Congenital Ceroid-Lipofuscinosis R i c h a r d J. B a r o h n , M D * , D o n n a C. D o w d , M D t , a n d K a t h l e e n S. K a g a n - H a l l e t ,
MD*
A term infant, observed at birth to be microcephalic, developed status epilepticus and died 36 hours later. At autopsy a markedly atrophic brain was found which, by microscopic examination, demonstrated changes consistent with neuronal ceroid-lipofuscinosis. Cerebral lipidosis with microcephaly presenting at birth is extremely rare. Congenital neuronal ceroid-lipofuscinosis is an atypical form of ceroid-lipofuscinosis and should be considered in the differential diagnosis of the microcephalic neonate with seizures. Barohn R J, Dowd DC, Kagan-Hallet KS. Congenital ceroid-lipofuscinosis. Pediatr Neurol 1992;8:54-9.
Introduction Neuronal ceroid-lipofuscinosis (NCL), or Batten disease, consists of a group of progressive neurodegenerative diseases characterized by the accumulation of autofluorescent ceroid-lipofuscin pigment in the brain and other tissues [1]. Typically, patients are normal at birth; subsequently, there is a relentless deterioration of intellect, vision, and motor function, usually in the presence of a seizure disorder. Four subtypes of NCL have traditionally been described: infantile (Haltia-Santavuori), late infantile (Jansky-Bielschowsky), juvenile (Spielmeyer-Vogt or Batten), or adult (Kufs) NCL [2]. The clinical expression of NCL at birth (i.e., so-called "congenital") has been only rarely identified. Four patients with neonatal "amaurotic idiocy" with microcephaly and seizures were reported prior to the technical ability to distinguish among the different types of cerebral lipidoses [3-5]. Since that time 3 NCL patients presenting at birth have been reported [6-8]. Microcephaly and seizures were observed in most of these patients. The cerebral lipidoses generally are not in the differential diagnosis of the microcephalic infant during the neonatal period. The following patient illustrates another example of this rare disorder and demonstrates the characteristic clinical and pathologic features of congenital NCL.
From the *Department of Medicine, Division of Neurology; and tDepartment of Pathology, Division of Neuropathology; University of Texas Health Science Center; San Antonio, Texas.
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Case Report A 40-week-gestation male infant was born to a 2~-ycar old caucasian G2,PI mother. A sonogram at approximately 20 v, eeks gestation had been normal. There was no history of intrauterine difficultx ,~r maternal illness; labor and delivery were uneventful. The mother's first child was nomaal and neither parent was of Jev~ish descent. At birth Ihe in. rant weighed 2,9(X) gin, measured 45 cm in length, and was \.isibl,,. microcephalic with head circumference 30 cm. The Apgar ~cores were 7 at I mitt and 8 at 5 rain. After arrival in the nursery, the in/ant began having generalized seizures and was transferred to the neonatal intensive care unit. The heart rate was 146 and the respirator3 ralc 48: the infant was afebrile. The patient had generalized lnotnr seizures with reflex sensitivity during which the infant would exhibit increased muscle tone diffusely and hyperactive muscle stretch reflexes throughout. The fundi were normal and the pupils reacted sluggishly to tight. The cranial fontanels were palpable. The general physical exanfination was normal and there was no evidence of organomegaly. Palm and sole creases were consistent with gestational age. A complete blood count and chemistry profile were normal except for an SGOT of 372 tilL (normal: 22-38 U/Lt and a total bilirubin of 7.3 mg/dl (124.8 ramol/L; normal: 0.0-1.5 mg/dl; 0.0-25.6 ,umol/Li. Lymphocyte chromosomal analysis was normal. TORCH antibt×ly titers all were negative. Abdominal sonogram visualized normal kidneys, liver, and spleen. Cranial computed tomography revealed microcephaly with loss of brain substance and enlargement of the subcr;miat space over the entire brain; the ventricles were not dilated, l'here was no intracranial calcification or hemorrhage. Phenytoin and then phenobarbital were administered and despite therapeutic blood levels of both (phenytoin 20.4 I.tg/ml [8t).8 ranol/L], phenobarbital 31.6 tag/ml [136 lamol/L]), he continued to have at least 2 generalized seizures per hour associated with cyanosis and bradycardia. He became progressively bradycardic and died 36 hours after birth. Cerebrospinal fluid examination and electroencephalograph 5 (EEG/ were not pedbrmed. Pathologic Findings. The brain was markedly atrophic, ,aeighing 85 gm lnormah approximately 380 gm). The