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Ulcerative Colitis in Children: Problems in Management
Ulcerative Colitis in Children Problems in Management
WILLIAM M. MICHENER, M.D.
A symposium on pediatric gastrointestinal problems would not be complete without a discussion of ulcerative colitis in childhood, since the cause of this disease continues to remain obscure and the program of management debatable. Progress both in the medical and in the surgical management of ulcerative colitis in children has been definite, but in the absence of knowledge of a specific cause, therapy must be highly individualized and must be considered nonspecific. It is beyond the scope of this paper to present an exhaustive review of the literature on ulcerative colitis; the purpose is to present an approach to therapy and to discuss some of the problems in the management of a child with ulcerative colitis. In 1923 Helmholz5 described ulcerative colitis occurring in childhood. Since that report, many others 6, 8, 9, 13, 19 have documented the occurrence of this disease in the child. Several authors 3, 4, 13 report the onset of ulcerative colitis in infancy, but the usual onset of symptoms occurs from age eight to fifteen years. 4 The disease is slightly more common in the male. It occurs infrequently in the lower socio-economic groups and rather frequently in middle-income families. This difference is readily evident when comparing the number of patients admitted to a city or county general hospital to the number seen in a university or referral medical institution. The familial occurrence of the disease is known. 1 In the Cleveland Clinic series of 125 children with ulcerative colitis, the disease occurred in a close relative (parent or brother or sister) in eight families. Investigation into the cause of ulcerative colitis has been both varied and extensive. To date the origin remains obscure. Infection, hypersensitivity, psychogenic factors, geographic location, socio-economic factors, nutritional deficiency, inherited enzymatic error, and neurogenic imbalance have all been evaluated as factors related to the cause of this disease. Davidson, Bloom and Kugler3 recently reviewed these factors in an From the Department of Pediatrics, The Cleveland Clinic Foundation, Cleveland, Ohio.
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excellent report. The relation of hypersensitivity and autoimmunity to the pathogenesis of ulcerative colitis has been summarized by Kirsner10 and by Broberger2 as well. Pathology
Present information indicates that the pathologic abnormalities associated with ulcerative colitis in children are the same as those in adults. 14 • 15. 21 This disease involves a destructive process producing gross ulcerations of the mucosa and an inflammatory reaction of the underlying supporting structures. Suction biopsy of the rectal mucosa has given us pathologic specimens from children in early stages of the disease. In one case associated with arthritis, erythema nodosum and no bowel symptoms, the proctoscopic examination was normal, but the suction biopsy specimen revealed an inflammatory cellular infiltration of the lamina propria. Three months later, diarrhea and typical proctologic signs of ulcerative colitis developed. Frequently associated with the cellular infiltration of the lamina propria mucosae are crypt abscesses. These changes may be nonspecific, but the experience at the Cleveland Clinic indicates that their occurrence in conditions other than ulcerative colitis is unusual. As the inflammatory process becomes extensive, the entire wall of the bowel is penetrated. When the disease becomes chronic, and healing of the colon begins to occur, scarring and contracture of the bowel ensue. Recently Hawk (personal communication) reviewed the pathologic material available from Cleveland Clinic patients with ulcerative colitis. Approximately half of these patients had pathologic changes suggestive of granulomatous colitis (Crohn's disease of the colon). This study is being extended into the pediatric patient group, and it is hoped that correlation between the clinical course and the pathologic changes in the colon in these patients will increase our information on inflammatory bowel disease in children. This differentiation is particularly important with reference to the development of carcinoma of the colon later in life, since the risk appears to be much less in the patient with granulomatous colitis than in the patient with ulcerative colitis. To date, it appears that granulomatous colitis in the extremely young is rare. Diagnosis Perhaps the main problem of this disease in childhood is establishment of the diagnosis early when the pathologic changes and symptoms are mild. When symptoms are mild and of short duration, the disease is better controlled by a medical program17 than when they are severe and chronic. The diagnosis of ulcerative colitis in children is not difficult to establish when the physician knows that the initial symptom in a child having this disease, with its extracolonic complications and systemic
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Table 1.
Presenting Complaints
PRESENTING COMPLAINT
Diarrhea ....... . Rectal bleeding ... . Weight loss ........ . Arthritis ........... . Growth failure ........ . Erythema nodosum .... . Anemia ............... . Pyoderma gangrenosum .. . Abdominal pain ....... . Total . ............. .
if Ulcerative
Colitis in Children NO. OF PATIENTS
.................. 67
26 12 5 3 2 3 1 6 .. 125
effects, is not always diarrhea. The presenting complaints of children seen at the Cleveland Clinic with ulcerative colitis are listed in Table 1. Too often when a child has a record of weight loss, retardation of growth, or of arthritis, a good history of bowel habits is not obtained. As most pediatricians know, children do not freely communicate their everyday bowel habits, and it is only through careful questioning of the child that a history of rectal bleeding or mildly loose bowel movements suggestive of early ulcerative colitis can be discovered. The duration of symptoms before the establishment of diagnosis is highly variable. Some children seem to have a typical acute gastrointestinal upset with diarrhea as their first symptom. Other children have vague complaints such as intermittent, mild abdominal cramps before the passage of a stool, occasional loose bowel movements or the passage of a formed stool with mucus and blood on the outside, for as long as one or two years before the onset of diarrhea. Several patients had arthritis and fever two or three years before the onset of diarrhea. Constipation associated with the occasional passage of bloody mucus on the exterior of a hard stool occurred one year before the onset of diarrhea in several patients. Failure to grow, persistent arthritis, pyoderma gangrenosum, erythema nodosum, unexplained anemia, weight loss and abdominal pain, alone or in any combinations with or without diarrhea, have occurred in children with ulcerative colitis. These symptoms alone do not suggest bowel disease unless the physician is aware of the extracolonic complications and systemic manifestations of the disease. Physical examination of the child suspected of having ulcerative colitis does not confirm the diagnosis. The nonspecific signs of a chronic illness such as weight loss, muscle wasting and pallor are sometimes seen. If the disease is of short duration, the child may appear well. In the ill-appearing child the abdominal examination may reveal a distended abdomen, and bowel sounds may be reduced or absent. When present,
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these signs indicate dilatation of the colon ("toxic dilatation") with perforation or impending perforation. The digital rectal examination is done at the time of proctologic examination. Examination of the anus and rectum by direct visualization frequently confirms the diagnosis of ulcerative colitis, and therefore is mandatory in all children suspected of having this disease. The technique and findings have been described in a previous report.17 As mentioned earlier, biopsy of the rectal mucosa may be diagnostically helpful in the patient who has minimal proctologic signs. Proctologic examination should also be utilized in evaluating the response to therapy. Roentgen examination of the barium-filled colon establishes the diagnosis of ulcerative colitis. 7 , 17 The success of this procedure depends on the interest of the radiologist and the preparation of the child. Good cleansing of the bowel is needed, but vigorous catharsis will often aggravate the colitis, if present. Complete explanation of the procedure to the child usually assures cooperation. Progress studies are needed, but occasionally will also initiate the onset of diarrhea. A frequent problem is that cleansing of the colon is incomplete, and the radiologist will interpret the evidence as that of a normal colon with poor preparation. When the colon is poorly prepared, the study is misleading because the early destructive changes of mucous membrane are not seen. When thp, disease is chronic, with periods of activity and of healing, the radiologist readily recognizes the narrowed, shortened bowel. An Approach to Therapy A detailed program for the medical therapy of the child with ulcerative colitis was published in 1964. 18 This program is outlined below. Again it must be emphasized that therapy is nonspecific and is designed to relieve symptoms, and hence must be planned for the individual child. 1. Hospitalization is recommended, since results seem to be better when the initial therapy begins in the hospital. A tranquilizer such as chloridazepoxide hydrochloride (Librium "') is usually given the child. 2. When diarrhea is profuse, a low-residue diet is administered initially, with rapid progression to a normal diet in three to five days. Frequently a restricted diet annoys the child, and this results in his refusal to eat. 3. Correction of anemia and blood electrolyte abnormalities with appropriate intravenous solutions and whole blood is done quickly. This alone often improves the general well-being of the child. 4. Antimotility agents, usually diphenoxylate hydrochloride with atropine sulfate (Lomotil '" "') or hyoscyamine sulfate, atropine sulfate, hyoscine hydrobromide, phenobarbital, kaolin, pectin, and opium U.S.P. "Roche Laboratories. G. D. Searle Co.
