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Ankylosing spondylitis
ANKYLOSING
SPONDYLITIS
2oi
ANKYLOSING SPONDYLITIS ITS HORMONAL BACKGROUND IN RELATION TO X-RAY THERAPY BY BASIL A. STOLL, F.F.R., D.M.R. (D. & T.), M.R.C.S. PETER MACCALLUM CLINIC~ MELBOURNE
IN view of the remarkable male predominance in ankylosing spondylitis and its earliest manifestations appearing at the age of maximum sexual activity, there has been considerable speculation as to the relation of the disease to hormone dysfunction. Thus, Davison, Koets, and Kuzell (1949) noted an increase in the 17-ketosteroid excretion in a group of cases of ankylosing spondylitis. In more recent years the value of cortisone and ACTH in the treatment of the disease has renewed interest in this problem. In connexion with these facts may be considered the observation that X-ray therapy is practically diagnostic in its ability to relieve the symptoms of the disease. If it be accepted that X-ray irradiation stimulates the secretion of its hormone by the adrenal cortex, it may be asked whether the beneficial effect of X-ray therapy in this disease is exerted directly by local action or indirectly by stimulation of the adrenal cortex.
AETIOLOGY The outstanding points in the aetiology of the disease will first be emphasized in order to establish its hormonal background. I. Sex D i s t r i b u t i o n . - - T h e predominance of male to female involvement varies between 5 : 4 and 20 : I in different series, according to the group reviewed, e.g., ex-servicemen or civilians (Parr, White, and Shipton, I95I), but in general is about io : i. 2. Age at O n s e t . - - T h e onset of symptoms is in young adult life, between 2o and 3° years of age in the majority of cases, although there is a total range of from 15 65 years (McWhirter, 1945 ; Mowbray, Latner, and Middlemiss, 19¢9). 3. Occupation and S t r e s s . - - T h e occupation of those affected among males is stated as 5° per cent light and medium manual work, 20 per cent heavy manual work, and 3° per cent sedentary occupations (Richmond, 1951) . Similar figures are quoted by Simpson and Stevenson (19¢9). Those subjected to mental stress are more particularly affected. Thus McWhirter (1945) states that the higher incidence of the disease in the Services is possibly associated with the additional strain and abnormal conditions of life making the disease declare itself at an earlier stage. 4. Hereditary F a c t o r s . - - T h e r e is a family history of rheumatic complaints in 28 per cent of cases, but of fairly definite or probable ankylosing spondylitis in only 9 per cent of all cases of typical ankylosing spondylifis (Sharp and Easson, 1954). Parr and others (1951) noted a familial history of spondylitis in i i per cent of cases. Many instances of brother-sister involvement are reported in the literature. 5- Female P a t i e n t s . - - I n some cases symptoms date back to the middle of a pregnancy, but in others appear soon after confinement. Occasionally, symptoms are decreased during pregnancy (unlike rheumatoid arthritis where symptoms practically disappear during pregnancy). In females the disease is usually not so rapidly progressive, and may abort spontaneously before ankylosis is established. 6. IritiS.--This is noted either in the history or in the course of the disease in 8 per cent of cases (Sharp and Easson, 195¢). Iritis in these cases yields quickly to cortisone therapy. 7. I7-Ketosteroid Excretion in the U r i n e . - - T h i s has been noted as raised in the disease (Davison and others, i949) , but the observation is not confirmed (Hart, Robinson, Allchin, and Maclagan, 1949 ; Mowbray and others, 19¢9). In a series of cases under the care of Dr. Frank i4
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Ellis at the London Hospital (Fig. 2oo) it appeared at first that the i7-ketosteroid level was correlated with the degree of activity of the disease. If, however, the level is correlated with the age of the patient, it is seen that the higher levels occur, as would be expected, in the younger age groups. 45. 40. 35.
2 of 14 above 18 level
8 of 15 I
above 18 level
30 25 20
h_
15 10 5
EARLY
MODERATE
ADVANCED
4of 12 above 18 level
3of 17 above 18 level
45'
40 39 ~-~
30.
25-
20'
10 of 13 above 18 level
L
2
15.
"1
10.
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30-39 AGE GROUP
UNDER 29
OVER 40
Fig. 2oo.--x7-ketosteroid level in urine of group of males with anky!osing spondylitis. disease.
B, Classified according to age group.
A, Classified according to stage o f
ANKYLOSING
SPONDYLITIS
203
In accordance with some of these aetiological observations, Funck (195i) has noted that ankylosing spondylitis is associated with the asthenic male type. He postulates toxic damage to the pituitary on the basis of a rheumatic diathesis, followed by increased secretion of gonadotrophin, and thus androgen production by the gonads. This may explain the benefits noted by the administration of oestrogens and the adrenal cortical hormone. He believes that the objective of therapy in this disease must be the regulation of hormone production. Liefmann (i95o), working on the stress basis of ankylosing spondylitis, suggested that the condition of stress (including cold, trauma, infection, or hypersensitivity) leads to anterior pituitary stimulation. The increased A C T H excretion leads to stimulation of the adrenal cortical hormone, and an increase in protein catabolism, and raised i7-ketosteroid excretion are seen in the disease. Thus he concludes that ankylosing spondylitis is due to endocrine imbalance associated with hyperadrenocorticism. In view of the response of the disease to the administration of cortisone, as seen later, it is possible that the aetiology of the disease involves long-continued demands on the adrenal cortex, finally leading to adrenocortical exhaustion. THE R E S P O N S E TO C O R T I S O N E A N D O T H E R H O R M O N E S C o r t i s o n e . - - T h e response to this hormone by ankylosing spondylitis is well established. Hart (1952) considers the hormone useful for the acute painful episodes, but there is no lasting effect--unlike X-ray therapy. This method of treatment, however, is preferred in young women to avoid damage by X-ray therapy to the ovaries. Bagnall, Traynor, and McIntosh (1953) reported II cases treated by cortisone IOO rag. daily for 1-2 months, further courses being repeated for j - i o days when recurrence of symptoms occurred. The E.S.R. fell during therapy but rose at varying intervals in the majority of cases. The i7-ketosteroid level in the urine also fell during treatment, but the eosinophil count showed no consistent variation. The authors prefer intermittent administration of the hormone to avoid resistance to the drug and the possibility of sideeffects. In io out of the I i cases there resulted an increased working capacity. The mode of action of cortisone in the disease is uncertain. It may act directly on the tissues by dampening the activity of the rheumatic process, and A C T H may cause similar relief by stimulating the adrenal function. Stilboestrol.--There are several reports that intramuscular administration of 2o mg. stilbmstrol daily gives a definite and lasting improvement in the spine flexibility, together with relief of pain. The disadvantage, however, is that in males mastitis and impotence often result, and there is no clinical improvement if these complications are not seen. Testosterone does not give similar relief, but it can be combined with the stilbmstrol to reduce the feminizing effects. In females, on the other hand, vaginal bleeding is a complication of the use of stilbcestrol, and although this can be treated by progesterone, such therapy decreases the relief of symptoms. Relief of symptoms by the use of stilbmstrol does not depend upon the age of the patient or on the extent of joint involvement. With regard to the mechanism of the relief following the use of stilbmstrol, it is thought possible that the sex hormones lead to inhibition of the gonadotrophic secretion of the anterior pituitary, and this is followed by a compensatory increase in the secretion of A C T H (Coste and Lacronique, I950). Other H o r m o n a l T r e a t m e n t . - - D O C A and ascorbic acid in combination have been tried extensively in the treatment of both ankylosing spondylitis and rheumatoid arthritis. Occasional patients will derive benefit, but it is difficult to obviate psychogenic benefit in many cases. Parathyroidectomy has been reported to have been used in this disease and occasional benefit noted.
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ANKYLOSING
SPONDYLITIS
205
Gold therapy has been noted to give relief in a minority of cases, and similar results are observed following the use of shock therapy, vaccines--e.g., T.A.B.--and fresh-blood transfusions. These may all act as non-specific forms of stress, causing increased secretion by the adrenal cortex.