overall gyral pattern was that of a brain of 32-35 weeks gestational age; the operctda were open. Surface examination revealed diffusely shrunken gyri with widening of the sulci (Fig I). The brainstem was slightly firm in texture. The cerebellum exhibited slight atrophy of the folia. Following fixation in 20% tbrmalin, the brain was serially sectioned to reveal marked atrophy with thinning of an ill-defined cortex to approximately 2-3 ram. and diffuse enlargement of the ventricles (Fig 2). The white matter was unduly firm; the basal ganglia and thalamic nuclei were unremarkable. Representative sections were routinely processed fnr embedding in paraffin, sectioned at 6 gm intervals, and stained by tile hematoxytin and eosin/Luxol-fast-blue (LFB) technique. An unstained section of paraffin-elnbedded cortex was examined under fluorescence. A small portion of cortex was minced in 20% glutaraldehyde, postlixed in 1% osmium tetraoxide, and embedded in epon lot ultrathin sectioning for electron microscopy. Examination of the cortex by light microscopy revealed ballooning of cortical neurons with marked cytoplasmic storage of lipid as evidenced by LFB staining (Fig 3). Some degree of neuronal loss was present and the intervening cortex was markedly gliotic. Lipid-containing macrophages were intermixed with the abnormal neurons. The cerebral white matter was extensively gliotic with many gemistocytic astrocytes: no myelin was observed. Lipid-coutaining neurons were present in all areas of brain, including the thalamus and basal ganglia, cranial nerve nuclei, inferior olives and medulla, neurons of the basis pontis, and fotia and roof nuclei of the cerebellum. As in the cerebrum, the back
Communications should be addressed to: Dr. Barohn; Department of Medicine; University of Texas Health Science Center; 771)3 Floyd Curl Drive: San Antonio, TX 78284-7883. Received May 22, 1991; accepted July 18, 1991.
Figure 1. Lateral view of brain revealing marked generalized atrophy.
ground neuropil was diffusely gliotic and myelination was entirely lacking. The unstained, paraffin-embedded cortex exhibited autofluorescence of neurons and lipid-containing macrophages (Fig 4). Electron microscopic examination of cortex disclosed aggregates of granular, electron-dense material within neuronal cytoplasm, as well as lamellated cytosomal bodies (Fig 5). Gross examination of lungs, liver, spleen, and other organs was unremarkable without evidence of enlargement or other abnormality. Microscopic examination, however, revealed LFB-positive material within the reticuloendothelial system, including Kupffer cells of the liver and within the sinusoidal macrophages of lymph nodes and spleen. Lipid material was also present within autonomic ganglia in the smooth muscle of the bladder and small and large intestine.
Discussion The traditional classification o f the N C L distinguishes 4 varieties [1,2]. A l t h o u g h it m a y vary in a n u m b e r o f clinical features, the p r i m a r y d i f f e r e n t i a t i n g c h a r a c t e r i s t i c a m o n g the various forms is the age of initial clinical expression; therefore, the onset o f the Haltia-Santavuori infantile type occurs during the first 2 years o f life [9]. T h e s e children appear to be n o r m a l at birth and subsequently b e t w e e n 8-18 m o n t h s o f age they d e v e l o p rapid intellectual, visual, and m o t o r deterioration with m y o c l o n i c sei-
Figure 2. Coronal section of brain at mid-thalamus with pronounced cortical atrophy and enlargement of the sylvian fissure.
Barohn et al: Ceroid-Lipofuscinosis
55
Figw'e 3. Representative section oJ cerebral cortex; neurons attd macrophage~ ~'ontain hlue-stamin,~, /ip(,/Us~~:: (hemato.rvlin and eosin/Luxol:[ast-bhce stain, original ma~nifi'cation, riO0).
zures. The brains are severely atrophic and the term "walnut kernel brain" has been applied [1 ]. The onset of the Jansky-Bielschowsky, or late infantile, variant occurs at 2-4 years of age. It is often associated with intractable
Figure 4. apparent.
seizures, a characteristic photic response on EEG [10], and the brain is severely atrophic at postmortem examination. The juvenile Spielmeyer-Vogt type begins between 5 years of age and puberty with progressive visual loss. Cerebral
Unstained paraffin-embedded cortex viewed under fluorescence; autofluorescerwe of ceroid material i~
56 PEDIATRICNEUROLOGY Vol. 8 No. 1
Figure 5. Electron micrograph of a cortical neuron demonstrating membrane-bound electrondense material arranged in a whorling, laminated pattern (original magnification, x29,110; original magnification of inset, x33,960).
