Journal ofthe Royal Society of Medicine Volume 72 November 1979
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the large 27S aggregates in the serum could have activated various inflammatory pathways, with consequent complement activation and release of local permeability factors.
References Krajny M & Pruzanski W (1976) Canadian Medical Association Journal 114, 899 Lin J H, Orofino D, Sherlock J, Letteri J & Duffy J L (1973) Nephron 10, 262 Martelo 0 J, Schultz D R, Pardo V & Perez Stablo E (1975) American Journal of Medicine 58, 567 Waldenstrom J (1944) Acta medica Scandinavica 117, 216
Diagnostic difficulties in Whipple's disease J Winfield MB MRCP R R Dounnashkin MD J M Gumpel BM FRCP Rheumatic Diseases Study Group, and Division of Electron Microscopy, Northwick Park Hospital and Clinical Research Centre, Harrow HA] 3UJ
Whipple's disease is a multisystem disorder which may present with features remote from the gastrointestinal tract. We describe a patient in whom arthropathy, personality change and neurological involvement were the principal features. The diagnosis of Whipple's disease, previously suspected, was delayed by a negative small-bowel biopsy but when the gastrointestinal symptoms became manifest, a positive biopsy with all the characteristic features of the disease was obtained. Several biopsies may need to be taken before Whipple's disease can be excluded. A man of 58 presented in 1975 to hospital with a 12-year history of migratory joint pains affecting knees, ankles and shoulders. He complained of pain and stiffness in the metacarpophalangeal and proximal interphalangeal joints of both hands and had noticed swelling of the left wrist. For eighteen months he had felt depressed and had lost 6 kg in weight over this time. He was otherwise fit and worked full-time as a sheet metal worker. In 1953 and 1955 he had been treated with carbimazole for thyrotoxicosis. He smoked 30 cigarettes a day and had a productive cough. He was a thin man who looked older than his years. He weighed 51.5 kg, height 1.78 m. The only abnormal physical signs were restricted lumbar spine movements and synovial swelling over the dorsum of the left wrist. He was seen regularly in outpatients as a case of seronegative polyarthritis. The only abnormal laboratory test was a persistently elevated ESR, usually 50100 mm in 1st hour (Westergren). The arthralgia, joint stiffness and occasional joint swelling responded well to non-steroidal anti-inflammatory drugs and no erosive changes were seen on serial radiographs. There was no weight loss between 1975 and 1976 nor any abdominal symptoms or diarrhoea. In February 1976 he complained of increasing lethargy and depression and of impotence for the first time. As no endocrine or neurological cause for the impotence could be found, and as there had been marital disharmony over many years, this was considered probably psychogenic. In November 1976 he was admitted to hospital after collapsing at home. He had become giddy and disorientated whilst returning from work and had noticed increasing weakness of his left arm and leg over one hour. On examination he had a left hemiplegia and a mild left seventh cranial nerve palsy; the other cranial nerves were normal. There were no other relevant signs and he was normotensive. An isotope brain scan showed an area of increased uptake in the right inferoposterior parietal region consistent with a vascular lesion; a CAT brain scan was normal, as was the cerebrospinal fluid. The ESR was elevated at 52 mm in 1 st 1 Case presented to Clinical Section, 21 July 1978. Accepted 1 August 1978
0141-0768/79/110859-05/$01.00/0
C-1 1979 The Royal Society of Medicine
860
Journal of the Royal Society of Medicine Volume 72 November 1979
hour. Over several weeks he made an almost total recovery, but developed episodic attacks of acute breathlessness particularly when he was anxious, and a soft apical systolic murmur was transiently audible. No cause could be found for these features and in particular there was no evidence of cardiorespiratory disease. Further investigations as an inpatient were carried out to elucidate the cause of his chronic illness. Polyarteritis nodosa, a bronchogenic carcinoma or other neoplasm, and Whipple's disease were all considered but were not supported by positive findings, nor was there evidence of weight loss. Two attempts to perform jejunal biopsies with a Crosby capsule were technically unsuccessful. A small-bowel biopsy (Dr A J Levi) was obtained endoscopically (Figure 1). There was no evidence of Whipple's disease. No firm diagnosis could be made at this stage.
