CASE REPORT

Multicystic encephalopathy following prolonged hypoxicischemic insult—a case report

Marcela Chisté & Morton Robinson & Steven Melnick &

Amilcar Castellano-Sanchez

Received: 18 August 2011 /Accepted: 28 December 2011 /Published online: 21 January 2012# Springer-Verlag 2012

Introduction

Multicystic encephalopathy (MCE) is a rare condition inwhich multiple cavities replace the newborn’s brain parenchy-ma [1]. It constitutes one of the abnormalities among thespectrum of pathologic changes that result from hypoxicischemic encephalopathy (HIE) [2]. The earliest recognizablechanges of HIE include minimal foci of brain infarcts andculminates withMCE showing massive necrosis with cavitarylesions reflecting the end stage of severe central nervoussystem (CNS) destruction [2]. HIE may occur in both termand preterm infants [1]. Several different etiological factors,including infectious diseases such as congenital syphilis, lis-teria, cytomegalovirus, toxoplasmosis, Hemophilus spp.,Escherichia coli, herpes simplex virus, and equine encepha-lomyelitis have been associated with MCE [2, 3]. MCE hasalso been shown to occur with maternal intoxication due tobutane or carbon monoxide, maternal trauma, maternal ane-mia, twinning, and complicated labor and delivery [1]. Inaddition, MCE may also be attributed to impaired placentalfunction in preeclampsia or intrauterine growth retardation[2]. After birth, MCE can result from sepsis, prolonged ven-tilation, cardiac arrest, or status epilepticus [4]. All theseentities may produce various degrees of ischemic damage tothe CNS, which is considered to be the driving mechanism ofdisease and most likely etiology of MCE [1, 3]. We report a

rare case of multicystic encephalopathy following hypoxicischemic insult with unique and extreme pathologic findings.

Case report

At 38 weeks of gestation, a 31-year-old primigravida wasadmitted for an urgent C-section because of non-reassuringfetal heart rate monitoring. The mother had adequate prena-tal care, without history of miscarriage or consanguinity;however, pregnancy was complicated by a treated group BStreptococcus infection at 37-week gestation and suspectedpremature rupture of membranes 2 days before delivery.Prenatal screening for syphilis, hepatitis, rubella, HIV, andherpes were negative. During delivery, the amniotic fluidwas meconium-stained and the infant’s APGAR scores were3/5/5 at 1, 5, and 10 min, respectively. Birth weight was2,970 g (95–98th percentile), with a head circumference of34 cm (25–50th percentile). The infant had no respiratoryeffort and no spontaneous movements after delivery andwas immediately intubated and transferred to the intensivecare unit for management of persistent pulmonary hyperten-sion and hypoxic ischemic encephalopathy. Neurologicphysical examination revealed a state of behavioral sleep,unable to arouse. The pupils were equal, round and fixed,nonreactive to light. There was no startle to noise, any gag,suck, and Moro reflexes. No palmar and plantar graspreflexes were seen. The patient had no purposeful move-ments, moving upper and lower extremities with stimula-tion. A hypertonic tonus was noted.

Subsequently, the patient developed multiple complicationssuch as electrolyte imbalance, hypothyroidism, hypoxemia,diabetes insipidus, hypoalbuminemia, thrombocytopenia, andKlebsiella pneumonia. Microscopic examination of the

M. Chisté (*) :M. Robinson :A. Castellano-SanchezDepartment of Pathology, Mount Sinai Medical Center,Miami, FL, USAe-mail: marcela_chiste@yahoo.com.br

S. MelnickDepartment of Pathology, Miami Children’s Hospital,Miami, FL, USA

Childs Nerv Syst (2012) 28:947–950DOI 10.1007/s00381-011-1671-y

placenta and umbilical cord showed chorioamnionitis andfunisitis, respectively.

During this hospital stay, a video electroencephalogramperformed 2 days after birth was markedly abnormal with adiffuse low-voltage background with no reactivity indicat-ing profound encephalopathy. A brain computerized tomog-raphy (CT) performed 6 days after birth showed absentintracerebral perfusion. A brain ultrasound done 12 daysafter birth showed a significantly abnormal brain parenchy-ma for the patient’s age with no convolutional markingsthought to be related to the hypoxic ischemia. There wasalso significant leukomalacia in the periventricular regionespecially on the left side and increased echogenicity in thechoroid plexus of both lateral ventricles, probably represent-ing some element of hemorrhage. Another brain ultrasounddone 24 days after birth continued to show significantprogression of periventricular leukomalacia and persistentbrain edema. Towards the end of the patient’s life, 45 daysafter birth, a brain CT showed a thin small cortical rim ofgray matter with diffuse hypodensity of the cerebral hemi-spheres, and bilateral serpentine calcifications consistentwith laminar necrosis; those findings were supportive ofsevere hypoxic ischemic injury. The patient expired4 months after birth. At autopsy, the patient’s head displayedan impressive turricephalic deformity (Fig. 1). Upon open-ing the calvarium, there were abundant, liquefied, yellowdegenerated, mutiloculated, and hemorrhagic intracranialcontents found in lieu of the brain, brainstem, or cerebellum.No obvious brain landmarks were seen upon examination ofthe intracranial contents. No overt malformations of theCNS or other organs were identified pre- or post-mortem.The striking appearance of this web-like, soft, creamy, andmembranous material was noted under the calvarium andthe base of the skull (Fig. 2a, b).