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(Donnagel-PGO), in adequate doses will rapidly decrease frequency of bowel movements and abdominal cramping. 5. SalicylazosuI£apyridine (Azulfidinef), from 4 to 8 Gm. daily, is also given to all patients. Initially a small child may have difficulty in swallowing these pills, but usually a patient nurse can overcome this problem. 6. Methylprednisolone acetate (Depo-MedroIO retention enemas are given to all patients as soon as the decreased frequency of diarrheal stools permits. The enemas are given nightly while the child is hospitalized and then usually every other night or three times a week for several weeks after discharge. Children seem to tolerate this procedure well. 7. A therapeutic vitamin supplement (Surbex with C) is given to all patients. 8. A close relation with the parents and child is established initially. While in the hospital and as the child improves, this relationship grows. These children frequently have the emotional problems common to any child with a chronic illness. Usually there has been insufficient education about their disease, along with the failure to recognize the child as a person. Frequently the parents' fears and overcompulsive attitudes in regard to the treatment create hostility and distrust in the child. A positive approach with frequent visits to the bedside by the physician is an important part of the therapy. With this program the disease will be controlled in about 50 per cent of children. Therapy should be continued for six to 12 months after the establishment of normal bowel habits. In the other children, adrenocorticotropin (ACTH), steroids given orally or surgical treatment is needed for adequate therapy. Steroids given orally as a part of the medical program are used infrequently. Problems in Therapy Six case histories have been selected to illustrate some of the problems faced in the care of the child with ulcerative colitis. The natural history of the disease is variable, and hence the response to medical therapy may be misinterpreted by the patient and the physician. 1l • 12. 20 The patient and his family must be reminded that therapy is nonspecific and directed toward relief of symptoms as long as the specific cause of the disease is not known. The role of surgery in the therapy of a child with this illness is important. A surgical procedure has too often been withheld too long from many children seriously debilitated from the colonic and extracolonic effects of this disease. The .. A. H. Robins, Co., Inc. t Pharmacia Laboratories, Inc. t The Upjohn Company.
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physician and the family of the child must accept the fact that a surgical procedure will almost always make the child healthy again. CASE 1. A 14-year-old girl was first examined at the Cleveland Clinic in July 1962 at the age of 10 years, because of intermittent diarrhea for five years. Her mother stated that "about 50 per cent of the time" her daughter had two or three loose watery bowel movements a day. She attended school regularly and lived normally. Findings on roentgen examination of the barium-filled colon were reported as normal. Results of a proctoscopic examination were also reported as normal, except that microscopic examination of the mucus in the colon revealed a few pus cells. No biopsy specimen was obtained. The patient was discharged from care with no therapy prescribed and was requested to return in six months if the diarrhea persisted. In March 1966, because of abdominal pain persisting for one week, an appendectomy was performed at another hospital. The appendix was reported as normal, and no report of other abdominal findings was made. On April 18, 1966, because postoperatively there was persistent abdominal pain, she returned to the Cleveland Clinic. She stated that during the last four years she had "never had a normal bowel movement" and had three or four loose watery bowel movements a day. She had attended school regularly, had grown 10 inches in height and had gained 37 pounds during those four years. Roentgen examination of the barium-filled colon revealed evidence of ulcerative colitis of the transverse, descending and sigmoid colon. Proctoscopic examination revealed a normal colon as far as 10 cm.-inches. She was admitted to the hospital, and a medical program consisting of regular diet, Azulfidine, Lomotil, Librium, vitamins and methylprednisolone acetate retention enemas was started. After two weeks she was having one formed stool a day; she was discharged from the hospital. Progress examination indicated continuance of well-being, and normal bowel habits.
Comment: Natural History of Ulcerative Colitis. This case points out certain inconsistencies and difficulties in evaluating the child with diarrhea. This girl had diarrhea for nine years, yet she felt well, attended school regularly, and grew normally. From outward appearances she was a healthy girl. The disease process in the colon was most likely present for nine years, but after five years the roentgenogram of the colon was normal and after four more years revealed changes of extensive ulcerative colitis, yet the patient had no change in symptoms during the entire nine years. Often the extent of the disease as estimated from the clinical symptoms and signs differs considerably from the extent of the disease as seen on barium studies of the colon. Therefore careful and prolonged follow-up is important and can be done only by proctologic and roentgenologic examination of the colon. Another inconsistency is the ease of control of the diarrhea by medical therapy. If a colon has been diseased for nine years, I would not expect the diarrhea to be easily controlled, yet within two weeks the patient was having one formed stool a day and has continued for three months with normal bowel movements. Certainly the history of this child (and others) makes one wonder how long the pathologic process exists before the diagnosis can be established clinically.
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CASE 2. Three weeks before admission to the Cleveland Clinic Hospital a 15-year-old white girl had loose watery stools three or four times a day. During the three weeks of illness she lost 20 pounds. Five days before hospitalization, nausea and vomiting developed. These symptoms continued, and on the day of admission to the hospital she passed approximately 300 m!. of bright red blood rectally. Her medical history disclosed no serious illnesses. The physical examination revealed an acutely ill, pale, restless girl who was having generalized abdominal pain. The abdomen was minimally distended with diffuse tenderness and voluntary guarding in both lower quadrants. The bowel sounds were hypoactive, but present. Bright red blood leaked from the anus. An abdominal survey roentgenogram revealed distention of the left and transverse colon with small amounts of air in the small intestine, She was started on therapy consisting of electrolyte solutions intravenously, Chloromycetin, Lomotil, ACTH intravenously and methylprednisolone acetate retention enemas. A total of 2500 mI. of whole blood was given intravenously over the next four days. She continued to have abdominal cramping, and lost approximately 300 to 500 mI. of blood rectally each day. Five days after admission to the hospital she had not improved, and the abdomen was increasingly distended and tender. Perforation of the colon was believed to be imminent, and operation was recommended. Under anesthesia, sigmoidoscopy revealed normal colonic mucosa for 16 cm.-inches. Exploratory laparotomy revealed the colon to be dilated and hyperemic. The terminal ileum showed evidence of severe ileitis, Six centimeters of ileum and the entire large bowel except 16 cm. of rectum were resected, and an ileorectal anastomosis was made. During the procedure 1000 ml. of whole blood was administered. The postoperative period was uneventful, and she was discharged from the hospital 12 days after operation, with instructions to eat a regular diet, to take Lomotil, 2.5 mg. three times a day orally, and to receive ACTH gel, 20 units intramuscularly twice weekly for three months. Re-evaluation 15 months after operation revealed a healthy girl who has gained 25 pounds and is having three to four formed stools a day. The proctologic examination was normal.
Comment: Acute Onset, Hemorrhage, Dilatation of the Colon and Failure of Medical Therapy. In contrast to the girl in case 1, this girl had a sudden onset of diarrhea with a rapid progression of the disease. Within three weeks after the onset of diarrhea rectal hemorrhage and dilatation of the colon developed. Replacement of blood losses, intravenously administered ACTH and other supportive measures failed to halt the pathologic process. Abdominal distention and tenderness associated with hypoactive bowel sounds has been termed toxic dilatation. Careful observation of the child with these signs is needed. Failure to improve or evidence of deterioration of the patient's general condition, such as a rising pulse rate or leukocyte count, or the appearance of fever or increasing abdominal tenderness, makes surgical intervention mandatory. If perforation of the colon occurs, the operative risk is greatly increased. One of two deaths in the Cleveland Clinic series of patients was that of a girl who was transferred from another hospital, with a perforation of the colon. She died of sepsis. In case 2 the acute onset of symptoms and freedom of the rectum from disease provided excellent conditions for ileorectal anastomosis.
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WILLIAM M. MICHENER
To date the patient has done well, and only time will answer the effectiveness of this approach to the ulcerative colitis. Perhaps in children this may be the operation of choice. CASE 3. At the age of seven years a boy had his first episodes of bloody diarrhea. Intermittent episodes of loose, watery bowel movements that contained blood continued for the next 18 months. The diagnosis of ulcerative colitis was established by proctoscopic examination. On two occasions he was hospitalized to receive blood transfusions. In October 1964, two years after the onset of diarrhea, severe diarrhea with abdominal cramping and profuse rectal hemorrhage developed. He was hospitalized for seven weeks, and was treated with steroids orally, intramuscular injections of ACTH, Azulfidine and a low-residue diet. After seven weeks of therapy in the hospital he was transferred to the Cleveland Clinic Hospital. On admission the examination revealed a chronically ill-appearing boy who was quite pale. Tenderness to palpation was present in both lower quadrants of the abdomen. The blood hemoglobin content was 5.5 gm. per 100 mI., and the hematocrit reading was 21. Proctoscopic examination revealed granularity of the entire rectum, and oozing of blood from all mucosal surfaces visualized. He was given 1500 ml. of whole blood intravenously during the next seven days. Azulfidine, ACTH intramuscularly, Lomotil, Donnagel-PG, vitamins and methylprednisolone acetate retention enemas were administered daily. After two weeks of therapy the stools were formed and contained no blood, and the proctoscopic examination revealed normal rectal mucosa except for slight granularity. Administration of retention enemas was continued three times a week for three months, and of Azulfidine and Lomotil for 12 months after discharge from the hospital. Roentgen examination of the barium-filled colon, and proctologic examination, were interpreted as normal one year after the institution of therapy. The progress of the patient has now been followed for 20 months since the first examination. He has had four episodes of loose bowel movements mixed with bloody mucus, lasting from three to five days. He has not been ill with these episodes and had perfect attendance at school this year.
