A thirteen- y ear-old girl was referred for evaluation of anemia. While being treated for encopresis, she was found to have a hemoglobin level of 8.0 g/dL with MCV 80. Upon review of her growth chart, she was noted to have gone from the 10th percentile in weight and height at 9 years to below the 5th percentile in both. Because she also was found to have an erythrocyte sedimentation rate (ESR) of 80 mm/h, the gastroenterologist treating her suspected inflammatory bowel disease (IBD). She had a normal barium study of the upper gastrointestinal tract, as well as a normal upper and lower endoscopy. Other than a long history of encopresis and enuresis to be described below, she had no symptoms such as vomiting, diarrhea, fevers, abdominal pain, arthritis, or rashes. Her diet was normal, and she denied any history of purging or laxative abuse.
Her past medical history was remarkable for a 2-year history of constipation, encopresis, and enuresis. The encopresis had been resistant to a number of treatments; however, for the preceding 6 months, while receiving MiraLax (polyethylene glycol), there had been no soiling and she had had a formed bowel movement each day. The history of enuresis was more nebulous; she had both day and nighttime enuresis for many years. In the past, she had been treated with Ditropan (oxybutynin) without relief of her symptoms. She had not had the onset of menses.
There were four cats and several gerbils combined in the two homes of her parents, who had been divorced for many years. She had traveled to Belgium and France several months before this evaluation. She lives in a wooded area and has done a great deal of camping. Since she's adopted, her family history is unknown.
On physical examination, she was a short, skinny girl. Her weight and height were below the 5th percentile. Her weight/height ratio was in the 25th percentile. Her vital signs were unremarkable. Her examination was entirely unremarkable, including the neurologic examination. She had Tanner II breasts and a Tanner I perineum.
Robert Listernick, MD, moderator: Before we evaluate the anemia, let's discuss encopresis. How should a primary care physician approach the evaluation of encopresis?
Timothy Sentongo, MD, pediatrie gastroenterologist: As with all aspects of medical care, a detailed history comes first. Children who have Hirschsprung disease invariably have a history of constipation dating to the neonatal period. Most of the children whom I see with soiling have secondary encopresis, which usually starts after a period of successful toilet training. Following a period of constipation, the rectum becomes distended and they lose their ability to sense this distention and the urge to defecate. When this happens, they can develop massive stool retention; liquid stool leaks around the fecal impaction leading to encopresis.
Dr: Listernick: Do such children need any diagnostic evaluation prior to instituting therapy?
Dr: Sentongo: First, they need a good general physical examination, especially looking for possible signs of hypothyroidism. A careful neurologic examination should be performed, particularly of the lower extremities, in order to exclude spinal tract pathology, such as a tethered cord or intraspinal mass. If the history of constipation extends to the neonatal period, a barium enema should be performed to exclude Hirschsprung disease. In general, no further evaluation is necessary.
Dr. Listernick: How do you treat these children?
Dr. Sentongo: First, the bowel needs to be cleaned out with a combination of enemas and stool softeners. Usually this takes 3 to 4 days. Next, I use stool softeners to promote daily defecation. I have found MiraLax extremely useful in these cases. Although we have used it for extended periods of time, its longterm safety has not yet been shown.
The rectal distention usually takes months to regress; until that time, the child won't feel the urge to defecate. They need to sit on the toilet at regular intervals so that there are no accidents. A behavior modification program with positive reinforcement can be very helpful.
Dr. Listernick: I've heard some physicians disagree with the use of enemas, seeing them as unnecessarily invasive.
Dr. Sentongo: In my experience, they're highly effective and easily tolerated after the parent and child overcome their initial fears.
Dr. Listernick: Obviously, this girl had very longstanding enuresis. How should one approach the more straightforward cases?
