Zeman and Dyken1 in 1969 introduced the name neuronal ceroid-lipofuscinosis (NCL) for a group of diseases showing neuronal accumulations of lipopigments of the ceroid-lipofuscin type. This group comprises a number of cases diagnosed clinically as the late infantile (Jánsky-Bielschowsky), the juvenile (SpielmeyerSjögren) or the adult (Kufs-Hallervorden) type of amaurotic idiocy. In contrast to the chemically well-defined gangliosidoses of which at least five enzymatically different varieties are known the neuronal ceroidlipofuscinoses do not reveal any primary disturbance of sphingolipid metabolism.2 Histopathological study of the retina in Spielmeyer-Sjogren-type of neuronal ceroid-lipofuscinosis revealed atrophy of the pigment epithelium, narrowing of the plexiform layer, and complete loss of the outer nuclear layer. Electron-microscopy revealed accumulation mainly of curvilinear bodies in the ganglion cells.3 The value of biopsy of the appendix for the diagnosis of this condition has been emphasized.4
An additional type of ceroid-lipofuscinosis has been recently described.5»6'7 The condition has been called infantile type of neuronal ceroid-lipofuscinosis (INCL). Altogether 46 patients exhibited rapid psychomotor retardation beginning at the age of 8-18 months, ataxia, muscular hypotony, visual failure, myoclonic jerks, and microcephaly.8 By the age of two years all patients were grossly mentally retarded without speech. There was severe visual failure and the patients died at a mean age of 6.6 years. The condition appears · to follow an autosomal recessive mode of inheritance. Neuropathological studies comprising nine autopsies and 18 biopsies revealed progressive loss of neurones in the cerebral and cerebellar cortex. The surviving neurones and other neuroectodermal cells as well as a number of extraneural cells showed accumulation of lipofuscin-like material which by electronmicroscopy showed a homogenous, finely granular internal structure.6'7'8 To date 52 clinical cases have been diagnosed.
Ophthalmological examination of 16 patients disclosed eight patients to be blind. Seven had light perception and only one, aged 20 months, followed moving objects and had normal pupillary reactions. Ophthalmoscopy at the late stage revealed optic atrophy, macular dystrophy, narrowing of the retinal vessels, and hypopigmentation. ERG was abolished.9
Ocular histopathology of the infantile type of ceroid-lipofuscinosis has been briefly described in one case.7 The retina showed severe atrophy with complete loss of ganglion, visual as well as bipolar cells, and proliferation of the glial elements. In addition, there were large pigment-laden macrophages containing granular deposits in their cytoplasm. No myelin sheaths were left in the atrophic and gliosed optic nerves. But as on the whole, very little information on the ocular pathology of this particular type of ceroid-lipofuscinosis is available, we thought it justified to describe our observations on ocular pathology of five autopsy cases in which the diagnosis had been confirmed at neuropathological autopsy.
PATIENTS AND METHODS CASE REPORTS
Patient No. 1
The patient was a 10-year-old Finnish boy who had been born normally at full term. His early development was normal until the age of one year when general deterioration and spasticity of the extremities started. At this stage he was examined at the Helsinki University Children's Hospital on two occasions. Spasticity of the extremities was present. Cerebrospinal fluid findings were not remarkable, protein electrophoresis being normal. All serological studies were negative. Biopsies of the sural nerve and of the rectum provided no evidence of metachromatic leucodystrophy. EEG revealed lowered over-all potentials. Air studies of the skull were suggestive of cerebral atrophy. Progressive dementia gradually developed and the patient was treated in a home for chronically-ill children. He was reported to have been spastic and had seizures. No information was available of his visual acuity. At the age of 10 years the patient died from an acute infection.
Relevant autopsy findings: A very cachetic body of a boy was seen at autopsy. The extremities were rigid with flexion contractures. Pneumonia was found to be the immediate cause of death. The skull was markedly thickened, and pronounced cerebral atrophy was present. The cerebral and cerebellar cortex showed severe neuronal loss and contained large macrophages laden with granular PAS-positive material. The nerve cells of the basal ganglia, dentate nucleus, spinal cord and the brain stem were better preserved although they also contained the same granular material. Furthermore, phagocytes containing the material were observed in many organs, particularly in the liver and the lymph nodes. The material gave strong reactions with PAS and Sudan Black B techniques.
