392 LOIN PAIN—RENAL OR PARIETAL?
SiR,—Mr Fox and Mr Saunders (Jan. 21, p. 115) reported that 78% of women presenting with loin pain had no demonstrable upper urinary-tract lesion and that an upper-urinarytract lesion was equally common whether or not there was a history of exacerbation of the pain by movement. I wonder whether a greater incidence of provocation by movement in those with no upper-urinary-tract lesions might have been shown if certain examination findings rather than just the history had been recorded. In my experience the pain complained of can often be reproduced by putting the spinal column through its full range of movement in patients who had not previously noted the effects of movement or posture. Some of the renal lesions were probably not the cause of pain, which might well have been parietal in origin. Confusion can arise where there is parietal involvement with visceral lesions, either directly from local inflamation or by visceroparietal reflexes causing segmental pain, which in each case can lead to provocation of the pain by movement. Fox and Saunders found that upper-urinary-tract lesions were indicated or excluded in 94% of patients before routine urography was taken into account. These results might suggest that urography is frequently superfluous but there is the problem of deciding when it may be omitted. Examination of patients with loin pain but normal urine and no urinary symptoms frequently reveals positive segmental features which suggest a spinal origin (spinal in either the vertebral or the cord sense). In these patients sustained relief has followed lignocaine block of the relevant intercostal or subcostal nerve more often than not,’ which nerve to inject being indicated by tenderness close to the costo-transverse joint. Sustained relief, over some weeks, implies that the pain had not been due to a structural vertebral or to an active visceral lesion but to a vicious circle of pain and spasm. When such relief occurs urography seems unnecessary although review of the patient after a few weeks is advisable. When intercostal block is ineffective the pain might still be parietal but an open mind should be kept on this. Urography is usually indicated when abnormal urine or urinary symptoms are present. St. Richard’s Hospital, Chichester PO19 4SE
not state
how
71 Victoria Rd, Oulton Broad, Lowestoft NR33 9LW
E. C. ASHBY
E. C. Ann. R. Coll. Surg. 1977, 59, 242 Eastwood, N. B., Bruce, R G., Wren, W. J. Jl R. Coll. gen. Practnrs, 1965, 10, 257. 3. Eastwood, N. B. Jl R. Coll. gen. Practnrs, 1972, 22, 464.
N. B. EASTWOOD
PUBERTAL FAILURE IN CONGENITAL ADRENAL HYPOPLASIA
SIR,-We have described
a patient with congenital adrenal hypogonadotrophic hypogonadism’ whose clinical course suggests a primary hypothalamic defect rather than a defect secondary to an adrenal cortical insufficiency as suggested by Dr Hay.2 Our patient had younger twin male siblings who presented
hypoplasia (C.A.H.)
SIR,--The paper by Mr Fox and Mr Saunders illustrates the difficulties experienced by both general practitioners and urologists in the evaluation of renal pain in women. It is an important symptom, not only because a minority (in their paper, 22%) have gross urological disease, but also because it is often a component of a large syndrome, common in women. In a 12-month survey of urinary-tract inflammation in this practice in 1963/64, 247 patients were recorded as having renal-angle tenderness in a practice of 7317 persons.2 Of the total female population registered with the practice, .5-3% presented with this feature at some time during the 12-month period. Urinary-tract inflammation with or without renal pain or tenderness is abundant here, and has been since I joined the practice in 1946. It accounts consistently for about 10% of my work. I usually pay more attention to renal tenderness than to renal pain, since, though renal pain is almost invariably accompanied by renal tenderness, the reverse is not true, as in patients recovering from pyelonephritis where renal tenderness can often be elicited after renal pain has ceased to be complained of. In a survey in this practice3 of 50 consecutive female patients aged fifteen and over and presenting with symptoms of urinary-tract inflammation, renal pain was present in 12 whereas 26 had renal tenderness on percussion. Fox and 1. 2.