X-RAY THERAPY TECHNIQUES Until Gilbert Scott, in 1939, wrote on the use of wide-field X-ray therapy, ankylosing spondylifts was mostly treated by postural methods (e.g., plaster-of-Paris bed), physiotherapy, and spinal supports, to prevent the development of deformity. There was little general attention to X-ray therapy until after 1945. There are five techniques of X-ray therapy, which are still in general use, and these techniques and results are summarized in Table 1. I. L o c a l i z e d : L o w - d o s e Technique.--Kahlmeter (1938), of Stockholm, was the first to report on the use of X-ray therapy for ankylosing spondylitis, and used a localized low-dose technique (45o-6oo r in one week). Kemen (1937) reported on a group of cases treated by a similar technique, and noted an improvement in 67 out of 77 cases at the completion of treatment. Smyth, Freyberg, and Lampe (1941) reported on 52 cases treated by the Kahlmeter technique. Subjective improvement was noted in 72 per cent and objective improvement in 5° per cent (objective improvement in 92 per cent of early cases, but 35 per cent of advanced cases). The experiment was controlled by exposing some cases with lead screening and no demonstrable benefit was shown in these cases. Oppenheimer (1943) used a localized technique with even lower doses (8o-12o r in one week). He reported relief of pain in the majority of 17 cases after a few days, and stated that higher dosage gave no better results. 2. Whole Spine: Low-dose Technique. Hare (194o) reported relief in 80 per cent of 35 cases after treatment of the whole spine and sacro-iliac joints by low doses of deep X-ray therapy (300 r in one week). Treatment was repeated after 3 weeks if necessary, and in the majority of cases only 1-2 areas required repeat of treatment. Pain-relief occurred within 1- 3 weeks of treatment. Sharp and Easson (1954) irradiated the whole spine and sacro-iliac joints with a small weekly dose of 15o r for IO weeks. They claim that this avoids constitutional and h~ematological complications. They claim relief of symptoms in 89 per cent of 275 cases so treated, but when atypical cases are excluded the percentage relieved is as high as 95 per cent. Relief is more likely when the duration of treatment is shorter, and when changes are confined to the sacro-iliac joints. Complications included I case of aplastic anaemia, i of reactivation of pulmonary tuberculosis, and 2 of possible acceleration of renal failure. Permanent amenorrhoea occurred in 16 of 47 young females treated, and temporary amenorrhoea in 3 other cases, as a result of which the tangential method of treating the sacro-iliac joints was adopted. 3. Wide-field T h e r a p y . - - G i l b e r t Scott (1939) reported on the use of wide-field treatment of the disease in 15o cases followed up for 3-5 years. These cases showed relief of pain and stiffness, but no improvement in their radiographs. The dose varied according to the degree of constitutional and h~ematological reaction to therapy (average 250 r in io weeks). HernamanJohnson (1945) reported remission of symptoms by this technique for periods of 5-I5 years, again with no evidence of radiographic improvement. Parr and others (1951) reported marked improvement in 86 per cent of cases and relief in a further IO per cent of a series of IOO cases treated by a similar technique. Such a method of treatment has the disadvantage of commonly inducing severe radiation sickness because of the large integral dose and occasionally leads to a decrease in the formed elements of the blood. Amenorrhoea also occasionally develops in young females.
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Kuhns and Morrison (i946) advocated a similar wide-field irradiation and claimed that 84 per cent of 98 cases showed relief of symptoms. Amenorrhcea developed in 2 out of 2I young women so treated. 4. Localized: Protracted Low-dose Technique.--Hart and others (i949) reported on the use of protracted X-ray dosage directed to the affected part (15oo r in 3 weeks). They reported relief of pain in 92 per cent of cases, usually beginning within i - 4 weeks, but sometimes delayed for 5-6 months. Treatment was repeated after 3 months if necessary. In acute cases, dosage was smaller. T h e y stress that dosage must never reach skin tolerance, and there must be n o danger of permanent damage of the underlying tissue. Simpson and Stevenson (1949) using a similar technique achieved relief of pain in 83 per cent of cases, most of which were at a fairly advanced stage. 5. Whole Spine : High-dose T e c h n i q u e . - - M c W h i r t e r (1945) advocated irradiation of the whole spine and sacro-iliac region irrespective of the symptoms. The dosage used (2500 r in 2 weeks) leads to dry desquamation of the skin, and radiation sickness is prominent. Windeyer (i952) recommended similar irradiation to a somewhat lower dose than McWhirter, and stressed that the peripheral joints should be treated only if causing symptoms. Sicher (I949), using a similar technique to McWhirter, claimed relief in 95 per cent of early cases.
COMPARISON OF TECHNIQUES Richmond (I95i) (see Table H) analysed for relief of pain i6o cases treated by high doses of deep X-ray therapy, in some of which the sacro-iliac joints alone had been treated, and in others the whole spine in addition. The former technique gave relief in 89 per cent of cases, and the Table H . - - C o M P A R I S O N OF SCOPE OF IRRADIATION FOR IMMEDIATE RELIEF AND FREEDOM FROM RECURRENCE IN ANKYLOSING SPONDYLITIS IN I 6 0 CASES (RICHMOND, I 9 5 I )
Sacro-iliac joints alone : 2 0 0 0 r in 4 weeks H.V.L., I'9 Cu
89 per cent of cases improved
In 53 per cent symptoms recurred within i year
Sacro-iliac joints and whole spine: dose as above
96 per cent of cases improved
In 20 per cent symptoms recurred within i year
latter relief in 96 per cent. From the long-term viewpoint, the locally treated cases required retreatment in 53 per cent, but those given wider treatment in only 2o per cent. Unfortunately, the follow-up of cases was only for one year. Desmarais (~953) (see Table III) used random sampling of patients to compare the effect of low-voltage and high-voltage therapy at different dose-levels. He also used a control group in which the current was not switched on during 'treatment '. He notes that dosage higher than iooo r in 4-6 weeks has no advantage over that of IOOOr, but 500 r in the same length of time gives poorer results [not statistically significant] and 300 r by low voltage is no better than the control group. He noted relief of pain after 2- 3 weeks, and all cases receiving higher dosage had maintained their improvement one year later. The pain was relieved irrespective of the stage of the disease, but there was no increase in mobility of the advanced cases. Table I V summarizes the results of 55 cases treated at the Royal Melbourne Hospital by a variety of techniques. It will be noted that the results are essentially similar in all groups, in spite of the variation in dose and size of field treated. It thus appears that there is little to choose between the higher and the lower dose-levels, from the point of view of : - -
ANKYLOSING
SPONDYLITIS
207
a. I m m e d i a t e relief of local s y m p t o m s in this disease. E v e n t h e s m a l l e s t doses in Table I gave relief in t h e vast m a j o r i t y of cases. T h i s applies e v e n to t h e G i l b e r t S c o t t t e c h n i q u e w h e r e the spinal l i g a m e n t s receive a d o s e as low as i o r weekly. b. P r e v e n t i o n o f p a i n r e c u r r e n c e in t h e t r e a t e d area. I t is well r e c o g n i z e d t h a t a m i n o r i t y of cases d e v e l o p r e c u r r e n c e o f s y m p t o m s w i t h i n a year o f t r e a t m e n t , a n d t h i s p r o p o r t i o n is essentially similar w h e t h e r h i g h or low dosage has b e e n given.
Table ///.--COMPARISON OF VARIOUS DOSE-LEVELS AND VOLTAGES OF RADIATION IN ANKYLOSING SPONDYLITIS (DESMARAIS, 1953)
PHYSICALFACTORS
High voltage (H.V.L., I"5 mm. Cu)
IMPROVEDCASE~
DOSE
500 r in 4-6 wk. lOOO r in 4 6 wk. 15oo-2ooo r in 4-6 wk.
Whole Spine
Other Sites
Together
9 of 14 15 of I7 I8 of 19
6of 7 1i of 11 9of 9
71 per cent 92 per cent 96 per cent
Low voltage (H.V.L., 7"5 mm. A1)
300 r in 4-6 wk.
5 of II
Control series
Nil
4of
9
45 per cent 3 of 5
50 per cent
H o w e v e r , t h e r e is no d o u b t t h a t i r r a d i a t i o n of t h e w h o l e s p i n e a n d sacro-iliac region at the first t r e a t m e n t will obviate t h e n e e d for t h e p a t i e n t to have n e w p a r t s t r e a t e d at s h o r t intervals. M o s t p a t i e n t s h a v e s o m e d e g r e e o f relief of p a i n o u t s i d e a t r e a t e d area for as long as t r e a t m e n t is given, b u t the effect is n o t s u s t a i n e d as it is in t h e t r e a t e d area.
Table IV.--COMPARISON OF VARIOUS TECHNIQUES AND DOSE-LEVELS FOR ANKYLOSING SPONDYLITIS IN 55 CASES TREATED AT THE ROYAL MELBOURNE HOSPITAL
VOLTAGE
High voltage (H.V.L.,
DOSE-LEVEL
High dose
1 mm. Cu)
Medium dose Low dose Low voltage (H.V.L., 2 mm. A1) Gilbert Scott Total
Wide field
TISSUE DOSE (DEPTH 3-6 CM.)
RELIEF
15OO-2OOO r in 3-5 wk. lOOO-14oo r in 3-5 wk. 7oo-9oo r in 3-5 wk.
I4 of i6 8 of io
lO of i2
RECURRENCEOF SYMPTOMS (AVERAGETIME) After in 6 After in 4 After in 3
9 mth. cases 6 mth. cases 12 mth. cases
IOO-ZOO r in 3 wk.
8of9
After 7 mth. in 4 cases
2oo-3oo r in 5-7 wk.
6 of 8
After i1 mth. in 3 cases
46 of 55
After 9 mth. in 20 cases
WHOLE SPINE TREATED
PARTSPINE TREATED
7 mth.
I5 mth.
7 mth.
5 mth.
io ruth.
14 mth.
8 mth. in 8 cases
11. mth. in 5 cases
T h e r e a p p e a r s to b e no n e e d to increase t h e dosage in t h e later stages o f t h e disease. I t is, however, i m p o r t a n t to give smaller dosage (and also w i d e r field cover) in t h e cases w i t h acute o n s e t or w i t h w i d e s p r e a d s y m p t o m s (Ellis, p e r s o n a l c o m m u n i c a t i o n ) .