Figure 1. Sections of small bowel biopsy. The initial small bowel biopsy taken 1 year before that in Figure 2. Multiple levels of this biopsy were examined but no evidence of Whipple's disease was seen. PAS. x 110
Figure 2. Small bowel biopsy taken in February 1978. This shows classical appearance of Whipple's disease with lamina propria filled with darkly staining PASpositive macrophages that are distorting the villous pattern (Dr A B Price). PAS. x 110
During 1977 his health deteriorated, with marked personality changes. He felt tired and lethargic, worthless and withdrawn. He resented company at home and became aggressive and hostile towards his family and friends, with emotional lability and depression. A psychiatric opinion was sought (Dr T J Crow). It was considered that the personality changes were entirely consistent with organic cerebral disease, possibly exacerbated by his cerebrovascular accident, and that the affective changes appeared to be secondary to that disease. Tricyclic antidepressants were tried with no effect; attendance at a psychiatric day hospital produced a marked improvement in his mood. Later he became slightly ataxic, with a prolonged relaxation phase to tendon reflexes. He staggered to the left and Romberg's test was positive. No other sensory or cerebellar signs could be elicited. There had been, up to this time, a substantial improvement in his hemiplegia and his ataxia was considered to be unrelated to this. Investigations, including a further CAT brain scan, were inconclusive. Hypothyroidism was considered but not substantiated biochemically. Endocrinological investigations, including thyroid function tests, a synacthen
Journal of the Royal Society of Medicine Volume 72 November 1979
861
test and cortisol estimations, and biochemical tests were all normal. His stools appeared normal, and a xylose absorption test showed minor abnormalities only. Prednisolone was started empirically in a dosage of 20 mg a day, in the hope of improving his general state; there was no improvement over four months. In November 1977 he was readmitted to investigate a history of painful swallowing, and a dull abdominal pain in the epigastrium and right iliac fossa. There was no weight loss and during observation in the ward there was no abnormality in the stools, and all symptoms cleared. Another barium meal and follow-through showed no
change from previous barium studies. In February 1978 he became cachectic, with diarrhoea, and had lost 8 kg in weight. On examination, the abdomen was distended and diffusely tender, but there was no lymphadenopathy, arthritis or pleural effusion. Gross steatorrhoea was noted for the first time. A barium meal and follow-through examination showed a widespread malabsorption pattern. The faecal fat content was 11.8 grams per 24 hours. Endoscopy was repeated, and an endoscopic small bowel biopsy now showed the typical appearance of Whipple's disease (Figure 2). Electron microscopy of the biopsy specimen showed large numbers of bacteria, almost entirely confined to the lamina propria. The bacteria were bacilli, 200 nm x 1000 nm, and possessing a distinct capsule external to the cell wall (Figure 3). The bacteria were mostly extracellular but some organisms in a partial state of digestion were seen within macrophages (Figure 4). These macrophages were present in large numbers and corresponded to the PASpositive-stained cells seen by light microscopy. Some of the macrophages contained partially digested organisms but most of them were filled with cell walls (Figure 5). These cell walls were identical to those seen in the viable organisms except that none of the capsular material or cytoplasm of the organisms remained. The mucosa of the jejunum appeared almost completely normal, except for very few bacilli. HLA typing (Dr D C 0 James) was 2, 9(?23), 5,7. Treatment was started immediately, with correction of his dehydration and electrolyte depletion. Liquid glucose and a synthetic low-residue diet were used to increase his calorie intake. Tetracycline was given orally in a dose of 2 grams per day, and later metronidazole was added. His clinical improvement has not continued after the improvement of the first two months. His weight has increased by 6 kg. Depression remains a major factor, and the longterm prognosis remains in doubt.
