Neuroradiologg
Neuroradiology(1981) 21:101-105
© Springer-Verlag 1981
Cranial CT in the Sj gren-Larsson Syndrome F. P. Probst 1, S. Jagell 2 and J. Heijbel 2 Departments of lNeuroradiologyand 2pediatrics, Universityof Ume~, Ume5, Sweden
S u m m a r y . Cranial computed tomography was per-
formed on five patients with the Sj6gren-Larsson syndrome (SLS). No specific morphological abnormalities were found, nor was there any indication of a reduction of brain mass. This result is in keeping with the findings on gross examination of brain specimens of subjects with SLS but not wkh some previously reported PEG findings. The lack of agreement is discussed. The slowly progressive destruction of neuronal substance in the course of the chronic, degenerative process in the brain and spinal cord is obviously not paralleled by a corresponding loss of brain mass nor does it result in any alteration of the shape of the brain. The probable tissue decomposition was not striking enough in our five patients to cause attenuation changes which can be detected by CT. Neuroradiological examinations, including CT, are of no practical value at present for the diagnosis, therapy or prognosis of the disease. K e y words: Sj6gren-Larsson syndrome -
Cranial
computed tomography - Human genetics
The Sj6gren-Larsson syndrome (SLS) is a genetically determined disease with an autosomal recessive inheritance. It is characterized by three cardinal signs: congenital ichthyosis, spastic di/tetraplegia and mental retardation. Its clinical and genetic aspects have been thoroughly evaluated [1-4]. Reports on the morphology of the central nervous system (CNS), based mainly on pneumoencephalography (PEG) are contradictory and inconclusive. PEG has been performed in previous investigations on 19 patients claimed to have SLS. Normal findings were reported in five cases [5-9]. Morphological abnormalities such
as microventriculy [10], porencephaly [11] and agenesis of the corpus callosum [12] were each found in one case. Cerebral atrophy was observed in 11 patients [12-22]. No reports of cerebral angiography or myelography on SLS patients are available. Autopsy has been performed on seven patients who were thought to have SLS but we recognize only three of them as such [4]. The patient described by Sylvester [23] showed no signs of atrophy and that of Baar and Galindo [24], moderate dilatation of the ventricles with the right hemisphere somewhat smaller than the left. The brain weights of these two patients were normal. Bredmose [25] found some atrophy of the frontal lobes but the brain was said to be "not microencephalic". Histological examination of the brains yielded evidence of a progressive neurodegenerative disorder which affected the central motor neurone system predominantly [23, 25]. The water content in white cerebral tissue was 79.4% in Sylvester's patient in contrast to 68-72% in his control patients. Both Bredmose and Sylvester observed marked atrophy of the corticospinal and vestibulospinal tracts in the spinal cord [23]. The cross-sectional area of both medullary pyramids was reduced in Sylvester's case. Myelin was deficient and the number of fibers was greatly decreased. The distal degenerative process ended at the decussation in the case of Bredmose. In Sylvester's case the degenerated anterior corticospinal and vestibulospinal tracts could be traced down to the mid-thoracic region, whereas the degenerated crossed corticospinal tracts were still evident down to the lumbar level. In contrast to the active degenerative process observed in the brain, the spinal cord affections had alreadey reached the final stage or at least slowed down in progression, as there was no histochemical or histological evidence of active myelin breakdown in the tracts of the spinal cord [23].
0028-3940/81/0021/0101/$01. O0
102 The introduction of computed tomography (CT) has made it possible to examine the skull and its contents with a less distressing method than PEG or angiography, and CT often provides more information. In the present study a CT investigation was made on SLS patients with the aim of determining whether morphological abnormalities or attenuation changes could be demonstrated in the brain.
Material Five SLS patients were selected and subjected to CT examination of the skull and brain. They were chosen to form a representative group of the Swedish SLS population with regard to age and severety of ichthyosis, spasticity and mental retardation. The youngest patients, however, were excluded because of difficulty in cooperating and the oldest because of possible unrelated presenile or senile brain changes. Consents were given by parents and patients and the study was approved by the ethical committee at the University Hospital, UmegL The individuals examined were selected from 35 SLS individuals extensively studied in other respects by Jagell in an investigation carried out in 1978. A total of 58 SLS patients were known in Sweden, of whom 35 were alive at that time. These 58 patients were numbered 1 to 58. The controls were five individuals matched as to age and sex to the SLS patients. They were selected from the group of patients who were examined with CT because of epilepsy and found to be normal. A brief description of the five SLS patients and their handicap will first be given below. Their numbers refer to the numbering mentioned above.