Earl Cheng, MD, pediatric urologist: History is also of paramount importance in the evaluation of enuresis. Her symptoms started when her parents divorced, a fairly common scenario. Primary enuresis, in which the child has never been dry, is often the result of anatomic problems. Secondary enuresis, which urologists call dysfunctional voiding, often coexists with constipation. The vast majority of these children have pelvic floor dysfunction; either during the toilet training years or following a urinary tract infection, they have learned to suppress the need to urinate or defecate by controlling the pelvic floor musculature. The smooth muscle of both the bladder and the bowel become distended; these children wet because they have urinary stasis and they have lost the sensation of needing to urinate. As Dr. Sentongo has said, it takes months before the smooth muscle can regain its tone. From a urologie standpoint, we want to know the child's bladder capacity. Is the bladder large, distended, and unable to be emptied, or is it very small, leading to overflow incontinence? This can be accompushed by checking a post-voiding residual urine volume by catheterization. An ultrasound of the bladder can give the same information.
Dr. Listernick: Once you've established the cause of the problem, how do you fix it?
Dr. Cheng: You have to teach the children how to empty their bladders. As I've said, most of them are constipated and the enuresis will never improve unless the encopresis is resolved.
Dr. Listernick: Do these children need any diagnostic evaluation?
Dr. Cheng: A thorough history and physical examination is more important than any testing. I ask the parents to keep a voiding diary so that I can assess the magnitude of the problem. In the office, I often obtain an estimate of the post-voiding bladder residual using an ultrasound.
Dr. Listernick: What about the need for medication?
Dr. Cheng: Although many urologists prescribe Ditropan reflexively whenever they have a child with this problem, I rarely use it. If they already have a full bladder, Ditropan may make it worse, as well as aggravating the coexistent constipation.
Dr. Listernick: Let's discuss the anemia.
Alexis Thompson, MD, pediatrie hematologist: This girl had a normochromic, normocytic anemia, which is the most difficult type of anemia to decipher. First, there are numerous hemoglobinopathies, including membrane defects (eg, hereditary spherocytosis) and red blood cell enzyme defects (eg, pyruvate kinase deficiency) that may lead to increased red blood cell turnover and anemia. Examination of the peripheral smear for abnormal forms can be helpful. Once these have been eliminated, there's a long list of systemic diseases that need to be looked for systematically. Finally, we shouldn't forget about occult, acute blood loss as a cause of this type of anemia.
Dr. Listernick: If the reticulocyte count is low and the peripheral smear normal, does this make a hemoglobinopathy unlikely?
Dr. Thompson: It certainly makes it less likely. However, the bone marrow may be in a hypoplastic state, causing the reticulocyte count to be low.
Dr. Listernick: What systemic diseases should be considered in the differential diagnosis of normocytic, normochromic anemias?
Dr. Thompson: I'd start with chronic liver or renal disease. Next, any chronic inflammatory or infectious process can cause anemia. Hopefully, the history or physical examination would provide clues. If not, I'd start the evaluation with a stool guaiac test, followed by tests of hepatic and renal function and a urinalysis. An ESR would be helpful in looking for evidence of occult inflammation.
Dr. Listernick: Dr. Sentongo, was the evaluation for IBD, including endoscopy, reasonable given the facts that were known at the time?
Dr. Sentongo: We have data that could support or refute the diagnosis of IBD. She certainly had anemia, poor growth and weight gain, and an elevated ESR. However, the anemia in IBD is typically hypochromic and microcytic. In addition, encopresis and enuresis generally are not associated with IBD, unless the child has fecal retention from perianal involvement of Crohn disease and associated rectal strictures.
Dr. Listernick: If you were to evaluate her for IBD, how would you proceed?
Dr. Sentongo: I'd start with a complete blood count (CBC) with differential, ESR, and a full chemistry panel including serum albumen. I might also perform a Prometheus panel looking for certain antibodies, such as p-antineutrophil cytoplasmic antibody (ANCA) and anti-sacchromyces cervisiae antibodies (ASCA), that are suggestive, but not diagnostic, for IBD. Finally, I would perform a barium study of the upper gastrointestinal tract and the distal small intestine. If any of these studies was suggestive of IBD, I would perform both endoscopy of the stomach and duodenum and colonoscopy to attempt to visualize and biopsy the terminal ileum.
Dr. Listernick: How helpful is the Prometheus panel?