Discussion
Patients with Whipple's disease may lack intestinal symptoms or develop these only as a late manifestation of the disease. Maizel et al. (1970), reviewing 114 cases of Whipple's disease, determined that 5% lacked weight loss, 22% lacked diarrhoea, and 40% lacked abdominal pain. Although a thin man, our patient denied any abdominal symptoms and did not lose weight over a two-year observation period. The major symptoms of diarrhoea, weight loss and abdominal pain appeared late in the course of his disease and it was at this time that a positive small bowel biopsy was obtained. Moorthy et al. (1977) have stressed that the intestinal lesion may be patchy and that multiple biopsies may need to be taken. Our initial normal biopsy did not exclude Whipple's disease, and it is likely that the endoscopic biopsy may have been obtained too high to show changes of Whipple's disease. Two small-bowel barium contrast studies carried out between 1975 and 1977 showed dilated and thickened duodenal and jejunal mucosal folds. Although nonspecific, these are the most common radiographic changes in Whipple's disease (Blum & Nathan 1959). Only in November 1977 was a marked malabsorption pattern apparent. The occurrence of arthritis in Whipple's disease is well documented (Kelly & Weisiger 1963, Delcambre et al. 1974). The ankles, wrists, knees and shoulders are the commonest joints to be affected, and several joints may be clinically involved over one or two days and rapidly resolve (Caughey & Bywaters 1963). Arthritis may precede the gastrointestinal symptoms by many years and the 12-year history of arthritis in our patient is not unusual. Synovial thickening and swelling were noted over the dorsum of the left wrist on several occasions but disappeared rapidly before a biopsy could be arranged. Synovial biopsy may be
862
Journal of the Royal Society of Medicine Volume 72 November 1979
Figure 4. Macrophages in lamina propria with intracellular and extracellular bacilli present. The intracellular bacilli are in the process of degradation x 2700
Figure 3. High magnification of bacilli in the lamina propria. x 33 850
Figure 5. Macrophages containing large num_
1
_
C
of cell walls x 8700 ~~~~~~~~~~~~~~~bers
diagnostically helpful, as Hawkins et al. (1976) detected, by electron microscopy, rod-shaped organisms in the synovial membrane identical to those present in the jejunal mucosa of a patient with Whipple's disease. Cardiac involvement in Whipple's disease is relatively common. Systolic murmurs or pericardial friction rubs may be audible during the course of this illness, and adhesive pericarditis and valvular deformity with vegetations, particularly on the mitral valve, may be apparent at post-mortem. The changes resemble those seen in chronic rheumatic heart disease but PAS-positive macrophages have been detected in the pericardium, myocardium and valves of such patients (McAllister & Fenoglio 1975). The intermittent soft systolic murmur detected in our patient may well have been due to mitral valve vegetations. Marked distortion of the mitral valve may also have occurred, since echocardiography showed markedly reduced excursion rates of the mitral valve leaflets. Histological involvement of the central nervous system is common in Whipple's disease and
Journal of the Royal Society of Medicine Volume 72 November 1979
863
microscopic foci of PAS-staining histiocytes have been found in many areas of the brain and spinal cord. Clinical manifestations of neurological involvement are, however, uncommon. Progressive dementia, intellectual impairment, visual disturbance, myoclonus and ophthalmoplegia have all been reported (Pallis & Lewis 1974). Our patient displayed a progressive and marked personality change with mental dullness, apathy, aggression and emotional lability. Most of these changes antedated his cerebrovascular accident and were probably secondary to diffuse cerebral infiltration with PAS-staining histiocytes. In addition, gliosis and neuronal loss in the cortex may occur, as observed by Lampert et al. (1962). Some of the affective changes, however, may have been secondary to the severity of his systemic disease. His right hemisphere cerebrovascular accident can probably be attributed directly to Whipple's disease, since PAS-positive material has been detected within small cerebral blood vessels (Smith et al. 1965, Caughey & Bywaters 1973). Moreover, the report of PAS-positive endocardial vegetations in 32 of 94 autopsied cases of Whipple's disease (Enzinger & Helwig 1963) suggests the possibility of an embolic vegetation being the cause of his stroke.
Acknowledgements: We are grateful to our colleagues who have contributed to the diagnosis and management of this case. References Blum L & Nathan H (1959) Southern Medical Journal, 52, 1428 Caughey D E & Bywaters E G L (1963) Annals of the Rheumatic Diseases 22, 327 Delcambre B, Lenz J, Leonardelli J, Paris J C, Mairesse M & Robert D'Eshouges J (1974) Semaine des hopitaux de Paris 50, 847 EnAzinger F M & Helwig E B (1963) Virchows Archivfur pathologische Anatomie 336, 238 Hawkins C F, Faff M, Morris C J, Hoare A M & Williamson N (1976) Annals of the Rheumatic Diseases 35, 502 Kelly J J & Weisiger B B (1963) Arthritis and Rheumatism 6, 615 Lampert P, Tom M I & Cumings J N (1962) Neurology (Minneapolis) 12, 65-71 Maizel H, Ruffin J M & Dobbins W 0 (1970) Medicine 49, 175-205 McAllister H A & Fenoglio J J (1975) Circulation 52, 152 Moorthy S, Nolley G & Hermos J A (1977) Gut 18, 152-155 Palis C A &.Lewis P D (1974) The Neurology of Gastrointestinal Disease, Saunders, London; pp 207-214 Smith W T, French J M, Gottsman M, Smith A J & Wakes-Miller J A (1965) Brain 88, 137-150
859
the large 27S aggregates in the serum could have activated various inflammatory pathways, with consequent complement activation and release of local permeability factors.
