging allows evaluationof normal layered structure of fetal brain aged 24 gesta-tional weeks (GW) and younger, which approximatesfindings on histology [1-3]. There is limited literature onfetal MRI in regard to early cerebral findings in fetuses ofless than 24 GW that might precede or predict develop-ment of polymicrogyria (PMG).

We report the case of a 23GW fetus with bilateral cere-bral cortical and subcortical “cyst-like” lesions thatevolved toward PMG in later fetal and postnatal imaging.The case review includes a comparison with normal 5-layer lamination pattern of the developing neocortex onfetal MRI. We emphasize how the alterations in normallamination pattern may be a clue to the pathogenesis ofPMG and what is available regarding the pathogenesis ofpolymicrogyria in the published literature to date.

CASE REPORT

A 28-year-old female, G1 P1 was referred for fetal MRIat 23 GW for evaluation of abnormal subcortical cystsseen on fetal ultrasound.

The fetus also had symmetrical intrauterine growthrestriction (IUGR) noted on the ultrasound examination.Axial, coronal and sagittal T2 weighted images (Figure 1)demonstrated numerous bilateral posterior frontal andanterior parietal lobes cortical and subcortical cysts.There were no germinolytic cysts.

Cortical zone, subplate and intermediate zone weredisrupted at the level of the cysts. Follow-up MRI at 34weeks (Figure 2) demonstrated complete resolution ofcortical and subcortical cysts. At this time, the cortexappeared nodular and irregular with abnormal gyral andsulcal pattern, consistent with polymicrogyria.

The placenta was found to be hydropic at birth, al-though a detailed pathological analysis was not avail-able. Amniocentesis was offered but refused by thepatient. The pregnancy was uneventful and the motherdelivered at 38 weeks 4 days GA. The birthweight was2360 grams.

Postnatal MRI done at 3 months of age (Figure 3)depicts the full extent of the bilateral perirolandic andoccipital polymicrogyria.

292 Lebanese Medical Journal 2018 • Volume 66 (5)

CCAASS CCLLIINNIIQQUUEE// CCAASSEE RREEPPOORRTTABNORMAL SUBPLATE T2 HYPERINTENSITY INVOLVING THE FETAL BRAININ THE SECOND TRIMESTER: A HERALDING SIGN OF POLYMICROGYRIAhttp://www.lebanesemedicaljournal.org/articles/66-5/case5.pdf

Lena NAFFAA1, Charbel SAADE1, Ghina BERJAWI1, Maria EL HOMSI1, Pascale JARJOURA2

Naffaa L, Saade C, Berjawi G, El Homsi M, Jarjoura P.Abnormal subplate T2 hyperintensity involving the fetal brainin the second trimester : a heralding sign of polymicrogyria. JMed Liban 2018 ; 66 (5) : 292-296.

Naffaa L, Saade C, Berjawi G, El Homsi M, Jarjoura P.Anormal T2 hyperintensité en sous-plaque impliquant le cer-veau fœtal dans le deuxième trimestre : un signe annonçant lapolymicrogyrie. J Med Liban 2018 ; 66 (5) : 292-296.

ABSTRACT • Fetal magnetic resonance imaging (MRI) hasa high sensitivity and specificity in the diagnosis of corticalbrain malformation in fetuses older than 24 weeks gestation-al age.

As sensitivity of fetal MRI diminishes for younger fetuses,radiologist should be familiar with early cerebral signs ap-pearing in the second trimester, heralding the formation ofcortical brain malformation later in fetal life. We focus onpolymicrogyria (PMG), we describe a case of unusual “cyst-like” brain lesions in a 23 gestational weeks fetus thatevolved toward polymicrogyria and we review all reportedcases to date with early cerebral findings that evolved to-ward polymicrogyria.

