Acta Neuropathologica
Acta Neuropathol. (Berl.) 43, 263-266 (1978)
(
Springer-Verlag 1978
Megalencephaly and Chromosomal Anomaly H. B u d k a Neurologisches Institut der Universit/it Wien, Schwarzspanierstrage 17, A-1090 Wien, Austria
Summary. A 6-year-old m e n t a l l y retarded boy died after cardiac surgery for F a l l o t ' s tetralogy. The b r a i n was o f e n o r m o u s size, weighing 2230 g a n d showing widespread p o l y m i c r o g y r i a a n d dysdifferentiation to regular large p y r a m i d a l n e u r o n s w i t h o u t increased D N A content. N u c l e a r Barr bodies indicated a X X Y c h r o m o s o m a l (Klinefelter) syndrome, which has n o t been previously reported in megalencephaly. T r u e m e g a l e n c e p h a l y (excluding the s y m p t o m a t i c forms) should r e m a i n a pathological diagnosis a n d restricted to cases with a n a b n o r m a l l y high b r a i n weight in a d d i t i o n to m o r p h o l o g i c a l alterations. There is evidence for a genetic base in m a n y cases of megalencephaly, a n d c h r o m o s o m a l studies m a y yield m o r e i n f o r m a t i o n in this respect.
Key words: M e g a l e n c e p h a l y - C h r o m o s o m a l a n o m a l y -
Klinefelter s y n d r o m e -
Malformation.
Size a n d weight of the h u m a n b r a i n have attracted m u c h interest in the past because of their supposed f u n c t i o n a l implications. Megalencephaly, a term coined by Fletcher (1900) to designate a diffuse hyperplasia o f the brain, is said to be n o t u n c o m m o n (Friede, 1975; T o w n s e n d et al., 1975) a l t h o u g h well d o c u m e n ted reports o f this c o n d i t i o n are rare a n d its p a t h o genesis is still undefined. It is the p u r p o s e of this paper to report a case of megalencephaly with d e v e l o p m e n t a l a n d c h r o m o s o m a l abnormalities, with some observations o n etiology, definition a n d m o r p h o l o g y o f the a b n o r m a l l y heavy brain.
Case Report A boy with uncontributory family and prenatal histories had, from birth, severe retardation of mental and somatic development. Although a cyanotic cardiac vitium dominated the clinical picture, slight head enlargement was noted soon after birth. At the age of 5 years he was admitted to hospital, where the diagnosis of Fallot's
tetralogy was made. Psychological testing yielded a developmental quotient of 39; active verbal contact was reduced to few barely comprehensible words. Ventricular puncture, performed for suspected hydrocephalus, showed a normal CSF pressure. Cerebral seizures were never reported. At the age of 6 the patient died from cardiopulmonary failure 4 days after operative total correction of Fallot's tetralogy. Autopsy confirmed the cardiological diagnosis; all organs were congested. Pulmonary hyaline membranes were accompanied by small intra-alveolar, subpleural and interstitial hemorrhages. A small cavernoma was found in the liver. The cranium was moderately enlarged, but without osseous abnormalities. The brain was abnormally large, weighing 2230 g. Numerous small irregular convolutions were prominent on the frontoparietal convexities, showing on coronal section an excessive piling-up of polymicrogyricand small subcortical heterotopic gray matter (Fig 1). For histological examination, several hemispheric slices (Fig. 2) and small blocks from various regions of both cerebral hemispheres,brain stem and cerebellum were embedded in paraffin and stained with H&E, cresylviolet, Kltiver-Barrera's, Bodian's and Kanzler's methods. Polymicrogyria was restricted to the lateral frontoparietotemporooccipital convexities, largely corresponding to the cortical supply areas of the middle cerebral arteries which were grossly and microscopicallynormal. The corpus callosum was abnormally thick (Fig. 2a, b), the white matter was wellmyelinated without any gliosis. A deeply invading fissure (arrows in Fig. 2c) "pseudo-opercularized" a dorsolateral "accessory" left parietal lobe. The cerebral cortex showed, both in the polymicrogyricareas (Fig. 3) and in normal gyri, a predominance of regular large pyramidal neurons without laminar arrangement (Fig. 4) even in cortical areas of granular type (coniocortex). The cerebellum was enlarged in proportion to cerebral enlargement, but without structural anomalies. The brain stem was both grossly and histologically normal. Feulgen-stained thick sections showed prominent nuclear Barr bodies (arrowheads in Fig. 5a, b), but microphotometric evaluation showed no evidenceof an increasedneuronal DNA content or diploid neurons 1.