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CLINICAL TRIAL OF A D R E N A L I R R A D I A T I O N In view of the theoretical conclusions derived from the study of treated series in the literature, and from clinical experience, I instituted a search in the available literature for a record of a previous author having instituted irradiation of the adrenal region in ankylosing spondylitis. Desgrez, Desgrez, and Painvin (1951) noted that when treating cases of chronic rheumatism, therapy to the dorsolumbar region led to relief of symptoms arising in the lumbosacral region. They suspected, therefore, that irradiation of the adrenal gland might mediate this benefit by the secretion of cortisone. Their technique for spondylitis involved the administration of a moderate dose of X rays (12oo r in 3-4 weeks, 18o kV., 0. 5 Cu, i A1) to the dorsolumbar region, and they note that irradiation of this particular region gives better clinical benefit than irradiation of any other part of the spine. They suggest that even if the major part of the effect is via the adrenal gland, one cannot exclude a local reaction by the X-ray therapy upon the dorsolumbar spine itself. They also point out the danger of suprarenal exhaustion if overdosage by X-ray therapy is given. These authors then proceed to discuss the possible use of short-wave diathermy to the adrenals in preference to X-ray therapy, because of the destructive effect of the latter compared to the stimulant effect of the former. Greinert (1951) quoted an advanced case of " deforming spondylitis " in which treatment by X rays of the lower dorsal vertebrze induced immediate improvement. The patient was enabled to do light work after having been confined to bed for several months. The dosage recommended is IO-I 5 r skin-dose to each adrenal gland, and the author reports 34 patients whom he has so treated for chronic arthritis. The dose is given to a Io × 15 cm. field on each side, and Greinert believes that this relatively tiny dose exerts an effect on the blood-supply of the adrenal, which results in a cortisone-like effect. Greinert's dosage of io-15 r to each adrenal was tried and found ineffective. On the other hand, the level of dosage suggested by Desgrez and others (i95i), i.e., i2oo r in 3 weeks, is of a level often given locally to the spine, and clinical experience shows that this dosage in the lumbodorsal region is just below that which, in the majority of cases, leads to radiation sickness. Therefore, I decided on a biologically similar dose of 75o-9oo r in lO-14 days. Theoretically, such a dose-level should stimulate the adrenal cortex without exhausting it--the latter state being considered related to radiation sickness. Result o f Irradiatlon.--Ten cases clinically diagnosed as ankylosing spondylitis and 8 of osteo-arthritis, or doubtful cases, have so far been treated, with the results shown in Tables V and V I . It is seen that in 9 of the cases there was almost complete relief of all symptoms ; in 2 cases partial relief ; and in 7 cases no relief of symptoms. Of the latter cases, I was relieved later by removal of a prolapsed intervertebral disk and another manifested a lyric area in the ilium, due to Hodgkin's disease, suggesting the diagnosis of ankylosing spondylitis as incorrect. Of the I1 relieved cases it is noteworthy that 6 had previously received orthodox spinal radiotherapy with similar results accruing from both techniques. As a control, a further 5 cases of degenerative osteo-arthritis received adrenal irradiation by a similar technique to that used for ankylosing spondylitis with no apparent benefit, which is what would be expected. An advantage of the adrenal irradiation technique is that it is simple and less time-consuming than irradiation of the whole spine and sacro-iliac region. In particular, it can be safely used in young females without danger of ovarian irradiation. In addition there is no danger of inducing changes in the marrow--the possibility of which has recently been suggested by Court Brown and Abbatt (1955). In the technique used, a skirt-dose of 15o r (including back scatter) was given to a field 15 cm. wide and io cm. long, centred over the midline at the level of the adrenal glands. The dose was repeated 5-6 times in lO-14 days (the H.V.L. being i mm. Cu) and in only i case was nausea complained of. Relief was usually apparent within 2- 3 weeks of starting
ANKYLOSING
SPONDYLITIS
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2II
treatment, and it is seen from the tables that relief of symptoms was not confined to the lumbar area treated but included all affected areas of the spine. Similarly, it is notable that all cases of ankylosing spondylitis, whether early or late, obtained equal relief of symptoms.
DISCUSSION Mode of Action of X Rays in Spondylitis.--In view of the relief of symptoms obtained in ankylosing spondylitis by means of very varying doses and techniques of X-ray therapy, there would appear to be three possible modes of action of radiotherapy in these cases : - I. Local action on the involved joints. • 2. Indirect effect via the autonomic system. 3. Indirect effect via the adrenal cortex. Local Effect.--This is the effect presumably obtained when radiation is used in the treatment .of degenerative osteo-arthritis, tendinitis, etc. An anti-inflammatory effect is suggested by Desjardins (I94o). Ewing describes the effect .of X rays in tissue as including the destruction of rapidly-growing cells, increasing the permeability of the cell membrane, inhibition of the cell enzymes, and promotion of vascular and lymphatic .exudation. The increased blood- and lymph-flow to the part, and subsequent proliferation of fibroblasts, may thus be responsible for the clinical improvement. Tillis (r944) , on the other hand, considers that the liberation of antibodies by the destruction of white blood-cells is the factor responsible for the relief of pain in such cases. Kaplan (1945) suggests that analgesia results by direct action upon the nerve-endings, and :also by relieving the tension in the nerve-sheath by the destruction of white blood-cells. Animal experiments on the effect of X-ray therapy in the resolution of joint effusions (Horwitz and Dillman, 1944) have shown microscopic evidence of disappearance of ¢edema, increase of fibrous tissue, diminution in the cellular reaction, and a tendency to endarteritis obliterans. Effect on Autonomic System.--Langer (1933) suggested that an important mode of action of X-ray therapy in the treatment of osteo-arthritis was through the spinal ganglia. He :suggested that irradiation affects the vegetative nervous system, causing at first a stimulation and later a paralysing effect (Charcot's joint illustrates the operation of nervous influences in producing an arthritis). Cases are noted where X-ray therapy in arthritis often, at first, causes exacerbation of pain (nerve-stimulating effect) and later relief of pain. Langer ascribes the better bloodsupply to a part after X-ray therapy to be due to an effect of the vegetative nervous system, and thus suggests treatment to the sympathetic ganglia of the lumbar region and neck in the case of peripheral arthritis. Finzi (1953) has recently revived this idea and reports benefit to arthritis of the hands following ,small doses of X-ray therapy to the neck (ioo-i3o r in air), and also benefit to arthritis of the hip following treatment to the lumbar region. He also mentions temporary increase of pain after this treatment for 24-48 hours, and regards this as a good prognostic sign. In this respect the benefit reported by Lievre and Leger (1949) in rheumatic disease following surgical denervation of the carotid sinus is of interest. Effect on Adrenal Glands.--Davison and others (i949) , after noting the high level of I7-ketosteroid excretion in ankylosing spondylitis, observed that clinical benefit derived from X-ray therapy is associated with a fall in the level of their excretion. Since the introduction of cortisone in the treatment of rheumatoid arthritis and spondylitis, I had felt that the action of irradiation in the treatment of ankylosing spondylitis might be to increase the level of cortisone in the blood so that the patient is treated by endogenous endocrine therapy. It is possible, therefore, that we may be able, by means of irradiation, to induce an effect similar to that of cortisone therapy on an underlying dysfunction of the adrenals. The
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advantage over cortisone administration is that there are no undesirable side-effects such as those of Cushing's syndrome. Most authors in the English and American literature, however, do not accept this mode of action of X-ray therapy. Hart (1952) assumes that all the effects of X-ray therapy are local and take place only in the area submitted to irradiation. He states that there is little evidence to support the employment of " homoeopathic wide-field therapy ". Sharp and Easson (1954) and also Smyth, Freyberg, and Lampe (1941) believe that the beneficial effects of X rays are due to local action on the irradiated tissues and not to an indirect effect mediated through the endocrine or other mechanisms. It must be pointed out that on this assumption it is difficult to explain the failure of X-ray therapy to yield relief in cases of rheumatoid arthritis. Gilbert Scott (I939) and HernamanJohnson (1945) believe, on the other hand, that X rays stimulate the defence mechanism of the body, but do not detail this mode of action. Ney (1949) published some blood-studies in an attempt to elucidate this point. T H E E F F E C T OF X-RAY T H E R A P Y IN S T I M U L A T I N G THE A D R E N A L S E C R E T I O N Selye (1952) notes that stress causes an increased demand for the adrenocortical hormone which is mediated by increased secretion of A C T H from the anterior pituitary. This increased activity of the adrenal cortex seems to be associated with reduction of its ascorbic acid and cholesterol content. Such changes are seen following administration of A C T H and also in animals exposed to stress, such as cold, burns, and h~emorrhage. This same change in the adrenals is also noted following whole-body X-ray irradiation to lethal and sub-lethal dosage (North and Nims, 1949). Hochman and Block-Frankelthal (1953) therefore suggest that some of the therapeutic effects of low dosage by X rays in some of the stress diseases, e.g., asthma, may find a partial explanation in the mobilization of the adrenocortical hormone. Ellinger (1948) suggests that irradiation of a sufficiently large volume of tissue results in the liberation of breakdown products such as histamine or a histamine-like substance. The literature shows an increase in the blood-histamine level in patients following X-ray treatment, and in addition histamine is capable of inducing most of the symptoms of radiation sickness, including a fall in the chloride and blood-cholesterol levels. It is thus suggested that the histaminelike substance liberated after irradiation causes the secretion of anterior pituitary hormone, which then stimulates the adrenal cortex. Experimental findings show that depletion of the sudanophil substance in the adrenal cortex (which indicates increased activity of the gland) appears either after direct irradiation over the adrenals or by irradiation of a part at a distance, possibly exerted as a result of liberation of decomposition products. Leblond and Segal (i942), in a well-planned series of experiments, demonstrated that heavy irradiation to the head and neck or lower abdomen of mice, with shielding of the rest of the body, leads to hypertrophy of the adrenal cortex with disappearance of the sudanophil substance and involution of distant lymphatic organs, including spleen, thymus, and lymphatic glands. These latter changes are prevented by adrenalectomy. Irradiation of lymphoid tissue causing involution of similar tissue at a distance is seen occasionally in the reticuloses, and is perhaps comparable to the effect of A C T H and cortisone in these diseases. Irradiation over the adrenal gland causes marked depletion of sudanophil substance in the cortex (Engelstad and Torgensen, I937) , although less marked changes are seen following irradiation of any part, even the ear of a rabbit. Jenkinson and Brown (1944) postulate that the adrenal cortex secretes a substance which maintains cellular permeability. Thus repeated insults to the body (e.g., stress or X-ray irradiation) lead to excessive secretion manifested by exhaustion of the cortical lipoids. Mild insults, on the other hand, at first lead to adrenal hypertrophy, but if long continued, finally lead to
ANKYLOSING
SPONDYLITIS
2i 3
atrophy- This effect on the adrenal may, of course, be mediated by the adrenocorticotrophic hormone of the pituitary. To sum up the experimental findings, it appears that increased activity of the adrenal cortex is seen following irradiation. These changes are seen even when the adrenal gland itself is not included in the field of irradiation. This effect may be mediated by the liberation of a histaminelike decomposition product causing increased secretion of A C T H .