only 9 patients with loin tenderness, but do they examined for it. Over forty years ago Mr Jennings Marshall at Charing Cross Hospital used to elicit renal tenderness by percussion over the renal angle, and I have consistently followed him in this respect. It is much more reliable as an indicator of renal tenderness than is bimanual palpation of the kidney during abdominal examination. When renal tenderness is under discussion it is important to state how the sign has been elicited, and I would strongly recommend percussion of the renal angle as the method of choice. A convenient way of doing this is to deliver a series of blows with the ulnar side of the fist downwards along a line from the inferior angle of the scapula and crossing the renal angle. Renal tenderness is a common feature of a large polysymptomatic syndrome comprising, usually but not invariably, lower urinary-tract symptoms and also symptoms remote from the urinary tract. It is not sufficient to state that a full history has been taken without indicating which symptoms have specifically been asked about. Besides the common "frequency, scalding, and urgency" there are symptoms which women do not usually complain of unless asked, such as those consistent with urethral obstruction-namely, infrequency of micturition, hesitancy, poor stream, and loss of the sense of bladder fullness or its replacement by an aching feeling in mid-hypogastrium. Common symptoms and signs remote from the urinary tract include frontal headache, pallor (more rarely a glossy red complexion), epigastric pain, abdominal distension, slight general cedema (especially in the legs) in the absence of albuminuria, tirednesss, insomnia, irritability, depression, and sacroiliac pain. Patients with this syndrome often have a normal urine and normal intravenous pyelogram and are a serious long-term problem for the general practitioner. Saunders found
and
with classical C.A.H., and he was therefore evaluated carefully. His symptomatic adrenal insufficiency did not manifest until age 10 years; before that 24 h 17-ketosteroids and 17-hydroxysteroids had been measured and were reported as normal for age. Puberty began at age 14 years, with testicular enlargement to 4 ml, and pubic hair to Tanner stage III. Subsequently puberty failed to progress, and now, some5 years later, he has hypogonadotrophic hypogonadism. Were the hypogonadotrophism only. a secondary manifestation of very early and total lack of adrenal androgen, hypogonadism should not have developed in a patient with lateonset C.A.H. and some evidence of puberty. His course, in contrast with that of Hay’s patient, cannot be considered different from many idiopathic Addison patients, yet he too has the associated hypogonadotrophic defect. We therefore postulate a more complex relationship between gonadotrophic hormone deficiency and C.A.H. The defect might be one of disordered hypothalamic regulation. If prenatal A.C.T.H. secretion was delayed and lacking at a critical period of adrenal induction, a hypoplastic adrenal could result which subsequently fails even under adequate A.c.T.H. stimulation. Postnatal failure to secrete gonadotrophin-releasing hormone could be part of the same hypothalamic dysfunction. In either case, Prader’s description3 clearly represents a as neonates
Ashby,
1. Golden, M. P., Lippe, B., Kaplan, S. A. Am. J. Dis. Child. 1977, 2. Hay, J. D. Lancet, 1977, ii, 1035, 1360. 3 Trader,A., Zachmann, M., Illig,R. J. Pediat. 1975, 86, 421.
131, 1117.
393 well-defined syndrome; further studies in these patients appear warranted in the attempt
to
learn
more
now
about this
as-
sociation. University of California School of Medicine, Los Angeles, Californa 90024, U.S.A.
BARBARA M. LIPPE MICHAEL GOLDEN
POST-MORTEM HANDLING AND BRAIN BIOCHEMISTRY
SiR-Dr Bird and his
on brain
colleagues, writing
dopa-
mine, glutamic-acid decarboxylase, and choline acetyltrans-
schizophrenia,’ note that "Post-mortem estimates of activity are considerably influenced by the agonal state by conditions of post-mortem handling and storage" but
ferase in G.A.D.