atrophy is less marked and seizures occur later in the disease. Finally, the adult type, or Kufs disease, begins in the third or fourth decade of life with dementia and seizures [11,12]. There are no visual abnormalities in this late-onset variant [12]. All of these forms have a progressive course, but the length of the illness can vary greatly. The pathologic hallmarks of NCL are the autofluorescent pigment in brain and other tissues and the ultrastructural intracytoplasmic deposits observed on electron microscopy. Attempts have been made to segregate the NCLs according to their various ultrastructural features (i.e., granular, curvilinear, or lamellar, or fingerprint cytosomes) [11], but the different clinical forms exhibit significant overlapping of findings on electron microscopy [13,14]. Dyken recently proposed an updated classification scheme for NCL in which there are major and minor (or "atypical") syndromes [15,16]. The major NCL syndromes consist of the 4 disorders noted above (Table 1). A number of minor NCL syndromes were proposed, all quite rare, including congenital NCL. A "congenital" form of NCL with onset at birth or during the first hours of life has not been widely appreciated [14]. Norman and Wood [3] and later Brown et al. [4] reported 1 sister each (from a family of 9 siblings) who were microcephalic at birth (Table 2). These infants developed seizures, decerebrate rigidity, and abnormal respiratory patterns within hours after uneventful deliveries. One sister died at 21/2 weeks and the other at 17 weeks of age. The general autopsy findings were normal, but the brains were extremely small and firm. Histologically, the cerebellar and cerebral cellular components had abundant accumulations of lipid material, resembling the brains seen in infantile amaurotic idiocy. Sandbank [5] reported 2 siblings with clinical presentations and pathologic features identical to those in the family described by Norman and
Wood [3] and Brown et al. [4]. Classification of these patients is difficult because they antedated the use of electron microscopy and the tissues were not examined for autofluorescence. Another patient with "congenital" amaurotic idiocy was reported by Hagberg et al. [17]; however, that child was normal at birth and developed seizures at 2 weeks of age. In addition, at autopsy the brain Table 1. Neuronal ceroid-lipofuscinosis classification*
Major NCL Syndromes
Eponyms
Infantile
Haltia-Santavuori
Late infantile
Jansky-Bielchowsky
Juvenile
Spielmeyer-Vogt
Adult
Kufs
Minor NCL Syndromes Congenital Acute
Norman-Wood
Chronic
Edathodu-Dyken
Chronic childhood
Edathodu-Dyken
Acute adult
Zeman-Dyken
Acute-subacute childhood
Bielchowsky variant
Juvenile with ataxia Chronic infantile with autism * Modified from Dyken [16]
Barohn et al: Ceroid-Lipofuscinosis 57
Table 2.
Congenital neuronal ceroid-lipofuscinosis literature review No. of
Clinical
Microceph-
Status
Author, Reference No.
Patients/ Sex
Onset at Birth
aly/Small Brain
Epilepticus
at I)eath
N o r m a n and W o o d [3]*
I/Fe
+
+/+
~
21,~ ~k~
B r o w n et al. [4]*
I/F•
+
+/+
+
t7 wk~
S a n d b a n k [5]*
1/M ° l/F °
+ +
NN/+ NN/+
+ +
24 hr~ 48 hr~
E d a t h o d u et al. [8] *
I/NN
+
NN/NN
+
Alive aI 5 yrs
H u m p h r e y s et al. [6]*
1/NN
+
NN/+
NN
29 hr~
G a r b o r g et al. [7] ~
1/M
+
+/+
+
Present patienff
I/M
+
+/+
+
• Presumed N C L .
o Siblings.
• Siblings.
* Definite NCL.
Age
9 days 36 hrs
Abbreviation: N N = Not noted
was not small and firm and biochemical analysis revealed the accumulated lipid to be the ganglioside, GD3, making it unlikely that the patient was an example of NCL. Unlike the cerebral lipidoses with known ganglioside accumulations due to specific enzyme deficiencies [18], the nature of the biochemical defect in NCL remains unknown [1,19]. The pathologic hallmarks of the NCLs are the accumulation of abnormal autofluorescent material as well as characteristic ultrastructural patterns observed on electron microscopy; therefore, the patients of Norman and Wood [3], Brown et al. [4], and Sandbank [5] can be classified only as familial cerebral lipidoses. It is unknown whether they represented a gangliosidosis, an NCL, or other types of lipid storage diseases. The clinical, gross, and light microscopic features, however, are identical to our patient and several others cited below. A preliminary report by Edathodu et al. briefly described a patient who developed refractory seizures, blindness, and developmental arrest during the neonatal period [8]. Electron microscopic examination disclosed curvilinear cytosomes in peripheral blood lymphocytes; the urine contained elevated dolichol levels. The patient was still alive at age 5 years [16] and was believed to have a "chronic congenital form" of NCL. More recently, Humphreys et al. described a patient with "congenital amaurotic idiocy" confirmed to be NCL [6]. Garbarg et al. also described a patient with congenital NCL in a child of Pakistani parents [7]. These infants died shortly after birth (Table 2). Both patients had extremely small, firm brains and the patient of Garbarg et al. had microcephaly [7]. Ultrastructural examination from autopsy material of these 2 patients revealed material consistent with ceroid-lipofuscin. Humphreys et al. reported both granular and lamellar material [6], while Garbarg et al. described only granular material [7].