Case 50 was a 14-year-old girl with severe mental retardation. She had moderate congenital ichthyosis with severe spastic diplegia, joint contractures and kyphosis. She could move herself only slightly, sitting in a wheel-chair. Case 51 was a 14-year-old boy with moderate mental retardation, severe congenital ichthyosis, and moderate spastic diplegia (Fig. 3). He walked easily with crutches, throwing his paretic legs forward, but could take only a few steps without support. PEG and gas myelography at the age of 2 years were normal. He was treated with anticonvulsive drugs because of epileptic seizures. Case 55 was a 6-year-old boy with moderate mental retardation, moderate congenital ichthyosis and slight spastic diplegia. He walked slowly without support.
Methods A Mark I EMI scanner with a scan time of 6.5 min (matrix 160 × 160) was used for the CT examinations. Collimation was 13mm. The three oldest patients were examined under general anesthesia as they were most handicapped and unable to remain immobile for the time required. The CT images were assessed visually as regards morphology and the attenuation values for white matter of the SLS patients were compared with those of the controls. In all instances the attenuation was calculated from 30 measurements forming a rectangle of 3 × 10 volume elements and situated in corresponding areas of the centrum semiovale (Fig. 4). The attenuation differences between patients and controls were determined by the F-test.
Case Reports
Results
Case 33 was a 40-year-old man with severe mental retardation, moderate congenital ichthyosis and severe spastic diplegia with joint contractures and severe kyphosis. His hand function was good and he moved himself around in a wheelchair.
Sku//s
Case 39 was a 22-year-old man with severe mental retardation who was unable to speak. He had slight congenital ichthyosis and severe spastic tetraplegia with scoliosis and joint contractures (Figs. 1 and 2). He had no functional activity in his arms and legs. He was treated with anticonvulsive drugs because of epileptic seizures.
One patient (Case 39) had markedly voluminous frontal sinuses (Figs. 1 and 2). All skulls were symmetrical in shape in the horizontal slices except Case 33 who had slight flattening of the posterior parietal region. He was also "round headed" with a maximum transverse head diameter (13.9 cm), only 1 cm less than the sagittal diameter (14.9 cm). The others were dolichocephalic, with sagittal measurements from 17 to 18 cm (mean 17.4 cm) and widths ranging from 12.5 to 13.5 cm (mean 13.0 cm); thus on the average the shape of the head did not differ from that
Fig. 1. Case 39, aged 22, with spastic tetraplegia, mental retardation and ichthyosis. Height 164 cm, weight 30 kg Fig. 2a-e. Case 39. Interhemispheric fissure and some frontal sulci are moderately widened (c-e). The significance of this abnormality is uncertain. It can scarcely explain the excessive pneumatization of the frontal sinus (a, b), which is thus an unrelated finding Fig. 3 a and b. Case 51, aged 14, with spastic diplegia, mental retardation and ichthyosis. Height 155 cm, weight 42 kg Fig. 4. Horizontal section through centrum semiovale with star indicating place from where attenuation values were taken for comparison of SLS patients with healthy controls
104 Table 1. Mean attenuation values (EMI-Units) in cerebral white matter for SLS individuals and paired healthy control group SLS group
Control group
Age in Patient years number
Mean EMIUnits
Age in Mean years EMIUnits
40 22 14 14 6
20.6 16.5 13.7 14.4 15.9
39 22 15 14 4
33 39 50 51 55
20.1 18.8 17.3 17.3 15.6
Difference SLS-control
0.5 -2.3 -3.6 -2.9 0.3
Table 2. Example of attenuation measurements (EMI-Units) for
two individuals SLS patient 40 years old
Control patient 39 years old
15 20 23 24 22 23 22 19 20 20 23 23 24 19 20 23 17 19 20 19 18 20 21 21 24 22 20 18 19 23 19 21 19 21 21 17 21 20 19 22 21 19 21 23 20 20 22 18 20 19 22 20 18 20 21 18 18 19 19 20 M = 20.6 M = 20.1
in the normal population. The cephalic index, defined as the ratio of head width to head length × 100, was 78 for the four long-headed patients and 93 for the round-headed one (Case 33). The head circumferences of the five patients were 54.0-58.0 cm (mean 56.0 cm). Brains In one patient (Case 39) a few sulci of the frontal poles, as well as the interhemispheric fissure between them, were moderately dilated (Figs. 1 and 2). Otherwise there were no abnormalities whatsoever in the infra- or supratentorial compartments. The ventricles were in general rather slender. In no instance, except frontally in Case 39, was there the slightest evidence of widening of cisterns or cortical sulci. The attenuation values in the central white matter were somewhat lower in the SLS group, c o m p a r e d with the controls, but the difference between the groups was not statistically significant (0.10 < P < 0.20) (Tables 1 and 2).
