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Some Origins of Mental Symptoms
LEADING ARTICLES
THE LANCET LONDON ::
Some
SATURDAY, OCT. 16,
1954
Origins of Mental Symptoms
THE brain cells, like directors of a large concern, expect the best of everything :-. nourishing food,
comfortable transport, an even temperature, a plentiful supply of oxygen, and perfect service all round the clock.. Sometimes the service breaks down : their food may lack some essential constituent or contain others which are distasteful ; or their cushioned ease may be shattered by collisions ; or the temperature may become inconveniently high, or the oxygen supply inconveniently low. Whatever the affront, the neurones take it badly, becoming erratic in their work ; and their aberrations are reflected in aberrant behaviour of the concern which they direct. Examples of two such affronts have lately appeared in our columns. Some weeks ago Dr. SHEILA SHERLOCK and others1 described mental symptoms caused by a metabolic disturbance of the neurones, which had resented the presence in their blood-supply of substances less objectionable to other body cells ; and in this issue, Dr. WILLIAM HuGHES and his colleagues describe mental symptoms caused by vascular changes in the region of the basal ganglia. HUGHES et al. review 51 such cases, 15 of which they were able to study post mortem. They found distinctive lesions, and suggest that such cases form a recognisable, though not so far recognised, group. All 51 patients had chronic arterial hypertension, with systolic pressures ranging from 140 to nearly 300 mm. Hg. and diastolic pressures ranging from 96 to 160 min. Hg ; all showed personality changes, emotional lability, and some degree of pseudobulbar palsy. Many of them had been hypertensive for a long time-one for at least eighteen years-but fluctuations in the blood-pressure could not be correlated with fluctuation in symptoms. After any acute episode (such as a stroke) the symptoms usually improved whether the blood-pressure rose or fell. Their emotional lability usually took the form of laughing or crying, but might manifest itself in outbursts of rage, very trying to relatives in the home or to other patients in the ward. The symptoms of pseudobulbar palsy included dysarthria, dysphagia (sometimes severe enough to reduce nutrition), and difficulty in phonation which seemed to come from an inability to use expiration in voice production. Some patients acquired the facial immobility, unblinking stare, and marche à petits pas which we associate with parkinsonism. In the early stages vertigo might be an incapacitating symptom, and there was evidence of numerous pyramidal and extrapyramidal lesions. The fundi showed arteriosclerotic changes. -
S., Summerskill, W. Lancet, Sept. 4, 1954, p. 453.
1. Sherlock.
H. J., White, L.
P., Phear, E. A.
795
The personality changes were striking. The patients became " out of sympathy " with their environment, caring nothing for the effect their behaviour might have on others. In many cases their excretory habits became offensive at a stage when they still gave the impression that they could control themselves if they liked. The effect of the dysphagia was to make some objectionable in their feeding habits : they wolfed their food like wild beasts. They declined into dementia, but the condition is so chronic that in some this took twenty years. Meanwhile their had alienated their friends and personality changes relations. The brains of the 15 cases examined post mortem contained multiple small lesions, showing various degrees of organisation of areas of ischsemic softening, in the region of the caudate nuclei and the anterior parts of the putamina ; about two-thirds had scattered lesions in the thalamus. Midbrain, pons, medulla, and cerebellum showed few lesions, and the cortex was usually unaffected. Though the lesions were clearly ischaemic there was no evidence that the vessels had ever been totally occluded. HuGHES et al. do not feel that vascular spasm alone would account for the lesions, and they invoke an ingenious explanation in terms of hydrodynamics. The 18 cases of cerebral disturbance in patients with liver disease, described by SHERLOCKE et al., also had a vascular aspect. In these patients, mental symptoms included clouding of consciousness, with confusion and apathy, progressing in some to coma. Emotional lability was common ; facial expression was blank but not immobile, for the patients might grimace or blink. Speech was slow and slurred, and gradually became irrational in content. Symptoms might vary from day "to day or hour to hour ; and signs included a " flapping type of tremor, which could affect not only the limbs but the neck, jaws, tongue, and eyelids. The gait was ataxic.
