Agyria-pachygyria: cerebral perfusion studies by 99mTc-HMPAO SPECT [corrected]

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Brain & Development 19 (1997) 138-143

Case report

Agyria-pachygyria: cerebral perfusion studies by 99mTc-HMPA O A b d u l R a h i m A 1 - S u h a i l i a, L~iszl6 S z t r i h a b,*, V a c l a v P r a i s a, M i c h a e l N o r k c aDepartment of Nuclear Medicine, Tawam Hospital, Al Ain, United Arab Emirates bDepartment of Paediatrics, FMHS, United Arab Emirates University, P 0 Box 17666, Al Ain, United Arab Emirates CDepartment of Radiology, Tawam Hospital, Al Ain, United Arab Emirates

Received 22 June 1995; accepted 23 May 1996


Cerebral perfusion was investigated in three patients with agyria-pachygyria by using 99mTc-HMPAO SPECT in order to study the distribution of blood flow. Diffuse cortical hypoperfusion was found in all three infants. The visual cortex was not identifiable in two of the cases. The basal ganglia and cerebellum were prominent by their normal high activity, while tracer uptake was very low in the thalamus. The possible role of improper development of interneuronal connections and abnormal vascular pattern in background of the perfusion defect is discussed. © 1997 Elsevier Science B.V. Keywords: Lissencephaly; Agyria-pachygyria-band spectrum; Cerebral perfusion; SPECT

1. Introduction

Classical lissencephaly or generalized agyria-pachygyria comprises a wide spectrum of malformations ranging from diffuse agyria to subcortical band heterotopia with an overlying pachygyric cortex [1]. These malformations result from the arrest of neurons during migration in the early stage (12-16 gestational weeks) of central nervous system development. Pathologically the condition is characterized by an abnormally thick cortex with four layers. A grading system, recommended by Dobyns and Truwit [1], reflects the severity of the migrational defect from diffuse agyria (Grade 1) to mixed pachygyria and subcortical band heterotopia (when the subcortical bands merge with the deeper layers of the pachygyric cortex) (Grade 5). Subcortical band heterotopia, completely separated from the usually pachygyric cortex [2], appears as Grade 6 in this classification. Lissencephaly can appear as an isolated malformation or can be associated with other abnormalities in several syndromes, the commonest of which is the Miller-Dieker syndrome. Visible or submicroscopic deletions of chromo* Corresponding author. Fax: +971 3 657649.

0387-7604/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved PII 0387-7604(96)00481-0

some 17p 13.3 have been found in most of the patients with Miller-Dieker syndrome and submicroscopic deletions of this region have been detected in some of the patients with isolated lissencephaly [1]. Isolated lissencephaly can be caused by extrinsic factors as well, such as intrauterine infection or perfusion failure [3]. An X-linked form of lissencephaly and subcortical band heterotopia has also been described [4]. Localized or diffuse migrational defects are highly epileptogenic probably due to abnormalities of the local-circuit (inhibitory) neurons [5]. Most of the patients with lissencephaly are epileptic [6]. Developmental disorders with migrational defects such as focal cortical dysplasia and hemimegalencephaly have been studied by SPECT and PET prior to epilepsy surgery [7-11]. Interictal hypoperfusion or hypometabolism of the affected areas were found in the majority of cases and the results were usually attributed to the epileptogenicity [7-11]. Little is known about the vascular supply and vascular reactivity of these brain areas, though their abnormalities could contribute to the development of perfusion and metabolic defects. We report on the perfusion abnormalities found by 99mTc-HMPAO SPECT studies in three children with agyria-pachygyria.

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2. Subjects and methods 2.1. Patient 1

A boy, born at term from an uneventful pregnancy to unrelated parents (birth weight 2850 g, normal perinatal history). Generalized tonic-clonic seizures appeared in infancy and his motor and mental development were severely delayed. He was 3 years old at the time of presentation. Tonic-clonic seizures recurred one or two times weekly and he was on sodium valproate treatment. He was not able to follow a face, opticokinetic nystagmus was not elicitable, funduscopy revealed bilateral optic atrophy. There was no response to acoustic stimuli. He had spastic tetraplegia. There was no evidence of Miller-Dieker syndrome. His two brothers developed normally. EEG, CT and brain SPECT were performed. 2.2. Patient 2