SUMMARY A review of the aetiological factors in ankylosing spondylitis suggests a hormonal basis to the condition, and its response to cortisone suggests that it belongs to the group of ' stress ' diseases. In examining the literature, one is impressed by the remarkable diversity in the dose of X rays given in this condition by different authors with, at the same time, remarkably uniform results. Experimental observations confirm that irradiation of various parts of the body, particularly of the adrenal gland, leads to a stress reaction with increased activity of the adrenal cortex. It is thus suggested that the action of X-ray therapy in ankylosing spondylitis is, in the main, by stimulation of the secretion of the adrenocortical hormone, rather than by a local action upon the involved ligaments and joints. X-ray therapy of the adrenal glands in :8 subjects with ankylosing spondylitis or osteoarthritis of the spine was carried out. The results confirm that adrenal irradiation gives relief of symptoms in ankylosing spondylitis, but none in degenerative osteo-arthritis. This would be expected from the non-hormone-dependent nature of the latter condition. The technique has the advantages that it is simple, without danger of damage to the ovaries, and unlikely to lead to the bone-marrow changes which have been stressed lately.
Acknowledgements.--I wish to acknowledge the permission of the Honorary Medical Staff of the Royal Melbourne Hospital for search of their records of treated cases of ankylosing spondylifts; and for the kind co-operation of Dr. W. P. Holman, the Medical Director of the Peter MacCallum Clinic, in this piece of clinical investigation ; Dr. Frank Ellis, of the London Hospital, for permission to publish the results of I7-ketosteroid investigation of patients under his care; and also to Mr. A. J. Brown, the Librarian, who assisted in the translation of foreign language material. Editor's N o t e . - - I n a further communication from the author, he states that of the cases shown in Table V, 8 have remained well to date, the period of follow-up varying from 9 to ~8 months. REFERENCES BAGNALL,A. W., TRAYNOR,J. A., and MClNTOSH, H. W. (1953), Canad. med. Ass. J., 68, 587. COSTE, F., and LACRONIQUE,F. (195o), Ann. rheum. Dis., 9, 305. COURTBROWN,W. M., and ABBATT,J. D. (I955) , Lancet, I, 1283. DAVlSON,R. A., KOETS,P., and KUZELL,W. C. (I949), J. clin. End..ocrin., 9, 79DESGPdSZ,H., DESGREZ,P., and PAINVIN,P. M. (:951), J. Radiol. Electrol., 32, 595. DESJAt:O:NS,A. V. (194o), Amer. J. Roentgenol., 44, 594. DESMARAIS,M. H. L. (1953), Ann. rheum. Dis., IZ, 25. ELLINGER,F. (I948), Radiology, 5I, 394. ENGELSTAD,R. B., and TORGENSEN,O. (:937), Acta radiol., Stockh., I8, 67:. FINZI, N. S. (I953) , Brit. J. Radiol., 26, 488. FUNCK,L. (I95I), Z. Rheumaforsch., IO, 320. GREINERT,E. (195I), Dtsch. Gesundheitswes., 6, :o:4. HAm~, H. F. (i94o), New Engl. J. Med., 223, 702. HART, F. D. (:952), Brit. med. J., L i88. - - --, ROBINSON,K. C., ALLCmN, F. M., and MACLAGAN,N. F. (1949), Quart. J. Med., I8, 217. HERNAMAN-JOHNSON,F. (1945), Brit. J. Radiol., 18, 3o6.
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HILL, L. (I952), Proc. R. Soc. Med., 45, 543. HOCHMAN, A., and BLOCK-FRANKELTHAL,L. (1953), Brit. J. Radiol., 26, 599. HORWITZ, T., and DILLMAN, M. A. (I944) , Amer. J. Roentgenol., 5I, 186. JENKINSON, E. L., and BROWN, W. H. (I944), Ibid., 51, 496. KAHLMETER, G. (I938), Acta radiol., Stockh., 19, 529. KAPLAN, I. I. (I945), N . Y . S t . J . Med., 45, 1339. KEMEN, A. (I937), Deutsche Gesellsch.f. Rheumabekampfs, 49, 46-54. KUHNS, J. G., and MORRISON, S. L. (1946), New Engl. J. Med., 235 , 399. LANGER, H. (I933), Radiology, 2o, 78. LEBLONB, C. P., and SEOAL, G. (I942), Amer. J. Roentgenol., 47, 3o2. LIEFMANN, R. (I95o), Acta reed. scand., 136, 226. LIEVRE, J. A., and LEGER, L. (I949), Bull. Soc. todd. H6p., Paris, 65, 1256. McWHIRTER, R. (I945), Brit. J. Radiol., 18, 3o2. MowBm~Y, R., LATNER, A. L., and MIDDLEMISS,J. H. (I949), Quart. J. Med., 18, 187. NEY, H. (I949), Ann. rheum. Dis., 8, 191. NORTH, N., and NIMS, L. F. (i949) , Fed. Proc., 8, 119. OPPENHEIMER, A. (I943) , Amer. J. Roentgenol., 49, 49. PABR, L. J. A., WHITE, P., and SHIPTON, E. (I95I), Med. J. Aust., I, 544. RICHMOND, J. J. (I95i), Proc. R. Soc. Med., 44, 443. SCOTT, S. G. (I939), Adolescent Spondylitis or Ankylosing Spondylitis. The Early Diagnosis and its Treatment by Wide-field X-ray Irradiation. London : Oxford University Press. SELYE, H. (I952), Annual Report on Stress. Montreal : Acta, Inc. SHARP, J., and EASSON, E. C. (1954), Brit. med. J., I, 619. SICHER, K. (i949), Ibid., I, 455. SIMPSON, N. R. W., and STEVENSON,C. J. (i949), Ibid., i, 2i 4. SMYTH, C. J., FREYBERG,R. H., and LAMPE, I. (I94I), ft. Amer. med. Ass., II7, 826. TILLIS, H. H. (I944), J. reed. Soc. N.J., 4 I, 374. WINDEYER,B. W. (I952), Proc. R. Soc. Med., 45, 546.
BOOK
REVIEWS
Angiocardiographic Interpretation in Congenital Heart Disease.
By HERBERT L. ABRAMS, M . D . , Assistant Professor of Radiology, Stanford U n i v e r s i t y School of Medicine ; and HENRY S. KAPLAN, M . D . , Professor of Radiology, Stanford U n i v e r s i t y School of Medicine. I I × 8½ in. PP. 233 + viii, with 163 illustrations. 1956. Springfield, Ill. : Charles C. Thomas, (Oxford : Blackwdl Scientific Publications.) 95s.
THIS hook, based on a large v o l u m e of personal material, constitutes a very full description of anglocardiography, including such features as the opaque media to be used, sensitivity tests, the risks of this type of examination, and the contra-indications to injection. It is interesting to note that the figures quoted for death-rates in intravenous urography and angiocardiography respectively are 0"0038 per cent in the former and 0-38 per cent in the latter. In Britain the last figure available of death-rate in angioeardiography was 1"7 per cent, which resu!ted from the very high proportion of investigations in congenital heart disease to those in other forms of cardiac and p u l m o n a r y disease. T h e authors stress the unreliability of sensitivity tests in general, and favour the routine injection of 0'5 c.c. of the m e d i u m as an intravenous test dose, followed by an observation period of IO-I5 minutes before the full injection is carried out. T h e y indicate that medical-legal considerations, rather than any efficiency of such tests, underlie their continued use. It is also suggested that the effect of the drug injected is due rather to the molecular content of the solution than to its iodine content. All radiographs in this book taken during angiocardiography are accompanied by line drawings, and practically all congenital heart conditions are comprehensively dealt with, but the value of the book would have been enhanced b y t h e inclusion of a plain radiograph of the chest to s h o w t h e cardiac contour, in order that comparison between the radiograph and the angiocardiographic appearances could have been made.
