1143
only a general tendency towards high or low pressure. To take advantage of this heterogeneity in the blood pressure values of offspring, Watt et al developed the four comers technique. 11,12 These researchers measured height, weight, and blood pressure in 864 adults aged 16-24 years from 603 families in which both parents had had their blood pressure measured 8 years before as part of the screening phase of the Medical Research Council (UK) trial." Individual Z scores were calculated by dividing deviations from the of the appropriate age-sex group of blood pressure within the standard deviation by group, and a scatter diagram was constructed with offspring Z scores on one axis and combined parental Z scores on the other. The diagram was used to select randomly groups of offspring with low (C) and high (A) pressure scores and parents with low scores, and groups of offspring with low (D) and high scores (B) with both parents with high scores. (Some parents were undergoing treatment for hypertension and their scores were adjusted accordingly.) It is important to recognise that most of the parents and all of the offspring were normotensive. Several phenotypic and genotypic variables were then examined. Thus the
mean blood pressure
technique provided four groups that were homogeneous with respect to age; the study design allowed comparison of individuals with contrasting family background but similar levels of pressure, but used epidemiological methods to contrive the most informative comparisons within a single population to identify familial and non-familial correlates of high blood pressure. The researchers concede that the study is exploratory and opportunistic, but some interesting data emerged. The main finding is that several phenotypic correlates of high blood pressure in young people seem to depend on parental blood pressure levels. Offspring with high blood pressure scores had increased body mass indices irrespective of parental blood pressure. In addition, high scores in young people were associated with higher concentrations of plasma angiotensinogen, cortisol, and 18-hydroxy corticosteroids, but only when parental blood pressure scores were high (B vs C). 27% of the offspring with high scores and high parental scores were homozygous for the larger allele of a restriction fragment polymorphism identified by a glucocorticoid receptor gene probe, compared with 9% of offspring with low blood scores from parents with low scores. The distribution of the polymorphism suggested that homozygosity for the larger allele is associated with lower blood pressure. This pattern was observed not only between those at highest and lowest genetic risk (B and C) but also between offspring with high and low scores within each of the two family groups (A vs C and B vs D). The researchers speculate that this genetic defect may be pathogenetically linked with the other phenotypic findings, cortisol being an important ligand for the glucocorticoid receptor.
tempting to suggest that this report heralds a breakthrough in our understanding of hypertension It is
but that would be premature. But, as Watt and colleagues acknowledge, the results have more bearing on why people have blood pressure levels above and below the mean than on why a few get hypertension. The structural defect in the glucocorticoid receptor gene shown by a restriction enzyme needs more vigorous assessment. Other restriction fragment length polymorphisms of this gene need to be studied, and above all the defect needs to be shown to co-segregate with hypertension in family studies. One thing is certain-the race to identify the genes responsible in hypertension is now well and truly on. 1.
Rapp JP. Dissecting the primary causes of genetic hypertension in rats. Hypertension 1991; 18 (suppl 1): I-18-I-28.
2. Tanase H, Suzuki Y, Ooshima A, Yamori Y, Okamoto K. Genetic analysis of blood pressure in spontaneously hypertensive rats. Jap Circ J 1970; 34: 1197-212. 3. Jacob H, Lander E, Dzau VJ. Progress towards a genetic map of the hypertensive rat. Hypertension 1991; 18: 399 (abstr). 4. Hilbert P, Lindpainter K, Beckman JS, et al. Chromosomal mapping of two genetic loci associated with blood pressure regulation in hereditary hypertensive rats. Nature 1991; 353: 521-29. 5. Jacob H, Lindpainter K, Lincoln DE, et al. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell 1991; 67: 213-24. 6. Mullins JJ, Peters J, Ganten D. Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 1990; 344: 541-44. 7. Kimura S, Mullins JJ, Bunnemann B, et al. High blood pressure in transgenic mice carrying the rat angiotensinogen gene. EMBO J 1992; 11: 821-27. 8. Bianchi G, Barlassina C. Renal function in essential hypertension. In: Genest J, Kuchel O, Hasnet P, Cantin M, eds. New York: McGraw Hill, 1983: 54-73. 9. Schelling P, Fischer H, Ganten D. Angiotensin and cell growth: a link to cardiovascular hypertrophy? J Hypertens 1991; 9: 3-16. 10. Mongeau J. Heredity and blood pressure. Semin Nephrol 1989; 9: 208-16. 11. Watt GCM, Foy CJW, Holton DW, Edwards HV. Prediction of high blood pressure: limited usefulness of parental blood pressure data. J Hypertens 1991; 9: 55-58. 12. Watt GCM, Harrap SB, Foy CJW, et al. Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four comers approach to the identification of genetic determinants of blood pressure. J Hypertens 1992; 10: 473-82. 13. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985; 291: 97-104.