A girl, born at term from uneventful first pregnancy to unrelated parents (birth weight 2860 g, head circumference 32 cm (below 5th percentile)). Infantile spasms appeared at the age of three months and sodium valproate treatment was started. The child had spastic tetraplegia and did not respond to visual and auditory stimuli. Serum CMV IgG titer was 168 EU/ml at this time, while the mother's titer was 60 EU/ml. The child has two sisters who developed normally. EEG was performed at 9 months, MRI and SPECT were performed and EEG repeated when the child was 2.5 years old. She was treated with sodium valproate and vigabatrin at that time. 2.3. Patient 3

A girl, first child of consanguinous parents. The pregnancy and labour were uneventful (birth weight 2900 g, head circumference at birth 32.5 cm (below 5th percentile)). She presented with the first seizures at the age of 3 days. The semiology of the seizures included sudden stiffening in the extremities, associated with respiratory difficulties. Phenobarbital treatment was started and changed to vigabatrin later on. She could not follow faces or objects with her eyes, opticokinetic nystagmus was not elicitable. There was no response to acoustic stimuli. Spastic tetraplegia developed quickly. EEG was performed at the age of 1 month. MRI, SPECT and repeated EEG were done when the child was 8 months old and treated with vigabatrin.


axial slices were taken from the base of the skull to the vertex. Slice thickness was 5 mm in the posterior fossa and 10 m m in the supratentorial areas. MRI was performed by a 1.5-Tesla superconducting unit (Siemens). A standard set of Tl-weighted (transaxial, coronal and sagittal) and T2-weighted (transaxial) images was acquired with spin-echo (SE) pulse sequences of 520 (repetition time in ms)/14 (echo time in ms) and 2550/90 respectively. Section thickness was 5 mm, with an intersection gap of 2.5 mm in all examinations. The field of view was 24 cm, with an acquisition and display matrix size of 256 × 256. EEG was performed with scalp electrodes using the international 10-20 system. In the third case only frontal, central, occipital and temporal electrodes were placed on the small head. Seven patients (four female, three male, aged 6 - 3 0 months) served as controls for the SPECT studies. Entirely normal children cannot be studied with SPECT for ethical reasons, therefore the controls were selected from a group of patients with transient neurological symptoms who were found completely normal by a pediatric neurologist at follow-up. For the SPECT study 99mTc-HMPAO (20 MBq/kg, Ceretec, Amersham) was administered intravenously when the patients were quiet. Seizures were not observed during or following the injection. Chloral hydrate (100 mg/kg orally) was given for sedation 15 min. following the HMPAO administration. SPECT scans were performed within 2 h after the HMPAO injection either with a GE 400 AC single-head rotating gamma camera (Patient 1) or a GE Maxxus dual head gamma camera (Patients 2 and 3). Low energy, high resolution parallel hole collimator was used. Acquisition was obtained in a 64 × 64 matrix over 360 ° rotation. Transaxial, coronal and sagittal slices were reconstructed by filtered back projection (Butterworth filter) after uniformity and attenuation correction (Chang method). Slice thickness was 6.8 mm. Visual interpretation of the CT or MRI and HMPAO SPECT images was performed independently. CT and MRI scans were read by an experienced neuroradiologist (M.N.) without knowledge of the patients' clinical status and SPECT results. SPECT images were interpreted by a nuclear medicine physician (A.R.S.) unaware of the patients' clinical state and CT or MRI results. The patients' CT or MRI and SPECT images were then compared. The patients' SPECT images were compared to those of the controls as well.

2.4. Examinations

3. Results

Chromosomal investigations and TORCH screening were performed in all three cases. CT scanning was performed before and after the administration of intravenous contrast material on a GE 9800 scanner. Contiguous trans-

3.1. Patient 1

Only CT was available and it showed a smooth cerebral surface, complete agyria with an open sylvian region, typi-