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PEDIATRIC NEUROLOGY
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Our patient, therefore, represents another example of congenital cerebral lipidosis that can be classified as an NCL by the application of autofluorescent and electron microscopic criteria (Table 2). In addition, he is only the eighth reported patient with cerebral lipidosis who was symptomatic on the first day of life [3-8]. It appears likely that the early patients with congenital amaurotic idiocy [3-5] also had congenital NCL. Most of these patients have consistent clinical presentations of microcephaly, respiratory failure, and status epilepticus with death occurring within hours, days, or weeks. These patients also are of interest because cerebral lipidosis is not usually considered in the differential diagnosis of microcephaly at birth [20]. A number of recent reports described the diagnosis of NCL during life by identifying typical electron micro, scopic inclusions in extraneural biopsy specimens, including rectal mucosa [21], skin [11,22], appendix [1 I], conjunctiva [22], skeletal muscle [ i 1], lymphocytes [23t, bone marrow [24], and urinary sediment [25]. Recently, NCL inclusions were identified prenatally in amniotic cells [261; after the child was born, the same curvitinear inclusions were found in the infant's lymphocytes and skin fibroblasts at 3 months of age [27]. Few clinical details were provided in this report regarding the infant, "although he presumably was clinically normal when the lymphoCytes and skin tissue were examined [27]. The child had an older sibling who had previously been diagnosed as having late infantile NCL with the development of symptoms at 3 years of age. We believe that the term "congenital" ceroidlipofuscinosis should be reserved for symptomatic patients; the storage material is most likely present at birth, regardless of whether the condition is clinically manifest during the neonatal period. Nevertheless, it is important for clinicians to be aware that NCL can become clinically
a p p a r e n t d u r i n g the n e o n a t a l p e r i o d , u s u a l l y i n t h e setting o f m i c r o c e p h a l y a n d seizures. F u r t h e r i d e n t i f i c a t i o n o f N C L p r e n a t a l l y m a y a d d to o u r u n d e r s t a n d i n g o f this unu s u a l p r e s e n t a t i o n o f the disease.
References
[1] Zeman W. The neuronal ceroid-lipofuscinoses. In: Zimmerman HM, ed. Progress in neuropathology. New York: Grune and Stratton, 1976;3:203 -23. [2] Swick HM. Diseases of gray matter. In: Swaiman KF, ed. Pediatric neurology: Principles and practice. St. Louis: CV Mosby, 1989; 777-81. [3] Norman RM, Wood N. Congenital form of amaurotic family idiocy. J Neurol Psychiatry 1941;4:175-90. [4] Brown NJ, Corner BD, Dodgson MCH. A second case in the same family of congenital familial cerebral lipidosis resembling amaurotic family idiocy. Arch Dis Child 1954;29:48-54. [5] Sandbank U. Congenital amaurotic idiocy. Pathol Eur 1968;3: 226-8. [6] Humphreys S, Lake BD, Schulz CL. Congenital amaurotic idiocy- A pathological, histochemical, biochemical, and ultrastructural study. Neuropathol Appl Neurobiol 1985;11:475-84. [7] Garbarg 1, Torvik A, Hals J, Tangerud SE, Lindemann R. Congenital neuronal ceroid-lipofuscinosis: A case report. Acta Pathol Microbiol Immunol Scand A 1987;95:119-25. [8] Edathodu AK, Dyken PR, Trefz JI, Kelloes CL. Two new forms of neuronal ceroid-lipofuscinoses: Expanded clinical, morphologic, and biochemical classification. Neurology 1984;34:150. [9] Santavuori P, Haltia MR, Raitta C. Infantile type of so-called neuronal ceroid-lipofuscinosis. J Neurol Sci 1973;19:257-67. [10] Westmoreland BF, Groover RV, Sharbrough FW. Electrographic findings in three types of cerebromacular degeneration. Mayo Clin Proc 1979;54:12-21. [11] Carpenter S, Karpati G, Andermann F, et al. The ultrastructural characteristics of the abnormal cytosomes in Batten-Kuf's disease. Brain 1977;100:137-56. [12] Berkovic SF, Carpenter S, A n d e r m a n n F, Jacob JC, Andermann E. Kufs' disease: A critical reappraisal. Brain 1988;111: 27-62.