Thalamic lesions in
infancy
Thirty years ago Rosales and Riggs1 described three infants with profound neurological abnormality
term
from birth who died between six and sixteen months of age. Necropsy revealed thalamic cell loss with astrogliosis and "fossilised neurons". The aetiology was uncertain. Eicke and colleagues2 lately reported six infants (five born at term) in whom they diagnosed symmetrical thalamic lesions. These babies showed lack of movement, poor respiratory effort, and absence of sucking and swallowing; only one had seizures. In two cases the clinical picture was the only diagnostic criterion; neither showed thalamic lesions on imaging and necropsy was refused in both. Three of the remaining infants had evidence of perinatal asphyxia, and septo-optic dysplasia was found in the fourth at necropsy. This report raises as many questions as it answers, so what have we learnt about
1144
neonatal thalamic lesions in the past thirty years? Asphyxia was identified as the antecedent event in a neuropathological study of three infants with thalamic neuron loss, gliosis, and cavitation. Ultrasound displayed thalamic lesions in six of eighty-three infants with hypoxic ischaemic encephalopathy in one series4 and in one of thirty-two in another.5 The asphyxial insult is severe, total, and may occur before birth,3,6 perinatally ,4,7 -9 or postnatally. 8,9 Most but not all infants reported were born at term;4,7-9 the most immature baby was born at 32 weeks’ gestation." The predilection of the thalamus to injury with increasing gestation probably reflects the increase in blood flow, metabolic rate, and oxygen requirements.4,6,9 The thalamic changes, whether identified by imaging or at necropsy, are always bilateral. 3,4,6--11 The ultrasound appearance is of a bilateral homogeneous echogenicity which may be present within twentyfour hours of birth7,8 or develop as late as four months.Later evolution to cystic change within the thalamus has been reported on imagingg9 and at necropsy.3There may be associated abnormalities such as cerebral oedema or parenchymal cysts. Computed tomography has also been used in diagnosis, and thalamic hyperintensity was found on magnetic resonance imaging (MRI) in two of thirty severely asphyxiated newborn babies,12 one at two weeks of age and the other at twenty-six months. MRI may be the most sensitive technique for lesions of the thalamus, basal ganglia, and brainstem.13 At necropsy, haemorrhagic7,8,11 and non-haemorrhagic8 thalamic necrosis have been seen. Increased thalamic blood flow,14 capillary proliferation, 15 and vasogenic oedema16 have also been proposed. Gliosis and calcification develop subsequently,36 and the persisting echodensity reported by Shen et al4 at seven months may signify the development of status marmoratus. This neuropathological entity, whose main feature is hypermyelination, has been noted by eight months of age. 17 All the infants reported showed profound neurological abnormalities from birth. Many died in the neonatal period or early childhood and all survivors have been severely handicapped. 49,10 Thalamic injury without cortical lesions has been associated with significant intellectual impairment, which suggests an important role for the thalamus in
cognitive development.17 Four previously healthy term infants with primary thalamic haemorrhage presented acutely aged eleven to fourteen days with seizures, opisthotonus, and facial weakness.18 Characteristic features were eye deviation to the side of the haemorrhage and early sunsetting-ie, downward deviation with sclera visible above the iris. These abnormalities were due to involvement of the frontomesencephalic tract and the vertical gaze centre, respectively, since both lie close to the thalamus. Hydrocephalus developed in three of these infants, and two needed a shunt. The neurological outcome was good: one child was normal
twenty months of age and the other three had mild spastic hemiparesis. In two term infants with thalamic haemorrhage seizures developed at five and seven days, respectively, and one baby had upward deviation of the eyes ;19 one of these children was normal at ten months and the other had a mild hemiparesis. Roland et aFo believe the thalamus is the primary site in nearly two-thirds of term infants with intraventricular haemorrhage. The ultrasound appearance of primary thalamic haemorrhage is of a heterogeneous, irregular, and unilateral echodensity and there may be blood within the ventricle. The aetiology is uncertain; there is no evidence of asphyxia, or vascular trauma, disorder, clotting malformation. 18,199 Occasionally germinal matrix haemorrhage in the preterm infant may extend into the thalamus but does not induce this characteristic at