Discussion Excessive size a n d weight of a well p r o p o r t i o n e d b r a i n m a y be due to a wide variety of conditions, most frequently to edema, storage a n d spongy dystrophies or 1 The author is indebted to Prof. Dr. W. Schnedl, head of the Human Genetics Department, Histological-EmbryologicalInstitute of the University of Vienna, for providing these results
0001-6322/78/0043/0263/$1.00
264
Figs. 1--5
Acta Neuropathol. (Berl.) 43 (1978)
H. Budka: Megalencephalyand Chromosomal Anomaly diffuse blastomatoses. However, in these latter conditions, increase of brain size and weight is only a symptom ("secondary megalencephaly" of Dekaban and Sakuragawa, 1977; "metabolic type" of DeMyer, 1972). If we exclude such cases, we are left with a small group of true megalencephaly, where a surplus of cerebral tissue components seems to be a pathological condition in its own right, although its etiology, pathogenesis and pathology may still be heterogeneous (Jacob, 1956; Dekaban and Sakuragawa, 1977), Several attempts have been made to define this group, by clinical criteria alone, as "anatomic" (DeMyer, 1972) or "primary" (Dekaban and Sakuragawa, 1977) megalencephaly but it is evident that some dystrophic or metabolic conditions (e. g., van Bogaert-Bertrand-Canavan's of Alexander's diseases) cannot be excluded merely on clinical grounds. Therefore, a definite diagnosis ofmegalencephaly must rest on examination of the structure of the brain. Megalencephaly has been defined as a brain weight surpassing 1600 g (Friede, 1975) of 1800 g (Escourolle and Poirier, 1971) or, more accurately, the 2.5 standard deviations for the respective age and sex (Dekaban and Sakuragawa, 1977), provided that edema and tumors are excluded. However, brain weight alone is not sufficient to define megalencephaly as a pathological condition, since there is a wide individual variability of normal brain weight, best shown by the well recorded, obviously nonpathological "~lite" brains of Tourgeniev, Cuvier, Lord Byron, Bismarck, and Thackeray, all exceeding 1600 g (Wilson, 1934). Therefore, additional clinical criteria (disorders of mentation, convulsions) were used in the definition of megalencephaly (de Lange, 1932), but again they are insufficient, since apparently asymptomatic patients also may show dysplastic brain enlargement (Tsinimakis, 1902). Even morphological abnormalities in the brain were not considered to be a reliable criterium for a definition of megalencephaly, since
Fig. 1. Coronal sectionsof frontal lobes with bilateral polygyriaand subcortical gray heterotopias Fig. 2a--d. Myelin preparations from left (a, c) and right (b, d) cerebral hemispheres showing extensive polymicrogyriaon lateral surfaces and thick corpus caltosum.Note "pseudo-opercularization" of left dorsolateral parietal lobe by incompletely dividing sulcus (small arrows in e). Kliiver-Barrera x 0.5 Fig. 3. Polymicrogyricleft frontal cortex with alaminar arrangement of large pyramidal neurons. Cresylvioletx 38 Fig. 4. Nonpolymicrogyricleft frontal cortexwith alaminar arrangement of large pyramidal neurons. Bodian x 95 Fig. 5a and b. Feulgen-stainedthick sections demonstrating nuclear Barr bodies (arrowheads). a x 945, b x 1.500
265 abnormally heavy brains without apparent histomorphological alterations were reported in mentally retarded and epileptic patients (Apley and Symons, 1947). However, it must be conceded that histological examination may not have been sufficiently comprehensive in some of the earlier reports. In a recent survey, 31 cases of megalencephaly were confirmed at autopsy and were all examined histologically; only in 26 ~ , abnormalities were not found (Dekaban and Sakuragawa, 1977). In conclusion, there seems to be no single criterium for a clear-cut diagnosis of megalencephaly; however, a