and claim that these conditions were similar for their control and schizophrenic groups. However, they state that "The mean time (+S.D.) between death and removal of the cadaver to a 4°C refrigerator in the control and psychotic groups was 1.7±0.5 h and 3.0+1.8 h, respectively". This difference seems
SIR, -With the evidence from Dr Perry and her colleagues and ourselves (Jan. 7 issue) that deficiencies in glutamic-acid decarboxylase (G.A.D.) in post-mortem brain are not specific to schizophrenia and are not observed in some series of schizophrenic brains, Dr Bird and his colleagues are surely right to concede the point that G.A.D. deficiencies may well be unrelated to the disease process. Although their findings on the effects of time before necropsy (Jan. 21, p. 156) apparently conflict with ours (Jan. 7, p. 37) we are reluctant to dismiss delay before deep-freezing as an important determinant of post-mortem G.A.D. activity. We conducted a study in which rats were decapitated and the brains were removed for immediate G.A.D. assay, deep-frozen for subsequent assay, or deep-frozen after 3 h at room temperature and varying lengths of time at 4°C in the skull (in this last respect the conditions differed from those in the study referred to by Bird et al.’ and may resemble more closely human post-mortem conditions). The results of this experiment (see figure) demonstrate that while deep-freezing alone is
significant to a high degree. Departments of Psychiatry University of Liverpool,
Liverpool L69
and
Psychology,
M. L. ROBINSON N. W. A. MARSH
3BX
*t*Dr Bird and his colleagues’ reply follows.-ED.L. SIR,--Dr Robinson and Mr Marsh
are
quite right
to
point
that the average delay between death and removal of the cadaver to a refrigerator in our 5,,,dy was 1.3h greater for the psychotic group than for the controls. However, in a separate study we measured the decline in human brain temperature after death and examined the effects of temperature on the biochemical variables we were interested in.2 The core temperature of the brain after the cadaver had been 1.7 h at room temperature was 33-4°C, and after 3 h at room temperature it was 31°C. The rate of brain cooling after the cadaver was placed in the 4°C refrigerator was 3°C/h for the first 3 h. The mean temperature for the control brains, therefore, can be estimated to have been 33.4-(1.3 x 3)=29 OC at the time the psychotic brains at 31 °C entered the refrigerator. In an animal model in which the rate of cooling of the dead animal brain was controlled to simulate the cooling of human brain in the routinely handled cadaver, there was no decrease in G.A.D. and C.A.T. activities during the period when brains were cooled from 33 to 30 °C. However, there was a substantial decrease in dopamine concentration.2 Our results on postmortem human brain3 indicated an increase in nucleus accumbens dopamine concentration in the psychotic group, in which the delay in refrigeration was We, therefore, believe that the increased dopamine concentration and decreased G.A.D. and C.A.T. activities noted in the psychotic group are real and not due to differences in the rate of brain cooling resulting from differences in post-mortem handling. As already noted, however (Jan. 21, p. 156) differences in agonal state between the control and psychotic groups may have exaggerated the extent of the decrease in brain G.A.D. activity that we out
greater.
reported.3 E. D. BIRD M.R.C. Neurochemical Pharmacology Unit and Department of
Neurological Surgery
and Neurology, Addenbrooke’s Hospital,
Cambridge CB2 2QQ Institute of Psychiatry, University of London
E. G. SPOKES
JOANNA BARNES A. V. P. MACKAY L. L. IVERSON MICHAEL SHEPHERD
1. Bird, E. D., Spokes, E. G., Barnes, J., Mackay, A. Shepherd, M. Lancet, 1977, ii, 1157; ibid. p. 1296. 2. Spokes, E. G., Koch, J. Neurochem. (in the press). 3. Bird, E. D., and others Lancet, 1977, ii, 1157.
V.
P., Iversen, L. L.,
Post-mortem decline of G.A.D.
activity.
Each point represents mean ± S.E.M. of G.A.D. brain of 10 rats. Absolute activity of fresh tissue 129+15 amot/mgprotein/h.
activity
in the whole
(mean + S.E.M.)