Keywords : polymicrogyria; fetalbrain; subplate signal

RÉSUMÉ • L’imagerie par résonance magnétique fœtale(IRM) a une sensibilité et une spécificité élevées dans le diag-nostic de malformations cérébrales chez les fœtus de plus de24 semaines d’aménorrhée. Puisque la sensibilité de l’IRMfœtale diminue pour les grossesses précoces, le radiologuedevrait systématiquement rechercher les premiers signes cé-rébraux apparaissant au cours du second trimestre, et pré-curseurs de la formation de malformations du cortex cérébraldans la vie fœtale. Nous nous intéressons particulièrement àla polymicrogyrie (PMG), décrivons un cas de lésions céré-brales inhabituelles de type kystique décelées dans un fœtusde 23 semaines d’aménorrhée ayant évolué en polymicrogyrie,et examinons tous les cas similaires signalés à ce jour ainsi queles résultats cérébraux précoces ayant évolué en poly-microgyrie].

Mots-clés : cerveau fetal; polymicrogyria; anomalie de lasous-plate

1Department of Diagnostic Radiology,American University ofof Beirut Medical Center, Lebanon. 2Department of Obstetricsand Gynecology, Bellevue Medical Center, Beirut, Lebanon.

*Corresponding author: Lena Naffaa, MD.e-mail: ln01@aub.edu.lb

DISCUSSION

As polymicrogyria is a disorder of cortical development,it is important to understand the sequence of brain devel-opment which starts at 7 GW and passes through 3 over-lapping phases; proliferation, migration, and organiza-tion [4-10].

The proliferative phase occurs between months 2-4,during which stem cells in the germinal matrix at theventricular surface differentiate into glial cells and neu-rons. The migratory phase takes place between months3-5 of gestation during which the glial cells send pro-cesses to the cortex creating a scaffold which guidesneurons to the cortical surface. The initial migrationforms a subpial preplate that prevents later migrationsfrom passing into meninges and subarachnoid space.Once this most superficial layer of the cortex, the sub-plate, is in place, it is followed by waves of neuronswhich pass through earlier layers in a pattern that hasbeen termed the inside-outside gradient which ultimate-ly forms a 6-layered cortex. The deepest layer (layer VI)is the first to be formed.

L. NAFFAA et al. – Subplate T2 hyperintensity heralding polymicrogyria Lebanese Medical Journal 2018 • Vol 66 (5) 293

Figure 1. Fetal brain MRI at 23 gestational weeksAxial a & b, coronal and sagittal SSh-TSE images* demonstrateabnormal T2 signal similar to CSF (consistent with the cysts seen onfetal sonogram) predominantly involving the perirolandic cortex andsubcortical parenchyma. There is disruption of the cortical plate,subcortical and intermediate zones. A subtle, but abnormal saw-toothappearance of the cortical rim – best appreciated on the sagittalimage – involves the posterior frontal cortex as compared with theanterior frontal lobe. The lateral ventricles are mildly dilated, likelysecondary to volume loss. In addition, microcephaly with prominentintracranial extra axial CSF spaces are observed.*SENSE-XL-Torso coil, 1.5 T magnet, FOV: 25 cm, TR: 12,500, TE: 120,ST: 3 mm, Slice spacing: 3 mm, Matrix 192 x 155

Figure 2. Fetal brain MRI at 34 gestational weeksAxial a & b, coronal c, and sagittal d, SSh-TSE images* demonstratecomplete resolution of the cortical and subcortical cysts. At this time,the cortex shows definite thickened, nodular surface (thicker low T2signal best seen on the coronal image) with small serrated gyriconsistent with polymicrogyria.*SENSE-XL-Torso coil, 1.5 T magnet, FOV: 25 cm, TR: 12,500, TE: 120,ST: 3 mm, Slice spacing: 3 mm, Matrix 192 x 155

Figure 3. Postnatal brain MRI at age of 3 monthsAxial SPIR T2 a & b*, coronal TSE T2** and sagittal T1 weightedimages demonstrate abnormal small serrated gyri in the cerebralcortices bilaterally with relative sparing of anterior frontal lobes,consistent with PMG. The findings are most apparent in axialimages a & b with abnormally thickened cortex posteriorly involv-ing the temporal and posterior frontal as well as parietal lobes.Note the indistinct gray to white matter interface on T2 weightedimages compared to the more anterior frontal lobe. The findingsare harder to appreciate on sagittal T1 weighted sequenceswhere there is an abnormally smooth contour of the perirolandiccortex with relatively more normal sulcation both anteriorly andin the occipital lobes.*Head coil, 1.5 T magnet, FOV: 23 cm, TR: 5200, TE: 100ST: 4 mm, Slice gaping: 4.4, Matrix: 256 x 203