References Krajny M & Pruzanski W (1976) Canadian Medical Association Journal 114, 899 Lin J H, Orofino D, Sherlock J, Letteri J & Duffy J L (1973) Nephron 10, 262 Martelo 0 J, Schultz D R, Pardo V & Perez Stablo E (1975) American Journal of Medicine 58, 567 Waldenstrom J (1944) Acta medica Scandinavica 117, 216
Diagnostic difficulties in Whipple's disease J Winfield MB MRCP R R Dounnashkin MD J M Gumpel BM FRCP Rheumatic Diseases Study Group, and Division of Electron Microscopy, Northwick Park Hospital and Clinical Research Centre, Harrow HA] 3UJ
Whipple's disease is a multisystem disorder which may present with features remote from the gastrointestinal tract. We describe a patient in whom arthropathy, personality change and neurological involvement were the principal features. The diagnosis of Whipple's disease, previously suspected, was delayed by a negative small-bowel biopsy but when the gastrointestinal symptoms became manifest, a positive biopsy with all the characteristic features of the disease was obtained. Several biopsies may need to be taken before Whipple's disease can be excluded. A man of 58 presented in 1975 to hospital with a 12-year history of migratory joint pains affecting knees, ankles and shoulders. He complained of pain and stiffness in the metacarpophalangeal and proximal interphalangeal joints of both hands and had noticed swelling of the left wrist. For eighteen months he had felt depressed and had lost 6 kg in weight over this time. He was otherwise fit and worked full-time as a sheet metal worker. In 1953 and 1955 he had been treated with carbimazole for thyrotoxicosis. He smoked 30 cigarettes a day and had a productive cough. He was a thin man who looked older than his years. He weighed 51.5 kg, height 1.78 m. The only abnormal physical signs were restricted lumbar spine movements and synovial swelling over the dorsum of the left wrist. He was seen regularly in outpatients as a case of seronegative polyarthritis. The only abnormal laboratory test was a persistently elevated ESR, usually 50100 mm in 1st hour (Westergren). The arthralgia, joint stiffness and occasional joint swelling responded well to non-steroidal anti-inflammatory drugs and no erosive changes were seen on serial radiographs. There was no weight loss between 1975 and 1976 nor any abdominal symptoms or diarrhoea. In February 1976 he complained of increasing lethargy and depression and of impotence for the first time. As no endocrine or neurological cause for the impotence could be found, and as there had been marital disharmony over many years, this was considered probably psychogenic. In November 1976 he was admitted to hospital after collapsing at home. He had become giddy and disorientated whilst returning from work and had noticed increasing weakness of his left arm and leg over one hour. On examination he had a left hemiplegia and a mild left seventh cranial nerve palsy; the other cranial nerves were normal. There were no other relevant signs and he was normotensive. An isotope brain scan showed an area of increased uptake in the right inferoposterior parietal region consistent with a vascular lesion; a CAT brain scan was normal, as was the cerebrospinal fluid. The ESR was elevated at 52 mm in 1 st 1 Case presented to Clinical Section, 21 July 1978. Accepted 1 August 1978
0141-0768/79/110859-05/$01.00/0
C-1 1979 The Royal Society of Medicine
860
Journal of the Royal Society of Medicine Volume 72 November 1979
hour. Over several weeks he made an almost total recovery, but developed episodic attacks of acute breathlessness particularly when he was anxious, and a soft apical systolic murmur was transiently audible. No cause could be found for these features and in particular there was no evidence of cardiorespiratory disease. Further investigations as an inpatient were carried out to elucidate the cause of his chronic illness. Polyarteritis nodosa, a bronchogenic carcinoma or other neoplasm, and Whipple's disease were all considered but were not supported by positive findings, nor was there evidence of weight loss. Two attempts to perform jejunal biopsies with a Crosby capsule were technically unsuccessful. A small-bowel biopsy (Dr A J Levi) was obtained endoscopically (Figure 1). There was no evidence of Whipple's disease. No firm diagnosis could be made at this stage.