Comment: Recurrent Bloody Diarrhea. Intermittent episodes of bloody diarrhea, not persistent diarrhea, have been the prominent clinical symptoms in this boy. A medical program seems to have controlled the disease or possibly initiated a spontaneous remission. As has been pointed out by others,3 the children with intermittent symptoms seem to respond to medical therapy when exacerbation of symptoms occurs. These children also have fewer extracolonic complications than do those with persistent diarrhea. Certainly when the clinical history indicates intermittent symptoms, a vigorous and prolonged medical program i s indicated. CASE 4. The patient at the age of one year began to have frequent (from five to 10 a day) foul-smelling, frothy stools. He was one of identical twins and had been in good health until the onset of diarrhea. At 15 months of age medical evaluation revealed no cause for the symptoms. During the next three years he was given trials of a variety of elimination diets and antimotility drugs. The bowel habits did not return to normal, but a gradual change in the type of stool occurred. The feces became more watery, contained mucus, and frequently were blood-tinged. During this period of three years his growth was much less than that of his twin.
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In November 1960, at age four years, he was first examined at the Cleveland Clinic because of persistent diarrhea. Many laboratory tests and roentgen examinations were reported normal. Proctoscopic examination revealed mucuscontaining pus, but was thought not to be diagnostic of ulcerative colitis. A strict gluten-free diet was prescribed, and he was discharged from the hospital. Three months later he returned with his mother, who reported that after an initial decrease in diarrhea for two weeks, the diarrhea had returned and persisted. He was readmitted to the hospital. Proctoscopic examination revealed extremely friable mucosa that bled freely when swabbed. A mucosal biopsy specimen was interpreted as showing leukocytic infiltration of the lamina propria, and crypt abscesses. Roentgen examination of the barium-filled colon also revealed, for the first time, the changes of ulcerative colitis. A program was prescribed consisting of a low-residue diet initially, Azulfidine, Lomotil, vitamins, methylprednisolone acetate retention enemas nightly and iron to be taken orally. Within two weeks the bowel movements were formed, contained no blood, and occurred once or twice a day. This program was continued for five months (except the methylprednisolone acetate retention enemas, which were stopped after 10 nightly administrations), and the child did well. In early August 1961, the twin brother had a severe influenza-like illness with fever, vomiting and diarrhea, lasting three days. Two days later the same symptoms developed in the patient. He did not recover from this illness and on the fifth day was readmitted to the Cleveland Clinic Hospital. Again the complete medical program listed above was instituted, and he slowly improved over the next two weeks, but continued to have two to four semiformed stools a day. During August, September, October and early November he was improved, but not cempletely well. On November 20, 1961, fever again developed, with abdominal cramps and frequent loose bowel movements. He was readmitted to the hospital on November 29, 1961. Despite therapy that included the program above, intravenous injections of ACTH and Decadron orally, profuse diarrhea continued, as did the fever and loss in weight. On the ninth hospital day an abdominal survey roentgenogram revealed dilatation of the entire colon. The leukocyte count was 21,600 per cubic millimeter, with 85 per cent polymorphonuclear leukocytes. A subtotal colectomy and ileostomy with retention of the rectal stump was performed. The postoperative period of recovery was uneventful. During the next eight months the patient did well and gained 15 pounds. In August 1962, vomiting and abdominal pain recurred. Exploratory laparotomy revealed an intestinal obstruction secondary to adhesions; lysis of the adhesions was performed. After this operation there were no further symptoms. He gained weight, ate well, and lived a normal life. In June 1965 he was readmitted to the hospital for reanastomosis of the ileum to the rectum; this was performed on July 10, 1965. Since then he has had three or four formed stools a day, has gained 10 pounds and continues to be quite normal. He is now the same height and weight as his twin brother.
Comment: Surgery in the Young Patient. The management of this boy's condition offered a unique opportunity, since an identical twin was always available for comparing the effects of the disease and therapy on growth and development. From the time of onset of diarrhea until subtotal colectomy was performed the patient was behind his twin in growth. After the establishment of the ileostomy and subtotal colectomy, he grew rapidly, and soon equaled his twin in height and weight. This
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MICHENER
Figure 1. A, Pyoderma gangrenosum lesion on the right ankle before operation (ileostomy and subtotal colectomy). B, The same lesion 7 weeks after ileostomy and subtotal colectomy.
has been our experience with almost every patient operated on in the early years. If the surgical procedure is not performed until the patient is 15 to 20 years of age, and growth in height is below the third percentile, these patients will not regain their normal expected height, but will usually grow a few inches. When puberty is delayed secondary to the extracolonic effect of the disease, removal of the diseased colon will usually allow the physical changes associated with puberty to begin in six to 12 months after operation. This is particularly true of girls in regard to the onset of menses. After three years of excellent health with an ileostomy, an ileorectal anastomosis was performed. The operation and postoperative course were uneventful. It is now one year after the ileorectal anastomosis, and the patient is healthy and has three or four formed stools a day and one at night. Again, only time will allow a long-term evaluation, but I wonder whether or not, in the young patient, a primary operation consisting of subtotal colectomy with ileostomy, then a delayed period to allow recovery from the effects of the disease before a second procedureileorectal anastomosis-is performed, may be a highly satisfactory therapeutic answer to the child with ulcerative colitis who needs surgical treatment. CASE 5. In July 1963, at the age of 10 years, a boy had the onset of migratory joint pains and swelling. Several days after the onset of the joint swelling, a purpuric rash developed over the lower extremities. He was admitted to a hospital, and a diagnosis of acute rheumatic fever was made by the family physician. While hospitalized he had three or four watery bowel movements a day, attributed to the side effects of ingested penicillin and aspirin
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preparations. The swelling and pain in the joints subsided. During August and September he continued to have almost daily loose watery bowel movements. The purpuric rash over the lower extremities varied in intensity, but never disappeared completely. During the winter of 1963-1964 the diarrhea became a problem, and in May 1964 the child was readmitted to the hospital and a diagnosis of "infectious colitis" was made. In June 1964 he was admitted to a children's hospital where the diagnosis of ulcerative colitis was established. Prednisone, Lomotil and vitamins were prescribed. During the next 12 months the diarrhea subsided, the purpuric rash disappeared completely, and he enjoyed good health. In August 1965 a large, weeping ulcerous lesion developed over the right medial malleolus. The prednisone was discontinued, but three days later pain and swelling in the left ankle and left knee developed, and an oral temperature of 104°F. At this time administration of prednisone was restarted, and he was transferred to the Cleveland Clinic Hospital. The family history is significant in that one maternal grandaunt is said to have ulcerative colitis. On admission to the hospital this boy appeared pale, chronically ill and wasted, and had the facies secondary to excessive cortisone administration. He was 57% inches tall and weighed 86 pounds. A large ulcer 3 inches in diameter covered the right medial malleolus; the surrounding skin was edematous and erythematous (Fig. 1). Multiple, deep punctate draining points were in the ulcer, and it was thought that this lesion was typical of pyoderma gangrenosum. There were no purpuric lesions. The abdomen was obese, and an edge of the liver was felt 1Yz inches below the costal margin. The spleen was not palpable. No tenderness was present. There was no swelling of the joints. The other results of the examination were normal. Proctologic examination revealed patchy mucosal changes with granularity, friability and slight bleeding. A mucosal biopsy specimen revealed "chronic inflammation compatible with ulcerative colitis." Roentgen examination of the barium-filled colon showed a shortened colon, complete destruction of haustral markings from the hepatic flexure distally, and prominent pseudopolyposis in the transverse colon, de-
Figure 2. Roentgenogram of right ankle showing periosteal elevation of the bone underlying the pyoderma gangrenosum lesion.
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scending colon, and sigmoid. Roentgen examination of the left tibia and ankle revealed minimal periosteal elevation in the proximal third of the tibia. There was also an increase in periosteal tissue beneath the lesion of pyoderma gangrenosum over the right medial malleolus (Fig. 2) . It was the opinion of all the physicians who examined this boy that ileostomy and subtotal colectomy were indicated, but the parents refused permission to perform the operation. He was then started on a course of prednisone, 5 mg. three times daily to be decreased slowly over the next six weeks; ACTH gel, 40 units intramuscularly three times weekly; Lomotil, 2.5 mg. four times a day; methylprednisolone acetate retention enemas, 40 units nightly; Chloromycetin, 250 mg. three times a day for 14 days; and Wescodyne soaks for the ankle lesion. During the next 21h weeks he made no progress. The size of the ankle lesion seemed to increase, and the left knee became painfully swollen. At the end of three weeks' therapy at home the parents requested that operation be performed. The boy was readmitted to the hospital and on November 19, 1965, subtotal colectomy with ileostomy was performed. During the two weeks after operation the lesion of pyoderma gangrenosum healed remarkably fast. He was discharged from the hospital with the advice to continue to take ACTH gel, 40 units intramuscularly twice weekly, and Lomotil, 2.5 mg. four times a day. The boy continued to gain weight and felt well during the next three months. Four months postoperatively a renal calculus of calcium phosphate was passed. During the fourth and fifth postoperative months a hard swelling appeared over the upper left tibia. Roentgenograms of this lesion revealed periosteal elevation suggestive of an inflammatory or neoplastic process (Fig. 3). He was readmitted to the hospital and under general anesthesia underwent biopsy. The specimen revealed a chronic osteomyelitis that was sterile to culture. Blood cultures were also sterile. It was believed that this lesion was most likely of the same origin as the lesions of pyoderma gangrenosum in association with ulcerative colitis, but because of the biopsy report, antibiotic therapy was advised. He
Figure 8. Roentgenogram of right upper leg showing periosteal elevation and thickening of the adjacent cortex of the upper third of the tibia.