pathological diagnosis of megalencephaly seems to be unequivocal when restricted to cases surpassing the brain weight limit defined by Dekaban and Sakuragawa (1977) and showing histomorphological abnormalities with or without a neuropsychiatric history. To our knowledge, the brain weight of our case ranges third in the literature after the 2850 g brain of an epileptic idiot reported by van Walsem (1899) and the 2480g brain of Simms' (1835) very early case. Malformations of other body organs, like the cardiac abnormality in our case, are frequently found in megalencephaly (Dekaban and Sakuragawa, 1977). Gross cerebral malformation, such as callosal agenesis and olfactory aplasia (Urich, 1976), have been previously observed, as well as neuronal heterotopias (Peter and Schliiter, 1927; de Lange, 1932; Urich, 1976) and polymicrogyria (Dennis et al., 1961 ; Dydyk and Kansy, 1975). In addition to the latter disorders of neuronal migration, our case presented evidence of widespread neuronal dysdifferentiation with predominance of large pyramidal neurons, which might explain, at least to some extent, the increased size and weight of the brain. However, these large regular neurons did not show any increase of D N A content, which was demonstrated by Bignami et al. (1968) in unilateral (hemi-) megalencephaly. There were further differences between our case and the features of hemimegalencephaly; in the latter, the frequently found irregular nerve and glia cell forms suggest a transition of this condition to the phakomatoses (Gross and Uiberrak, 1955 ; Dom and Brucher, 1969, Townsend et al., 1975). The etiology and pathogenesis of megalencephaly are still unclear. The male predominance in a proportion of 4:1 and familiality with presumably autosomal dominant heredity (De Myer, 1972) favor a genetically determined disorder; this is also supported by combinations with achondroplasia (Dennis et al., 1961) and congenital lipo-angiomatosis (Bannayan, 1971). The presence of Barr bodies in our male patient seems to be unique, indicating a XXYchromosomal (Klinefelter-) syndrome; chromosomal aberration in megalencephaly was previously described
266
by Brun and Gustavson (1972) in a case of XYYsyndrome. Clearly, these two cases do not allow any general conclusions concerning the role of sex chromosome aberration in cerebral malformations, especially megalencephaly, but stress the importance of further studies in this field. References Apley, J., Symons, M. : Megalencephaly: a report of two cases. Arch. Dis. Child. 22, 172-174 (1947) Bannayan, G. A. : Lipomatosis, angiomatosis, and macrencephalia. A previously undescribed congenital syndrome. Arch. Pathol. Lab. Med. 92, 1 - 5 (1971) Bignami A., Palladini G., Zappella M. : Unilateral megalencephaly with nerve cell hypertrophy. An anatomical and quantitative histochemical study. Brain Res. 9, 103-114 (1968) Brun, A., Gustavson, K. H. : Cerebral malformations in the XYY syndrome. Acta Pathol. Microbiol. Scand. [A] 80, 627-633 (1972) Dekaban, A. S., Sakuragawa, N. : Megalencephaly. In: Handb. clin. Neurol. (Vinken, P. J., Bruyn, G. W., eds.) Vol. 30, pp. 647660. Amsterdam-New York-Oxford: North Holland 1977 DeMyer, W. : Megalencephaly in children. Clinical syndromes, genetic patterns, and differential diagnosis from other causes of megalocephaly. Neurology (Minneap.) 22, 634-643 (1972) Dennis, J. P., Rosenberg, H. S., Alvord, E. C. jr. : Megalencephaly, internal hydrocephalus and other neurological aspects of achondroplasia. Brain 84, 427-445 (1961) Dora, R., Brucher, J.-M. : Hamartoblastome (gangliocytome diffus) unilat6ral de l'6corce c6rObrale associ6 ~t une d6g6n6rescence soudanophile de la substance blanche du c6t6 oppos& Rev. Nenrol. (Paris) 120, 307-318 (1969) Dydyk, L., Kansy, J. : Megalencephaly with polymicrogyria - case report (in Polish). Neuropathol. Pol. 13, 137-141 (1975)