[13] Allen RJ, Dyken PR. Disorder primarily of grey matter. In: Swalman KF, Wright FS, eds. The practice of pediatric neurology, 2nd ed. St. Louis: CV Mosby, 1982;900-14. [14] Zeman W, Donahue S, Dyken P, Green J. The neuronal ceroid-lipofuscinoses (Batten-Vogt syndrome). In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology, 10th ed. Amsterdam: North Holland Publishing, 1970;588-679. [15] Dyken PR. Reconsideration of the classification of the neuronal ceroid-lipofuscinoses. Am J Med Genet 1988;5:69-84. [16] Dyken PR. The neuronal ceroid-lipofuscinoses. J Child Neurol 1989;4:165-74. [17] Hagberg B, Hultquist G, Ohman R, Svennerholm L. Congenital amaurotic idiocy. Acta Pediatr Scand 1965;54:116-30. [18] Svennerholm L. The chemical structure of normal human brain and Tay-Sachs gangliosides. Biochem Biophys Res Commun 1962;9:436-41. [19] Zeman W, Dyken P. Neuronal ceroid-lipofuscinosis (Batten's disease): Relationship to amaurotic family idiocy? Pediatrics 1969;44: 570-83. [20] Ross J, Frias JL. Microcephaly. In: Vinken PJ, Bruyn GW, eds. Handbook of clinical neurology. Amsterdam: North-Holland Publishing, 1977;30:507-24. [211 Rapola J, Santavuori P, Savilahti E. Suction biopsy of rectal mucosa in the diagnosis of infantile and juvenile types of neuronal ceroid-lipofuscinoses. Hum Pathol 1984;15:353-60. [22] Arsenio-Nunes ML, Goutieres F, Aicardi J. An ultramicroscopic study of skin and conjunctival biopsies in chronic neurological disorders of childhood. Ann Neurol 1980;9:163-73. [23] Curless RG, Parker JC, Flynn JT. Neuronal ceroid-lipofuscinosis: Diagnosis by semithin plastic-embedded sections of peripheral blood lymphocytes from a patient with a normal blood smear. Arch Neurol 1982;39:308-10. [24] Miley CE, Gilbert EF, France TD, O'Brien JF, Chun RWM. Clinical and extraneural histologic diagnosis of neuronal ceroid-lipofuscinosis. Neurology 1978;28:1008-11. [25] De Baecque C. Diagnosis of neuronal ceroid-lipofuscinosis by electron microscopy of urinary sediment. N Engl J Med 1975;292: 1408. [26] MacLeod PM, Dolman CL, Nickel RE, Chang E, Zonana J, Silvey K. Prenatal diagnosis of neuronal ceroid-lipofuscinosis. N Engl J Med 1984;310:595. [27] McLeod P, Dolman C, Nickel R, et al. Prenatal diagnosis of neuronal ceroid-lipofuscinosis. Am J Med Genet 1985;22:781-9.
Barohn et al: Ceroid-Lipofuscinosis
59
MD*
A term infant, observed at birth to be microcephalic, developed status epilepticus and died 36 hours later. At autopsy a markedly atrophic brain was found which, by microscopic examination, demonstrated changes consistent with neuronal ceroid-lipofuscinosis. Cerebral lipidosis with microcephaly presenting at birth is extremely rare. Congenital neuronal ceroid-lipofuscinosis is an atypical form of ceroid-lipofuscinosis and should be considered in the differential diagnosis of the microcephalic neonate with seizures. Barohn R J, Dowd DC, Kagan-Hallet KS. Congenital ceroid-lipofuscinosis. Pediatr Neurol 1992;8:54-9.
Introduction Neuronal ceroid-lipofuscinosis (NCL), or Batten disease, consists of a group of progressive neurodegenerative diseases characterized by the accumulation of autofluorescent ceroid-lipofuscin pigment in the brain and other tissues [1]. Typically, patients are normal at birth; subsequently, there is a relentless deterioration of intellect, vision, and motor function, usually in the presence of a seizure disorder. Four subtypes of NCL have traditionally been described: infantile (Haltia-Santavuori), late infantile (Jansky-Bielschowsky), juvenile (Spielmeyer-Vogt or Batten), or adult (Kufs) NCL [2]. The clinical expression of NCL at birth (i.e., so-called "congenital") has been only rarely identified. Four patients with neonatal "amaurotic idiocy" with microcephaly and seizures were reported prior to the technical ability to distinguish among the different types of cerebral lipidoses [3-5]. Since that time 3 NCL patients presenting at birth have been reported [6-8]. Microcephaly and seizures were observed in most of these patients. The cerebral lipidoses generally are not in the differential diagnosis of the microcephalic infant during the neonatal period. The following patient illustrates another example of this rare disorder and demonstrates the characteristic clinical and pathologic features of congenital NCL.
From the *Department of Medicine, Division of Neurology; and tDepartment of Pathology, Division of Neuropathology; University of Texas Health Science Center; San Antonio, Texas.