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was given intravenous injections of Staphcillin for ten days and Tego Pen orally, 250 mg. four times a day for six weeks. Three months later he no longer had pain while walking. The boy's weight had not changed, and he was attending school. No rectal discharge was present.
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Comment: Arthritis, Vascular Purpura and Pyoderma Gangrenosum. In this boy the extracolonic complications of arthritis, vascular purpura and pyoderma gangrenosum produced more disability than did diarrhea. The masking of the underlying disease by arthritis is not an uncommon occurrence, and, as in this patient, the diagnosis of rheumatic fever is made. Diarrhea mayor may not be present, and usually only direct questioning of the child will reveal its presence. The older the child is the less likely is it that the parents will have a detailed knowledge of the child's bowel habits. Pyoderma gangrenosum is a rare extracolonic complication of ulcerative colitis in children and, in the experience at the Cleveland Clinic, has occurred in only two patients less than 15 years of age. In each case the lesion was not affected by medical therapy of the disease, but disappeared rapidly after removal of the colon. The extracolonic complications of arthritis, vascular purpura and pyoderma gangrenosum occasionally regress with medical therapy of the diseased colon, but most often they persist or recur until the colon is removed. Dramatic healing of the lesions of pyoderma gangrenosum and disappearance of the arthritis and purpura after subtotal colectomy and ileostomy have occurred in all cases. Disease in the retained rectal stump has not caused the extracolonic complications to remain active, though hemorrhage from the retained rectal stump has necessitated its removal in two cases. Retention of the rectal stump is desirable, since it offers the patient, the parents and the physician the hope that an ileorectal anastomosis may be constructed in the future. The thought of a permanent ileostomy is difficult for many parents to accept, and their feelings are usually transferred to the child. Most children less than 12 years of age freely accept an ileostomy. Though there is a definite but small risk of development of carcinoma in the rectal stump, retention of the stump seems justified. The periosteal elevation beneath the lesion of pyoderma gangrenosum is secondary to the increased vascularity accompanying the lesion. The periosteal elevation on the anterior surface of the upper third of the tibia simulated a bone malignancy or osteomyelitis. Biopsy revealed osteomyelitis, but cultures from the bone and blood for bacteria and fungi were sterile. This type of lesion has not been seen in other patients with ulcerative colitis and may well be a pathologic process in bone not unlike a lesion of pyoderma gangrenosum. The passage of a renal calculus by patients with ileostomies occurred in 10 per cent of cases in one series. 16 This has been attributed to the occurrence of water and electrolyte abnormalities. The child of case 5 is the only child at the Cleveland Clinic who has had such a nroblem.
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CASE 6. In January 1966 an eight-year-old girl had the onset of loose bowel movements associated with low abdominal cramping and the passing of bright red· blood with each movement. After two weeks of diarrhea the stools again became formed, but for four weeks she continued to pass bright red blood with each bowel movement. In February she was brought to the Cleveland Clinic. During the entire six weeks of her illness she felt well, was afebrile, and attended school regularly. Roentgenograms of the barium-filled small intestine and colon were interpreted as normal. Proctoscopic examination revealed diffuse edema and granularity of the rectum for 4 inches above the dentate line. The mucosa bled freely when touched with a swab. Rectal biopsy revealed a lymphocytic and plasma cell infiltration of the lamina propria, as well as crypt abscesses. Therapy consisted of Azulfidine, Lomotil, Librium, a regular diet, and DepoMedrol enemas nightly (for 10 days, then every other night for three weeks). Three days after starting treatment the bleeding stopped. For the last four months she has had one normal stool, with no blood, daily.
Comment: Ulcerative Colitis Confined to the Rectum. Ulcerative colitis confined to the rectum and sigmoid colon is a more benign disease in all age groups than that extending throughout the colon. In a recent study of 124 patients (all ages) with this diagnosis seen at the Cleveland Clinic the principal symptom was rectal bleeding (R. G. Farmer and C. H. Brown: personal communication). In a follow-up study it was found that 20 patients had extension of the disease to a more proximal portion of the colon, and 10 required operations for colitis. This form of the disease is not common in children, but when present is more easily managed than when the entire colon is affected. CONCLUSION In this clinic I have attempted to emphasize the following points regarding ulcerative colitis in childhood. 1. The presenting symptoms of a child with this disease may be varied and not suggest bowel disease. An awareness of the extracolonic complications and systemic manifestations will usually aid in early diagnosis. 2. Frequently delay in diagnosis is secondary to the physician's hesitancy to order roentgen examination of the barium-filled colon and proctologic examination. 3. Early diagnosis is important, since the patient with mild disease of short duration seems to respond best to a medical program. 4. No two cases follow the same course, and the physician must be flexible in his approach to therapy. 5. The role of surgery in the therapy of this disease in childhood has not received proper recognition. A variety of surgical procedures is available and usually will make the child well. Ileostomy and subtotal colectomy with retention of the rectal stump effect a dramatic improve-
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ment in a chronically ill child. Children tolerate an ileostomy and continue to grow. If the rectum heals, an ileorectal anastomosis can be performed later when the child is healthy and there is less operative risk. Prolonged follow-up results are not yet available on a sufficient number of children WJ:lO have undergone this operation, but it is possible that this may be the procedure of choice for the child with ulcerative colitis who needs surgical treatment. REFERENCES 1. Barker, W. F.: Familial History of Patients with Ulcerative Colitis. Am. J. Surg., 103:25, 1962. 2. Broberger, 0.: Immunologic Studies in Ulcerative Colitis. Gastroenterology, 47: 229,1964. 3. Davidson, M., Bloom, A. A., and Kugler, M. M.: Chronic Ulcerative Colitis of Childhood. J. Pediat., 67:471, 1965. 4. Enzer, N. B., and Hijmans, J. C.: Ulcerative Colitis Beginning in Infancy. J. Pediat., 63:437, 1963. 5. Helmholz, H. F.: Chronic Ulcerative Colitis in Childhood. Am. J. Dis. Child., 26:418, 1923. 6. Hijmans, J. C., and Enzer, N. D.: Ulcerative Colitis in Childhood: Study of 43 Cases. Pediatrics, 29:389, 1962. 7. Hodgson, J. R, and Kennedy, R L. J.: Roentgenologic Aspects of Chronic Ulcerative Colitis in Children. Radiology, 65:671, 1955. 8. Jackman, R J., Bargen, J. A., and Helmholz, H. F.: Life Histories of 95 Children with Chronic Ulcerative Colitis: Statistical Study Based on Comparison with Whole Group of 871 Patients. Am. J. Dis. Child., 59:459, 1940. 9. Kirsner, J. B., Raskin, H. F., and Palmer, W. L.: Ulcerative Colitis in Children: Observations in Selected Patients. A.M.A. J. Dis. Child., 90:141, 1955. 10. Kirsner, J. F.: The Immunologic Response of the Colon. J.A.M.A., 191:105, 1965. 11. Korelitz, B. I., and Gribetz, D.: Prognosis of Ulcerative Colitis with Onset in Childhood. II. Steroid Era. Ann. Int. Med., 57:592, 1962. 12. Korelitz, B. I., Gribetz, D., and Danziger, I.: Prognosis of Ulcerative Colitis with Onset in Childhood.!. Pre-Steroid Era. Ann. Int. Med., 57 :582, 1962. 13. Lagercrantz, R: Ulcerative Colitis in Children. Acta Paediat. (Stockholm) (Supp.), 75:89, 1949. 14. Lumb, G.: Pathology of Ulcerative Colitis. Gastroenterology, 40:290, 1961. 15. Lumb, G., and Protheroe, R H. B.: The Early Lesions in Ulcerative Colitis. Gastroenterology, 33:457, 1957. 16. Maratka, Z., Nedbal, J., and Chytilova, D.: Disorders in Water and Electrolyte Balance Following Surgical Treatment of Ulcerative Colitis. I. Effect on Urolithiasis Development. (C2) Cas. Lek. Cesk., 104:1061, 1965. 17. Michener, W. M., Brown, C. H., and Turnbull, R B.: Ulcerative Colitis in Children. 1. Diagnosis. Am. J. Dis. Child., 108:230, 1964. 18. Idem: Ulcerative Colitis in Children. II. Medical and Surgical Therapy. Am. J. Dis. Child., 108:236, 1964. 19. Michener, W. M., and others: Prognosis of Chronic Ulcerative Colitis in Children. New England J. Med., 265:1075, 1961. 20. Platt, J. W., Schlesinger, B. K, and Benson, P. F.: Ulcerative Colitis in Childhood; A Study of its Natural History. Quart. J. Med. (new ser.), 29:257,1960. 21. Svartz, N.: Ulcerative Colitis: Changes in the Intestinal Walls and Therapeutic Considerations. J. Intemat. Call. Surgeons, 41-2:134, 1964. Cleveland Clinic 2020 E. 93rd St. Cleveland, Ohio 44106
WILLIAM M. MICHENER, M.D.