Acta Neuropathol. (Berl.) 43 (1978) Escourolle, R., Poirier, J. : Manuel Ol6mentaire de neuropathologie. Paris: Masson 1971 Fletcher, H. M. : A case of megalencephaly. Path. Soc. London 51, 230-232 (1900) Friede, R. L. : Developmental neuropathology. Wien-New York: Springer 1975 Gross, H., Uiberrak, B.: Klinisch-anatomische Befunde bei Hemimegalencephalie (Qber die Stellung der cerebralen Hyperplasie und des 6rtlichen Riesenwuchses innerhalb der Phakomatosen). Virchows Arch. 327, 577-589 (1955) Jacob, H. : Angeborener erblicher Schwachsinn einschlieBlich ,,befundlose Idiotien", sowie Megalencephalie bei angeborenem Schwachsinn. In: Handb. spez. path. Anat. Histol. (Lubarsch, O., Henke, F., R6ssle, R., eds.) Bd. XIII/4, 58-81. BerlinG6ttingen-Heidelberg: Springer 1956 Lange, C. de: Uber Megalencephalie. Acta psychiat, neurol, scand. 7, 955-980 (1932) Peter, K., Schlfiter, K. : fiber Megalencephalie als Grundlage der Idiotic. Z. ges. Neurol. Psychiat. 108, 21-40 (1927) Simms: On hypertrophy and atrophy of the brain. Med. Chirurg. Transact. Soc. London 19, (1835) Townsend, J. J., Nielsen, S. L., Malamud, N. : Unilateral megalencephaly: hamartoma or neoplasm? Neurology (Minneap.) 25, 448-453 (1975) Tsinimakis, K. : Zur Kenntnis der reinen Hypertrophic des Gehirns. Arb. neurol. Inst. Univ. Wien 9, 169 (1902) Urich, H.: Malformations of the nervous system, perinatal damage and related conditions in early life. In: Greendfield's Neuropathology (Blackwood, W., Corsellis, J. A. N., eds.), 361-469. London: Arnold 1976 Walsem, G. C. van: fiber das Gewicht des schwersten bisher jetzt beschriebenen Gehirns. Neurol. Centralbl. (Leipzig) 18, 578580 (1899) Wilson, S. A. K. : Megalencephaly. J. Neurol. Psychopath. 14, 193 216 (1934) Received March 29, 1978/Accepted April 21, 1978
Acta Neuropathol. (Berl.) 43, 263-266 (1978)
(
Springer-Verlag 1978
Megalencephaly and Chromosomal Anomaly H. B u d k a Neurologisches Institut der Universit/it Wien, Schwarzspanierstrage 17, A-1090 Wien, Austria
Summary. A 6-year-old m e n t a l l y retarded boy died after cardiac surgery for F a l l o t ' s tetralogy. The b r a i n was o f e n o r m o u s size, weighing 2230 g a n d showing widespread p o l y m i c r o g y r i a a n d dysdifferentiation to regular large p y r a m i d a l n e u r o n s w i t h o u t increased D N A content. N u c l e a r Barr bodies indicated a X X Y c h r o m o s o m a l (Klinefelter) syndrome, which has n o t been previously reported in megalencephaly. T r u e m e g a l e n c e p h a l y (excluding the s y m p t o m a t i c forms) should r e m a i n a pathological diagnosis a n d restricted to cases with a n a b n o r m a l l y high b r a i n weight in a d d i t i o n to m o r p h o l o g i c a l alterations. There is evidence for a genetic base in m a n y cases of megalencephaly, a n d c h r o m o s o m a l studies m a y yield m o r e i n f o r m a t i o n in this respect.
Key words: M e g a l e n c e p h a l y - C h r o m o s o m a l a n o m a l y -
Klinefelter s y n d r o m e -
Malformation.
Size a n d weight of the h u m a n b r a i n have attracted m u c h interest in the past because of their supposed f u n c t i o n a l implications. Megalencephaly, a term coined by Fletcher (1900) to designate a diffuse hyperplasia o f the brain, is said to be n o t u n c o m m o n (Friede, 1975; T o w n s e n d et al., 1975) a l t h o u g h well d o c u m e n ted reports o f this c o n d i t i o n are rare a n d its p a t h o genesis is still undefined. It is the p u r p o s e of this paper to report a case of megalencephaly with d e v e l o p m e n t a l a n d c h r o m o s o m a l abnormalities, with some observations o n etiology, definition a n d m o r p h o l o g y o f the a b n o r m a l l y heavy brain.