54
PEDIATRIC NEUROLOGY
Vol. 8 No. 1
Case Report A 40-week-gestation male infant was born to a 2~-ycar old caucasian G2,PI mother. A sonogram at approximately 20 v, eeks gestation had been normal. There was no history of intrauterine difficultx ,~r maternal illness; labor and delivery were uneventful. The mother's first child was nomaal and neither parent was of Jev~ish descent. At birth Ihe in. rant weighed 2,9(X) gin, measured 45 cm in length, and was \.isibl,,. microcephalic with head circumference 30 cm. The Apgar ~cores were 7 at I mitt and 8 at 5 rain. After arrival in the nursery, the in/ant began having generalized seizures and was transferred to the neonatal intensive care unit. The heart rate was 146 and the respirator3 ralc 48: the infant was afebrile. The patient had generalized lnotnr seizures with reflex sensitivity during which the infant would exhibit increased muscle tone diffusely and hyperactive muscle stretch reflexes throughout. The fundi were normal and the pupils reacted sluggishly to tight. The cranial fontanels were palpable. The general physical exanfination was normal and there was no evidence of organomegaly. Palm and sole creases were consistent with gestational age. A complete blood count and chemistry profile were normal except for an SGOT of 372 tilL (normal: 22-38 U/Lt and a total bilirubin of 7.3 mg/dl (124.8 ramol/L; normal: 0.0-1.5 mg/dl; 0.0-25.6 ,umol/Li. Lymphocyte chromosomal analysis was normal. TORCH antibt×ly titers all were negative. Abdominal sonogram visualized normal kidneys, liver, and spleen. Cranial computed tomography revealed microcephaly with loss of brain substance and enlargement of the subcr;miat space over the entire brain; the ventricles were not dilated, l'here was no intracranial calcification or hemorrhage. Phenytoin and then phenobarbital were administered and despite therapeutic blood levels of both (phenytoin 20.4 I.tg/ml [8t).8 ranol/L], phenobarbital 31.6 tag/ml [136 lamol/L]), he continued to have at least 2 generalized seizures per hour associated with cyanosis and bradycardia. He became progressively bradycardic and died 36 hours after birth. Cerebrospinal fluid examination and electroencephalograph 5 (EEG/ were not pedbrmed. Pathologic Findings. The brain was markedly atrophic, ,aeighing 85 gm lnormah approximately 380 gm). The overall gyral pattern was that of a brain of 32-35 weeks gestational age; the operctda were open. Surface examination revealed diffusely shrunken gyri with widening of the sulci (Fig I). The brainstem was slightly firm in texture. The cerebellum exhibited slight atrophy of the folia. Following fixation in 20% tbrmalin, the brain was serially sectioned to reveal marked atrophy with thinning of an ill-defined cortex to approximately 2-3 ram. and diffuse enlargement of the ventricles (Fig 2). The white matter was unduly firm; the basal ganglia and thalamic nuclei were unremarkable. Representative sections were routinely processed fnr embedding in paraffin, sectioned at 6 gm intervals, and stained by tile hematoxytin and eosin/Luxol-fast-blue (LFB) technique. An unstained section of paraffin-elnbedded cortex was examined under fluorescence. A small portion of cortex was minced in 20% glutaraldehyde, postlixed in 1% osmium tetraoxide, and embedded in epon lot ultrathin sectioning for electron microscopy. Examination of the cortex by light microscopy revealed ballooning of cortical neurons with marked cytoplasmic storage of lipid as evidenced by LFB staining (Fig 3). Some degree of neuronal loss was present and the intervening cortex was markedly gliotic. Lipid-containing macrophages were intermixed with the abnormal neurons. The cerebral white matter was extensively gliotic with many gemistocytic astrocytes: no myelin was observed. Lipid-coutaining neurons were present in all areas of brain, including the thalamus and basal ganglia, cranial nerve nuclei, inferior olives and medulla, neurons of the basis pontis, and fotia and roof nuclei of the cerebellum. As in the cerebrum, the back
Communications should be addressed to: Dr. Barohn; Department of Medicine; University of Texas Health Science Center; 771)3 Floyd Curl Drive: San Antonio, TX 78284-7883. Received May 22, 1991; accepted July 18, 1991.
Figure 1. Lateral view of brain revealing marked generalized atrophy.
ground neuropil was diffusely gliotic and myelination was entirely lacking. The unstained, paraffin-embedded cortex exhibited autofluorescence of neurons and lipid-containing macrophages (Fig 4). Electron microscopic examination of cortex disclosed aggregates of granular, electron-dense material within neuronal cytoplasm, as well as lamellated cytosomal bodies (Fig 5). Gross examination of lungs, liver, spleen, and other organs was unremarkable without evidence of enlargement or other abnormality. Microscopic examination, however, revealed LFB-positive material within the reticuloendothelial system, including Kupffer cells of the liver and within the sinusoidal macrophages of lymph nodes and spleen. Lipid material was also present within autonomic ganglia in the smooth muscle of the bladder and small and large intestine.