Patient No. 2
The mother of this A-twin boy was a 33-year-old midwife who had given birth to one healthy child before. The twins were born normally at full term. The ?-twin was a boy weighing 2200 gm and he received 9 Apgar points. The B- twin was a girl who weighed 2100 gm and received 6 Apgar points. The B-twin died at the age of six days of meningitis. The ?-twin developed normally until the age of 1.5 years when rapid deterioration started. Already at the age of three years the patient was unable to sit and had apparently no contacts to his surroundings or attending personnel. The patient appeared to be blind, too. His pupils showed no reaction to light, the optic discs were pale, and the fundi hypopigmented. The patient died at the age of nine years and infantile type of neuronal ceroid- lipofuscinosis was disclosed at neuropathological autopsy.
Patient No. 3
The patient was a girl, the first child of healthy parents, who developed normally until the age of six months. At the age of one year a rapid retardation developed. A thorough neurological examination including brain biopsy was carried out at the age of two years at the Helsinki University Children's Hospital and infantile type of ceroid- lipofuscinosis was disclosed. The patient died at the age of 4.5 years.
Patient No. 4
The patient was a boy who developed normally until the age of one year when deterioration started. On pediatric examination at the age of 1.5 years, myoclonia and a slow EEG were noted. The patient became blind, severely retarded, and died at the age of nine years. The diagnosis of infantile type of ceroid- lipofuscinosis was confirmed at neuropathological autopsy.
Patient No. 5
The patient was a girl who was born normally at full term, with the birth weight of 3280 gm. Her parents were healthy and family history for retarded or blind family members was negative. The patient developed normally until the age of six months when her mother noticed weakness of the lower legs. At the age of one year retardation developed and the patient was admitted to the Helsinki University Children's Hospital for examination. The patient was hypotonic and could no longer raise her head. At this stage her hearing and vision appeared normal and normal fundi were also reported after ophthalmoscopy. Her general condition deteriorated and at the age of two years she appeared to be blind with no contacts with the caring personnel. She did not react to voices either. Her legs were hypotonic and the tendon reflexes symmetrical. Pneumoencephalography revealed a marked cerebral and cerebellar atrophy. On ophthalmoscopy the optic discs appeared pale but the pigmentation of the fundus was normal. The patient died at the age of nine years of pneumonia. Infantile type of ceroid- lipofuscinosis was established at the neuropathological autopsy.
Summary of the Relevant Clinical Features
The material included three boys and two girls with normal birth weights except in one case. The development of the patients had been normal until the age of six months to 1.5 years when rapid psychomotor deterioration started, The patients became totally blind and pale discs with otherwise normal or hypopigmented fundi were reported by ophthalmoscopy. The patients died varying from the age of 4.5 to 10 years.
All eyes of the five patients were removed within 24 hours after death, fixed in 10 percent neutral formalin, opened in horizontal plane, and embedded in paraffin. Sections were stained with naematoxylirt and eosin, van Gieson, periodic acid Schiff (PAS), Alcian blue, Sudan black B, Ziehl-Nelsen (acid-fast lipofuscin), Nile-Blue, and Nassar reticulin stains. Pieces of the retina were also removed from paraffin blocks and processed for electronmicroscopy according to the methods of Zimmerman, Font, Tso, and Fine.10
The results of neuropathological studies have been described in detail elsewhere.6'7 An extraordinary degree of brain atrophy was disclosed due to total loss of neurons from the cerebral and cerebellar cortex and to an advanced degree of neuronal destruction in most subcortical centers (Fig. 1). The surviving neurons, other neuroectodermal cells and a number of extraneural cell types showed accumulations of autofluorescent, PAS-positive, sudanophilic granules, resistant to lipid solvents in their cytoplasm (Fig. 2). Ultrastructural Iy, these granules were of the residual body type, consisting of membrane-bound gonglomerations of spherical g lobules 0.2-0.5 urn in diameter with a homogenous, finely granular internal structure (Fig. 3). These lesions were associated with a pronounced astrocytic and mesenchymal reaction with the presence of large numbers of phagocytic cells in the grey matter of the central nervous system and to a lesser extent, In other tissues. Furthermore, there was an almost total loss of myelin from the brain.