**TR: 3200, TE: 110, ST: 4 mm, Slice gaping: 4.4, Matrix: 272x204

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The organizational phase is dependent on normalmigration and has the longest duration beginning around22 GW and may last up to the age of 2 years. This organ-ization phase is regulated by protein complexes whichare the products of numerous genes [11]. As a result, asingle gene can interfere at different stages of corticaldevelopment and may control development of multiplecerebral structures such as the commissures includingcorpus callosum, the cerebellum, brainstem and the eyes[12].

The imaging corollaries to the different phases of adeveloping neocortex are seen on Fetal MRI by age-spe-cific lamination patterns [13-15].

Fetal brain MRI is used as early as 20 GW once anybrain abnormality is detected by fetal US [8]. As mostfetal MRIs rely on T2 weighted imaging, Widjaja et al.studied this lamination pattern utilizing T2 criteria inprenatal and postmortem brain MRI of fetuses aged 18 to26 GW [3]. As there is approximately twice as muchwater content in the fetal brain as in an adult brain, thefluid signal intensity helps delineate the different layersof cellular matter (lower T2 intensity). The MRI findingsfor T2 signal intensity on fetal MRIs normally remainrelatively constant between 18 and 23 GW (Figure 4).The outermost layer of lower T2 signal is known as thecortical plate. The relatively higher T2 signal intensitysubplate zone is rich in neuronal processes, but is most-ly comprised of extracellular matrix. This zone containsprocesses from subcortical fibers which have not yetfound their final destination in the cortical plate [2,3,15].The third layer (from superficial to deep) is the interme-diate zone which has relatively lower T2 signal intensityas it contains cell bodies of migrating neurons, prolifer-ating astrocytes and oligodendrocytes. This constitutesthe foundation of fetal white matter [2,3]. The fourth

layer from the surface is the periventricular fiber richzone again, relatively T2 hyperintense as it containsmostly axons, some of which will go on to form the cor-pus callosum. The fifth layer is typically associated withthe germinal matrix and is also known as the ventricularzone. This layer, like the cortical plate, is typically quitelow in T2 intensity as it is highly cellular. The delinea-tion between the subplate layer and its adjacent two lay-ers is typically the easiest to identify at this point. By 25GW, however, the signal of the intermediate zone be-comes similar to the subplate layer.

Signal alterations in the normal subplate and interme-diate zones appearance of a developing neocortex be-tween 18-25 GW can be used as indirect signs for thedetermination of the course of cerebral cortical develop-ment. In our case, the laminar pattern had already beendisrupted as is evident in the images from 23 weeks(Figure 1).

In the classification of malformations of cortical de-velopment, polymicrogyria is commonly accepted toresult from abnormal cortical organization. Neuronalorganization, however, is dependent upon the precedingstep of neuronal migration being undisturbed. It has beenshown that ventricular cells are sensitive to external cues,which can be conveyed by cortical neurons through theirprojecting axons [16]. In our case, the cortical plate wasdisrupted on the images obtained at 23 GW, indicatingan insult during the migrational phase of development.

Abnormal organizational phase of development leadsto disruption of the normal lamination of the cortex. Theresult is a cortex characterized by many small convolu-tions separated by shallow, underdeveloped sulci. Byterm (36-40 GW), the cortex has an irregular, nodularappearance along the pial surface and lacks the typicalsharply defined grey-white matter interface.

294 Lebanese Medical Journal 2018 • Vol 66 (5) L. NAFFAA et al. – Subplate T2 hyperintensity heralding polymicrogyria

Figure 4. Comparison between abnormal (a) and abnormal (b) brain on T2 weighted of 22 gestational weeks fetus.Cystic changes are seen in the periventricular white matter with increased signal intensity.