Discussion The traditional classification o f the N C L distinguishes 4 varieties [1,2]. A l t h o u g h it m a y vary in a n u m b e r o f clinical features, the p r i m a r y d i f f e r e n t i a t i n g c h a r a c t e r i s t i c a m o n g the various forms is the age of initial clinical expression; therefore, the onset o f the Haltia-Santavuori infantile type occurs during the first 2 years o f life [9]. T h e s e children appear to be n o r m a l at birth and subsequently b e t w e e n 8-18 m o n t h s o f age they d e v e l o p rapid intellectual, visual, and m o t o r deterioration with m y o c l o n i c sei-
Figure 2. Coronal section of brain at mid-thalamus with pronounced cortical atrophy and enlargement of the sylvian fissure.
Barohn et al: Ceroid-Lipofuscinosis
55
Figw'e 3. Representative section oJ cerebral cortex; neurons attd macrophage~ ~'ontain hlue-stamin,~, /ip(,/Us~~:: (hemato.rvlin and eosin/Luxol:[ast-bhce stain, original ma~nifi'cation, riO0).
zures. The brains are severely atrophic and the term "walnut kernel brain" has been applied [1 ]. The onset of the Jansky-Bielschowsky, or late infantile, variant occurs at 2-4 years of age. It is often associated with intractable
Figure 4. apparent.
seizures, a characteristic photic response on EEG [10], and the brain is severely atrophic at postmortem examination. The juvenile Spielmeyer-Vogt type begins between 5 years of age and puberty with progressive visual loss. Cerebral
Unstained paraffin-embedded cortex viewed under fluorescence; autofluorescerwe of ceroid material i~
56 PEDIATRICNEUROLOGY Vol. 8 No. 1
Figure 5. Electron micrograph of a cortical neuron demonstrating membrane-bound electrondense material arranged in a whorling, laminated pattern (original magnification, x29,110; original magnification of inset, x33,960).
atrophy is less marked and seizures occur later in the disease. Finally, the adult type, or Kufs disease, begins in the third or fourth decade of life with dementia and seizures [11,12]. There are no visual abnormalities in this late-onset variant [12]. All of these forms have a progressive course, but the length of the illness can vary greatly. The pathologic hallmarks of NCL are the autofluorescent pigment in brain and other tissues and the ultrastructural intracytoplasmic deposits observed on electron microscopy. Attempts have been made to segregate the NCLs according to their various ultrastructural features (i.e., granular, curvilinear, or lamellar, or fingerprint cytosomes) [11], but the different clinical forms exhibit significant overlapping of findings on electron microscopy [13,14]. Dyken recently proposed an updated classification scheme for NCL in which there are major and minor (or "atypical") syndromes [15,16]. The major NCL syndromes consist of the 4 disorders noted above (Table 1). A number of minor NCL syndromes were proposed, all quite rare, including congenital NCL. A "congenital" form of NCL with onset at birth or during the first hours of life has not been widely appreciated [14]. Norman and Wood [3] and later Brown et al. [4] reported 1 sister each (from a family of 9 siblings) who were microcephalic at birth (Table 2). These infants developed seizures, decerebrate rigidity, and abnormal respiratory patterns within hours after uneventful deliveries. One sister died at 21/2 weeks and the other at 17 weeks of age. The general autopsy findings were normal, but the brains were extremely small and firm. Histologically, the cerebellar and cerebral cellular components had abundant accumulations of lipid material, resembling the brains seen in infantile amaurotic idiocy. Sandbank [5] reported 2 siblings with clinical presentations and pathologic features identical to those in the family described by Norman and
Wood [3] and Brown et al. [4]. Classification of these patients is difficult because they antedated the use of electron microscopy and the tissues were not examined for autofluorescence. Another patient with "congenital" amaurotic idiocy was reported by Hagberg et al. [17]; however, that child was normal at birth and developed seizures at 2 weeks of age. In addition, at autopsy the brain Table 1. Neuronal ceroid-lipofuscinosis classification*
Major NCL Syndromes
Eponyms
Infantile
Haltia-Santavuori
Late infantile
Jansky-Bielchowsky
Juvenile
Spielmeyer-Vogt
Adult
Kufs
Minor NCL Syndromes Congenital Acute
Norman-Wood
Chronic
Edathodu-Dyken
Chronic childhood
Edathodu-Dyken
Acute adult
Zeman-Dyken
Acute-subacute childhood
Bielchowsky variant
Juvenile with ataxia Chronic infantile with autism * Modified from Dyken [16]
Barohn et al: Ceroid-Lipofuscinosis 57
Table 2.