syndrome. What else may cause thalamic abnormality in the neonatal period? Intrauterine infection with cytomegalovirus, rubella, or toxoplasma may result in echodensity and calcification of the thalamus and basal ganglia, among other manifestations. 16,17,2122 Perivascular microcalcification has been identified at necropsy.16,21 Two term infants with congenital cytomegalovirus infection showed bilateral thalamic echogenicity compatible with calcification, and both developed spastic quadriplegia." Bilateral basal ganglia echodensity has also been described in neonatal streptococcaF1 and pneumococcahb meningitis; the former went on to "mild neurological deficit". Occasionally, genetic factors are important. Two siblings with severe neurological abnormalities from birth died at three weeks and two months, respectively.Z3 Necropsy revealed neuronal loss and gliosis, especially in the thalamus. A rare pattern of autosomal recessive encephalopathy may produce neurological abnormality from birth, with basal ganglia or thalamic calcification seen on scanning at a few weeks of age.24,25 Chromosomal trisomies 21 and 13 have also been linked with thalamic echogenicity in newborn babies. 2122 Thus there are clearly two distinct patterns of thalamic haemorrhagic insult in infants, with different aetiology, clinical presentation, scan appearance, and prognosis. Infection and genetic factors enter the differential diagnosis. Riggs HE. Symmetrical thalamic degeneration in infants. J Neuropathol Exp Neurol 1962; 21: 372-76. 2. Eicke M, Briner J, Willi U, Uehlinger J, Boltshauser E. Symmetrical 1. Rosales RK,
thalamic lesions in infants. Arch Dis Child 1992; 67: 15-19. 3. Norman MG. Antenatal neuronal loss and gliosis of the reticular formation, thalamus, and hypothalamus. Neurology 1972; 22: 910-16. 4. Shen EY, Huang CC, Chyou SC, Hung HY, Hsu CH, Huang FY. Sonographic finding of the bright thalamus. Arch Dis Child 1986; 61: 1096-99. 5. Siegel MJ, Shackleford GD, Perlman JM, Fulling KH. Hypoxicischemic encephalopathy in term infants: diagnosis and prognosis evaluated by ultrasound. Radiology 1984; 152: 395-99. 6. Parisi JE, Collins GH, Kim RC, Crosley CJ. Prenatal symmetrical thalamic degeneration with flexion spasticity at birth. Ann Neurol 1983; 13: 94-97.
1145
7. Kreusser KL, Schmidt RE, Shackleford GD, Volpe JJ. Value of ultrasound for identification of acute hemorrhagic necrosis of thalamus and basal ganglia in an asphyxiated term infant. Ann Neurol 1984: 16: 361-63. 8. Voit T, Lemburg P. Damage of thalamus and basal ganglia in asphyxiated full-term neonates. Neuropediatrics 1987; 18: 176-181. 9. Cabanas F, Pellicer A. Perez-Higueras A, Garica-Alix A, Roche C, Quero J. Ultrasonographic findings in thalamus and basal ganglia in term asphyxiated infants. Pediatric Neurology 1991; 7: 211-15. 10. DiMario FJ, Clancy R. Symmetrical thalamic degeneration with calcifications of infancy. Am J Dis Child 1989; 143: 1056-60. 11. Shen EY, Lin JCT, Shih CC. Pathological echogenicity of the thalamus in newborn and young infants. J Formosan Med Assoc 1988; 87: 891-97. 12. Steinlin M, Dirr R, Martin E, et al. MRI following severe perinatal asphyxia: preliminary experience. Pediatr Neurol 1991; 7: 164-70. 13. Pasternak JF, Predey TA, Mikhael MA. Neonatal asphyxia: vulnerability of basal ganglia, thalamus and brainstem. Pediatr Neurol 1991; 7: 147-49. 14. Babcock DS, Ball W. Postasphyxial encephalopathy in full-term infants: ultrasound diagnosis. Radiology 1983; 148: 417-23. 15. Shewmon DA, Fine M, Masdeu JC, Palacios E. Postischemic hypervascularity of infancy: a stage in the evolution of ischemic brain damage with characteristic CT scan. Ann Neurol 1981; 9: 358-65. 16. Levene MI, Williams JL, Fawer C-L. Ultrasound of the infant brain. Oxford: Blackwell, 1985. 17. Volpe JJ. Neurology of the newborn. 2nd ed. Philadelphia: WB Saunders, 1987. 18. Trounce JQ, Dodd KL, Fawer C-L, Fielder AR, Punt J, Levene MI. Primary thalamic haemorrhage in the newborn: a new clinical entity. Lancet 1985; i: 190-92. 19. Adams C, Hochhauser L, Logan WJ. Primary thalamic and caudate hemorrhage in term neonates presenting with seizures. Pediatr Neurol
1988; 4: 175-77. 20. Roland EH, Flodmark O, Hill A. Thalamic hemorrhage with intraventricular hemorrhage in the full-term newborn. Pediatrics 1990; 85: 737-42. 21. Teele RL, Hernanz-Schulman M, Sotrel A. Echogenic vasculature in the basal ganglia of neonates: a sonographic sign of vasculopathy. Radiology 1988; 169: 423-27. 22. Hughes P, Weinberger E, Shaw DWW. Linear areas of echogenicity in the thalami and basal ganglia of neonates: an expanded association.