Case Report A boy with uncontributory family and prenatal histories had, from birth, severe retardation of mental and somatic development. Although a cyanotic cardiac vitium dominated the clinical picture, slight head enlargement was noted soon after birth. At the age of 5 years he was admitted to hospital, where the diagnosis of Fallot's
tetralogy was made. Psychological testing yielded a developmental quotient of 39; active verbal contact was reduced to few barely comprehensible words. Ventricular puncture, performed for suspected hydrocephalus, showed a normal CSF pressure. Cerebral seizures were never reported. At the age of 6 the patient died from cardiopulmonary failure 4 days after operative total correction of Fallot's tetralogy. Autopsy confirmed the cardiological diagnosis; all organs were congested. Pulmonary hyaline membranes were accompanied by small intra-alveolar, subpleural and interstitial hemorrhages. A small cavernoma was found in the liver. The cranium was moderately enlarged, but without osseous abnormalities. The brain was abnormally large, weighing 2230 g. Numerous small irregular convolutions were prominent on the frontoparietal convexities, showing on coronal section an excessive piling-up of polymicrogyricand small subcortical heterotopic gray matter (Fig 1). For histological examination, several hemispheric slices (Fig. 2) and small blocks from various regions of both cerebral hemispheres,brain stem and cerebellum were embedded in paraffin and stained with H&E, cresylviolet, Kltiver-Barrera's, Bodian's and Kanzler's methods. Polymicrogyria was restricted to the lateral frontoparietotemporooccipital convexities, largely corresponding to the cortical supply areas of the middle cerebral arteries which were grossly and microscopicallynormal. The corpus callosum was abnormally thick (Fig. 2a, b), the white matter was wellmyelinated without any gliosis. A deeply invading fissure (arrows in Fig. 2c) "pseudo-opercularized" a dorsolateral "accessory" left parietal lobe. The cerebral cortex showed, both in the polymicrogyricareas (Fig. 3) and in normal gyri, a predominance of regular large pyramidal neurons without laminar arrangement (Fig. 4) even in cortical areas of granular type (coniocortex). The cerebellum was enlarged in proportion to cerebral enlargement, but without structural anomalies. The brain stem was both grossly and histologically normal. Feulgen-stained thick sections showed prominent nuclear Barr bodies (arrowheads in Fig. 5a, b), but microphotometric evaluation showed no evidenceof an increasedneuronal DNA content or diploid neurons 1.
Discussion Excessive size a n d weight of a well p r o p o r t i o n e d b r a i n m a y be due to a wide variety of conditions, most frequently to edema, storage a n d spongy dystrophies or 1 The author is indebted to Prof. Dr. W. Schnedl, head of the Human Genetics Department, Histological-EmbryologicalInstitute of the University of Vienna, for providing these results
0001-6322/78/0043/0263/$1.00
264
Figs. 1--5
Acta Neuropathol. (Berl.) 43 (1978)
H. Budka: Megalencephalyand Chromosomal Anomaly diffuse blastomatoses. However, in these latter conditions, increase of brain size and weight is only a symptom ("secondary megalencephaly" of Dekaban and Sakuragawa, 1977; "metabolic type" of DeMyer, 1972). If we exclude such cases, we are left with a small group of true megalencephaly, where a surplus of cerebral tissue components seems to be a pathological condition in its own right, although its etiology, pathogenesis and pathology may still be heterogeneous (Jacob, 1956; Dekaban and Sakuragawa, 1977), Several attempts have been made to define this group, by clinical criteria alone, as "anatomic" (DeMyer, 1972) or "primary" (Dekaban and Sakuragawa, 1977) megalencephaly but it is evident that some dystrophic or metabolic conditions (e. g., van Bogaert-Bertrand-Canavan's of Alexander's diseases) cannot be excluded merely on clinical grounds. Therefore, a definite diagnosis ofmegalencephaly must rest on