A.R. Al-Suhaili et al. /Brain & Development 19 (1997) 138-143

cal 'figure-of-eight' appearance (Grade 1, Fig. 1). The brain mantle was thin without white-gray matter differentiation. All parts of the lateral ventricles and the third ventricle were dilated with agenesis of the corpus callosum. Thalamus, caudate and lentiform nuclei could be identified. Gyri and white-gray matter differentiation were recognizable in the cerebellum, but fourth ventricle dilatation was observed in association with hypoplasia of the vermis. On the EEG bilateral synchronous and asynchronous sharp waves interrupted the slow background activity. SPECT revealed remarkable cerebral cortical hypoperfusion mainly over the anterior frontal, temporal and occipital regions. The visual cortex, which is prominent by its very high tracer uptake in control cases, was not recognizable in the occipital area (Fig. 2). The thalamus, which also has high perfusion normally, was not identifiable. Somewhat higher activity was observed in the posterior frontal, parietal regions and basal ganglia, while the cerebellum showed normal high tracer uptake. 3.2. P a t i e n t 2

The MRI revealed smooth, broad gyri typical of pachygyria which was more severe over the posterior than anterior regions (Grade 3, Fig. 3). The cortex was thick, whitegray matter interdigitations were attenuated, the white matter was thin and the corpus callosum was hypoplastic. The lateral ventricles were dilated; mainly the posterior horns with rounded margins. Thalamus, caudate and lentiform nuclei were easily recognizable and the cerebellum was normal. EEG examination showed hypsarrhythmia at the age of 9 months and diffuse slowing without epileptiform discharges at the age of 2.5 years. SPECT revealed diffuse low cortical perfusion (Fig. 4).

Fig. 1. Patient 1. CT shows complete agyria-pachygyria (Grade 1) and relatively easily identifiable basal ganglia.

In this case the visual cortex could be identified by high tracer uptake. The thalamus was not recognizable, while high activity corresponding to the basal ganglia was seen. Cerebellar perfusion was normal. An intrauterine cytomegalovirus infection is a possible etiology in this case. 3.3. P a t i e n t 3

The MRI showed diffuse pachygyria with no areas of agyria (Grade 4, Fig. 5), enlarged ventricles with rounded margins, hypoplastic corpus callosum and abnormal white matter. The thalamus, caudate and lentiform nuclei were recognizable, and the cerebellum and brain stem were normal. The EEG showed diffuse slow activity and a few multifocal epileptic discharges at the age of 1 month and diffuse slowing without epileptiform activity at the age of 8 months. SPECT revealed diffuse low cortical tracer uptake in all areas, including the visual cortex. High perfusion was found in the basal ganglia, while thalamic uptake was low (Fig. 6). Cerebellar activity was normal. Chromosomal analysis showed normal karyotype in all three cases.

Fig. 2. Transaxial (upper) and coronal (lower) SPECT images of Patient 1 show low cortical tracer uptake mainly in the frontopolar, temporal and occipital regions. The visual cortex is not recognizable, The basal ganglia have high perfusion, while the thalamic uptake is extremely low. (Unfortunately the CT slice, shown on Fig. 1 is not completely parallel with the transaxial SPECT slice. The latter includes the visual cortex and not the cerebellum.)

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Fig. 3. Patient 2. Tl-weighted transaxial MRI image shows smooth, broad gyri typical of pachygyria, more severe over the posterior regions (Grade 3). Thick cortex, thin white matter, dilated posterior horns of the lateral ventricles. Thalami, caudate and lentiform nuclei are easily recognizable. 4. Discussion In agyria-pachygyria (lissencephaly type I according to the former terminology) the cortex usually shows a fourlayer structure such as molecular, superficial cellular, sparsely cellular and deep cellular layers [12,13]. A true cortex appears superficially (molecular and superficial cellular layers) with cells that have completed the migration, while below is the heterotopic zone (deep cellular layer) with cells arrested in migration [12]. In Golgi impregnations, most neurons in the true cortex show normal configurations, alignments and dendrite spines; however some pyramidal neurons have an inverted orientation. In the sparsely cellular layer fibrous astrocytes are found which may form a scar. In the deep cellular layer pyramidal and polymorphic neurons are mixed and some neurons have an inverted polarity. It has been suggested that the sparsely cellular layer, as a necrotic lamina, separates the cerebral wall into two cellular layers [12,14]. Immunohistochemical staining for synaptophysin, myelin basic protein and glial fibrillary acidic protein revealed further details of the structural organization of the cortex in agyria-pachygyria [14]. An intense synaptophysin staining, not seen in normal cortex, was observed in the subpial molecular layer in addition to the superficial cellular layer. This finding indicates an abnormally large amount of synapses on the apical dendrites. The sparsely cellular layer shows linear myelination, weak synaptophysin staining and many glial fibrillary acidic protein positive astrocytes. As these astrocytes appear in the fetal brain a few months later than the time of the migrational arrest, their