Radiology 1991; 179: 103-05. 23. Abuelo DN, Barsel-Bowers G, Tutschka BG, Ambler M, Singer DB. Symmetrical infantile thalamic degeneration in two sibs. J Med Genet 1981; 18: 448-50. 24. Aicardi J, Goutieres F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 1984; 15: 49-54. 25. Mehta L, Trounce JQ, Moore JR, Young ID. Familial calcification of the basal ganglia with cerebrospinal fluid pleocytosis. J Med Genet 1986; 23: 157-60.
Endoprostheses for bony metastases
Bony metastases
seldom
kill, but they
can
weaken
the skeleton and cause severe pain.12 If they replace enough bone, the skeleton fails by pathological fracture. The principles behind the management of bony metastases have not changed substantially over the past twenty years, but there has been a transformation in the means by which they are realised as implant design has improved. Surgical intervention should be considered if metastatic bone pain cannot be relieved by other means; if fracture is likely, as indicated by the loss of more than half the cortical bone thickness;3 or if a fracture has already occurred. The extent to which the skeleton is involved can be mapped by plain radiographs and radionuclide scans; computed tomography and magnetic resonance imaging are occasionally needed to plan an operation in greater
detail. Methods that restore mechanical stability must be used to ensure that full weightbearing is possible immediately after the operation. Implants of insufficient strength will eventually fracture and those that fail to stabilise the skeleton will loosen unless supported by new bone formation or by the use of polymethyhnethacrylate (PMMA) cement.44 If a patient has multiple metastases, any theoretical concern about spreading tumour further by intramedullary nailing is virtually dispelled. Most diaphyseal pathological fractures of proximal limb bones should be stabilised by use of a modem interlocking nail system, with PMMA cement if the lesion is extensive. Adjunctive radiotherapy, chemotherapy, or hormonal manipulation may be started once the wounds have healed. Some lesions defy nailing: they may lie too near a joint to permit restoration of stability, or may present in smaller bones such as radius and ulna for which intramedullary nailing is inappropriate. Most of these lesions can be stabilised with a combination of plates, screws, and PMMA cement. Deposits around the hip or shoulder cannot be treated satisfactorily by either method, but may be amenable to replacement with a standard hip or shoulder prosthesis. Endoprosthetic replacement, with implants originally designed for the treatment of primary bone tumours, has a clearly defined place in the treatment of secondary deposits; this approach was lately reviewed by Chan and co-workers.5 These researchers restricted their use of endoprostheses to compliant patients with an anticipated survival of more than six months who could not be treated by other methods, or in whom alternative methods had failed. Local infection and previous radiotherapy of a dose likely to wound were other healing prejudice contraindications. Two-thirds of the patients had solitary metastases, and more than three-quarters had femoral deposits. This work suggests that solitary metastases, especially from a hypernephroma, should be excised with wide margins and an intact covering of normal tissue as for a primary malignant bone tumour. Patients with solitary deposits from breast or prostate tumours may be treated in the same way but will not survive as long. The extent and location of the resultant defect will determine the method of reconstruction,6but endoprosthetic replacement is needed for large metaphyseal lesions. 1.
Portenoy
RK. Cancer
pain: pathophysiology
and
syndromes. Lancet
1992; 339: 1026-31. 2. Hanks GW, Justins DM. Cancer pain: management. Lancet 1992; 339: 1031-36. 3. Fidler M. Prophylactic internal fixation of secondary neoplastic deposits in long bones. Br Med J 1973; i: 341-43. 4. Harrington KD, Sim FH, Enis JE, Johnston JO, Dick HM, Gristina AG. Methylmethacrylate as an adjunct in the internal fixation of pathological fractures. J Bone Joint Surg 1976; 58A: 1047-55. 5. Chan D, Carter SR, Grimer RJ, Sneath RS. Endoprosthetic replacement for bony metastases. Ann R Coll Surg Engl 1992; 74: 13-18. 6. Editorial. Bridging the gap: reconstructing large defects in the skeleton. Lancet 1990; 336: 1101-03.