was
associated with a non-significant drop in enzyme activity, duration of storage at 4°C is associated with a progressive decrease in G.A.D. activity over the first 40 h but remains thereafter at 78% of values seen in samples assayed immediately after removal of the brains. Therefore while the simple dichotomy (more or less than 48 h between death and necropsy) which we applied does not reveal the post-mortem decay in Bird’s sample that we found in our own, we feel that even in the Cambridge sample there may be time-dependent changes hidden within the large variances which we all observe. Examination of the data provided by Bird et al. in their original paper (Dec. 3, p. 1157) reveals a difference between patient and control groups in time before removal to the mortuary, the statistical significance of which (t=5.35, p
SiR,—Mr Fox and Mr Saunders (Jan. 21, p. 115) reported that 78% of women presenting with loin pain had no demonstrable upper urinary-tract lesion and that an upper-urinarytract lesion was equally common whether or not there was a history of exacerbation of the pain by movement. I wonder whether a greater incidence of provocation by movement in those with no upper-urinary-tract lesions might have been shown if certain examination findings rather than just the history had been recorded. In my experience the pain complained of can often be reproduced by putting the spinal column through its full range of movement in patients who had not previously noted the effects of movement or posture. Some of the renal lesions were probably not the cause of pain, which might well have been parietal in origin. Confusion can arise where there is parietal involvement with visceral lesions, either directly from local inflamation or by visceroparietal reflexes causing segmental pain, which in each case can lead to provocation of the pain by movement. Fox and Saunders found that upper-urinary-tract lesions were indicated or excluded in 94% of patients before routine urography was taken into account. These results might suggest that urography is frequently superfluous but there is the problem of deciding when it may be omitted. Examination of patients with loin pain but normal urine and no urinary symptoms frequently reveals positive segmental features which suggest a spinal origin (spinal in either the vertebral or the cord sense). In these patients sustained relief has followed lignocaine block of the relevant intercostal or subcostal nerve more often than not,’ which nerve to inject being indicated by tenderness close to the costo-transverse joint. Sustained relief, over some weeks, implies that the pain had not been due to a structural vertebral or to an active visceral lesion but to a vicious circle of pain and spasm. When such relief occurs urography seems unnecessary although review of the patient after a few weeks is advisable. When intercostal block is ineffective the pain might still be parietal but an open mind should be kept on this. Urography is usually indicated when abnormal urine or urinary symptoms are present. St. Richard’s Hospital, Chichester PO19 4SE
not state
how
71 Victoria Rd, Oulton Broad, Lowestoft NR33 9LW
E. C. ASHBY
E. C. Ann. R. Coll. Surg. 1977, 59, 242 Eastwood, N. B., Bruce, R G., Wren, W. J. Jl R. Coll. gen. Practnrs, 1965, 10, 257. 3. Eastwood, N. B. Jl R. Coll. gen. Practnrs, 1972, 22, 464.
N. B. EASTWOOD
PUBERTAL FAILURE IN CONGENITAL ADRENAL HYPOPLASIA
SIR,-We have described
a patient with congenital adrenal hypogonadotrophic hypogonadism’ whose clinical course suggests a primary hypothalamic defect rather than a defect secondary to an adrenal cortical insufficiency as suggested by Dr Hay.2 Our patient had younger twin male siblings who presented
hypoplasia (C.A.H.)
SIR,--The paper by Mr Fox and Mr Saunders illustrates the difficulties experienced by both general practitioners and urologists in the evaluation of renal pain in women. It is an important symptom, not only because a minority (in their paper, 22%) have gross urological disease, but also because it is often a component of a large syndrome, common in women. In a 12-month survey of urinary-tract inflammation in this practice in 1963/64, 247 patients were recorded as having renal-angle tenderness in a practice of 7317 persons.2 Of the total female population registered with the practice, .5-3% presented with this feature at some time during the 12-month period. Urinary-tract inflammation with or without renal pain or tenderness is abundant here, and has been since I joined the practice in 1946. It accounts consistently for about 10% of my work. I usually pay more attention to renal tenderness than to renal pain, since, though renal pain is almost invariably accompanied by renal tenderness, the reverse is not true, as in patients recovering from pyelonephritis where renal tenderness can often be elicited after renal pain has ceased to be complained of. In a survey in this practice3 of 50 consecutive female patients aged fifteen and over and presenting with symptoms of urinary-tract inflammation, renal pain was present in 12 whereas 26 had renal tenderness on percussion. Fox and 1. 2.