Figure 1. Sections of small bowel biopsy. The initial small bowel biopsy taken 1 year before that in Figure 2. Multiple levels of this biopsy were examined but no evidence of Whipple's disease was seen. PAS. x 110
Figure 2. Small bowel biopsy taken in February 1978. This shows classical appearance of Whipple's disease with lamina propria filled with darkly staining PASpositive macrophages that are distorting the villous pattern (Dr A B Price). PAS. x 110
During 1977 his health deteriorated, with marked personality changes. He felt tired and lethargic, worthless and withdrawn. He resented company at home and became aggressive and hostile towards his family and friends, with emotional lability and depression. A psychiatric opinion was sought (Dr T J Crow). It was considered that the personality changes were entirely consistent with organic cerebral disease, possibly exacerbated by his cerebrovascular accident, and that the affective changes appeared to be secondary to that disease. Tricyclic antidepressants were tried with no effect; attendance at a psychiatric day hospital produced a marked improvement in his mood. Later he became slightly ataxic, with a prolonged relaxation phase to tendon reflexes. He staggered to the left and Romberg's test was positive. No other sensory or cerebellar signs could be elicited. There had been, up to this time, a substantial improvement in his hemiplegia and his ataxia was considered to be unrelated to this. Investigations, including a further CAT brain scan, were inconclusive. Hypothyroidism was considered but not substantiated biochemically. Endocrinological investigations, including thyroid function tests, a synacthen
Journal of the Royal Society of Medicine Volume 72 November 1979
861
test and cortisol estimations, and biochemical tests were all normal. His stools appeared normal, and a xylose absorption test showed minor abnormalities only. Prednisolone was started empirically in a dosage of 20 mg a day, in the hope of improving his general state; there was no improvement over four months. In November 1977 he was readmitted to investigate a history of painful swallowing, and a dull abdominal pain in the epigastrium and right iliac fossa. There was no weight loss and during observation in the ward there was no abnormality in the stools, and all symptoms cleared. Another barium meal and follow-through showed no
change from previous barium studies. In February 1978 he became cachectic, with diarrhoea, and had lost 8 kg in weight. On examination, the abdomen was distended and diffusely tender, but there was no lymphadenopathy, arthritis or pleural effusion. Gross steatorrhoea was noted for the first time. A barium meal and follow-through examination showed a widespread malabsorption pattern. The faecal fat content was 11.8 grams per 24 hours. Endoscopy was repeated, and an endoscopic small bowel biopsy now showed the typical appearance of Whipple's disease (Figure 2). Electron microscopy of the biopsy specimen showed large numbers of bacteria, almost entirely confined to the lamina propria. The bacteria were bacilli, 200 nm x 1000 nm, and possessing a distinct capsule external to the cell wall (Figure 3). The bacteria were mostly extracellular but some organisms in a partial state of digestion were seen within macrophages (Figure 4). These macrophages were present in large numbers and corresponded to the PASpositive-stained cells seen by light microscopy. Some of the macrophages contained partially digested organisms but most of them were filled with cell walls (Figure 5). These cell walls were identical to those seen in the viable organisms except that none of the capsular material or cytoplasm of the organisms remained. The mucosa of the jejunum appeared almost completely normal, except for very few bacilli. HLA typing (Dr D C 0 James) was 2, 9(?23), 5,7. Treatment was started immediately, with correction of his dehydration and electrolyte depletion. Liquid glucose and a synthetic low-residue diet were used to increase his calorie intake. Tetracycline was given orally in a dose of 2 grams per day, and later metronidazole was added. His clinical improvement has not continued after the improvement of the first two months. His weight has increased by 6 kg. Depression remains a major factor, and the longterm prognosis remains in doubt.