only a general tendency towards high or low pressure. To take advantage of this heterogeneity in the blood pressure values of offspring, Watt et al developed the four comers technique. 11,12 These researchers measured height, weight, and blood pressure in 864 adults aged 16-24 years from 603 families in which both parents had had their blood pressure measured 8 years before as part of the screening phase of the Medical Research Council (UK) trial." Individual Z scores were calculated by dividing deviations from the of the appropriate age-sex group of blood pressure within the standard deviation by group, and a scatter diagram was constructed with offspring Z scores on one axis and combined parental Z scores on the other. The diagram was used to select randomly groups of offspring with low (C) and high (A) pressure scores and parents with low scores, and groups of offspring with low (D) and high scores (B) with both parents with high scores. (Some parents were undergoing treatment for hypertension and their scores were adjusted accordingly.) It is important to recognise that most of the parents and all of the offspring were normotensive. Several phenotypic and genotypic variables were then examined. Thus the
mean blood pressure
technique provided four groups that were homogeneous with respect to age; the study design allowed comparison of individuals with contrasting family background but similar levels of pressure, but used epidemiological methods to contrive the most informative comparisons within a single population to identify familial and non-familial correlates of high blood pressure. The researchers concede that the study is exploratory and opportunistic, but some interesting data emerged. The main finding is that several phenotypic correlates of high blood pressure in young people seem to depend on parental blood pressure levels. Offspring with high blood pressure scores had increased body mass indices irrespective of parental blood pressure. In addition, high scores in young people were associated with higher concentrations of plasma angiotensinogen, cortisol, and 18-hydroxy corticosteroids, but only when parental blood pressure scores were high (B vs C). 27% of the offspring with high scores and high parental scores were homozygous for the larger allele of a restriction fragment polymorphism identified by a glucocorticoid receptor gene probe, compared with 9% of offspring with low blood scores from parents with low scores. The distribution of the polymorphism suggested that homozygosity for the larger allele is associated with lower blood pressure. This pattern was observed not only between those at highest and lowest genetic risk (B and C) but also between offspring with high and low scores within each of the two family groups (A vs C and B vs D). The researchers speculate that this genetic defect may be pathogenetically linked with the other phenotypic findings, cortisol being an important ligand for the glucocorticoid receptor.
tempting to suggest that this report heralds a breakthrough in our understanding of hypertension It is
but that would be premature. But, as Watt and colleagues acknowledge, the results have more bearing on why people have blood pressure levels above and below the mean than on why a few get hypertension. The structural defect in the glucocorticoid receptor gene shown by a restriction enzyme needs more vigorous assessment. Other restriction fragment length polymorphisms of this gene need to be studied, and above all the defect needs to be shown to co-segregate with hypertension in family studies. One thing is certain-the race to identify the genes responsible in hypertension is now well and truly on. 1.
Rapp JP. Dissecting the primary causes of genetic hypertension in rats. Hypertension 1991; 18 (suppl 1): I-18-I-28.
2. Tanase H, Suzuki Y, Ooshima A, Yamori Y, Okamoto K. Genetic analysis of blood pressure in spontaneously hypertensive rats. Jap Circ J 1970; 34: 1197-212. 3. Jacob H, Lander E, Dzau VJ. Progress towards a genetic map of the hypertensive rat. Hypertension 1991; 18: 399 (abstr). 4. Hilbert P, Lindpainter K, Beckman JS, et al. Chromosomal mapping of two genetic loci associated with blood pressure regulation in hereditary hypertensive rats. Nature 1991; 353: 521-29. 5. Jacob H, Lindpainter K, Lincoln DE, et al. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell 1991; 67: 213-24. 6. Mullins JJ, Peters J, Ganten D. Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 1990; 344: 541-44. 7. Kimura S, Mullins JJ, Bunnemann B, et al. High blood pressure in transgenic mice carrying the rat angiotensinogen gene. EMBO J 1992; 11: 821-27. 8. Bianchi G, Barlassina C. Renal function in essential hypertension. In: Genest J, Kuchel O, Hasnet P, Cantin M, eds. New York: McGraw Hill, 1983: 54-73. 9. Schelling P, Fischer H, Ganten D. Angiotensin and cell growth: a link to cardiovascular hypertrophy? J Hypertens 1991; 9: 3-16. 10. Mongeau J. Heredity and blood pressure. Semin Nephrol 1989; 9: 208-16. 11. Watt GCM, Foy CJW, Holton DW, Edwards HV. Prediction of high blood pressure: limited usefulness of parental blood pressure data. J Hypertens 1991; 9: 55-58. 12. Watt GCM, Harrap SB, Foy CJW, et al. Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four comers approach to the identification of genetic determinants of blood pressure. J Hypertens 1992; 10: 473-82. 13. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985; 291: 97-104.