Discussion
The SLS patients chosen for this examination are fairly representative of this disease entity as far as the different degrees of clinical impairment, as ichthyosis, di/tetraplegia and mental retardation are concerned. However, Cases 39 and 50 are two of the most handicapped SLS patients in Sweden. With
respect to the size and shape of the skull there was no deviation from the general average. The circumferences were normal both in the group examined with CT and in the remainder of the 35 patients included in the study of Jagell [26]. We conclude that none of the five patients examined by CT was microcranial or microencephalic. Microventriculy, a finding mentioned by Chlond [10], is difficult to appreciate, as this term does not cover any known pathological condition. It m a y be recalled in this context that ordinarily the cerebral ventricles vary in shape and size from extremely slender to rather voluminous. Our patients had predominantly very gracile ventricular systems. Porencephaly, as in the case reported by Gandullia [11], is a condition which occurs prenatally or later as a result of an encephaloclastic process and is reasonably not related to SLS. Systemic malformations such as congenital defects of the corpus callosum are not [27] associated with SLS. The case of Pitt et al. [12], and some other patients from the literature [10, 14, 16, 18, 20] who had morphological cerebral abnormalities are not recognized by us as true SLS patients and surely represent other clinical entities. We consider gross congenital morphological cerebral abnormalities not causally involved or regularly associated with SLS. The absence of any dilatation of the ventricles or general widening of the cortical sulci in our patients would seem to exclude a loss of brain mass. T h e regional widening of the frontal subarachnoid spaces in Case 39 is difficult to evaluate owing to the normal range of variability. Excessive pneumatization of the frontal b o n e is a recognized feature associated with subnormal development of the frontal lobes or of the brain in general. The abnormality in Case 39 seems to be too restricted to be responsible for the extensive pneumatization of the frontal bone. W e regard this as of uncertain significance and not related to the syndrome in question. Statements in the literature about cerebral morphology in SLS, based on P E G , mainly refer to patients in w h o m the P E G was performed in the 1950s and 1960s, with varying techniques and various standards of assessment. In the early 1970s the p h e n o m e n o m of altered cerebral morphology induced by gas pressure received increased attention. The gas distension of the ventricles on P E G has been determined metrically [28-31 ]. Presumably, the same p h e n o m e n o n will apply to the outer subarachnoid spaces. 'Dilated ventricles' and 'widened sulci' may be created by excessive gas filling. For these reasons the previously reported encephalographic findings of brain atrophy in SLS, mentioned above, appear questionable. This might explain our negative findings.
105
In contrast to the tissue losses demonstrated in the spinal cord, the available autopsy reports provide no evidence of a reduction of brain substance recognizable by inspection of the surface or sections of the brain. This is in keeping with our CT findings. It is supposed that the losses due to the extensive degenerative processes, as described by Sylvester [23], are replaced by glial tissue and by the increase of water content in the cerebral white matter reported by the same author. According to Sylvester [23] the peripheral axon degeneration of the pyramidal tracts precedes the degeneration of the cerebral grey matter and the demyelination of the central white matter. None of the brains examined pathologically or by CT seemed to have reached the terminal stage of degeneration that was present in the spinal cords [23, 25]. This is compatible with a slowly progressing, chronic course of the degenerative cerebral process. Concerning CT examination, it is probable that decomposition of the cerebral substance also changes its attenuation properties. The attenuation values of the white matter of the SLS patients were lower than those of the matched controls, but the differences were not statistically significant which may be due to the small material. It is concluded that neuroradiological examinations, including CT, are of no practical value for the diagnosis, therapy or prognosis of this disease. Acknowledgements. The authors are grateful to P.-~. Hofer, Department of Pathology for valuable advice and to J. Chotai and L. Gustavson for statistical analyses. The present work was supported by the O. Hansson Foundation and Sfivstaholmsf6reningen.