Discussion
Patients with Whipple's disease may lack intestinal symptoms or develop these only as a late manifestation of the disease. Maizel et al. (1970), reviewing 114 cases of Whipple's disease, determined that 5% lacked weight loss, 22% lacked diarrhoea, and 40% lacked abdominal pain. Although a thin man, our patient denied any abdominal symptoms and did not lose weight over a two-year observation period. The major symptoms of diarrhoea, weight loss and abdominal pain appeared late in the course of his disease and it was at this time that a positive small bowel biopsy was obtained. Moorthy et al. (1977) have stressed that the intestinal lesion may be patchy and that multiple biopsies may need to be taken. Our initial normal biopsy did not exclude Whipple's disease, and it is likely that the endoscopic biopsy may have been obtained too high to show changes of Whipple's disease. Two small-bowel barium contrast studies carried out between 1975 and 1977 showed dilated and thickened duodenal and jejunal mucosal folds. Although nonspecific, these are the most common radiographic changes in Whipple's disease (Blum & Nathan 1959). Only in November 1977 was a marked malabsorption pattern apparent. The occurrence of arthritis in Whipple's disease is well documented (Kelly & Weisiger 1963, Delcambre et al. 1974). The ankles, wrists, knees and shoulders are the commonest joints to be affected, and several joints may be clinically involved over one or two days and rapidly resolve (Caughey & Bywaters 1963). Arthritis may precede the gastrointestinal symptoms by many years and the 12-year history of arthritis in our patient is not unusual. Synovial thickening and swelling were noted over the dorsum of the left wrist on several occasions but disappeared rapidly before a biopsy could be arranged. Synovial biopsy may be
862
Journal of the Royal Society of Medicine Volume 72 November 1979
Figure 4. Macrophages in lamina propria with intracellular and extracellular bacilli present. The intracellular bacilli are in the process of degradation x 2700
Figure 3. High magnification of bacilli in the lamina propria. x 33 850
Figure 5. Macrophages containing large num_
1
_
C
of cell walls x 8700 ~~~~~~~~~~~~~~~bers
diagnostically helpful, as Hawkins et al. (1976) detected, by electron microscopy, rod-shaped organisms in the synovial membrane identical to those present in the jejunal mucosa of a patient with Whipple's disease. Cardiac involvement in Whipple's disease is relatively common. Systolic murmurs or pericardial friction rubs may be audible during the course of this illness, and adhesive pericarditis and valvular deformity with vegetations, particularly on the mitral valve, may be apparent at post-mortem. The changes resemble those seen in chronic rheumatic heart disease but PAS-positive macrophages have been detected in the pericardium, myocardium and valves of such patients (McAllister & Fenoglio 1975). The intermittent soft systolic murmur detected in our patient may well have been due to mitral valve vegetations. Marked distortion of the mitral valve may also have occurred, since echocardiography showed markedly reduced excursion rates of the mitral valve leaflets. Histological involvement of the central nervous system is common in Whipple's disease and
Journal of the Royal Society of Medicine Volume 72 November 1979
863
microscopic foci of PAS-staining histiocytes have been found in many areas of the brain and spinal cord. Clinical manifestations of neurological involvement are, however, uncommon. Progressive dementia, intellectual impairment, visual disturbance, myoclonus and ophthalmoplegia have all been reported (Pallis & Lewis 1974). Our patient displayed a progressive and marked personality change with mental dullness, apathy, aggression and emotional lability. Most of these changes antedated his cerebrovascular accident and were probably secondary to diffuse cerebral infiltration with PAS-staining histiocytes. In addition, gliosis and neuronal loss in the cortex may occur, as observed by Lampert et al. (1962). Some of the affective changes, however, may have been secondary to the severity of his systemic disease. His right hemisphere cerebrovascular accident can probably be attributed directly to Whipple's disease, since PAS-positive material has been detected within small cerebral blood vessels (Smith et al. 1965, Caughey & Bywaters 1973). Moreover, the report of PAS-positive endocardial vegetations in 32 of 94 autopsied cases of Whipple's disease (Enzinger & Helwig 1963) suggests the possibility of an embolic vegetation being the cause of his stroke.
Acknowledgements: We are grateful to our colleagues who have contributed to the diagnosis and management of this case. References Blum L & Nathan H (1959) Southern Medical Journal, 52, 1428 Caughey D E & Bywaters E G L (1963) Annals of the Rheumatic Diseases 22, 327 Delcambre B, Lenz J, Leonardelli J, Paris J C, Mairesse M & Robert D'Eshouges J (1974) Semaine des hopitaux de Paris 50, 847 EnAzinger F M & Helwig E B (1963) Virchows Archivfur pathologische Anatomie 336, 238 Hawkins C F, Faff M, Morris C J, Hoare A M & Williamson N (1976) Annals of the Rheumatic Diseases 35, 502 Kelly J J & Weisiger B B (1963) Arthritis and Rheumatism 6, 615 Lampert P, Tom M I & Cumings J N (1962) Neurology (Minneapolis) 12, 65-71 Maizel H, Ruffin J M & Dobbins W 0 (1970) Medicine 49, 175-205 McAllister H A & Fenoglio J J (1975) Circulation 52, 152 Moorthy S, Nolley G & Hermos J A (1977) Gut 18, 152-155 Palis C A &.Lewis P D (1974) The Neurology of Gastrointestinal Disease, Saunders, London; pp 207-214 Smith W T, French J M, Gottsman M, Smith A J & Wakes-Miller J A (1965) Brain 88, 137-150