Congenital neuronal ceroid-lipofuscinosis literature review No. of
Clinical
Microceph-
Status
Author, Reference No.
Patients/ Sex
Onset at Birth
aly/Small Brain
Epilepticus
at I)eath
N o r m a n and W o o d [3]*
I/Fe
+
+/+
~
21,~ ~k~
B r o w n et al. [4]*
I/F•
+
+/+
+
t7 wk~
S a n d b a n k [5]*
1/M ° l/F °
+ +
NN/+ NN/+
+ +
24 hr~ 48 hr~
E d a t h o d u et al. [8] *
I/NN
+
NN/NN
+
Alive aI 5 yrs
H u m p h r e y s et al. [6]*
1/NN
+
NN/+
NN
29 hr~
G a r b o r g et al. [7] ~
1/M
+
+/+
+
Present patienff
I/M
+
+/+
+
• Presumed N C L .
o Siblings.
• Siblings.
* Definite NCL.
Age
9 days 36 hrs
Abbreviation: N N = Not noted
was not small and firm and biochemical analysis revealed the accumulated lipid to be the ganglioside, GD3, making it unlikely that the patient was an example of NCL. Unlike the cerebral lipidoses with known ganglioside accumulations due to specific enzyme deficiencies [18], the nature of the biochemical defect in NCL remains unknown [1,19]. The pathologic hallmarks of the NCLs are the accumulation of abnormal autofluorescent material as well as characteristic ultrastructural patterns observed on electron microscopy; therefore, the patients of Norman and Wood [3], Brown et al. [4], and Sandbank [5] can be classified only as familial cerebral lipidoses. It is unknown whether they represented a gangliosidosis, an NCL, or other types of lipid storage diseases. The clinical, gross, and light microscopic features, however, are identical to our patient and several others cited below. A preliminary report by Edathodu et al. briefly described a patient who developed refractory seizures, blindness, and developmental arrest during the neonatal period [8]. Electron microscopic examination disclosed curvilinear cytosomes in peripheral blood lymphocytes; the urine contained elevated dolichol levels. The patient was still alive at age 5 years [16] and was believed to have a "chronic congenital form" of NCL. More recently, Humphreys et al. described a patient with "congenital amaurotic idiocy" confirmed to be NCL [6]. Garbarg et al. also described a patient with congenital NCL in a child of Pakistani parents [7]. These infants died shortly after birth (Table 2). Both patients had extremely small, firm brains and the patient of Garbarg et al. had microcephaly [7]. Ultrastructural examination from autopsy material of these 2 patients revealed material consistent with ceroid-lipofuscin. Humphreys et al. reported both granular and lamellar material [6], while Garbarg et al. described only granular material [7].
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Our patient, therefore, represents another example of congenital cerebral lipidosis that can be classified as an NCL by the application of autofluorescent and electron microscopic criteria (Table 2). In addition, he is only the eighth reported patient with cerebral lipidosis who was symptomatic on the first day of life [3-8]. It appears likely that the early patients with congenital amaurotic idiocy [3-5] also had congenital NCL. Most of these patients have consistent clinical presentations of microcephaly, respiratory failure, and status epilepticus with death occurring within hours, days, or weeks. These patients also are of interest because cerebral lipidosis is not usually considered in the differential diagnosis of microcephaly at birth [20]. A number of recent reports described the diagnosis of NCL during life by identifying typical electron micro, scopic inclusions in extraneural biopsy specimens, including rectal mucosa [21], skin [11,22], appendix [1 I], conjunctiva [22], skeletal muscle [ i 1], lymphocytes [23t, bone marrow [24], and urinary sediment [25]. Recently, NCL inclusions were identified prenatally in amniotic cells [261; after the child was born, the same curvitinear inclusions were found in the infant's lymphocytes and skin fibroblasts at 3 months of age [27]. Few clinical details were provided in this report regarding the infant, "although he presumably was clinically normal when the lymphoCytes and skin tissue were examined [27]. The child had an older sibling who had previously been diagnosed as having late infantile NCL with the development of symptoms at 3 years of age. We believe that the term "congenital" ceroidlipofuscinosis should be reserved for symptomatic patients; the storage material is most likely present at birth, regardless of whether the condition is clinically manifest during the neonatal period. Nevertheless, it is important for clinicians to be aware that NCL can become clinically
a p p a r e n t d u r i n g the n e o n a t a l p e r i o d , u s u a l l y i n t h e setting o f m i c r o c e p h a l y a n d seizures. F u r t h e r i d e n t i f i c a t i o n o f N C L p r e n a t a l l y m a y a d d to o u r u n d e r s t a n d i n g o f this unu s u a l p r e s e n t a t i o n o f the disease.
References
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