Fig. 1. Macroscopic appearance of the brain of the patient with infantile type of neuronal ceroidlipofuscinosis shows extreme generalized atrophy of the cerebral grey and white matter and ventricular dilatation.
Fig. 2. Cerebral cortex from a four-year-old boy with infantile type of neuronal ceroid-lipofuscinosis shows total disappearance of neurons and an abundant number of phagocytes containing PASpositive deposits. (PAS original magnification x 790)
Macroscopically all 10 eyes were of normal size. The cornea, lens, and the vitreous were not remarkable. The optic discs appeared pale (Fig. 4). The posterior retina appeared oedematous with some pigment dispersion in the equatorial region (Fig. 5). Microscopically the cornea and sclera appeared normal. However, the nonpigmented ciliary epithelium of the pars plana area showed granular, PAS-positive deposits mainly in the apical parts of the nonpigmented cells (Fig. 6). The pigment epithelium of this area appeared normal.
In the retina, a complete destruction of the retinal architecture was observed (Fig. 7). The visual cells, the bipolar cells and the ganglion cells were replaced by marked glial proliferation (Fig. 8). Loss of pigment of the retinal pigment epithelium had taken place in some extent. With PASstain granular material was detected in the retina and the pigment epithelium. Furthermore, the retina contained large pigmentladen macrophages with PAS-positive deposits in the cytoplasm (Fig. 9). The optic nerve was atrophic and gliosed with complete loss of myelin sheaths (Fig. 10). Same PAS-positive material could also be detected in the optic nerve. The granular deposits in the eye could be stained with the PAS, silver, Sudan black B, ZiehlNelsen (acid-fast lipofuscin) and the NileBlue stains.
By electronmicroscopy, granular osmiophilic deposits were observed in the cytoplasm of great many retinal cells (Fig. 11). Postmortem autolysis and inadequate fixation had caused artefacts to the cellular structures. No specific association of the storage material with the normal cell organelles could be detected.
The infantile type of neuronal ceroid-lipofuscinosis is clinically characterized by its age of onset from eight to 18 months, rapid psychomotor retardation, ataxia, and muscular hypotony.8 The patients become blind by the age of two years with optic atrophy and retinal hypopigmentation as the main ophthalmoscopic features.9 The late infantile type of neuronal ceroid-lipofuscinosis, (Jansky-Bielschowsky), on the other hand, becomes clinically manifest usually between two to five years of age with seizures. In great majority of cases there are retinal manifestations with granular degeneration of the macula and peripheral pigmentary retinopathy as the main features.2 In the infantile type of ceroid-lipofuscinosis macular cherry-red spot is never seen and the cases with cherry-red spot described in the literature as ceroid-lipofuscinosis may be cases of gangliosidosis. Combined histological, histochemical, and biochemical studies have excluded known forms of neurolipidosis, leucodystrophies, poliodystrophies and axonal dystrophies, and the name infantile type of ceroid-lipofuscinosis is based on the morphological and histochemical characteristics and on the appearance of symptoms at an early age.6
Fig. 3. Cytoplasm of a motor neuron from the spinal cord shows partly membrane- bound osmiophilic deposits with finely granular interior structure, (original magnification x 20.000)
Fig. 4. Macroscopic appearance of the posterior fundus of an autopsy eye in infantile type of neuronal ceroid-lipofuscinosis shows an extremely atrophic optic disc, posterior edema and fine pigmentary deposits.
Fig. 5. Macroscopic appearance of an autopsy eye in infantile type of neuronal ceroid- lipofuscinosis reveals pigment proliferation in the equatorial region.