Thalamic lesions in
infancy
Thirty years ago Rosales and Riggs1 described three infants with profound neurological abnormality
term
from birth who died between six and sixteen months of age. Necropsy revealed thalamic cell loss with astrogliosis and "fossilised neurons". The aetiology was uncertain. Eicke and colleagues2 lately reported six infants (five born at term) in whom they diagnosed symmetrical thalamic lesions. These babies showed lack of movement, poor respiratory effort, and absence of sucking and swallowing; only one had seizures. In two cases the clinical picture was the only diagnostic criterion; neither showed thalamic lesions on imaging and necropsy was refused in both. Three of the remaining infants had evidence of perinatal asphyxia, and septo-optic dysplasia was found in the fourth at necropsy. This report raises as many questions as it answers, so what have we learnt about
1144
neonatal thalamic lesions in the past thirty years? Asphyxia was identified as the antecedent event in a neuropathological study of three infants with thalamic neuron loss, gliosis, and cavitation. Ultrasound displayed thalamic lesions in six of eighty-three infants with hypoxic ischaemic encephalopathy in one series4 and in one of thirty-two in another.5 The asphyxial insult is severe, total, and may occur before birth,3,6 perinatally ,4,7 -9 or postnatally. 8,9 Most but not all infants reported were born at term;4,7-9 the most immature baby was born at 32 weeks’ gestation." The predilection of the thalamus to injury with increasing gestation probably reflects the increase in blood flow, metabolic rate, and oxygen requirements.4,6,9 The thalamic changes, whether identified by imaging or at necropsy, are always bilateral. 3,4,6--11 The ultrasound appearance is of a bilateral homogeneous echogenicity which may be present within twentyfour hours of birth7,8 or develop as late as four months.Later evolution to cystic change within the thalamus has been reported on imagingg9 and at necropsy.3There may be associated abnormalities such as cerebral oedema or parenchymal cysts. Computed tomography has also been used in diagnosis, and thalamic hyperintensity was found on magnetic resonance imaging (MRI) in two of thirty severely asphyxiated newborn babies,12 one at two weeks of age and the other at twenty-six months. MRI may be the most sensitive technique for lesions of the thalamus, basal ganglia, and brainstem.13 At necropsy, haemorrhagic7,8,11 and non-haemorrhagic8 thalamic necrosis have been seen. Increased thalamic blood flow,14 capillary proliferation, 15 and vasogenic oedema16 have also been proposed. Gliosis and calcification develop subsequently,36 and the persisting echodensity reported by Shen et al4 at seven months may signify the development of status marmoratus. This neuropathological entity, whose main feature is hypermyelination, has been noted by eight months of age. 17 All the infants reported showed profound neurological abnormalities from birth. Many died in the neonatal period or early childhood and all survivors have been severely handicapped. 49,10 Thalamic injury without cortical lesions has been associated with significant intellectual impairment, which suggests an important role for the thalamus in
cognitive development.17 Four previously healthy term infants with primary thalamic haemorrhage presented acutely aged eleven to fourteen days with seizures, opisthotonus, and facial weakness.18 Characteristic features were eye deviation to the side of the haemorrhage and early sunsetting-ie, downward deviation with sclera visible above the iris. These abnormalities were due to involvement of the frontomesencephalic tract and the vertical gaze centre, respectively, since both lie close to the thalamus. Hydrocephalus developed in three of these infants, and two needed a shunt. The neurological outcome was good: one child was normal
twenty months of age and the other three had mild spastic hemiparesis. In two term infants with thalamic haemorrhage seizures developed at five and seven days, respectively, and one baby had upward deviation of the eyes ;19 one of these children was normal at ten months and the other had a mild hemiparesis. Roland et aFo believe the thalamus is the primary site in nearly two-thirds of term infants with intraventricular haemorrhage. The ultrasound appearance of primary thalamic haemorrhage is of a heterogeneous, irregular, and unilateral echodensity and there may be blood within the ventricle. The aetiology is uncertain; there is no evidence of asphyxia, or vascular trauma, disorder, clotting malformation. 18,199 Occasionally germinal matrix haemorrhage in the preterm infant may extend into the thalamus but does not induce this characteristic at