SPONDYLITIS
2oi
ANKYLOSING SPONDYLITIS ITS HORMONAL BACKGROUND IN RELATION TO X-RAY THERAPY BY BASIL A. STOLL, F.F.R., D.M.R. (D. & T.), M.R.C.S. PETER MACCALLUM CLINIC~ MELBOURNE
IN view of the remarkable male predominance in ankylosing spondylitis and its earliest manifestations appearing at the age of maximum sexual activity, there has been considerable speculation as to the relation of the disease to hormone dysfunction. Thus, Davison, Koets, and Kuzell (1949) noted an increase in the 17-ketosteroid excretion in a group of cases of ankylosing spondylitis. In more recent years the value of cortisone and ACTH in the treatment of the disease has renewed interest in this problem. In connexion with these facts may be considered the observation that X-ray therapy is practically diagnostic in its ability to relieve the symptoms of the disease. If it be accepted that X-ray irradiation stimulates the secretion of its hormone by the adrenal cortex, it may be asked whether the beneficial effect of X-ray therapy in this disease is exerted directly by local action or indirectly by stimulation of the adrenal cortex.
AETIOLOGY The outstanding points in the aetiology of the disease will first be emphasized in order to establish its hormonal background. I. Sex D i s t r i b u t i o n . - - T h e predominance of male to female involvement varies between 5 : 4 and 20 : I in different series, according to the group reviewed, e.g., ex-servicemen or civilians (Parr, White, and Shipton, I95I), but in general is about io : i. 2. Age at O n s e t . - - T h e onset of symptoms is in young adult life, between 2o and 3° years of age in the majority of cases, although there is a total range of from 15 65 years (McWhirter, 1945 ; Mowbray, Latner, and Middlemiss, 19¢9). 3. Occupation and S t r e s s . - - T h e occupation of those affected among males is stated as 5° per cent light and medium manual work, 20 per cent heavy manual work, and 3° per cent sedentary occupations (Richmond, 1951) . Similar figures are quoted by Simpson and Stevenson (19¢9). Those subjected to mental stress are more particularly affected. Thus McWhirter (1945) states that the higher incidence of the disease in the Services is possibly associated with the additional strain and abnormal conditions of life making the disease declare itself at an earlier stage. 4. Hereditary F a c t o r s . - - T h e r e is a family history of rheumatic complaints in 28 per cent of cases, but of fairly definite or probable ankylosing spondylitis in only 9 per cent of all cases of typical ankylosing spondylifis (Sharp and Easson, 1954). Parr and others (1951) noted a familial history of spondylitis in i i per cent of cases. Many instances of brother-sister involvement are reported in the literature. 5- Female P a t i e n t s . - - I n some cases symptoms date back to the middle of a pregnancy, but in others appear soon after confinement. Occasionally, symptoms are decreased during pregnancy (unlike rheumatoid arthritis where symptoms practically disappear during pregnancy). In females the disease is usually not so rapidly progressive, and may abort spontaneously before ankylosis is established. 6. IritiS.--This is noted either in the history or in the course of the disease in 8 per cent of cases (Sharp and Easson, 195¢). Iritis in these cases yields quickly to cortisone therapy. 7. I7-Ketosteroid Excretion in the U r i n e . - - T h i s has been noted as raised in the disease (Davison and others, i949) , but the observation is not confirmed (Hart, Robinson, Allchin, and Maclagan, 1949 ; Mowbray and others, 19¢9). In a series of cases under the care of Dr. Frank i4
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Ellis at the London Hospital (Fig. 2oo) it appeared at first that the i7-ketosteroid level was correlated with the degree of activity of the disease. If, however, the level is correlated with the age of the patient, it is seen that the higher levels occur, as would be expected, in the younger age groups. 45. 40. 35.
2 of 14 above 18 level
8 of 15 I
above 18 level
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4of 12 above 18 level
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30.
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L
2
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Fig. 2oo.--x7-ketosteroid level in urine of group of males with anky!osing spondylitis. disease.
B, Classified according to age group.
A, Classified according to stage o f
ANKYLOSING
SPONDYLITIS
203
In accordance with some of these aetiological observations, Funck (195i) has noted that ankylosing spondylitis is associated with the asthenic male type. He postulates toxic damage to the pituitary on the basis of a rheumatic diathesis, followed by increased secretion of gonadotrophin, and thus androgen production by the gonads. This may explain the benefits noted by the administration of oestrogens and the adrenal cortical hormone. He believes that the objective of therapy in this disease must be the regulation of hormone production. Liefmann (i95o), working on the stress basis of ankylosing spondylitis, suggested that the condition of stress (including cold, trauma, infection, or hypersensitivity) leads to anterior pituitary stimulation. The increased A C T H excretion leads to stimulation of the adrenal cortical hormone, and an increase in protein catabolism, and raised i7-ketosteroid excretion are seen in the disease. Thus he concludes that ankylosing spondylitis is due to endocrine imbalance associated with hyperadrenocorticism. In view of the response of the disease to the administration of cortisone, as seen later, it is possible that the aetiology of the disease involves long-continued demands on the adrenal cortex, finally leading to adrenocortical exhaustion. THE R E S P O N S E TO C O R T I S O N E A N D O T H E R H O R M O N E S C o r t i s o n e . - - T h e response to this hormone by ankylosing spondylitis is well established. Hart (1952) considers the hormone useful for the acute painful episodes, but there is no lasting effect--unlike X-ray therapy. This method of treatment, however, is preferred in young women to avoid damage by X-ray therapy to the ovaries. Bagnall, Traynor, and McIntosh (1953) reported II cases treated by cortisone IOO rag. daily for 1-2 months, further courses being repeated for j - i o days when recurrence of symptoms occurred. The E.S.R. fell during therapy but rose at varying intervals in the majority of cases. The i7-ketosteroid level in the urine also fell during treatment, but the eosinophil count showed no consistent variation. The authors prefer intermittent administration of the hormone to avoid resistance to the drug and the possibility of sideeffects. In io out of the I i cases there resulted an increased working capacity. The mode of action of cortisone in the disease is uncertain. It may act directly on the tissues by dampening the activity of the rheumatic process, and A C T H may cause similar relief by stimulating the adrenal function. Stilboestrol.--There are several reports that intramuscular administration of 2o mg. stilbmstrol daily gives a definite and lasting improvement in the spine flexibility, together with relief of pain. The disadvantage, however, is that in males mastitis and impotence often result, and there is no clinical improvement if these complications are not seen. Testosterone does not give similar relief, but it can be combined with the stilbmstrol to reduce the feminizing effects. In females, on the other hand, vaginal bleeding is a complication of the use of stilbcestrol, and although this can be treated by progesterone, such therapy decreases the relief of symptoms. Relief of symptoms by the use of stilbmstrol does not depend upon the age of the patient or on the extent of joint involvement. With regard to the mechanism of the relief following the use of stilbmstrol, it is thought possible that the sex hormones lead to inhibition of the gonadotrophic secretion of the anterior pituitary, and this is followed by a compensatory increase in the secretion of A C T H (Coste and Lacronique, I950). Other H o r m o n a l T r e a t m e n t . - - D O C A and ascorbic acid in combination have been tried extensively in the treatment of both ankylosing spondylitis and rheumatoid arthritis. Occasional patients will derive benefit, but it is difficult to obviate psychogenic benefit in many cases. Parathyroidectomy has been reported to have been used in this disease and occasional benefit noted.
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Gold therapy has been noted to give relief in a minority of cases, and similar results are observed following the use of shock therapy, vaccines--e.g., T.A.B.--and fresh-blood transfusions. These may all act as non-specific forms of stress, causing increased secretion by the adrenal cortex.