only 9 patients with loin tenderness, but do they examined for it. Over forty years ago Mr Jennings Marshall at Charing Cross Hospital used to elicit renal tenderness by percussion over the renal angle, and I have consistently followed him in this respect. It is much more reliable as an indicator of renal tenderness than is bimanual palpation of the kidney during abdominal examination. When renal tenderness is under discussion it is important to state how the sign has been elicited, and I would strongly recommend percussion of the renal angle as the method of choice. A convenient way of doing this is to deliver a series of blows with the ulnar side of the fist downwards along a line from the inferior angle of the scapula and crossing the renal angle. Renal tenderness is a common feature of a large polysymptomatic syndrome comprising, usually but not invariably, lower urinary-tract symptoms and also symptoms remote from the urinary tract. It is not sufficient to state that a full history has been taken without indicating which symptoms have specifically been asked about. Besides the common "frequency, scalding, and urgency" there are symptoms which women do not usually complain of unless asked, such as those consistent with urethral obstruction-namely, infrequency of micturition, hesitancy, poor stream, and loss of the sense of bladder fullness or its replacement by an aching feeling in mid-hypogastrium. Common symptoms and signs remote from the urinary tract include frontal headache, pallor (more rarely a glossy red complexion), epigastric pain, abdominal distension, slight general cedema (especially in the legs) in the absence of albuminuria, tirednesss, insomnia, irritability, depression, and sacroiliac pain. Patients with this syndrome often have a normal urine and normal intravenous pyelogram and are a serious long-term problem for the general practitioner. Saunders found
and
with classical C.A.H., and he was therefore evaluated carefully. His symptomatic adrenal insufficiency did not manifest until age 10 years; before that 24 h 17-ketosteroids and 17-hydroxysteroids had been measured and were reported as normal for age. Puberty began at age 14 years, with testicular enlargement to 4 ml, and pubic hair to Tanner stage III. Subsequently puberty failed to progress, and now, some5 years later, he has hypogonadotrophic hypogonadism. Were the hypogonadotrophism only. a secondary manifestation of very early and total lack of adrenal androgen, hypogonadism should not have developed in a patient with lateonset C.A.H. and some evidence of puberty. His course, in contrast with that of Hay’s patient, cannot be considered different from many idiopathic Addison patients, yet he too has the associated hypogonadotrophic defect. We therefore postulate a more complex relationship between gonadotrophic hormone deficiency and C.A.H. The defect might be one of disordered hypothalamic regulation. If prenatal A.C.T.H. secretion was delayed and lacking at a critical period of adrenal induction, a hypoplastic adrenal could result which subsequently fails even under adequate A.c.T.H. stimulation. Postnatal failure to secrete gonadotrophin-releasing hormone could be part of the same hypothalamic dysfunction. In either case, Prader’s description3 clearly represents a as neonates
Ashby,
1. Golden, M. P., Lippe, B., Kaplan, S. A. Am. J. Dis. Child. 1977, 2. Hay, J. D. Lancet, 1977, ii, 1035, 1360. 3 Trader,A., Zachmann, M., Illig,R. J. Pediat. 1975, 86, 421.
131, 1117.
393 well-defined syndrome; further studies in these patients appear warranted in the attempt
to
learn
more
now
about this
as-
sociation. University of California School of Medicine, Los Angeles, Californa 90024, U.S.A.
BARBARA M. LIPPE MICHAEL GOLDEN
POST-MORTEM HANDLING AND BRAIN BIOCHEMISTRY
SiR-Dr Bird and his
on brain
colleagues, writing
dopa-
mine, glutamic-acid decarboxylase, and choline acetyltrans-
schizophrenia,’ note that "Post-mortem estimates of activity are considerably influenced by the agonal state by conditions of post-mortem handling and storage" but
ferase in G.A.D.