Microscopically, multiple areas of the specimen demon-strated a layer of dense fibrous tissue, likely representing thedura mater devoid of inflammation or increased vascularity.The underlying tissue showed areas of necrosis, extensiveareas of calcification, increased small and intermediate sizedblood vessels with congestion, and only a minute amount ofresidual nervous tissue was identified (Fig. 3a, b). Suchchanges are similar to those seen in the late stages of aninfarct; which likely corresponds to the pathophysiologythat is thought to explain these cases [1, 3]. We estimatethat the increased number of small blood vessels may be theresult of an angiogenic factor activator driven in these casesby chronic hypoxia/ischemia. In addition, a Luxol fast bluestain for myelin and glial fibrillary acidic protein (GFAP) forglial tissues disclosed a minute amount of glial tissue with-out myelination (Fig. 3c, d).

Discussion

We report on a neonate with severe hypoxic ischemic injuryleading to MCE with its clinical onset shortly after birth.The diagnosis of progressive ischemic damage was con-firmed by subsequent neuroimaging studies and corroborat-ed by autopsy findings described above; such features havebeen described as specific macroscopic and microscopicneuropathological changes after severe, sustained, and pro-found perinatal hypoxia–ischemia [4].

The most recent publication on MCE by Golden andHarding [4] disclosed the findings in a term infant with adevastating encephalopathy and severe neuronal dysfunc-tion immediately after delivery without a known antecedentof prenatal or perinatal hypoxia or distress. The autopsyrevealed replacement of much of the cortex and white matterby a gliotic irregular cystic network, reduction in the volumeof pontine gray matter with loss of neurons, relatively littlegliosis and neovascularization, and finally tegmental brain-stem and thalamic necrosis with extreme loss of neurons andreplacement by fibrillary astrocytes, findings that are re-markably similar to those in our case.

Dambska et al. [5] presented six cases with cysticchanges specifically within the white matter in infantbrains and discussed the variants of this type of neuro-pathological lesions of the developing brain. All casesdescribed by this author showed necrotic changes withinthe hemispheric white matter, leading to formation ofcavities, with or without additional damage of otherbrain structures.

In 1984, Garten et al. [3] reported on 11 cases of severeMCE in young infants and in a 2-year-old child and dis-cussed the various etiologic aspects of this phenomenonoccurring in early infancy. The macroscopic and microscop-ic findings indicated that multicystic degeneration was notFig. 1 Turricephalic deformity of patient’s skull after removal of scalp

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only restricted to the white matter of the forebrain but thatthe cortex was significantly involved, sometimes totally, butmostly with preservation of the severely gliotic molecularlayer. Similar microscopic changes were often true for thebasal ganglia including the thalamus, which nearly alwaysdemonstrated more or less extensive necrosis. The forebrain,the lower brainstem, and the cerebellum were, as a rule, farbetter preserved, and almost never cystic except for in onecase where the midbrain was involved. In two instances, thecerebellum displayed pronounced atrophy of the folia adja-cent to the central white matter. This geographic preserva-tion of certain areas of the brain was not seen in our case andhas not been the experience of other authors.

Weidenheim et al. [1] elucidated the pathogenesis of MCEin eight cases with destructive lesions in gray and whitematter. Neuropathological lesions consisted of extensive

tissue destruction, neuronal loss and gliosis in hemisphericwhite matter, cerebral cortex, basal ganglia, thalamus, cere-bellum, and brainstem tegmentum. All cases showed multiplecysts in the white matter associated with variable degrees ofcortical damage. In the most severely affected cases, thecortical ribbon was almost completely destroyed and only athin rim of gliotic brain tissue containing a few ferruginatedneurons covered the cysts, as was observed in our case.Microscopic examination revealed that neuronal loss wasmore severe in the deeper cortical layers, producing a laminarpattern. There was neuronal loss and gliosis, sometimes withcyst formation, in the brainstem tegmentum, pontine base,medullary olives, and pyramids. Despite a grossly normalappearance in half of the cases, cerebellar pathology wasnoted in most of them (six out of seven) and consisted of focalsclerosis at the folial depths. The extreme pathology of our

Fig. 2 a Opening of the skullrevealing yellow web-likemembranous material. b Lique-fied aspect of intracranialcontents

Fig. 3 a Microscopic pictureshowing areas necrosis,calcifications, and congestedintermediate-sized blood ves-sels. b Layer of dense fibroustissue with increased vasculari-ty. c GFAP stain highlightsminute amounts of glial tissue(arrow). d Luxol fast blue stainshows glial tissue withoutmyelination (arrow)

Childs Nerv Syst (2012) 28:947–950 949

case was devoid of areas of reactive gliosis or classic laminarnecrosis morphology.

Our case is unique due to the extreme, diffuse plethora ofpathology, where the intracranial contents consisted of mul-tiple membranous fragments of pale, yellow soft tissueadmixed with pink–gray membranous tissue. No definitelandmarks of brain tissue were grossly visualized. The mi-croscopic features are similar to those previously describedby others, however, of interest; there is no clear cut etiologythat can explain the massive brain destruction driven byhypoxia–ischemia, nor was there an obvious inherited dis-ease, malformation, or infection that could account for thesesevere pathologic findings.

References

1. Weidenheim KM, Bodhireddy SR, Nuovo GJ (1995) Multicysticencephalopathy: review of eight cases with etiologic considerations.J Neuropathol Exp Neurol 54(2):268–275

2. Schmitt HP (1984) Multicystic encephalopathy—a polyetiologiccondition in early infancy: morphologic, pathogenetic and clinicalaspects. Brain Dev 6:1–9

3. Garten L, Hueseman D, Stoltenburg-Didinger G (2007) Progressivemulticystic encephalopathy: is there more than hypoxia-ischemia? JChild Neurol 22(5):645–649

4. Golden JA, Harding BN (2004) Pathology & genetics: developmentalneuropathology. ISN Neuropath Press, Basel, p 386

5. DambskaM, Kuchna I, Nowicki K (1994) Neuropathological variantsof cystic encephalopathy in infants. Folia Neuropathol 32(1):31–35

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