Fig. 4. Transaxial (upper) and coronal (lower) SPECT images of Patient 2 show low cortical perfusion. The visual cortex is recognizable by its high activity. Prominent uptake in the basal ganglia and extremely low activity over the thalamic area are seen. presence in the sparsely cellular layer does not indicate laminar necrosis as suggested earlier. Immunohistochemistry revealed multiple islets of neurons surrounded by a reticular pattern of myelin in the deep cellular layer [14}. Positron emission tomography allowed the two layers of the cortex in patients with the 'isolated lissencephaly sequence' to be differentiated [15]. The inner layer which may represent the inner cellular layer showed a higher glucose uptake than the outer layer which can correspond to the molecular, outer cellular and cell-sparse layers. Although the resolution of cerebral blood flow by SPECT does not allow differentiation of several cortical layers, it provides insight into the perfusion abnormalities in agyria-pachygyria. The low cortical perfusion can be attributed to two factors: 1. Functional hypoactivity due to improper positioning and failing connections of the cell groups associated with failure of biochemical differentiation and low level input and output processes. Cerebral activity, glucose consumption and blood flow are closely coupled [16], therefore the cortical hypoperfusion in agyriapachygyria may reflect the reduced functional activity. 2. Abnormal vascular patterns and reactivity can be taken into account as factors that contribute to the perfusion


A.R. AI-Suhaili et al. / Brain & Development 19 (1997) 138-143

Fig. 5. Patient 3. Tl-weighted coronal MRI image shows diffuse pachygyria with no areas of agyria (Grade 4). Enlarged ventricles with rounded margins, hypoplastic corpus callosum and abnormal white matter can be seen. The thalami and basal ganglia are recognizable.

abnormalities. The microvasculature has not been studied in agyria-pachygyria or other migrational defects but abnormal vascular drainage of pachygyric cortex has been described [17]. High tracer uptake can be seen by HMPAO SPECT in the visual cortex of control patients. Abnormalities in the perfusion of the visual cortex have been documented by SPECT in patients with cortical visual loss [18]. In Patients 1 and 3 the visual cortex was not identifiable by SPECT in agreement with the clinical findings. In addition to the probably abnormal cortical structure, the lack of input of visual stimuli due to abnormalities of the visual pathways can explain the absence of visual cortical activity. In Patient 2 the abnormal visual behaviour and the funduscopy findings were similar to those of the other two patients, therefore the tracer uptake over the visual cortex remains unexplained thus far. Pathological studies in lissencephaly showed minor or no anomalies in the putamen and pallidum, and the thalamic architecture was characterized as 'blurred' [19]. The high perfusion observed in the basal ganglia by SPECT indicates a high functional activity of these regions. The thalamus was well visible on CT and MRI in our cases but SPECT showed very low thalamic tracer uptake. The thalamus constitutes a major relay and integrative centre of sensory, motor and limbic pathways and shows high glucose uptake and blood flow from birth [20]. The hypoperfusion reflects low functional activity most likely due to improper cellular differentiation and lack of connections. The morphologically and functionally poorly developed thalamo-cortical connections may result in low level activation of the thalamo-cortical-thalamic circuits which gives rise to thalamic hypoperfusion and contributes to cortical hypoperfusion.

Fig. 6. Transaxiat (upper) and coronal (lower) SPECT images of Patient 3 show diffuse cortical and thalamic hypoperfusion and high tracer uptake in the basal ganglia.

Tracer uptake was normal in the cerebellum, which is an unexpected finding despite the near normal appearance of the cerebellar structure on CT and MRI. Low cerebellar perfusion, and crossed or ipsilateral cerebellar diaschisis, have been described in cases with lesions to the corticocerebellar pathways [21]. These tracts are probably not normally developed in lissencephaly, but the gross cerebellar structure and perfusion appear to be retained without proper cortical connections. We can conclude that SPECT provides information on the functional activity of various brain regions in a severe defect of neuronal migration, such as agyria-pachygyria.

Acknowledgements This study was supported by grants from FMHS, United Arab Emirates University (16/95 and CP/96/01) and the Hungarian Research Fund (OTKA, T 5091).

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