syndrome. What else may cause thalamic abnormality in the neonatal period? Intrauterine infection with cytomegalovirus, rubella, or toxoplasma may result in echodensity and calcification of the thalamus and basal ganglia, among other manifestations. 16,17,2122 Perivascular microcalcification has been identified at necropsy.16,21 Two term infants with congenital cytomegalovirus infection showed bilateral thalamic echogenicity compatible with calcification, and both developed spastic quadriplegia." Bilateral basal ganglia echodensity has also been described in neonatal streptococcaF1 and pneumococcahb meningitis; the former went on to "mild neurological deficit". Occasionally, genetic factors are important. Two siblings with severe neurological abnormalities from birth died at three weeks and two months, respectively.Z3 Necropsy revealed neuronal loss and gliosis, especially in the thalamus. A rare pattern of autosomal recessive encephalopathy may produce neurological abnormality from birth, with basal ganglia or thalamic calcification seen on scanning at a few weeks of age.24,25 Chromosomal trisomies 21 and 13 have also been linked with thalamic echogenicity in newborn babies. 2122 Thus there are clearly two distinct patterns of thalamic haemorrhagic insult in infants, with different aetiology, clinical presentation, scan appearance, and prognosis. Infection and genetic factors enter the differential diagnosis. Riggs HE. Symmetrical thalamic degeneration in infants. J Neuropathol Exp Neurol 1962; 21: 372-76. 2. Eicke M, Briner J, Willi U, Uehlinger J, Boltshauser E. Symmetrical 1. Rosales RK,
thalamic lesions in infants. Arch Dis Child 1992; 67: 15-19. 3. Norman MG. Antenatal neuronal loss and gliosis of the reticular formation, thalamus, and hypothalamus. Neurology 1972; 22: 910-16. 4. Shen EY, Huang CC, Chyou SC, Hung HY, Hsu CH, Huang FY. Sonographic finding of the bright thalamus. Arch Dis Child 1986; 61: 1096-99. 5. Siegel MJ, Shackleford GD, Perlman JM, Fulling KH. Hypoxicischemic encephalopathy in term infants: diagnosis and prognosis evaluated by ultrasound. Radiology 1984; 152: 395-99. 6. Parisi JE, Collins GH, Kim RC, Crosley CJ. Prenatal symmetrical thalamic degeneration with flexion spasticity at birth. Ann Neurol 1983; 13: 94-97.
1145
7. Kreusser KL, Schmidt RE, Shackleford GD, Volpe JJ. Value of ultrasound for identification of acute hemorrhagic necrosis of thalamus and basal ganglia in an asphyxiated term infant. Ann Neurol 1984: 16: 361-63. 8. Voit T, Lemburg P. Damage of thalamus and basal ganglia in asphyxiated full-term neonates. Neuropediatrics 1987; 18: 176-181. 9. Cabanas F, Pellicer A. Perez-Higueras A, Garica-Alix A, Roche C, Quero J. Ultrasonographic findings in thalamus and basal ganglia in term asphyxiated infants. Pediatric Neurology 1991; 7: 211-15. 10. DiMario FJ, Clancy R. Symmetrical thalamic degeneration with calcifications of infancy. Am J Dis Child 1989; 143: 1056-60. 11. Shen EY, Lin JCT, Shih CC. Pathological echogenicity of the thalamus in newborn and young infants. J Formosan Med Assoc 1988; 87: 891-97. 12. Steinlin M, Dirr R, Martin E, et al. MRI following severe perinatal asphyxia: preliminary experience. Pediatr Neurol 1991; 7: 164-70. 13. Pasternak JF, Predey TA, Mikhael MA. Neonatal asphyxia: vulnerability of basal ganglia, thalamus and brainstem. Pediatr Neurol 1991; 7: 147-49. 14. Babcock DS, Ball W. Postasphyxial encephalopathy in full-term infants: ultrasound diagnosis. Radiology 1983; 148: 417-23. 15. Shewmon DA, Fine M, Masdeu JC, Palacios E. Postischemic hypervascularity of infancy: a stage in the evolution of ischemic brain damage with characteristic CT scan. Ann Neurol 1981; 9: 358-65. 16. Levene MI, Williams JL, Fawer C-L. Ultrasound of the infant brain. Oxford: Blackwell, 1985. 17. Volpe JJ. Neurology of the newborn. 2nd ed. Philadelphia: WB Saunders, 1987. 18. Trounce JQ, Dodd KL, Fawer C-L, Fielder AR, Punt J, Levene MI. Primary thalamic haemorrhage in the newborn: a new clinical entity. Lancet 1985; i: 190-92. 19. Adams C, Hochhauser L, Logan WJ. Primary thalamic and caudate hemorrhage in term neonates presenting with seizures. Pediatr Neurol
1988; 4: 175-77. 20. Roland EH, Flodmark O, Hill A. Thalamic hemorrhage with intraventricular hemorrhage in the full-term newborn. Pediatrics 1990; 85: 737-42. 21. Teele RL, Hernanz-Schulman M, Sotrel A. Echogenic vasculature in the basal ganglia of neonates: a sonographic sign of vasculopathy. Radiology 1988; 169: 423-27. 22. Hughes P, Weinberger E, Shaw DWW. Linear areas of echogenicity in the thalami and basal ganglia of neonates: an expanded association.