A symposium on pediatric gastrointestinal problems would not be complete without a discussion of ulcerative colitis in childhood, since the cause of this disease continues to remain obscure and the program of management debatable. Progress both in the medical and in the surgical management of ulcerative colitis in children has been definite, but in the absence of knowledge of a specific cause, therapy must be highly individualized and must be considered nonspecific. It is beyond the scope of this paper to present an exhaustive review of the literature on ulcerative colitis; the purpose is to present an approach to therapy and to discuss some of the problems in the management of a child with ulcerative colitis. In 1923 Helmholz5 described ulcerative colitis occurring in childhood. Since that report, many others 6, 8, 9, 13, 19 have documented the occurrence of this disease in the child. Several authors 3, 4, 13 report the onset of ulcerative colitis in infancy, but the usual onset of symptoms occurs from age eight to fifteen years. 4 The disease is slightly more common in the male. It occurs infrequently in the lower socio-economic groups and rather frequently in middle-income families. This difference is readily evident when comparing the number of patients admitted to a city or county general hospital to the number seen in a university or referral medical institution. The familial occurrence of the disease is known. 1 In the Cleveland Clinic series of 125 children with ulcerative colitis, the disease occurred in a close relative (parent or brother or sister) in eight families. Investigation into the cause of ulcerative colitis has been both varied and extensive. To date the origin remains obscure. Infection, hypersensitivity, psychogenic factors, geographic location, socio-economic factors, nutritional deficiency, inherited enzymatic error, and neurogenic imbalance have all been evaluated as factors related to the cause of this disease. Davidson, Bloom and Kugler3 recently reviewed these factors in an From the Department of Pediatrics, The Cleveland Clinic Foundation, Cleveland, Ohio.
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excellent report. The relation of hypersensitivity and autoimmunity to the pathogenesis of ulcerative colitis has been summarized by Kirsner10 and by Broberger2 as well. Pathology
Present information indicates that the pathologic abnormalities associated with ulcerative colitis in children are the same as those in adults. 14 • 15. 21 This disease involves a destructive process producing gross ulcerations of the mucosa and an inflammatory reaction of the underlying supporting structures. Suction biopsy of the rectal mucosa has given us pathologic specimens from children in early stages of the disease. In one case associated with arthritis, erythema nodosum and no bowel symptoms, the proctoscopic examination was normal, but the suction biopsy specimen revealed an inflammatory cellular infiltration of the lamina propria. Three months later, diarrhea and typical proctologic signs of ulcerative colitis developed. Frequently associated with the cellular infiltration of the lamina propria mucosae are crypt abscesses. These changes may be nonspecific, but the experience at the Cleveland Clinic indicates that their occurrence in conditions other than ulcerative colitis is unusual. As the inflammatory process becomes extensive, the entire wall of the bowel is penetrated. When the disease becomes chronic, and healing of the colon begins to occur, scarring and contracture of the bowel ensue. Recently Hawk (personal communication) reviewed the pathologic material available from Cleveland Clinic patients with ulcerative colitis. Approximately half of these patients had pathologic changes suggestive of granulomatous colitis (Crohn's disease of the colon). This study is being extended into the pediatric patient group, and it is hoped that correlation between the clinical course and the pathologic changes in the colon in these patients will increase our information on inflammatory bowel disease in children. This differentiation is particularly important with reference to the development of carcinoma of the colon later in life, since the risk appears to be much less in the patient with granulomatous colitis than in the patient with ulcerative colitis. To date, it appears that granulomatous colitis in the extremely young is rare. Diagnosis Perhaps the main problem of this disease in childhood is establishment of the diagnosis early when the pathologic changes and symptoms are mild. When symptoms are mild and of short duration, the disease is better controlled by a medical program17 than when they are severe and chronic. The diagnosis of ulcerative colitis in children is not difficult to establish when the physician knows that the initial symptom in a child having this disease, with its extracolonic complications and systemic
161
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Table 1.
Presenting Complaints
PRESENTING COMPLAINT
Diarrhea ....... . Rectal bleeding ... . Weight loss ........ . Arthritis ........... . Growth failure ........ . Erythema nodosum .... . Anemia ............... . Pyoderma gangrenosum .. . Abdominal pain ....... . Total . ............. .
if Ulcerative
Colitis in Children NO. OF PATIENTS
.................. 67
26 12 5 3 2 3 1 6 .. 125
effects, is not always diarrhea. The presenting complaints of children seen at the Cleveland Clinic with ulcerative colitis are listed in Table 1. Too often when a child has a record of weight loss, retardation of growth, or of arthritis, a good history of bowel habits is not obtained. As most pediatricians know, children do not freely communicate their everyday bowel habits, and it is only through careful questioning of the child that a history of rectal bleeding or mildly loose bowel movements suggestive of early ulcerative colitis can be discovered. The duration of symptoms before the establishment of diagnosis is highly variable. Some children seem to have a typical acute gastrointestinal upset with diarrhea as their first symptom. Other children have vague complaints such as intermittent, mild abdominal cramps before the passage of a stool, occasional loose bowel movements or the passage of a formed stool with mucus and blood on the outside, for as long as one or two years before the onset of diarrhea. Several patients had arthritis and fever two or three years before the onset of diarrhea. Constipation associated with the occasional passage of bloody mucus on the exterior of a hard stool occurred one year before the onset of diarrhea in several patients. Failure to grow, persistent arthritis, pyoderma gangrenosum, erythema nodosum, unexplained anemia, weight loss and abdominal pain, alone or in any combinations with or without diarrhea, have occurred in children with ulcerative colitis. These symptoms alone do not suggest bowel disease unless the physician is aware of the extracolonic complications and systemic manifestations of the disease. Physical examination of the child suspected of having ulcerative colitis does not confirm the diagnosis. The nonspecific signs of a chronic illness such as weight loss, muscle wasting and pallor are sometimes seen. If the disease is of short duration, the child may appear well. In the ill-appearing child the abdominal examination may reveal a distended abdomen, and bowel sounds may be reduced or absent. When present,
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these signs indicate dilatation of the colon ("toxic dilatation") with perforation or impending perforation. The digital rectal examination is done at the time of proctologic examination. Examination of the anus and rectum by direct visualization frequently confirms the diagnosis of ulcerative colitis, and therefore is mandatory in all children suspected of having this disease. The technique and findings have been described in a previous report.17 As mentioned earlier, biopsy of the rectal mucosa may be diagnostically helpful in the patient who has minimal proctologic signs. Proctologic examination should also be utilized in evaluating the response to therapy. Roentgen examination of the barium-filled colon establishes the diagnosis of ulcerative colitis. 7 , 17 The success of this procedure depends on the interest of the radiologist and the preparation of the child. Good cleansing of the bowel is needed, but vigorous catharsis will often aggravate the colitis, if present. Complete explanation of the procedure to the child usually assures cooperation. Progress studies are needed, but occasionally will also initiate the onset of diarrhea. A frequent problem is that cleansing of the colon is incomplete, and the radiologist will interpret the evidence as that of a normal colon with poor preparation. When the colon is poorly prepared, the study is misleading because the early destructive changes of mucous membrane are not seen. When thp, disease is chronic, with periods of activity and of healing, the radiologist readily recognizes the narrowed, shortened bowel. An Approach to Therapy A detailed program for the medical therapy of the child with ulcerative colitis was published in 1964. 18 This program is outlined below. Again it must be emphasized that therapy is nonspecific and is designed to relieve symptoms, and hence must be planned for the individual child. 1. Hospitalization is recommended, since results seem to be better when the initial therapy begins in the hospital. A tranquilizer such as chloridazepoxide hydrochloride (Librium "') is usually given the child. 2. When diarrhea is profuse, a low-residue diet is administered initially, with rapid progression to a normal diet in three to five days. Frequently a restricted diet annoys the child, and this results in his refusal to eat. 3. Correction of anemia and blood electrolyte abnormalities with appropriate intravenous solutions and whole blood is done quickly. This alone often improves the general well-being of the child. 4. Antimotility agents, usually diphenoxylate hydrochloride with atropine sulfate (Lomotil '" "') or hyoscyamine sulfate, atropine sulfate, hyoscine hydrobromide, phenobarbital, kaolin, pectin, and opium U.S.P. "Roche Laboratories. G. D. Searle Co.