"--Objective signs," these observers say, " indicate major involvement of the basal ganglia (which are particularly prone to toxic influences), the frontal cortex, and pyramidal systems ; but critical appraisal suggests a diffuse cerebral disturbance." Three clinical factors combined, in varying degrees, to produce these disorders : serious liver disease, extensive portalsystemic venous collaterals, and a rise in nitrogenous substances in the blood. SHERLOCK et al. found that the neurological signs could be precipitated or enhanced either by giving ammonium chloride or methionine, or by increasing dietary protein above 60 g. daily. The evidence suggests that nitrogenous substances which normally pass through the liver and become metabolised were reaching the general circulation unchanged and proving toxic to the cerebral neurones. Blood in the portal vein is normally rich in nitrogenous material derived from the intestine ; in the hepatic veins the level is much lower. But if the portal blood is by-passing the liver (because the portal vein is thrombosed or occluded), or if the damaged liver cannot metabolise these nitrogenous substances, they are liable to appear in the general circulation in much higher concentrations than usual ; and, in fact, in these patients such was the case. The study was completed by withdrawing a large part of the nitrogenous content of the diet, when the mental symptoms remitted. Several patients, indeed, were restored to and maintained in good
796
mental health
by
diets
containing less
than 20 g. of
protein. These
findings, of course, have an important practical application. High-protein diets, casein ammo-acid hydrolysates, supplements, and ammonium chloride have had moderate success in the treatment of some forms of liver disease, and are widely used. It is as well to realise, as SHERLOCK and her colleagues point out, that they have potential dangers which are quite clear-cut ; and that the patient who develops mental symptoms while being treated along these lines can be restored to reason by a reversal of the method of therapy. But these two diverse groups of cases bring home Ia more general message. The well-being of the cerebral neurones can be disturbed by gross and permanent factors, such as deprivation of blood, or by subtle and temporary factors, such as changes-even perhaps minute changes-in the blood chemistry. The patient to whom they belong, however, has only a limited number of ways in which he can express their disorder : his repertoire of mental symptoms is relatively small, and cannot be a precise guide to the cause of his trouble. The tendency to classify mental diseases according to the bizarre behaviour or delusional ideas of patients has been very strong in the past and may well have hindered the growth of our understanding of mental disease. Studies such as the two discussed here help us to think more imaginatively of what is going on behind the facade of confusion, tears and
These observations suggested that the diuretic response to a water-load involved both a neural and a hormonal stage in transmission ; but the precise nature of the stimulus initiating the chain of response could not directly be deduced. The most critical group of experiments in this regard was reported in 1947.5 In dogs it was found that injection of hypertonic solutions of sodium chloride and sodium sulphate into the exposed carotid artery promptly inhibited water diuresis. Dextrose solutions of the same were not quite so effective as the sodium tonicity and salts ; hypertonic urea did not inhibit the diuresis at all. It was concluded that the effective stimulus to the production of antidiuretic hormone (A.D.H.) was an increase in the osmolarity of the blood
was normally present in the intact animal. VERNEY has now traced " the experimental enquiry that has since been made into the events that underlie the ostensibly simple phenomenon of water diuresis." Circumstantial evidence on the type of mechanism involved was obtained from experiments showing that there was a lag of fifteen minutes between the maximum water-load and the maximum diuresis 3 ; and that emotional stimuli inhibited the diuretic response to a water-load, this emotional inhibition not being significantly affected by renal denervation.4
the carotid artery ; the relevant osmotically active substances were, like sodium salts, limited in their capacity to enter cells and were not, like urea, free to enter them. Search for an end-organ likely to be sensitive to osmotic pressure of the surrounding fluid revealed in the supra-optic nuclei vacuoles, which were tentatively termed osmoceptors " ; these were thought to be the site of origin of a response, triggered off by a rise in ambient osmotic pressure, transmitted neurally to the posterior pituitary, and thence by the intermediation of A.D.H. to the renal tubule cells. Further work has filled in some of the details of the picture so convincingly outlined in 1947. It is now known that diuresis is inhibited by infusion over longer periods of solutions whose hypertonicity lies within a range that may reasonably be regarded as physiological."1 Further studies with ligation of branches of the internal carotid artery have narrowed the search for the receptors to the hypothalamus; and the posterior lobe itself has been excluded as a possible site.6 The supra-optic vacuoles have been found to lie within cells of the nuclear clump of neurons.7 Increase in the effective osmotic pressure of plasma seems to be well established as a stimulus to A.D.H. output. VERNEY considers the difficulty arising from the observations that men on a low-salt diet do not remain in a state of water diuresis, while on the other hand water diuresis can be elicited in people retaining considerable amounts of previously ingested salt.s He suggests that under these circumstances change in A.D.H. activity is masked by change in the filtered load of salt and water. This explanation is not entirely satisfactory ; for water diuresis may be lacking after very moderate salt deprivation, without detectable change in glomerular filtration-rate ; and in Addison’s disease and hypopituitarism the failure of water diuresis persists after adequate treatment with salt and deoxycortone acetate, but can be corrected by cortisone. Possibly the A.D.H. mechanism is the basis of a short-term response " to acute changes in the osmolarity of body-fluid, but the volume (as opposed to the concentration) of body-fluid is regulated by mechanisms acting primarily on the excretion of sodium rather than of water, and mediated by adrenocortical hormones.99 No single mechanism can be to explain expected everything ; and it is the measure
1. Verney, E. B. Irish J. med. Sci. 1954, p. 377. 2. Verney, E. B., Starling, E. H. J. Physiol. 1922, 56, 353. 3. Klisiecki, A., Pickford, M., Rothschild, P., Verney, E. B. Proc. roy. Soc. B. 1933, 112, 496. 4. Rydin, H., Verney, E. B. Quart. J. exp. Physiol. 1938, 27, 343.