Radiology 1991; 179: 103-05. 23. Abuelo DN, Barsel-Bowers G, Tutschka BG, Ambler M, Singer DB. Symmetrical infantile thalamic degeneration in two sibs. J Med Genet 1981; 18: 448-50. 24. Aicardi J, Goutieres F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 1984; 15: 49-54. 25. Mehta L, Trounce JQ, Moore JR, Young ID. Familial calcification of the basal ganglia with cerebrospinal fluid pleocytosis. J Med Genet 1986; 23: 157-60.
Endoprostheses for bony metastases
Bony metastases
seldom
kill, but they
can
weaken
the skeleton and cause severe pain.12 If they replace enough bone, the skeleton fails by pathological fracture. The principles behind the management of bony metastases have not changed substantially over the past twenty years, but there has been a transformation in the means by which they are realised as implant design has improved. Surgical intervention should be considered if metastatic bone pain cannot be relieved by other means; if fracture is likely, as indicated by the loss of more than half the cortical bone thickness;3 or if a fracture has already occurred. The extent to which the skeleton is involved can be mapped by plain radiographs and radionuclide scans; computed tomography and magnetic resonance imaging are occasionally needed to plan an operation in greater
detail. Methods that restore mechanical stability must be used to ensure that full weightbearing is possible immediately after the operation. Implants of insufficient strength will eventually fracture and those that fail to stabilise the skeleton will loosen unless supported by new bone formation or by the use of polymethyhnethacrylate (PMMA) cement.44 If a patient has multiple metastases, any theoretical concern about spreading tumour further by intramedullary nailing is virtually dispelled. Most diaphyseal pathological fractures of proximal limb bones should be stabilised by use of a modem interlocking nail system, with PMMA cement if the lesion is extensive. Adjunctive radiotherapy, chemotherapy, or hormonal manipulation may be started once the wounds have healed. Some lesions defy nailing: they may lie too near a joint to permit restoration of stability, or may present in smaller bones such as radius and ulna for which intramedullary nailing is inappropriate. Most of these lesions can be stabilised with a combination of plates, screws, and PMMA cement. Deposits around the hip or shoulder cannot be treated satisfactorily by either method, but may be amenable to replacement with a standard hip or shoulder prosthesis. Endoprosthetic replacement, with implants originally designed for the treatment of primary bone tumours, has a clearly defined place in the treatment of secondary deposits; this approach was lately reviewed by Chan and co-workers.5 These researchers restricted their use of endoprostheses to compliant patients with an anticipated survival of more than six months who could not be treated by other methods, or in whom alternative methods had failed. Local infection and previous radiotherapy of a dose likely to wound were other healing prejudice contraindications. Two-thirds of the patients had solitary metastases, and more than three-quarters had femoral deposits. This work suggests that solitary metastases, especially from a hypernephroma, should be excised with wide margins and an intact covering of normal tissue as for a primary malignant bone tumour. Patients with solitary deposits from breast or prostate tumours may be treated in the same way but will not survive as long. The extent and location of the resultant defect will determine the method of reconstruction,6but endoprosthetic replacement is needed for large metaphyseal lesions. 1.
Portenoy
RK. Cancer
pain: pathophysiology
and
syndromes. Lancet
1992; 339: 1026-31. 2. Hanks GW, Justins DM. Cancer pain: management. Lancet 1992; 339: 1031-36. 3. Fidler M. Prophylactic internal fixation of secondary neoplastic deposits in long bones. Br Med J 1973; i: 341-43. 4. Harrington KD, Sim FH, Enis JE, Johnston JO, Dick HM, Gristina AG. Methylmethacrylate as an adjunct in the internal fixation of pathological fractures. J Bone Joint Surg 1976; 58A: 1047-55. 5. Chan D, Carter SR, Grimer RJ, Sneath RS. Endoprosthetic replacement for bony metastases. Ann R Coll Surg Engl 1992; 74: 13-18. 6. Editorial. Bridging the gap: reconstructing large defects in the skeleton. Lancet 1990; 336: 1101-03.