examination of the structure of the brain. Megalencephaly has been defined as a brain weight surpassing 1600 g (Friede, 1975) of 1800 g (Escourolle and Poirier, 1971) or, more accurately, the 2.5 standard deviations for the respective age and sex (Dekaban and Sakuragawa, 1977), provided that edema and tumors are excluded. However, brain weight alone is not sufficient to define megalencephaly as a pathological condition, since there is a wide individual variability of normal brain weight, best shown by the well recorded, obviously nonpathological "~lite" brains of Tourgeniev, Cuvier, Lord Byron, Bismarck, and Thackeray, all exceeding 1600 g (Wilson, 1934). Therefore, additional clinical criteria (disorders of mentation, convulsions) were used in the definition of megalencephaly (de Lange, 1932), but again they are insufficient, since apparently asymptomatic patients also may show dysplastic brain enlargement (Tsinimakis, 1902). Even morphological abnormalities in the brain were not considered to be a reliable criterium for a definition of megalencephaly, since
Fig. 1. Coronal sectionsof frontal lobes with bilateral polygyriaand subcortical gray heterotopias Fig. 2a--d. Myelin preparations from left (a, c) and right (b, d) cerebral hemispheres showing extensive polymicrogyriaon lateral surfaces and thick corpus caltosum.Note "pseudo-opercularization" of left dorsolateral parietal lobe by incompletely dividing sulcus (small arrows in e). Kliiver-Barrera x 0.5 Fig. 3. Polymicrogyricleft frontal cortex with alaminar arrangement of large pyramidal neurons. Cresylvioletx 38 Fig. 4. Nonpolymicrogyricleft frontal cortexwith alaminar arrangement of large pyramidal neurons. Bodian x 95 Fig. 5a and b. Feulgen-stainedthick sections demonstrating nuclear Barr bodies (arrowheads). a x 945, b x 1.500
265 abnormally heavy brains without apparent histomorphological alterations were reported in mentally retarded and epileptic patients (Apley and Symons, 1947). However, it must be conceded that histological examination may not have been sufficiently comprehensive in some of the earlier reports. In a recent survey, 31 cases of megalencephaly were confirmed at autopsy and were all examined histologically; only in 26 ~ , abnormalities were not found (Dekaban and Sakuragawa, 1977). In conclusion, there seems to be no single criterium for a clear-cut diagnosis of megalencephaly; however, a pathological diagnosis of megalencephaly seems to be unequivocal when restricted to cases surpassing the brain weight limit defined by Dekaban and Sakuragawa (1977) and showing histomorphological abnormalities with or without a neuropsychiatric history. To our knowledge, the brain weight of our case ranges third in the literature after the 2850 g brain of an epileptic idiot reported by van Walsem (1899) and the 2480g brain of Simms' (1835) very early case. Malformations of other body organs, like the cardiac abnormality in our case, are frequently found in megalencephaly (Dekaban and Sakuragawa, 1977). Gross cerebral malformation, such as callosal agenesis and olfactory aplasia (Urich, 1976), have been previously observed, as well as neuronal heterotopias (Peter and Schliiter, 1927; de Lange, 1932; Urich, 1976) and polymicrogyria (Dennis et al., 1961 ; Dydyk and Kansy, 1975). In addition to the latter disorders of neuronal migration, our case presented evidence of widespread neuronal dysdifferentiation with predominance of large pyramidal neurons, which might explain, at least to some extent, the increased size and weight of the brain. However, these large regular neurons did not show any increase of D N A content, which was demonstrated by Bignami et al. (1968) in unilateral (hemi-) megalencephaly. There were further differences between our case and the features of hemimegalencephaly; in the latter, the frequently found irregular nerve and glia cell forms suggest a transition of this condition to the phakomatoses (Gross and Uiberrak, 1955 ; Dom and Brucher, 1969, Townsend et al., 1975). The etiology and pathogenesis of megalencephaly are still unclear. The male predominance in a proportion of 4:1 and familiality with presumably autosomal dominant heredity (De Myer, 1972) favor a genetically determined disorder; this is also supported by combinations with achondroplasia (Dennis et al., 1961) and congenital lipo-angiomatosis (Bannayan, 1971). The presence of Barr bodies in our male patient seems to be unique, indicating a XXYchromosomal (Klinefelter-) syndrome; chromosomal aberration in megalencephaly was previously described