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(Donnagel-PGO), in adequate doses will rapidly decrease frequency of bowel movements and abdominal cramping. 5. SalicylazosuI£apyridine (Azulfidinef), from 4 to 8 Gm. daily, is also given to all patients. Initially a small child may have difficulty in swallowing these pills, but usually a patient nurse can overcome this problem. 6. Methylprednisolone acetate (Depo-MedroIO retention enemas are given to all patients as soon as the decreased frequency of diarrheal stools permits. The enemas are given nightly while the child is hospitalized and then usually every other night or three times a week for several weeks after discharge. Children seem to tolerate this procedure well. 7. A therapeutic vitamin supplement (Surbex with C) is given to all patients. 8. A close relation with the parents and child is established initially. While in the hospital and as the child improves, this relationship grows. These children frequently have the emotional problems common to any child with a chronic illness. Usually there has been insufficient education about their disease, along with the failure to recognize the child as a person. Frequently the parents' fears and overcompulsive attitudes in regard to the treatment create hostility and distrust in the child. A positive approach with frequent visits to the bedside by the physician is an important part of the therapy. With this program the disease will be controlled in about 50 per cent of children. Therapy should be continued for six to 12 months after the establishment of normal bowel habits. In the other children, adrenocorticotropin (ACTH), steroids given orally or surgical treatment is needed for adequate therapy. Steroids given orally as a part of the medical program are used infrequently. Problems in Therapy Six case histories have been selected to illustrate some of the problems faced in the care of the child with ulcerative colitis. The natural history of the disease is variable, and hence the response to medical therapy may be misinterpreted by the patient and the physician. 1l • 12. 20 The patient and his family must be reminded that therapy is nonspecific and directed toward relief of symptoms as long as the specific cause of the disease is not known. The role of surgery in the therapy of a child with this illness is important. A surgical procedure has too often been withheld too long from many children seriously debilitated from the colonic and extracolonic effects of this disease. The .. A. H. Robins, Co., Inc. t Pharmacia Laboratories, Inc. t The Upjohn Company.
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physician and the family of the child must accept the fact that a surgical procedure will almost always make the child healthy again. CASE 1. A 14-year-old girl was first examined at the Cleveland Clinic in July 1962 at the age of 10 years, because of intermittent diarrhea for five years. Her mother stated that "about 50 per cent of the time" her daughter had two or three loose watery bowel movements a day. She attended school regularly and lived normally. Findings on roentgen examination of the barium-filled colon were reported as normal. Results of a proctoscopic examination were also reported as normal, except that microscopic examination of the mucus in the colon revealed a few pus cells. No biopsy specimen was obtained. The patient was discharged from care with no therapy prescribed and was requested to return in six months if the diarrhea persisted. In March 1966, because of abdominal pain persisting for one week, an appendectomy was performed at another hospital. The appendix was reported as normal, and no report of other abdominal findings was made. On April 18, 1966, because postoperatively there was persistent abdominal pain, she returned to the Cleveland Clinic. She stated that during the last four years she had "never had a normal bowel movement" and had three or four loose watery bowel movements a day. She had attended school regularly, had grown 10 inches in height and had gained 37 pounds during those four years. Roentgen examination of the barium-filled colon revealed evidence of ulcerative colitis of the transverse, descending and sigmoid colon. Proctoscopic examination revealed a normal colon as far as 10 cm.-inches. She was admitted to the hospital, and a medical program consisting of regular diet, Azulfidine, Lomotil, Librium, vitamins and methylprednisolone acetate retention enemas was started. After two weeks she was having one formed stool a day; she was discharged from the hospital. Progress examination indicated continuance of well-being, and normal bowel habits.
Comment: Natural History of Ulcerative Colitis. This case points out certain inconsistencies and difficulties in evaluating the child with diarrhea. This girl had diarrhea for nine years, yet she felt well, attended school regularly, and grew normally. From outward appearances she was a healthy girl. The disease process in the colon was most likely present for nine years, but after five years the roentgenogram of the colon was normal and after four more years revealed changes of extensive ulcerative colitis, yet the patient had no change in symptoms during the entire nine years. Often the extent of the disease as estimated from the clinical symptoms and signs differs considerably from the extent of the disease as seen on barium studies of the colon. Therefore careful and prolonged follow-up is important and can be done only by proctologic and roentgenologic examination of the colon. Another inconsistency is the ease of control of the diarrhea by medical therapy. If a colon has been diseased for nine years, I would not expect the diarrhea to be easily controlled, yet within two weeks the patient was having one formed stool a day and has continued for three months with normal bowel movements. Certainly the history of this child (and others) makes one wonder how long the pathologic process exists before the diagnosis can be established clinically.
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CASE 2. Three weeks before admission to the Cleveland Clinic Hospital a 15-year-old white girl had loose watery stools three or four times a day. During the three weeks of illness she lost 20 pounds. Five days before hospitalization, nausea and vomiting developed. These symptoms continued, and on the day of admission to the hospital she passed approximately 300 m!. of bright red blood rectally. Her medical history disclosed no serious illnesses. The physical examination revealed an acutely ill, pale, restless girl who was having generalized abdominal pain. The abdomen was minimally distended with diffuse tenderness and voluntary guarding in both lower quadrants. The bowel sounds were hypoactive, but present. Bright red blood leaked from the anus. An abdominal survey roentgenogram revealed distention of the left and transverse colon with small amounts of air in the small intestine, She was started on therapy consisting of electrolyte solutions intravenously, Chloromycetin, Lomotil, ACTH intravenously and methylprednisolone acetate retention enemas. A total of 2500 mI. of whole blood was given intravenously over the next four days. She continued to have abdominal cramping, and lost approximately 300 to 500 mI. of blood rectally each day. Five days after admission to the hospital she had not improved, and the abdomen was increasingly distended and tender. Perforation of the colon was believed to be imminent, and operation was recommended. Under anesthesia, sigmoidoscopy revealed normal colonic mucosa for 16 cm.-inches. Exploratory laparotomy revealed the colon to be dilated and hyperemic. The terminal ileum showed evidence of severe ileitis, Six centimeters of ileum and the entire large bowel except 16 cm. of rectum were resected, and an ileorectal anastomosis was made. During the procedure 1000 ml. of whole blood was administered. The postoperative period was uneventful, and she was discharged from the hospital 12 days after operation, with instructions to eat a regular diet, to take Lomotil, 2.5 mg. three times a day orally, and to receive ACTH gel, 20 units intramuscularly twice weekly for three months. Re-evaluation 15 months after operation revealed a healthy girl who has gained 25 pounds and is having three to four formed stools a day. The proctologic examination was normal.
Comment: Acute Onset, Hemorrhage, Dilatation of the Colon and Failure of Medical Therapy. In contrast to the girl in case 1, this girl had a sudden onset of diarrhea with a rapid progression of the disease. Within three weeks after the onset of diarrhea rectal hemorrhage and dilatation of the colon developed. Replacement of blood losses, intravenously administered ACTH and other supportive measures failed to halt the pathologic process. Abdominal distention and tenderness associated with hypoactive bowel sounds has been termed toxic dilatation. Careful observation of the child with these signs is needed. Failure to improve or evidence of deterioration of the patient's general condition, such as a rising pulse rate or leukocyte count, or the appearance of fever or increasing abdominal tenderness, makes surgical intervention mandatory. If perforation of the colon occurs, the operative risk is greatly increased. One of two deaths in the Cleveland Clinic series of patients was that of a girl who was transferred from another hospital, with a perforation of the colon. She died of sepsis. In case 2 the acute onset of symptoms and freedom of the rectum from disease provided excellent conditions for ileorectal anastomosis.
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To date the patient has done well, and only time will answer the effectiveness of this approach to the ulcerative colitis. Perhaps in children this may be the operation of choice. CASE 3. At the age of seven years a boy had his first episodes of bloody diarrhea. Intermittent episodes of loose, watery bowel movements that contained blood continued for the next 18 months. The diagnosis of ulcerative colitis was established by proctoscopic examination. On two occasions he was hospitalized to receive blood transfusions. In October 1964, two years after the onset of diarrhea, severe diarrhea with abdominal cramping and profuse rectal hemorrhage developed. He was hospitalized for seven weeks, and was treated with steroids orally, intramuscular injections of ACTH, Azulfidine and a low-residue diet. After seven weeks of therapy in the hospital he was transferred to the Cleveland Clinic Hospital. On admission the examination revealed a chronically ill-appearing boy who was quite pale. Tenderness to palpation was present in both lower quadrants of the abdomen. The blood hemoglobin content was 5.5 gm. per 100 mI., and the hematocrit reading was 21. Proctoscopic examination revealed granularity of the entire rectum, and oozing of blood from all mucosal surfaces visualized. He was given 1500 ml. of whole blood intravenously during the next seven days. Azulfidine, ACTH intramuscularly, Lomotil, Donnagel-PG, vitamins and methylprednisolone acetate retention enemas were administered daily. After two weeks of therapy the stools were formed and contained no blood, and the proctoscopic examination revealed normal rectal mucosa except for slight granularity. Administration of retention enemas was continued three times a week for three months, and of Azulfidine and Lomotil for 12 months after discharge from the hospital. Roentgen examination of the barium-filled colon, and proctologic examination, were interpreted as normal one year after the institution of therapy. The progress of the patient has now been followed for 20 months since the first examination. He has had four episodes of loose bowel movements mixed with bloody mucus, lasting from three to five days. He has not been ill with these episodes and had perfect attendance at school this year.