and claim that these conditions were similar for their control and schizophrenic groups. However, they state that "The mean time (+S.D.) between death and removal of the cadaver to a 4°C refrigerator in the control and psychotic groups was 1.7±0.5 h and 3.0+1.8 h, respectively". This difference seems
SIR, -With the evidence from Dr Perry and her colleagues and ourselves (Jan. 7 issue) that deficiencies in glutamic-acid decarboxylase (G.A.D.) in post-mortem brain are not specific to schizophrenia and are not observed in some series of schizophrenic brains, Dr Bird and his colleagues are surely right to concede the point that G.A.D. deficiencies may well be unrelated to the disease process. Although their findings on the effects of time before necropsy (Jan. 21, p. 156) apparently conflict with ours (Jan. 7, p. 37) we are reluctant to dismiss delay before deep-freezing as an important determinant of post-mortem G.A.D. activity. We conducted a study in which rats were decapitated and the brains were removed for immediate G.A.D. assay, deep-frozen for subsequent assay, or deep-frozen after 3 h at room temperature and varying lengths of time at 4°C in the skull (in this last respect the conditions differed from those in the study referred to by Bird et al.’ and may resemble more closely human post-mortem conditions). The results of this experiment (see figure) demonstrate that while deep-freezing alone is
significant to a high degree. Departments of Psychiatry University of Liverpool,
Liverpool L69
and
Psychology,
M. L. ROBINSON N. W. A. MARSH
3BX
*t*Dr Bird and his colleagues’ reply follows.-ED.L. SIR,--Dr Robinson and Mr Marsh
are
quite right
to
point
that the average delay between death and removal of the cadaver to a refrigerator in our 5,,,dy was 1.3h greater for the psychotic group than for the controls. However, in a separate study we measured the decline in human brain temperature after death and examined the effects of temperature on the biochemical variables we were interested in.2 The core temperature of the brain after the cadaver had been 1.7 h at room temperature was 33-4°C, and after 3 h at room temperature it was 31°C. The rate of brain cooling after the cadaver was placed in the 4°C refrigerator was 3°C/h for the first 3 h. The mean temperature for the control brains, therefore, can be estimated to have been 33.4-(1.3 x 3)=29 OC at the time the psychotic brains at 31 °C entered the refrigerator. In an animal model in which the rate of cooling of the dead animal brain was controlled to simulate the cooling of human brain in the routinely handled cadaver, there was no decrease in G.A.D. and C.A.T. activities during the period when brains were cooled from 33 to 30 °C. However, there was a substantial decrease in dopamine concentration.2 Our results on postmortem human brain3 indicated an increase in nucleus accumbens dopamine concentration in the psychotic group, in which the delay in refrigeration was We, therefore, believe that the increased dopamine concentration and decreased G.A.D. and C.A.T. activities noted in the psychotic group are real and not due to differences in the rate of brain cooling resulting from differences in post-mortem handling. As already noted, however (Jan. 21, p. 156) differences in agonal state between the control and psychotic groups may have exaggerated the extent of the decrease in brain G.A.D. activity that we out
greater.
reported.3 E. D. BIRD M.R.C. Neurochemical Pharmacology Unit and Department of
Neurological Surgery
and Neurology, Addenbrooke’s Hospital,
Cambridge CB2 2QQ Institute of Psychiatry, University of London
E. G. SPOKES
JOANNA BARNES A. V. P. MACKAY L. L. IVERSON MICHAEL SHEPHERD
1. Bird, E. D., Spokes, E. G., Barnes, J., Mackay, A. Shepherd, M. Lancet, 1977, ii, 1157; ibid. p. 1296. 2. Spokes, E. G., Koch, J. Neurochem. (in the press). 3. Bird, E. D., and others Lancet, 1977, ii, 1157.
V.
P., Iversen, L. L.,
Post-mortem decline of G.A.D.
activity.
Each point represents mean ± S.E.M. of G.A.D. brain of 10 rats. Absolute activity of fresh tissue 129+15 amot/mgprotein/h.
activity
in the whole
(mean + S.E.M.)
was
associated with a non-significant drop in enzyme activity, duration of storage at 4°C is associated with a progressive decrease in G.A.D. activity over the first 40 h but remains thereafter at 78% of values seen in samples assayed immediately after removal of the brains. Therefore while the simple dichotomy (more or less than 48 h between death and necropsy) which we applied does not reveal the post-mortem decay in Bird’s sample that we found in our own, we feel that even in the Cambridge sample there may be time-dependent changes hidden within the large variances which we all observe. Examination of the data provided by Bird et al. in their original paper (Dec. 3, p. 1157) reveals a difference between patient and control groups in time before removal to the mortuary, the statistical significance of which (t=5.35, p