X-RAY THERAPY TECHNIQUES Until Gilbert Scott, in 1939, wrote on the use of wide-field X-ray therapy, ankylosing spondylifts was mostly treated by postural methods (e.g., plaster-of-Paris bed), physiotherapy, and spinal supports, to prevent the development of deformity. There was little general attention to X-ray therapy until after 1945. There are five techniques of X-ray therapy, which are still in general use, and these techniques and results are summarized in Table 1. I. L o c a l i z e d : L o w - d o s e Technique.--Kahlmeter (1938), of Stockholm, was the first to report on the use of X-ray therapy for ankylosing spondylitis, and used a localized low-dose technique (45o-6oo r in one week). Kemen (1937) reported on a group of cases treated by a similar technique, and noted an improvement in 67 out of 77 cases at the completion of treatment. Smyth, Freyberg, and Lampe (1941) reported on 52 cases treated by the Kahlmeter technique. Subjective improvement was noted in 72 per cent and objective improvement in 5° per cent (objective improvement in 92 per cent of early cases, but 35 per cent of advanced cases). The experiment was controlled by exposing some cases with lead screening and no demonstrable benefit was shown in these cases. Oppenheimer (1943) used a localized technique with even lower doses (8o-12o r in one week). He reported relief of pain in the majority of 17 cases after a few days, and stated that higher dosage gave no better results. 2. Whole Spine: Low-dose Technique. Hare (194o) reported relief in 80 per cent of 35 cases after treatment of the whole spine and sacro-iliac joints by low doses of deep X-ray therapy (300 r in one week). Treatment was repeated after 3 weeks if necessary, and in the majority of cases only 1-2 areas required repeat of treatment. Pain-relief occurred within 1- 3 weeks of treatment. Sharp and Easson (1954) irradiated the whole spine and sacro-iliac joints with a small weekly dose of 15o r for IO weeks. They claim that this avoids constitutional and h~ematological complications. They claim relief of symptoms in 89 per cent of 275 cases so treated, but when atypical cases are excluded the percentage relieved is as high as 95 per cent. Relief is more likely when the duration of treatment is shorter, and when changes are confined to the sacro-iliac joints. Complications included I case of aplastic anaemia, i of reactivation of pulmonary tuberculosis, and 2 of possible acceleration of renal failure. Permanent amenorrhoea occurred in 16 of 47 young females treated, and temporary amenorrhoea in 3 other cases, as a result of which the tangential method of treating the sacro-iliac joints was adopted. 3. Wide-field T h e r a p y . - - G i l b e r t Scott (1939) reported on the use of wide-field treatment of the disease in 15o cases followed up for 3-5 years. These cases showed relief of pain and stiffness, but no improvement in their radiographs. The dose varied according to the degree of constitutional and h~ematological reaction to therapy (average 250 r in io weeks). HernamanJohnson (1945) reported remission of symptoms by this technique for periods of 5-I5 years, again with no evidence of radiographic improvement. Parr and others (1951) reported marked improvement in 86 per cent of cases and relief in a further IO per cent of a series of IOO cases treated by a similar technique. Such a method of treatment has the disadvantage of commonly inducing severe radiation sickness because of the large integral dose and occasionally leads to a decrease in the formed elements of the blood. Amenorrhoea also occasionally develops in young females.
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Kuhns and Morrison (i946) advocated a similar wide-field irradiation and claimed that 84 per cent of 98 cases showed relief of symptoms. Amenorrhcea developed in 2 out of 2I young women so treated. 4. Localized: Protracted Low-dose Technique.--Hart and others (i949) reported on the use of protracted X-ray dosage directed to the affected part (15oo r in 3 weeks). They reported relief of pain in 92 per cent of cases, usually beginning within i - 4 weeks, but sometimes delayed for 5-6 months. Treatment was repeated after 3 months if necessary. In acute cases, dosage was smaller. T h e y stress that dosage must never reach skin tolerance, and there must be n o danger of permanent damage of the underlying tissue. Simpson and Stevenson (1949) using a similar technique achieved relief of pain in 83 per cent of cases, most of which were at a fairly advanced stage. 5. Whole Spine : High-dose T e c h n i q u e . - - M c W h i r t e r (1945) advocated irradiation of the whole spine and sacro-iliac region irrespective of the symptoms. The dosage used (2500 r in 2 weeks) leads to dry desquamation of the skin, and radiation sickness is prominent. Windeyer (i952) recommended similar irradiation to a somewhat lower dose than McWhirter, and stressed that the peripheral joints should be treated only if causing symptoms. Sicher (I949), using a similar technique to McWhirter, claimed relief in 95 per cent of early cases.
COMPARISON OF TECHNIQUES Richmond (I95i) (see Table H) analysed for relief of pain i6o cases treated by high doses of deep X-ray therapy, in some of which the sacro-iliac joints alone had been treated, and in others the whole spine in addition. The former technique gave relief in 89 per cent of cases, and the Table H . - - C o M P A R I S O N OF SCOPE OF IRRADIATION FOR IMMEDIATE RELIEF AND FREEDOM FROM RECURRENCE IN ANKYLOSING SPONDYLITIS IN I 6 0 CASES (RICHMOND, I 9 5 I )
Sacro-iliac joints alone : 2 0 0 0 r in 4 weeks H.V.L., I'9 Cu
89 per cent of cases improved
In 53 per cent symptoms recurred within i year
Sacro-iliac joints and whole spine: dose as above
96 per cent of cases improved
In 20 per cent symptoms recurred within i year
latter relief in 96 per cent. From the long-term viewpoint, the locally treated cases required retreatment in 53 per cent, but those given wider treatment in only 2o per cent. Unfortunately, the follow-up of cases was only for one year. Desmarais (~953) (see Table III) used random sampling of patients to compare the effect of low-voltage and high-voltage therapy at different dose-levels. He also used a control group in which the current was not switched on during 'treatment '. He notes that dosage higher than iooo r in 4-6 weeks has no advantage over that of IOOOr, but 500 r in the same length of time gives poorer results [not statistically significant] and 300 r by low voltage is no better than the control group. He noted relief of pain after 2- 3 weeks, and all cases receiving higher dosage had maintained their improvement one year later. The pain was relieved irrespective of the stage of the disease, but there was no increase in mobility of the advanced cases. Table I V summarizes the results of 55 cases treated at the Royal Melbourne Hospital by a variety of techniques. It will be noted that the results are essentially similar in all groups, in spite of the variation in dose and size of field treated. It thus appears that there is little to choose between the higher and the lower dose-levels, from the point of view of : - -
ANKYLOSING
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207
a. I m m e d i a t e relief of local s y m p t o m s in this disease. E v e n t h e s m a l l e s t doses in Table I gave relief in t h e vast m a j o r i t y of cases. T h i s applies e v e n to t h e G i l b e r t S c o t t t e c h n i q u e w h e r e the spinal l i g a m e n t s receive a d o s e as low as i o r weekly. b. P r e v e n t i o n o f p a i n r e c u r r e n c e in t h e t r e a t e d area. I t is well r e c o g n i z e d t h a t a m i n o r i t y of cases d e v e l o p r e c u r r e n c e o f s y m p t o m s w i t h i n a year o f t r e a t m e n t , a n d t h i s p r o p o r t i o n is essentially similar w h e t h e r h i g h or low dosage has b e e n given.
Table ///.--COMPARISON OF VARIOUS DOSE-LEVELS AND VOLTAGES OF RADIATION IN ANKYLOSING SPONDYLITIS (DESMARAIS, 1953)
PHYSICALFACTORS
High voltage (H.V.L., I"5 mm. Cu)
IMPROVEDCASE~
DOSE
500 r in 4-6 wk. lOOO r in 4 6 wk. 15oo-2ooo r in 4-6 wk.
Whole Spine
Other Sites
Together
9 of 14 15 of I7 I8 of 19
6of 7 1i of 11 9of 9
71 per cent 92 per cent 96 per cent
Low voltage (H.V.L., 7"5 mm. A1)
300 r in 4-6 wk.
5 of II
Control series
Nil
4of
9
45 per cent 3 of 5
50 per cent
H o w e v e r , t h e r e is no d o u b t t h a t i r r a d i a t i o n of t h e w h o l e s p i n e a n d sacro-iliac region at the first t r e a t m e n t will obviate t h e n e e d for t h e p a t i e n t to have n e w p a r t s t r e a t e d at s h o r t intervals. M o s t p a t i e n t s h a v e s o m e d e g r e e o f relief of p a i n o u t s i d e a t r e a t e d area for as long as t r e a t m e n t is given, b u t the effect is n o t s u s t a i n e d as it is in t h e t r e a t e d area.
Table IV.--COMPARISON OF VARIOUS TECHNIQUES AND DOSE-LEVELS FOR ANKYLOSING SPONDYLITIS IN 55 CASES TREATED AT THE ROYAL MELBOURNE HOSPITAL
VOLTAGE
High voltage (H.V.L.,
DOSE-LEVEL
High dose
1 mm. Cu)
Medium dose Low dose Low voltage (H.V.L., 2 mm. A1) Gilbert Scott Total
Wide field
TISSUE DOSE (DEPTH 3-6 CM.)
RELIEF
15OO-2OOO r in 3-5 wk. lOOO-14oo r in 3-5 wk. 7oo-9oo r in 3-5 wk.
I4 of i6 8 of io
lO of i2
RECURRENCEOF SYMPTOMS (AVERAGETIME) After in 6 After in 4 After in 3
9 mth. cases 6 mth. cases 12 mth. cases
IOO-ZOO r in 3 wk.
8of9
After 7 mth. in 4 cases
2oo-3oo r in 5-7 wk.
6 of 8
After i1 mth. in 3 cases
46 of 55
After 9 mth. in 20 cases
WHOLE SPINE TREATED
PARTSPINE TREATED
7 mth.
I5 mth.
7 mth.
5 mth.
io ruth.
14 mth.
8 mth. in 8 cases
11. mth. in 5 cases
T h e r e a p p e a r s to b e no n e e d to increase t h e dosage in t h e later stages o f t h e disease. I t is, however, i m p o r t a n t to give smaller dosage (and also w i d e r field cover) in t h e cases w i t h acute o n s e t or w i t h w i d e s p r e a d s y m p t o m s (Ellis, p e r s o n a l c o m m u n i c a t i o n ) .