5. Verney, E. B. Proc. roy. Soc. B. 1947, 135, 25. 6. Jewell, P. A., Verney, E. B. J. Endocrin. 1952, 9, 7. Jowell, P. A. J. Physiol. 1953, 121, 167. 8. Baldes, E. J., Smirk, F. H. Ibid, 1934, 82, 62. 9. Black, D. A. K. In The Kidney. London, 1954.
laughter, anger, apathy, self-blame, or whatever
offensive habits, else cuts off the
suspicion, mentally
ill person from his fellows.
Water Diuresis IN this age of increasing organisation and diminishing returns in pure physiological research, not many could claim to have established the stimulus and mediation of a basic physiological response, either by themselves or with the help of a few others. Such a claim could, it seems, be fairly made by Prof. E. B. VERNEY, F.R.S. The evidence is contained in a John Malet Purser lecture which he delivered in Dublin earlier this year.1 The story begins in 1922, when STARLING and VERNEY observed that the isolated perfused dog kidney secreted a profuse and watery urine, and that this diuresis could be inhibited by adding posteriorpituitary extract to the perfusing blood.2 The suggestion was made at that time that some substance with an action similar to that of posterior-pituitary extract
perfusing
"
’
’
"
p. ii.
THE LANCET LONDON ::
Some
SATURDAY, OCT. 16,
1954
Origins of Mental Symptoms
THE brain cells, like directors of a large concern, expect the best of everything :-. nourishing food,
comfortable transport, an even temperature, a plentiful supply of oxygen, and perfect service all round the clock.. Sometimes the service breaks down : their food may lack some essential constituent or contain others which are distasteful ; or their cushioned ease may be shattered by collisions ; or the temperature may become inconveniently high, or the oxygen supply inconveniently low. Whatever the affront, the neurones take it badly, becoming erratic in their work ; and their aberrations are reflected in aberrant behaviour of the concern which they direct. Examples of two such affronts have lately appeared in our columns. Some weeks ago Dr. SHEILA SHERLOCK and others1 described mental symptoms caused by a metabolic disturbance of the neurones, which had resented the presence in their blood-supply of substances less objectionable to other body cells ; and in this issue, Dr. WILLIAM HuGHES and his colleagues describe mental symptoms caused by vascular changes in the region of the basal ganglia. HUGHES et al. review 51 such cases, 15 of which they were able to study post mortem. They found distinctive lesions, and suggest that such cases form a recognisable, though not so far recognised, group. All 51 patients had chronic arterial hypertension, with systolic pressures ranging from 140 to nearly 300 mm. Hg. and diastolic pressures ranging from 96 to 160 min. Hg ; all showed personality changes, emotional lability, and some degree of pseudobulbar palsy. Many of them had been hypertensive for a long time-one for at least eighteen years-but fluctuations in the blood-pressure could not be correlated with fluctuation in symptoms. After any acute episode (such as a stroke) the symptoms usually improved whether the blood-pressure rose or fell. Their emotional lability usually took the form of laughing or crying, but might manifest itself in outbursts of rage, very trying to relatives in the home or to other patients in the ward. The symptoms of pseudobulbar palsy included dysarthria, dysphagia (sometimes severe enough to reduce nutrition), and difficulty in phonation which seemed to come from an inability to use expiration in voice production. Some patients acquired the facial immobility, unblinking stare, and marche à petits pas which we associate with parkinsonism. In the early stages vertigo might be an incapacitating symptom, and there was evidence of numerous pyramidal and extrapyramidal lesions. The fundi showed arteriosclerotic changes. -
S., Summerskill, W. Lancet, Sept. 4, 1954, p. 453.