266
by Brun and Gustavson (1972) in a case of XYYsyndrome. Clearly, these two cases do not allow any general conclusions concerning the role of sex chromosome aberration in cerebral malformations, especially megalencephaly, but stress the importance of further studies in this field. References Apley, J., Symons, M. : Megalencephaly: a report of two cases. Arch. Dis. Child. 22, 172-174 (1947) Bannayan, G. A. : Lipomatosis, angiomatosis, and macrencephalia. A previously undescribed congenital syndrome. Arch. Pathol. Lab. Med. 92, 1 - 5 (1971) Bignami A., Palladini G., Zappella M. : Unilateral megalencephaly with nerve cell hypertrophy. An anatomical and quantitative histochemical study. Brain Res. 9, 103-114 (1968) Brun, A., Gustavson, K. H. : Cerebral malformations in the XYY syndrome. Acta Pathol. Microbiol. Scand. [A] 80, 627-633 (1972) Dekaban, A. S., Sakuragawa, N. : Megalencephaly. In: Handb. clin. Neurol. (Vinken, P. J., Bruyn, G. W., eds.) Vol. 30, pp. 647660. Amsterdam-New York-Oxford: North Holland 1977 DeMyer, W. : Megalencephaly in children. Clinical syndromes, genetic patterns, and differential diagnosis from other causes of megalocephaly. Neurology (Minneap.) 22, 634-643 (1972) Dennis, J. P., Rosenberg, H. S., Alvord, E. C. jr. : Megalencephaly, internal hydrocephalus and other neurological aspects of achondroplasia. Brain 84, 427-445 (1961) Dora, R., Brucher, J.-M. : Hamartoblastome (gangliocytome diffus) unilat6ral de l'6corce c6rObrale associ6 ~t une d6g6n6rescence soudanophile de la substance blanche du c6t6 oppos& Rev. Nenrol. (Paris) 120, 307-318 (1969) Dydyk, L., Kansy, J. : Megalencephaly with polymicrogyria - case report (in Polish). Neuropathol. Pol. 13, 137-141 (1975)
Acta Neuropathol. (Berl.) 43 (1978) Escourolle, R., Poirier, J. : Manuel Ol6mentaire de neuropathologie. Paris: Masson 1971 Fletcher, H. M. : A case of megalencephaly. Path. Soc. London 51, 230-232 (1900) Friede, R. L. : Developmental neuropathology. Wien-New York: Springer 1975 Gross, H., Uiberrak, B.: Klinisch-anatomische Befunde bei Hemimegalencephalie (Qber die Stellung der cerebralen Hyperplasie und des 6rtlichen Riesenwuchses innerhalb der Phakomatosen). Virchows Arch. 327, 577-589 (1955) Jacob, H. : Angeborener erblicher Schwachsinn einschlieBlich ,,befundlose Idiotien", sowie Megalencephalie bei angeborenem Schwachsinn. In: Handb. spez. path. Anat. Histol. (Lubarsch, O., Henke, F., R6ssle, R., eds.) Bd. XIII/4, 58-81. BerlinG6ttingen-Heidelberg: Springer 1956 Lange, C. de: Uber Megalencephalie. Acta psychiat, neurol, scand. 7, 955-980 (1932) Peter, K., Schlfiter, K. : fiber Megalencephalie als Grundlage der Idiotic. Z. ges. Neurol. Psychiat. 108, 21-40 (1927) Simms: On hypertrophy and atrophy of the brain. Med. Chirurg. Transact. Soc. London 19, (1835) Townsend, J. J., Nielsen, S. L., Malamud, N. : Unilateral megalencephaly: hamartoma or neoplasm? Neurology (Minneap.) 25, 448-453 (1975) Tsinimakis, K. : Zur Kenntnis der reinen Hypertrophic des Gehirns. Arb. neurol. Inst. Univ. Wien 9, 169 (1902) Urich, H.: Malformations of the nervous system, perinatal damage and related conditions in early life. In: Greendfield's Neuropathology (Blackwood, W., Corsellis, J. A. N., eds.), 361-469. London: Arnold 1976 Walsem, G. C. van: fiber das Gewicht des schwersten bisher jetzt beschriebenen Gehirns. Neurol. Centralbl. (Leipzig) 18, 578580 (1899) Wilson, S. A. K. : Megalencephaly. J. Neurol. Psychopath. 14, 193 216 (1934) Received March 29, 1978/Accepted April 21, 1978