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CLINICAL TRIAL OF A D R E N A L I R R A D I A T I O N In view of the theoretical conclusions derived from the study of treated series in the literature, and from clinical experience, I instituted a search in the available literature for a record of a previous author having instituted irradiation of the adrenal region in ankylosing spondylitis. Desgrez, Desgrez, and Painvin (1951) noted that when treating cases of chronic rheumatism, therapy to the dorsolumbar region led to relief of symptoms arising in the lumbosacral region. They suspected, therefore, that irradiation of the adrenal gland might mediate this benefit by the secretion of cortisone. Their technique for spondylitis involved the administration of a moderate dose of X rays (12oo r in 3-4 weeks, 18o kV., 0. 5 Cu, i A1) to the dorsolumbar region, and they note that irradiation of this particular region gives better clinical benefit than irradiation of any other part of the spine. They suggest that even if the major part of the effect is via the adrenal gland, one cannot exclude a local reaction by the X-ray therapy upon the dorsolumbar spine itself. They also point out the danger of suprarenal exhaustion if overdosage by X-ray therapy is given. These authors then proceed to discuss the possible use of short-wave diathermy to the adrenals in preference to X-ray therapy, because of the destructive effect of the latter compared to the stimulant effect of the former. Greinert (1951) quoted an advanced case of " deforming spondylitis " in which treatment by X rays of the lower dorsal vertebrze induced immediate improvement. The patient was enabled to do light work after having been confined to bed for several months. The dosage recommended is IO-I 5 r skin-dose to each adrenal gland, and the author reports 34 patients whom he has so treated for chronic arthritis. The dose is given to a Io × 15 cm. field on each side, and Greinert believes that this relatively tiny dose exerts an effect on the blood-supply of the adrenal, which results in a cortisone-like effect. Greinert's dosage of io-15 r to each adrenal was tried and found ineffective. On the other hand, the level of dosage suggested by Desgrez and others (i95i), i.e., i2oo r in 3 weeks, is of a level often given locally to the spine, and clinical experience shows that this dosage in the lumbodorsal region is just below that which, in the majority of cases, leads to radiation sickness. Therefore, I decided on a biologically similar dose of 75o-9oo r in lO-14 days. Theoretically, such a dose-level should stimulate the adrenal cortex without exhausting it--the latter state being considered related to radiation sickness. Result o f Irradiatlon.--Ten cases clinically diagnosed as ankylosing spondylitis and 8 of osteo-arthritis, or doubtful cases, have so far been treated, with the results shown in Tables V and V I . It is seen that in 9 of the cases there was almost complete relief of all symptoms ; in 2 cases partial relief ; and in 7 cases no relief of symptoms. Of the latter cases, I was relieved later by removal of a prolapsed intervertebral disk and another manifested a lyric area in the ilium, due to Hodgkin's disease, suggesting the diagnosis of ankylosing spondylitis as incorrect. Of the I1 relieved cases it is noteworthy that 6 had previously received orthodox spinal radiotherapy with similar results accruing from both techniques. As a control, a further 5 cases of degenerative osteo-arthritis received adrenal irradiation by a similar technique to that used for ankylosing spondylitis with no apparent benefit, which is what would be expected. An advantage of the adrenal irradiation technique is that it is simple and less time-consuming than irradiation of the whole spine and sacro-iliac region. In particular, it can be safely used in young females without danger of ovarian irradiation. In addition there is no danger of inducing changes in the marrow--the possibility of which has recently been suggested by Court Brown and Abbatt (1955). In the technique used, a skirt-dose of 15o r (including back scatter) was given to a field 15 cm. wide and io cm. long, centred over the midline at the level of the adrenal glands. The dose was repeated 5-6 times in lO-14 days (the H.V.L. being i mm. Cu) and in only i case was nausea complained of. Relief was usually apparent within 2- 3 weeks of starting
ANKYLOSING
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treatment, and it is seen from the tables that relief of symptoms was not confined to the lumbar area treated but included all affected areas of the spine. Similarly, it is notable that all cases of ankylosing spondylitis, whether early or late, obtained equal relief of symptoms.
DISCUSSION Mode of Action of X Rays in Spondylitis.--In view of the relief of symptoms obtained in ankylosing spondylitis by means of very varying doses and techniques of X-ray therapy, there would appear to be three possible modes of action of radiotherapy in these cases : - I. Local action on the involved joints. • 2. Indirect effect via the autonomic system. 3. Indirect effect via the adrenal cortex. Local Effect.--This is the effect presumably obtained when radiation is used in the treatment .of degenerative osteo-arthritis, tendinitis, etc. An anti-inflammatory effect is suggested by Desjardins (I94o). Ewing describes the effect .of X rays in tissue as including the destruction of rapidly-growing cells, increasing the permeability of the cell membrane, inhibition of the cell enzymes, and promotion of vascular and lymphatic .exudation. The increased blood- and lymph-flow to the part, and subsequent proliferation of fibroblasts, may thus be responsible for the clinical improvement. Tillis (r944) , on the other hand, considers that the liberation of antibodies by the destruction of white blood-cells is the factor responsible for the relief of pain in such cases. Kaplan (1945) suggests that analgesia results by direct action upon the nerve-endings, and :also by relieving the tension in the nerve-sheath by the destruction of white blood-cells. Animal experiments on the effect of X-ray therapy in the resolution of joint effusions (Horwitz and Dillman, 1944) have shown microscopic evidence of disappearance of ¢edema, increase of fibrous tissue, diminution in the cellular reaction, and a tendency to endarteritis obliterans. Effect on Autonomic System.--Langer (1933) suggested that an important mode of action of X-ray therapy in the treatment of osteo-arthritis was through the spinal ganglia. He :suggested that irradiation affects the vegetative nervous system, causing at first a stimulation and later a paralysing effect (Charcot's joint illustrates the operation of nervous influences in producing an arthritis). Cases are noted where X-ray therapy in arthritis often, at first, causes exacerbation of pain (nerve-stimulating effect) and later relief of pain. Langer ascribes the better bloodsupply to a part after X-ray therapy to be due to an effect of the vegetative nervous system, and thus suggests treatment to the sympathetic ganglia of the lumbar region and neck in the case of peripheral arthritis. Finzi (1953) has recently revived this idea and reports benefit to arthritis of the hands following ,small doses of X-ray therapy to the neck (ioo-i3o r in air), and also benefit to arthritis of the hip following treatment to the lumbar region. He also mentions temporary increase of pain after this treatment for 24-48 hours, and regards this as a good prognostic sign. In this respect the benefit reported by Lievre and Leger (1949) in rheumatic disease following surgical denervation of the carotid sinus is of interest. Effect on Adrenal Glands.--Davison and others (i949) , after noting the high level of I7-ketosteroid excretion in ankylosing spondylitis, observed that clinical benefit derived from X-ray therapy is associated with a fall in the level of their excretion. Since the introduction of cortisone in the treatment of rheumatoid arthritis and spondylitis, I had felt that the action of irradiation in the treatment of ankylosing spondylitis might be to increase the level of cortisone in the blood so that the patient is treated by endogenous endocrine therapy. It is possible, therefore, that we may be able, by means of irradiation, to induce an effect similar to that of cortisone therapy on an underlying dysfunction of the adrenals. The
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advantage over cortisone administration is that there are no undesirable side-effects such as those of Cushing's syndrome. Most authors in the English and American literature, however, do not accept this mode of action of X-ray therapy. Hart (1952) assumes that all the effects of X-ray therapy are local and take place only in the area submitted to irradiation. He states that there is little evidence to support the employment of " homoeopathic wide-field therapy ". Sharp and Easson (1954) and also Smyth, Freyberg, and Lampe (1941) believe that the beneficial effects of X rays are due to local action on the irradiated tissues and not to an indirect effect mediated through the endocrine or other mechanisms. It must be pointed out that on this assumption it is difficult to explain the failure of X-ray therapy to yield relief in cases of rheumatoid arthritis. Gilbert Scott (I939) and HernamanJohnson (1945) believe, on the other hand, that X rays stimulate the defence mechanism of the body, but do not detail this mode of action. Ney (1949) published some blood-studies in an attempt to elucidate this point. T H E E F F E C T OF X-RAY T H E R A P Y IN S T I M U L A T I N G THE A D R E N A L S E C R E T I O N Selye (1952) notes that stress causes an increased demand for the adrenocortical hormone which is mediated by increased secretion of A C T H from the anterior pituitary. This increased activity of the adrenal cortex seems to be associated with reduction of its ascorbic acid and cholesterol content. Such changes are seen following administration of A C T H and also in animals exposed to stress, such as cold, burns, and h~emorrhage. This same change in the adrenals is also noted following whole-body X-ray irradiation to lethal and sub-lethal dosage (North and Nims, 1949). Hochman and Block-Frankelthal (1953) therefore suggest that some of the therapeutic effects of low dosage by X rays in some of the stress diseases, e.g., asthma, may find a partial explanation in the mobilization of the adrenocortical hormone. Ellinger (1948) suggests that irradiation of a sufficiently large volume of tissue results in the liberation of breakdown products such as histamine or a histamine-like substance. The literature shows an increase in the blood-histamine level in patients following X-ray treatment, and in addition histamine is capable of inducing most of the symptoms of radiation sickness, including a fall in the chloride and blood-cholesterol levels. It is thus suggested that the histaminelike substance liberated after irradiation causes the secretion of anterior pituitary hormone, which then stimulates the adrenal cortex. Experimental findings show that depletion of the sudanophil substance in the adrenal cortex (which indicates increased activity of the gland) appears either after direct irradiation over the adrenals or by irradiation of a part at a distance, possibly exerted as a result of liberation of decomposition products. Leblond and Segal (i942), in a well-planned series of experiments, demonstrated that heavy irradiation to the head and neck or lower abdomen of mice, with shielding of the rest of the body, leads to hypertrophy of the adrenal cortex with disappearance of the sudanophil substance and involution of distant lymphatic organs, including spleen, thymus, and lymphatic glands. These latter changes are prevented by adrenalectomy. Irradiation of lymphoid tissue causing involution of similar tissue at a distance is seen occasionally in the reticuloses, and is perhaps comparable to the effect of A C T H and cortisone in these diseases. Irradiation over the adrenal gland causes marked depletion of sudanophil substance in the cortex (Engelstad and Torgensen, I937) , although less marked changes are seen following irradiation of any part, even the ear of a rabbit. Jenkinson and Brown (1944) postulate that the adrenal cortex secretes a substance which maintains cellular permeability. Thus repeated insults to the body (e.g., stress or X-ray irradiation) lead to excessive secretion manifested by exhaustion of the cortical lipoids. Mild insults, on the other hand, at first lead to adrenal hypertrophy, but if long continued, finally lead to
ANKYLOSING
SPONDYLITIS
2i 3
atrophy- This effect on the adrenal may, of course, be mediated by the adrenocorticotrophic hormone of the pituitary. To sum up the experimental findings, it appears that increased activity of the adrenal cortex is seen following irradiation. These changes are seen even when the adrenal gland itself is not included in the field of irradiation. This effect may be mediated by the liberation of a histaminelike decomposition product causing increased secretion of A C T H .