Fig. 6. Ciliary epithelium of the pars plana area reveals PAS-positive deposits in the apical portions of the non-pigmented cells. (PAS original magnification x 250)
Fig. 7. Total destruction of the normal architecture with reactive gliosis of the retina in infantile type of ceroid-lipofuscinosis, (original magnification PAS x 120)
Fig. 8. The retinal pigment epithelium shows marked loss of pigment and the retina an extreme degree of gliosis in infantile type of neuronal ceroid-lipofuscinosis. Haematoxylin and eosin (original magnification x 780)
Fig. 9. PAS-stain reveals PAS-positive granular material in the retina and the pigment epithelium; also some large pigment-laden macrophages are visible in infantile type of neuronal ceroid-lipofuscinosis. (PAS original magnification x 180)
Fig. 10. Optic nerve in infantile type of neuronal ceroid- lipofuscinosis shows complete loss of myelinated axons with severe reactive gliosis. The astrocytes contain PAS-positive deposits in their cytoplasm. (PAS original magnification x 400)
Fig. 11. Electronmicrograph of a glial cell from the retina in infantile type of neuronal ceroid- lipofuscinosis shows intracytoplasmic granular deposits, (original magnification x 10.000)
Ocular pathology in the infantile type of ceroid-lipofuscinosis is characterized by striking destruction of retinal architecture, optic atrophy, accumulation of PASpositive granular material in the nonpigmented ciliary epithelium, the retina, retinal pigment epithelium, and the optic nerve. The pathological changes found in the present study on Finnish material have been confirmed by Danis" who studied the autopsy eyes of a small boy of Turkish extraction. The patient had become retarded and blind at an early age and neuropathological autopsy revealed changes compatible with infantile type of ceroidlipofuscinosis.
Ocular pathology in the other types of ceroid-lipofuscinosis has been well documented in the literature and also confirmed by personal observations. In general, less damage of the neuroectodermal structures of the eye has been reported.2 In the late infantile type the ganglion cells are swollen in the macular region and loaded with PAS-positive material. The bipolar cells are preserved and the granular material is seen also in this layer as well as in the remaining photoreceptor cells. There is migration of the pigment into the retina, and the optic nerve appears often normal.2,12 In the juvenile type the ganglion cells show some rounding of their contours and an accumulation of PAS-positive pigment which also stains with Sudan black B. There is marked loss of the visual cells. The pigment epithelium is atrophic and often devoid of melanin. Optic atrophy has been reported but it may well be secondary to retinal atrophy.3 No information is available of the ocular histopathology in the adult type of ceroid-lipofuscinosis.
In the late infantile and juvenile types of ceroid-lipofuscinosis electronmicroscopy has revealed intracytoplasmic inclusions of either curvilinear and/or fingerprint types,3'14 while the infantile type is characterized by inclusions with a finely granular internal structure.7 Typical curvilinear and/or fingerprint bodies were not observed in the retina in the infantile type in the present study and hence the retinal findings do not seem to differ from what has been found in other central nervous system structures.
To date no specific enzymatic deficiency as the etiology of the condition is known. In the infantile type the retinal architecture is destroyed but in addition such nonsensory structures as the ciliary epithelium, the pigment epithelium of the retina and the optic nerve are involved. Hence one may assume a simultaneous involvement of all neuroectodermal structures of the eye instead of specific involvement of the eg. ganglion cells or the visual cells only. As we all know in the Tay-Sachs Disease (Gangliosidosis GM2 Type I) the essential morphological alterations are manifested in the ganglion cells. The importance of differentiating these two classes of amaurotic familial idiocy is emphasized13'14'15 and ophthalmic pathology may be helpful in the study of the basic pathology and it may be useful in the differential diagnosis of the various types of ceroid-lipofuscinosis.
Ocular pathology of the infantile type of ceroid-lipofuscinosis is reported. The material comprised 10 eyes of five autopsies in which the diagnosis had been confirmed by neuropathological autopsy. The condition is clinically characterized by its age of onset from eight to 18 months, rapid psychomotor retardation, ataxia, and muscular hypotony. The patients become blind by the age of two years with optic atrophy and retinal hypopigmentation as the main ophthalmoscopic features. In the retina a complete disappearance of the visual cells, the bipolar cells and the ganglion cells was observed with marked reactive gliosis. Loss of pigment from the retinal pigment epithelium had taken place. The optic nerve showed atrophy and gliosis with complete loss of myelin sheaths. Granular deposits stainable with PAS, and Sudan black B stains were observed in the nonpigmented ciliary epithelium of the pars plana, the pigment epithelium as well as the glial cells of the optic nerve. Granular deposits were also noted in the cytoplasm of large pigmentladen macrophages in the retina. Electronmicroscopy revealed osmiophilic granular deposits in the cytoplasm of many retinal glial cells.
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