1. Sherlock.
H. J., White, L.
P., Phear, E. A.
795
The personality changes were striking. The patients became " out of sympathy " with their environment, caring nothing for the effect their behaviour might have on others. In many cases their excretory habits became offensive at a stage when they still gave the impression that they could control themselves if they liked. The effect of the dysphagia was to make some objectionable in their feeding habits : they wolfed their food like wild beasts. They declined into dementia, but the condition is so chronic that in some this took twenty years. Meanwhile their had alienated their friends and personality changes relations. The brains of the 15 cases examined post mortem contained multiple small lesions, showing various degrees of organisation of areas of ischsemic softening, in the region of the caudate nuclei and the anterior parts of the putamina ; about two-thirds had scattered lesions in the thalamus. Midbrain, pons, medulla, and cerebellum showed few lesions, and the cortex was usually unaffected. Though the lesions were clearly ischaemic there was no evidence that the vessels had ever been totally occluded. HuGHES et al. do not feel that vascular spasm alone would account for the lesions, and they invoke an ingenious explanation in terms of hydrodynamics. The 18 cases of cerebral disturbance in patients with liver disease, described by SHERLOCKE et al., also had a vascular aspect. In these patients, mental symptoms included clouding of consciousness, with confusion and apathy, progressing in some to coma. Emotional lability was common ; facial expression was blank but not immobile, for the patients might grimace or blink. Speech was slow and slurred, and gradually became irrational in content. Symptoms might vary from day "to day or hour to hour ; and signs included a " flapping type of tremor, which could affect not only the limbs but the neck, jaws, tongue, and eyelids. The gait was ataxic.
"--Objective signs," these observers say, " indicate major involvement of the basal ganglia (which are particularly prone to toxic influences), the frontal cortex, and pyramidal systems ; but critical appraisal suggests a diffuse cerebral disturbance." Three clinical factors combined, in varying degrees, to produce these disorders : serious liver disease, extensive portalsystemic venous collaterals, and a rise in nitrogenous substances in the blood. SHERLOCK et al. found that the neurological signs could be precipitated or enhanced either by giving ammonium chloride or methionine, or by increasing dietary protein above 60 g. daily. The evidence suggests that nitrogenous substances which normally pass through the liver and become metabolised were reaching the general circulation unchanged and proving toxic to the cerebral neurones. Blood in the portal vein is normally rich in nitrogenous material derived from the intestine ; in the hepatic veins the level is much lower. But if the portal blood is by-passing the liver (because the portal vein is thrombosed or occluded), or if the damaged liver cannot metabolise these nitrogenous substances, they are liable to appear in the general circulation in much higher concentrations than usual ; and, in fact, in these patients such was the case. The study was completed by withdrawing a large part of the nitrogenous content of the diet, when the mental symptoms remitted. Several patients, indeed, were restored to and maintained in good
796
mental health
by
diets
containing less
than 20 g. of
protein. These
findings, of course, have an important practical application. High-protein diets, casein ammo-acid hydrolysates, supplements, and ammonium chloride have had moderate success in the treatment of some forms of liver disease, and are widely used. It is as well to realise, as SHERLOCK and her colleagues point out, that they have potential dangers which are quite clear-cut ; and that the patient who develops mental symptoms while being treated along these lines can be restored to reason by a reversal of the method of therapy. But these two diverse groups of cases bring home Ia more general message. The well-being of the cerebral neurones can be disturbed by gross and permanent factors, such as deprivation of blood, or by subtle and temporary factors, such as changes-even perhaps minute changes-in the blood chemistry. The patient to whom they belong, however, has only a limited number of ways in which he can express their disorder : his repertoire of mental symptoms is relatively small, and cannot be a precise guide to the cause of his trouble. The tendency to classify mental diseases according to the bizarre behaviour or delusional ideas of patients has been very strong in the past and may well have hindered the growth of our understanding of mental disease. Studies such as the two discussed here help us to think more imaginatively of what is going on behind the facade of confusion, tears and