References 1. Si6gren T, Larsson T (1957) Oligophrenia in combination with congenital ichthyosis and spastic disorders. A clinical and genetic study. Acta Psychiatr Scand 32; (Suppl): 113:1-113 2. RichardsBW (1972) Sj6gren-Larsson syndrome. In: Vinken PJ, Bruyn GW (eds) Handbook of clinical neurology. North-Holland, Amsterdam, pp 468-482 3. Theile U (1974) Sj6gren-Larsson syndrome. Humangenetik 22:91-118 4. Jagell S, Gustavson K-H, Holmgren G (1981) Sj6gren-Larsson syndrome in Sweden. A genetic study. Clin Genet (in press) 5. Gomes da Costa MG, Menano H (1963) Sindroma de Sj6gren e Larsson. Rev Port Ped Puericult 26:6-31 6. Guilleminault C, HarpeyJP, Lafourcade J (1973) Sj6grenLarsson syndrome. Neurology 23:367--73 7. Heijer A, Reed WB (1965) Sj6gren-Larsson syndrome. Arch Dermatol 92:545-52
8. Maiya PP (1977) Sj6gren-Larssons syndrome. A case report. Indian Pediatr 1:89-91 9. Rohmer F, Temp6 ID (1964) Apropos du syndrome de Sj6gren et Larsson. Rev Otoneuroophtalmol 36:179-86 10. ChlondH (1963) Beschreibung eines Falles yon Ichthyosis Oligophrenie und spastischer Tetraplegie (Sj6gren-Larsson Syndrom). Kinderaerztl Prax 31:355-59 11. Gandullia E (1963) La sindrome di Sj6gren-Larsson. Minerva Pediatr 15:979-82 12. Pitt D, Roboz P, Williams A, McD Anderson R (1967) A case of Sj6gren-Larsson syndrome. Aust Paediatr 3 : 5 4 - 7 13. Baar HS, Frigyesi T, Mautner V (1960) The Sj6gren-Larssons syndrome. J Maine Med Assoc 51:189-96 14. Beringer U, Mumenthaler M, Zala L (1977) The Sj/SgrenLarsson syndrome. J Neurol 214:217-24 15. Boucharlat J, Ldopold P, Wolf R, Pellat J, Franco A (1969) Le syndrome de Sj6gren Larsson. Ann Med Psycho1127:293-96 16. Fehlow P, Tennstedt A (1975) Beitrag zum Sj6gren-Larsson Syndrom. Psychiatr Neurol Med Psychol (Leipz) 6:341-47 17. Gilbert WR, Smith JL, Nyhan WL (1968) The Sj/Sgren-Larsson syndrome. Arch Ophthalmol 80:308-16 18. Kissel P, Andr6 JM, Andr6 M (1973) Coexistence dans la m6me famille d'un syndrome de Sj6gren-Larsson et d'un syndrome de Rud. J Genet Hum 1:15-22 19. L6opold P, Boucharlat J, Tavernier J (1969) Le syndrome de Sj6gren-Larsson. Bull Mem Soc Fr Ophthalmol 5:612-615 20. Maia M (1974) Sj/Sgren-Larsson syndrome in two sibs with peripheral nerve involvement and bisalbuminaemia. J Neurol Neurosurg Psychiatry 37:1306-15 21. Richards BW, Rundle A, Wilding ASt (1957) Congenital ichthyosis, spastic diplegia and mental deficiency. J Ment Defic Res 1:118-29 22. S6derhjehn L, Enell H (1957) Iktyos, spastisk diplegi i nedre extremiteterna och oligofreni - e t t sfirskilt syndrom. Nord Med 17:624-25 23. Sylvester PE (1969) Pathological findings in Sj/Sgren-Larsson syndrome. J Ment Defic Res 13:267-75 24. Baar HS, Galindo J (1965) Pathology of the Sj6gren-Larsson syndrome. J Maine Med Assoc 56:223-26 25. Bredmose GV (1940) Et tilfaelde af mongoloid idioti og ichthyosis med neurohistologiske forandringer. Nord Med 5: 440-42 26. Jagell S (1981) Medical dissertation. University of Umeh 27. Probst FP (1973) Congenital defects of the corpus callosum. Acta Radiol (Suppl) 331:1-152 28. Oberson R, Candardjis G, RaadN (1969) Height of fourth ventricle. Normal variability during pneumoencephalography. Acta Radiol [Diagn] 9:193-98 29. Lim ST, Potts DG, Deck MDF (1972) Changes in the ventricular size during fractionated encephalography. Radiology 104:585-92 30. Probst FP (1972) Rapid changes in the volume of the lateral ventricles at encephalography. Acta Radiol 12:757-67 31. Probst FP (1973) Gas distension of the lateral ventricles at encephalography. Acta Radiol 14:1-4 Received: 28 October 1980 Dr. S. Jagell Department of Pediatrics University Hospital of Umeh S-90185 Ume~, Sweden