SUMMARY A review of the aetiological factors in ankylosing spondylitis suggests a hormonal basis to the condition, and its response to cortisone suggests that it belongs to the group of ' stress ' diseases. In examining the literature, one is impressed by the remarkable diversity in the dose of X rays given in this condition by different authors with, at the same time, remarkably uniform results. Experimental observations confirm that irradiation of various parts of the body, particularly of the adrenal gland, leads to a stress reaction with increased activity of the adrenal cortex. It is thus suggested that the action of X-ray therapy in ankylosing spondylitis is, in the main, by stimulation of the secretion of the adrenocortical hormone, rather than by a local action upon the involved ligaments and joints. X-ray therapy of the adrenal glands in :8 subjects with ankylosing spondylitis or osteoarthritis of the spine was carried out. The results confirm that adrenal irradiation gives relief of symptoms in ankylosing spondylitis, but none in degenerative osteo-arthritis. This would be expected from the non-hormone-dependent nature of the latter condition. The technique has the advantages that it is simple, without danger of damage to the ovaries, and unlikely to lead to the bone-marrow changes which have been stressed lately.
Acknowledgements.--I wish to acknowledge the permission of the Honorary Medical Staff of the Royal Melbourne Hospital for search of their records of treated cases of ankylosing spondylifts; and for the kind co-operation of Dr. W. P. Holman, the Medical Director of the Peter MacCallum Clinic, in this piece of clinical investigation ; Dr. Frank Ellis, of the London Hospital, for permission to publish the results of I7-ketosteroid investigation of patients under his care; and also to Mr. A. J. Brown, the Librarian, who assisted in the translation of foreign language material. Editor's N o t e . - - I n a further communication from the author, he states that of the cases shown in Table V, 8 have remained well to date, the period of follow-up varying from 9 to ~8 months. REFERENCES BAGNALL,A. W., TRAYNOR,J. A., and MClNTOSH, H. W. (1953), Canad. med. Ass. J., 68, 587. COSTE, F., and LACRONIQUE,F. (195o), Ann. rheum. Dis., 9, 305. COURTBROWN,W. M., and ABBATT,J. D. (I955) , Lancet, I, 1283. DAVlSON,R. A., KOETS,P., and KUZELL,W. C. (I949), J. clin. End..ocrin., 9, 79DESGPdSZ,H., DESGREZ,P., and PAINVIN,P. M. (:951), J. Radiol. Electrol., 32, 595. DESJAt:O:NS,A. V. (194o), Amer. J. Roentgenol., 44, 594. DESMARAIS,M. H. L. (1953), Ann. rheum. Dis., IZ, 25. ELLINGER,F. (I948), Radiology, 5I, 394. ENGELSTAD,R. B., and TORGENSEN,O. (:937), Acta radiol., Stockh., I8, 67:. FINZI, N. S. (I953) , Brit. J. Radiol., 26, 488. FUNCK,L. (I95I), Z. Rheumaforsch., IO, 320. GREINERT,E. (195I), Dtsch. Gesundheitswes., 6, :o:4. HAm~, H. F. (i94o), New Engl. J. Med., 223, 702. HART, F. D. (:952), Brit. med. J., L i88. - - --, ROBINSON,K. C., ALLCmN, F. M., and MACLAGAN,N. F. (1949), Quart. J. Med., I8, 217. HERNAMAN-JOHNSON,F. (1945), Brit. J. Radiol., 18, 3o6.
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HILL, L. (I952), Proc. R. Soc. Med., 45, 543. HOCHMAN, A., and BLOCK-FRANKELTHAL,L. (1953), Brit. J. Radiol., 26, 599. HORWITZ, T., and DILLMAN, M. A. (I944) , Amer. J. Roentgenol., 5I, 186. JENKINSON, E. L., and BROWN, W. H. (I944), Ibid., 51, 496. KAHLMETER, G. (I938), Acta radiol., Stockh., 19, 529. KAPLAN, I. I. (I945), N . Y . S t . J . Med., 45, 1339. KEMEN, A. (I937), Deutsche Gesellsch.f. Rheumabekampfs, 49, 46-54. KUHNS, J. G., and MORRISON, S. L. (1946), New Engl. J. Med., 235 , 399. LANGER, H. (I933), Radiology, 2o, 78. LEBLONB, C. P., and SEOAL, G. (I942), Amer. J. Roentgenol., 47, 3o2. LIEFMANN, R. (I95o), Acta reed. scand., 136, 226. LIEVRE, J. A., and LEGER, L. (I949), Bull. Soc. todd. H6p., Paris, 65, 1256. McWHIRTER, R. (I945), Brit. J. Radiol., 18, 3o2. MowBm~Y, R., LATNER, A. L., and MIDDLEMISS,J. H. (I949), Quart. J. Med., 18, 187. NEY, H. (I949), Ann. rheum. Dis., 8, 191. NORTH, N., and NIMS, L. F. (i949) , Fed. Proc., 8, 119. OPPENHEIMER, A. (I943) , Amer. J. Roentgenol., 49, 49. PABR, L. J. A., WHITE, P., and SHIPTON, E. (I95I), Med. J. Aust., I, 544. RICHMOND, J. J. (I95i), Proc. R. Soc. Med., 44, 443. SCOTT, S. G. (I939), Adolescent Spondylitis or Ankylosing Spondylitis. The Early Diagnosis and its Treatment by Wide-field X-ray Irradiation. London : Oxford University Press. SELYE, H. (I952), Annual Report on Stress. Montreal : Acta, Inc. SHARP, J., and EASSON, E. C. (1954), Brit. med. J., I, 619. SICHER, K. (i949), Ibid., I, 455. SIMPSON, N. R. W., and STEVENSON,C. J. (i949), Ibid., i, 2i 4. SMYTH, C. J., FREYBERG,R. H., and LAMPE, I. (I94I), ft. Amer. med. Ass., II7, 826. TILLIS, H. H. (I944), J. reed. Soc. N.J., 4 I, 374. WINDEYER,B. W. (I952), Proc. R. Soc. Med., 45, 546.
BOOK
REVIEWS
Angiocardiographic Interpretation in Congenital Heart Disease.
By HERBERT L. ABRAMS, M . D . , Assistant Professor of Radiology, Stanford U n i v e r s i t y School of Medicine ; and HENRY S. KAPLAN, M . D . , Professor of Radiology, Stanford U n i v e r s i t y School of Medicine. I I × 8½ in. PP. 233 + viii, with 163 illustrations. 1956. Springfield, Ill. : Charles C. Thomas, (Oxford : Blackwdl Scientific Publications.) 95s.
THIS hook, based on a large v o l u m e of personal material, constitutes a very full description of anglocardiography, including such features as the opaque media to be used, sensitivity tests, the risks of this type of examination, and the contra-indications to injection. It is interesting to note that the figures quoted for death-rates in intravenous urography and angiocardiography respectively are 0"0038 per cent in the former and 0-38 per cent in the latter. In Britain the last figure available of death-rate in angioeardiography was 1"7 per cent, which resu!ted from the very high proportion of investigations in congenital heart disease to those in other forms of cardiac and p u l m o n a r y disease. T h e authors stress the unreliability of sensitivity tests in general, and favour the routine injection of 0'5 c.c. of the m e d i u m as an intravenous test dose, followed by an observation period of IO-I5 minutes before the full injection is carried out. T h e y indicate that medical-legal considerations, rather than any efficiency of such tests, underlie their continued use. It is also suggested that the effect of the drug injected is due rather to the molecular content of the solution than to its iodine content. All radiographs in this book taken during angiocardiography are accompanied by line drawings, and practically all congenital heart conditions are comprehensively dealt with, but the value of the book would have been enhanced b y t h e inclusion of a plain radiograph of the chest to s h o w t h e cardiac contour, in order that comparison between the radiograph and the angiocardiographic appearances could have been made.