These observations suggested that the diuretic response to a water-load involved both a neural and a hormonal stage in transmission ; but the precise nature of the stimulus initiating the chain of response could not directly be deduced. The most critical group of experiments in this regard was reported in 1947.5 In dogs it was found that injection of hypertonic solutions of sodium chloride and sodium sulphate into the exposed carotid artery promptly inhibited water diuresis. Dextrose solutions of the same were not quite so effective as the sodium tonicity and salts ; hypertonic urea did not inhibit the diuresis at all. It was concluded that the effective stimulus to the production of antidiuretic hormone (A.D.H.) was an increase in the osmolarity of the blood
was normally present in the intact animal. VERNEY has now traced " the experimental enquiry that has since been made into the events that underlie the ostensibly simple phenomenon of water diuresis." Circumstantial evidence on the type of mechanism involved was obtained from experiments showing that there was a lag of fifteen minutes between the maximum water-load and the maximum diuresis 3 ; and that emotional stimuli inhibited the diuretic response to a water-load, this emotional inhibition not being significantly affected by renal denervation.4
the carotid artery ; the relevant osmotically active substances were, like sodium salts, limited in their capacity to enter cells and were not, like urea, free to enter them. Search for an end-organ likely to be sensitive to osmotic pressure of the surrounding fluid revealed in the supra-optic nuclei vacuoles, which were tentatively termed osmoceptors " ; these were thought to be the site of origin of a response, triggered off by a rise in ambient osmotic pressure, transmitted neurally to the posterior pituitary, and thence by the intermediation of A.D.H. to the renal tubule cells. Further work has filled in some of the details of the picture so convincingly outlined in 1947. It is now known that diuresis is inhibited by infusion over longer periods of solutions whose hypertonicity lies within a range that may reasonably be regarded as physiological."1 Further studies with ligation of branches of the internal carotid artery have narrowed the search for the receptors to the hypothalamus; and the posterior lobe itself has been excluded as a possible site.6 The supra-optic vacuoles have been found to lie within cells of the nuclear clump of neurons.7 Increase in the effective osmotic pressure of plasma seems to be well established as a stimulus to A.D.H. output. VERNEY considers the difficulty arising from the observations that men on a low-salt diet do not remain in a state of water diuresis, while on the other hand water diuresis can be elicited in people retaining considerable amounts of previously ingested salt.s He suggests that under these circumstances change in A.D.H. activity is masked by change in the filtered load of salt and water. This explanation is not entirely satisfactory ; for water diuresis may be lacking after very moderate salt deprivation, without detectable change in glomerular filtration-rate ; and in Addison’s disease and hypopituitarism the failure of water diuresis persists after adequate treatment with salt and deoxycortone acetate, but can be corrected by cortisone. Possibly the A.D.H. mechanism is the basis of a short-term response " to acute changes in the osmolarity of body-fluid, but the volume (as opposed to the concentration) of body-fluid is regulated by mechanisms acting primarily on the excretion of sodium rather than of water, and mediated by adrenocortical hormones.99 No single mechanism can be to explain expected everything ; and it is the measure
1. Verney, E. B. Irish J. med. Sci. 1954, p. 377. 2. Verney, E. B., Starling, E. H. J. Physiol. 1922, 56, 353. 3. Klisiecki, A., Pickford, M., Rothschild, P., Verney, E. B. Proc. roy. Soc. B. 1933, 112, 496. 4. Rydin, H., Verney, E. B. Quart. J. exp. Physiol. 1938, 27, 343.
5. Verney, E. B. Proc. roy. Soc. B. 1947, 135, 25. 6. Jewell, P. A., Verney, E. B. J. Endocrin. 1952, 9, 7. Jowell, P. A. J. Physiol. 1953, 121, 167. 8. Baldes, E. J., Smirk, F. H. Ibid, 1934, 82, 62. 9. Black, D. A. K. In The Kidney. London, 1954.
laughter, anger, apathy, self-blame, or whatever
offensive habits, else cuts off the
suspicion, mentally
ill person from his fellows.
Water Diuresis IN this age of increasing organisation and diminishing returns in pure physiological research, not many could claim to have established the stimulus and mediation of a basic physiological response, either by themselves or with the help of a few others. Such a claim could, it seems, be fairly made by Prof. E. B. VERNEY, F.R.S. The evidence is contained in a John Malet Purser lecture which he delivered in Dublin earlier this year.1 The story begins in 1922, when STARLING and VERNEY observed that the isolated perfused dog kidney secreted a profuse and watery urine, and that this diuresis could be inhibited by adding posteriorpituitary extract to the perfusing blood.2 The suggestion was made at that time that some substance with an action similar to that of posterior-pituitary extract
perfusing
"
’
’
"
p. ii.