Comment: Recurrent Bloody Diarrhea. Intermittent episodes of bloody diarrhea, not persistent diarrhea, have been the prominent clinical symptoms in this boy. A medical program seems to have controlled the disease or possibly initiated a spontaneous remission. As has been pointed out by others,3 the children with intermittent symptoms seem to respond to medical therapy when exacerbation of symptoms occurs. These children also have fewer extracolonic complications than do those with persistent diarrhea. Certainly when the clinical history indicates intermittent symptoms, a vigorous and prolonged medical program i s indicated. CASE 4. The patient at the age of one year began to have frequent (from five to 10 a day) foul-smelling, frothy stools. He was one of identical twins and had been in good health until the onset of diarrhea. At 15 months of age medical evaluation revealed no cause for the symptoms. During the next three years he was given trials of a variety of elimination diets and antimotility drugs. The bowel habits did not return to normal, but a gradual change in the type of stool occurred. The feces became more watery, contained mucus, and frequently were blood-tinged. During this period of three years his growth was much less than that of his twin.
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In November 1960, at age four years, he was first examined at the Cleveland Clinic because of persistent diarrhea. Many laboratory tests and roentgen examinations were reported normal. Proctoscopic examination revealed mucuscontaining pus, but was thought not to be diagnostic of ulcerative colitis. A strict gluten-free diet was prescribed, and he was discharged from the hospital. Three months later he returned with his mother, who reported that after an initial decrease in diarrhea for two weeks, the diarrhea had returned and persisted. He was readmitted to the hospital. Proctoscopic examination revealed extremely friable mucosa that bled freely when swabbed. A mucosal biopsy specimen was interpreted as showing leukocytic infiltration of the lamina propria, and crypt abscesses. Roentgen examination of the barium-filled colon also revealed, for the first time, the changes of ulcerative colitis. A program was prescribed consisting of a low-residue diet initially, Azulfidine, Lomotil, vitamins, methylprednisolone acetate retention enemas nightly and iron to be taken orally. Within two weeks the bowel movements were formed, contained no blood, and occurred once or twice a day. This program was continued for five months (except the methylprednisolone acetate retention enemas, which were stopped after 10 nightly administrations), and the child did well. In early August 1961, the twin brother had a severe influenza-like illness with fever, vomiting and diarrhea, lasting three days. Two days later the same symptoms developed in the patient. He did not recover from this illness and on the fifth day was readmitted to the Cleveland Clinic Hospital. Again the complete medical program listed above was instituted, and he slowly improved over the next two weeks, but continued to have two to four semiformed stools a day. During August, September, October and early November he was improved, but not cempletely well. On November 20, 1961, fever again developed, with abdominal cramps and frequent loose bowel movements. He was readmitted to the hospital on November 29, 1961. Despite therapy that included the program above, intravenous injections of ACTH and Decadron orally, profuse diarrhea continued, as did the fever and loss in weight. On the ninth hospital day an abdominal survey roentgenogram revealed dilatation of the entire colon. The leukocyte count was 21,600 per cubic millimeter, with 85 per cent polymorphonuclear leukocytes. A subtotal colectomy and ileostomy with retention of the rectal stump was performed. The postoperative period of recovery was uneventful. During the next eight months the patient did well and gained 15 pounds. In August 1962, vomiting and abdominal pain recurred. Exploratory laparotomy revealed an intestinal obstruction secondary to adhesions; lysis of the adhesions was performed. After this operation there were no further symptoms. He gained weight, ate well, and lived a normal life. In June 1965 he was readmitted to the hospital for reanastomosis of the ileum to the rectum; this was performed on July 10, 1965. Since then he has had three or four formed stools a day, has gained 10 pounds and continues to be quite normal. He is now the same height and weight as his twin brother.
Comment: Surgery in the Young Patient. The management of this boy's condition offered a unique opportunity, since an identical twin was always available for comparing the effects of the disease and therapy on growth and development. From the time of onset of diarrhea until subtotal colectomy was performed the patient was behind his twin in growth. After the establishment of the ileostomy and subtotal colectomy, he grew rapidly, and soon equaled his twin in height and weight. This
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MICHENER
Figure 1. A, Pyoderma gangrenosum lesion on the right ankle before operation (ileostomy and subtotal colectomy). B, The same lesion 7 weeks after ileostomy and subtotal colectomy.
has been our experience with almost every patient operated on in the early years. If the surgical procedure is not performed until the patient is 15 to 20 years of age, and growth in height is below the third percentile, these patients will not regain their normal expected height, but will usually grow a few inches. When puberty is delayed secondary to the extracolonic effect of the disease, removal of the diseased colon will usually allow the physical changes associated with puberty to begin in six to 12 months after operation. This is particularly true of girls in regard to the onset of menses. After three years of excellent health with an ileostomy, an ileorectal anastomosis was performed. The operation and postoperative course were uneventful. It is now one year after the ileorectal anastomosis, and the patient is healthy and has three or four formed stools a day and one at night. Again, only time will allow a long-term evaluation, but I wonder whether or not, in the young patient, a primary operation consisting of subtotal colectomy with ileostomy, then a delayed period to allow recovery from the effects of the disease before a second procedureileorectal anastomosis-is performed, may be a highly satisfactory therapeutic answer to the child with ulcerative colitis who needs surgical treatment. CASE 5. In July 1963, at the age of 10 years, a boy had the onset of migratory joint pains and swelling. Several days after the onset of the joint swelling, a purpuric rash developed over the lower extremities. He was admitted to a hospital, and a diagnosis of acute rheumatic fever was made by the family physician. While hospitalized he had three or four watery bowel movements a day, attributed to the side effects of ingested penicillin and aspirin
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preparations. The swelling and pain in the joints subsided. During August and September he continued to have almost daily loose watery bowel movements. The purpuric rash over the lower extremities varied in intensity, but never disappeared completely. During the winter of 1963-1964 the diarrhea became a problem, and in May 1964 the child was readmitted to the hospital and a diagnosis of "infectious colitis" was made. In June 1964 he was admitted to a children's hospital where the diagnosis of ulcerative colitis was established. Prednisone, Lomotil and vitamins were prescribed. During the next 12 months the diarrhea subsided, the purpuric rash disappeared completely, and he enjoyed good health. In August 1965 a large, weeping ulcerous lesion developed over the right medial malleolus. The prednisone was discontinued, but three days later pain and swelling in the left ankle and left knee developed, and an oral temperature of 104°F. At this time administration of prednisone was restarted, and he was transferred to the Cleveland Clinic Hospital. The family history is significant in that one maternal grandaunt is said to have ulcerative colitis. On admission to the hospital this boy appeared pale, chronically ill and wasted, and had the facies secondary to excessive cortisone administration. He was 57% inches tall and weighed 86 pounds. A large ulcer 3 inches in diameter covered the right medial malleolus; the surrounding skin was edematous and erythematous (Fig. 1). Multiple, deep punctate draining points were in the ulcer, and it was thought that this lesion was typical of pyoderma gangrenosum. There were no purpuric lesions. The abdomen was obese, and an edge of the liver was felt 1Yz inches below the costal margin. The spleen was not palpable. No tenderness was present. There was no swelling of the joints. The other results of the examination were normal. Proctologic examination revealed patchy mucosal changes with granularity, friability and slight bleeding. A mucosal biopsy specimen revealed "chronic inflammation compatible with ulcerative colitis." Roentgen examination of the barium-filled colon showed a shortened colon, complete destruction of haustral markings from the hepatic flexure distally, and prominent pseudopolyposis in the transverse colon, de-
Figure 2. Roentgenogram of right ankle showing periosteal elevation of the bone underlying the pyoderma gangrenosum lesion.
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scending colon, and sigmoid. Roentgen examination of the left tibia and ankle revealed minimal periosteal elevation in the proximal third of the tibia. There was also an increase in periosteal tissue beneath the lesion of pyoderma gangrenosum over the right medial malleolus (Fig. 2) . It was the opinion of all the physicians who examined this boy that ileostomy and subtotal colectomy were indicated, but the parents refused permission to perform the operation. He was then started on a course of prednisone, 5 mg. three times daily to be decreased slowly over the next six weeks; ACTH gel, 40 units intramuscularly three times weekly; Lomotil, 2.5 mg. four times a day; methylprednisolone acetate retention enemas, 40 units nightly; Chloromycetin, 250 mg. three times a day for 14 days; and Wescodyne soaks for the ankle lesion. During the next 21h weeks he made no progress. The size of the ankle lesion seemed to increase, and the left knee became painfully swollen. At the end of three weeks' therapy at home the parents requested that operation be performed. The boy was readmitted to the hospital and on November 19, 1965, subtotal colectomy with ileostomy was performed. During the two weeks after operation the lesion of pyoderma gangrenosum healed remarkably fast. He was discharged from the hospital with the advice to continue to take ACTH gel, 40 units intramuscularly twice weekly, and Lomotil, 2.5 mg. four times a day. The boy continued to gain weight and felt well during the next three months. Four months postoperatively a renal calculus of calcium phosphate was passed. During the fourth and fifth postoperative months a hard swelling appeared over the upper left tibia. Roentgenograms of this lesion revealed periosteal elevation suggestive of an inflammatory or neoplastic process (Fig. 3). He was readmitted to the hospital and under general anesthesia underwent biopsy. The specimen revealed a chronic osteomyelitis that was sterile to culture. Blood cultures were also sterile. It was believed that this lesion was most likely of the same origin as the lesions of pyoderma gangrenosum in association with ulcerative colitis, but because of the biopsy report, antibiotic therapy was advised. He
Figure 8. Roentgenogram of right upper leg showing periosteal elevation and thickening of the adjacent cortex of the upper third of the tibia.