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Cortical Plate

Subplate Zone

Intermediate Zone

PeriventricularFiber ZoneGerminal Matrix

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The presence of abnormal T2 hyperintensity along thecortical plate of our 23 GW fetal brain, combined withthe absence of the expected laminar pattern is a strongindicator of a disruption involving the cortical subplateand possibly intermediate zones. In this patient, the find-ings were in the context of IUGR and a hydropic placen-ta. These additional findings are commonly associatedwith fetal perfusion abnormalities. As a result, it is like-ly that a hypoxic ischemic insult occurred to the devel-oping neocortex prior to 22 GW. An additional observa-tion for our patient was that the Sylvian and callosalsulci are well-formed, which would help narrow the timeframe for an injury to between 14 and 22 GW.

Furthermore, there is literature documenting that thesubplate is selectively vulnerable to hypoxic-ischemicinjury in preterm infants [17-18]. As the subplate iswhere the thalamo-cortical afferent neurons reside, andis the site of earliest synaptogenesis along with the mar-ginal zone [2,3,15], an insult to normal development ofthese layers could logically evolve toward cortical brainmalformations (Polymicrogyria in our case).

It may, therefore, be important to recognize that thepresence of T2 hyperintensity involving the subplatelayer during a mid-second trimester fetal MRI could be apotential precursor of cortical malformations. The subse-quent imaging in this case allows us to see longitudinalprogression of the finding. If the finding were related totrue cysts, it would be difficult to explain near completeresolution on 34 GW and postnatal imaging. Anotherexplanation to consider for the finding would be a zoneof relatively increased fluid and reduced extracellularmatrix/axons involving the subplate zone which subtendsa thinned cortical plate. These possibilities should be con-sidered in the context of additional published cases re-garding polymicrogyria.

Cases with coexistent encephaloclastic changes andpolymicrogyria have been reported on brain autopsy inmonochorionic twins at 25 GW by Bordarier et al. [19]and in a 27 GW fetus by Richman et al. [20] as well byLevine et al. [21]. These cases likely support our casereport being along the milder continuum of injury duringbrain development. The brain injury seen in the twincases could represent areas damaged beyond repair,while others regions have not been as extensively hit bythe event and suffer sequelae in subsequent phases ofbrain development.

Additional fetal cases of polymicrogyria, gray matterheterotopias and brain damage have been reported onautopsy specimens in monozygotic twins between 22 to32 GW by Laroche et al. [21] and in a 26 GW monozy-gotic twin by Norman [23]. In the 26 GW twin, the insultwas also postulated to occur prior to completion ofmigrational phase due to associated heterotopias. Ano-

ther fetal MRI case report from a 23 GW survivor ofmono-chorionic intrauterine co-twin death described alarge area of encephalomalacia in the left parietal andfrontal lobes associated with multiple abnormal corticalinfoldings which evolved toward polymicrogyria onpostnatal MRI obtained at 5 months of age [24].

Our case adds to a growing body of evidence thatseems to indicate a potential spectrum of brain insultsduring the migrational phase which when milder innature can play an important role in the pathogenesis ofpolymicrogyria. This observation is also concordantwith induced brain injury in newborn rats which resultsin the formation of focal cortical dysgenesis resemblinghuman 4-layer microgyria [25-29]. The contribution tothe evolving body of knowledge from our case is thesequence of events illustrated on fetal MRI which de-monstrates the longitudinal pathogenesis of polymicro-gyria in a singleton gestation without accompanyingencephalomalacia.

A study performed by Rhigini et al. [30.31] demon-strated that lissencephaly may evolve towards polymi-crogyria.

In conclusion, fetal brain MRI can be used as early as20 GW for the detection of any abnormality suspectedon fetal ultrasound. This case along with the others in theliterature emphasizes the potential relationship of a usu-ally nonspecific imaging finding of thinned cortical plateand abnormal T2 hyperintensity in the subplate as beingassociated with polymicrogyria without imaging evi-dence of encephalomalacia. Disturbance of normal lami-nation pattern in developing neocortex of young fetusesare early precursors of polymicrogyria on Fetal MRI. Itis important for the interpreting physician to recognizethis as it has significant implication on patient manage-ment and prognosis.

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