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was given intravenous injections of Staphcillin for ten days and Tego Pen orally, 250 mg. four times a day for six weeks. Three months later he no longer had pain while walking. The boy's weight had not changed, and he was attending school. No rectal discharge was present.
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Comment: Arthritis, Vascular Purpura and Pyoderma Gangrenosum. In this boy the extracolonic complications of arthritis, vascular purpura and pyoderma gangrenosum produced more disability than did diarrhea. The masking of the underlying disease by arthritis is not an uncommon occurrence, and, as in this patient, the diagnosis of rheumatic fever is made. Diarrhea mayor may not be present, and usually only direct questioning of the child will reveal its presence. The older the child is the less likely is it that the parents will have a detailed knowledge of the child's bowel habits. Pyoderma gangrenosum is a rare extracolonic complication of ulcerative colitis in children and, in the experience at the Cleveland Clinic, has occurred in only two patients less than 15 years of age. In each case the lesion was not affected by medical therapy of the disease, but disappeared rapidly after removal of the colon. The extracolonic complications of arthritis, vascular purpura and pyoderma gangrenosum occasionally regress with medical therapy of the diseased colon, but most often they persist or recur until the colon is removed. Dramatic healing of the lesions of pyoderma gangrenosum and disappearance of the arthritis and purpura after subtotal colectomy and ileostomy have occurred in all cases. Disease in the retained rectal stump has not caused the extracolonic complications to remain active, though hemorrhage from the retained rectal stump has necessitated its removal in two cases. Retention of the rectal stump is desirable, since it offers the patient, the parents and the physician the hope that an ileorectal anastomosis may be constructed in the future. The thought of a permanent ileostomy is difficult for many parents to accept, and their feelings are usually transferred to the child. Most children less than 12 years of age freely accept an ileostomy. Though there is a definite but small risk of development of carcinoma in the rectal stump, retention of the stump seems justified. The periosteal elevation beneath the lesion of pyoderma gangrenosum is secondary to the increased vascularity accompanying the lesion. The periosteal elevation on the anterior surface of the upper third of the tibia simulated a bone malignancy or osteomyelitis. Biopsy revealed osteomyelitis, but cultures from the bone and blood for bacteria and fungi were sterile. This type of lesion has not been seen in other patients with ulcerative colitis and may well be a pathologic process in bone not unlike a lesion of pyoderma gangrenosum. The passage of a renal calculus by patients with ileostomies occurred in 10 per cent of cases in one series. 16 This has been attributed to the occurrence of water and electrolyte abnormalities. The child of case 5 is the only child at the Cleveland Clinic who has had such a nroblem.
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CASE 6. In January 1966 an eight-year-old girl had the onset of loose bowel movements associated with low abdominal cramping and the passing of bright red· blood with each movement. After two weeks of diarrhea the stools again became formed, but for four weeks she continued to pass bright red blood with each bowel movement. In February she was brought to the Cleveland Clinic. During the entire six weeks of her illness she felt well, was afebrile, and attended school regularly. Roentgenograms of the barium-filled small intestine and colon were interpreted as normal. Proctoscopic examination revealed diffuse edema and granularity of the rectum for 4 inches above the dentate line. The mucosa bled freely when touched with a swab. Rectal biopsy revealed a lymphocytic and plasma cell infiltration of the lamina propria, as well as crypt abscesses. Therapy consisted of Azulfidine, Lomotil, Librium, a regular diet, and DepoMedrol enemas nightly (for 10 days, then every other night for three weeks). Three days after starting treatment the bleeding stopped. For the last four months she has had one normal stool, with no blood, daily.
Comment: Ulcerative Colitis Confined to the Rectum. Ulcerative colitis confined to the rectum and sigmoid colon is a more benign disease in all age groups than that extending throughout the colon. In a recent study of 124 patients (all ages) with this diagnosis seen at the Cleveland Clinic the principal symptom was rectal bleeding (R. G. Farmer and C. H. Brown: personal communication). In a follow-up study it was found that 20 patients had extension of the disease to a more proximal portion of the colon, and 10 required operations for colitis. This form of the disease is not common in children, but when present is more easily managed than when the entire colon is affected. CONCLUSION In this clinic I have attempted to emphasize the following points regarding ulcerative colitis in childhood. 1. The presenting symptoms of a child with this disease may be varied and not suggest bowel disease. An awareness of the extracolonic complications and systemic manifestations will usually aid in early diagnosis. 2. Frequently delay in diagnosis is secondary to the physician's hesitancy to order roentgen examination of the barium-filled colon and proctologic examination. 3. Early diagnosis is important, since the patient with mild disease of short duration seems to respond best to a medical program. 4. No two cases follow the same course, and the physician must be flexible in his approach to therapy. 5. The role of surgery in the therapy of this disease in childhood has not received proper recognition. A variety of surgical procedures is available and usually will make the child well. Ileostomy and subtotal colectomy with retention of the rectal stump effect a dramatic improve-
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ment in a chronically ill child. Children tolerate an ileostomy and continue to grow. If the rectum heals, an ileorectal anastomosis can be performed later when the child is healthy and there is less operative risk. Prolonged follow-up results are not yet available on a sufficient number of children WJ:lO have undergone this operation, but it is possible that this may be the procedure of choice for the child with ulcerative colitis who needs surgical treatment. REFERENCES 1. Barker, W. F.: Familial History of Patients with Ulcerative Colitis. Am. J. Surg., 103:25, 1962. 2. Broberger, 0.: Immunologic Studies in Ulcerative Colitis. Gastroenterology, 47: 229,1964. 3. Davidson, M., Bloom, A. A., and Kugler, M. M.: Chronic Ulcerative Colitis of Childhood. J. Pediat., 67:471, 1965. 4. Enzer, N. B., and Hijmans, J. C.: Ulcerative Colitis Beginning in Infancy. J. Pediat., 63:437, 1963. 5. Helmholz, H. F.: Chronic Ulcerative Colitis in Childhood. Am. J. Dis. Child., 26:418, 1923. 6. Hijmans, J. C., and Enzer, N. D.: Ulcerative Colitis in Childhood: Study of 43 Cases. Pediatrics, 29:389, 1962. 7. Hodgson, J. R, and Kennedy, R L. J.: Roentgenologic Aspects of Chronic Ulcerative Colitis in Children. Radiology, 65:671, 1955. 8. Jackman, R J., Bargen, J. A., and Helmholz, H. F.: Life Histories of 95 Children with Chronic Ulcerative Colitis: Statistical Study Based on Comparison with Whole Group of 871 Patients. Am. J. Dis. Child., 59:459, 1940. 9. Kirsner, J. B., Raskin, H. F., and Palmer, W. L.: Ulcerative Colitis in Children: Observations in Selected Patients. A.M.A. J. Dis. Child., 90:141, 1955. 10. Kirsner, J. F.: The Immunologic Response of the Colon. J.A.M.A., 191:105, 1965. 11. Korelitz, B. I., and Gribetz, D.: Prognosis of Ulcerative Colitis with Onset in Childhood. II. Steroid Era. Ann. Int. Med., 57:592, 1962. 12. Korelitz, B. I., Gribetz, D., and Danziger, I.: Prognosis of Ulcerative Colitis with Onset in Childhood.!. Pre-Steroid Era. Ann. Int. Med., 57 :582, 1962. 13. Lagercrantz, R: Ulcerative Colitis in Children. Acta Paediat. (Stockholm) (Supp.), 75:89, 1949. 14. Lumb, G.: Pathology of Ulcerative Colitis. Gastroenterology, 40:290, 1961. 15. Lumb, G., and Protheroe, R H. B.: The Early Lesions in Ulcerative Colitis. Gastroenterology, 33:457, 1957. 16. Maratka, Z., Nedbal, J., and Chytilova, D.: Disorders in Water and Electrolyte Balance Following Surgical Treatment of Ulcerative Colitis. I. Effect on Urolithiasis Development. (C2) Cas. Lek. Cesk., 104:1061, 1965. 17. Michener, W. M., Brown, C. H., and Turnbull, R B.: Ulcerative Colitis in Children. 1. Diagnosis. Am. J. Dis. Child., 108:230, 1964. 18. Idem: Ulcerative Colitis in Children. II. Medical and Surgical Therapy. Am. J. Dis. Child., 108:236, 1964. 19. Michener, W. M., and others: Prognosis of Chronic Ulcerative Colitis in Children. New England J. Med., 265:1075, 1961. 20. Platt, J. W., Schlesinger, B. K, and Benson, P. F.: Ulcerative Colitis in Childhood; A Study of its Natural History. Quart. J. Med. (new ser.), 29:257,1960. 21. Svartz, N.: Ulcerative Colitis: Changes in the Intestinal Walls and Therapeutic Considerations. J. Intemat. Call. Surgeons, 41-2:134, 1964. Cleveland Clinic 2020 E. 93rd St. Cleveland, Ohio 44106