Dr. Sentongo: That's somewhat controversial. It can have both false positives and negatives. I use it as just one more piece of evidence in deciding how to proceed when the history is atypical.
Dr. Listernick: At the outside hospital, endoscopies of the upper intestine and colon were normal. She was referred to me for evaluation of the anemia. She was found to have blood urea nitrogen 39 mg/dL, creatinine 2.3 mg/dL, and albumen 3.5 mg/dL. A urinalysis had a specific gravity of 1.010, small amounts of occult blood and protein, 6 to 10 red blood cells per high-powered field, and more than 100 white blood cells per high-powered field. She clearly had chronic renal failure. This highlights the need for a systematic, logical approach to diagnostic evaluations; her endoscopies could have been avoided.
Jerry Lane, MD, pediatrie nephrologist: In my experience, chronic anemia is not an unusual presentation of chronic renal insufficiency. Certainly, her unusual story of day and night enuresis should have been a clue.
Douglas Nordli, MD, pediatrie neurologist: You said that she had a normal neurologic examination. Did she have sacral anesthesia or an absent anal wink?
Dr. Listernick: I admit that I did not look for either. Why do you ask?
Dr. Nordli: An abnormal exam would be evidence of distal sacral pathology from S2 to S4, perhaps caused by a tethered cord or intraspinal mass.
Dr. Listernick: What's the differential diagnosis of chronic renal failure in an adolescent?
Dr. Lane: First, I would consider chronic inflammatory diseases, such as systemic lupus erythematosus. However, the long history of enuresis suggests an obstructive uropathy. I would perform tests for antinuclear antibodies, anti-double stranded DNA, and complement function.
Although we both thought that inflammatory disease was a strong possibility, the urinalysis speaks against glomerulonephritis. There were no red blood cell casts and only minimal proteinuria. In order to examine her anatomy, I would start with a renal ultrasound and a voiding cystourethrogram (VCUG).
Dr. Listernick: Let's look at her x-rays.
Mary Wyers, MD, pediatrie radiologist: Her renal ultrasound demonstrated marked bilateral hydronephrosis with dilated ureters. There was significant thinning of the renal cortices with poor corticalmedullary differentiation, hi addition, there was a thickened bladder wall with trabeculations.
The VCUG showed a coneshaped bladder with multiple diverticula. The left ureter is tortuous and dilated with Grade HI reflux; there was no reflux into the right ureter. These are all findings that we see in a chronic, neurogenic bladder.
Earl Cheng, MD, pediatrie urologist: This child has another radiographie finding, "a spinning top urethra." She has outpouchings just proximal to the external sphincter when she voids, telling us that she is bearing down abnormally on her external sphincter during voiding. This is seen in pelvic floor dysfunction.
Hydronephrosis does not necessarily indicate that there's obstruction. In this case, the pressure in the bladder is so high that urine from the upper tracts can't drain, leading to a back-up of the pressure and a physiologic obstruction.
Dr. Nordli: Other than the "spinning top" urethra, this sounds like a neurogenic bladder. As I stated before, I would have looked for other signs of lower motor neuron dysfunction. The differential diagnosis would include a tethered cord, sacral agenesis, a peripheral neuropathy, or a distal spinal cord mass. A lateral plain film of the sacrum would have been helpful in looking for sacral agenesis. However, she certainly needed a magnetic resonance imaging (MRI) scan of her spine with contrast enhancement.
Anthony Mancini, MD, pediatrie dermatologist: She should have had a thorough examination of the skin and subcutaneous tissue of her lower back, sacrum, and gluteal cleft, looking for signs of occult dysraphism such as port wine stains, tufts of hak, congenital nevi, gluteal cleft deviations, or deep sacral dimples.
Dr. Listernick: The MRI scan was normal. This was very puzzling to me and I wasn't sure where to look next.
Dr. Cheng: The key is in the history. She was dry until her parents' divorce, ie, secondary enuresis. That, and the normal physical examination, speaks strongly against a tethered cord or sacral agenesis. You didn't mention that she was wearing an adult diaper during the day for over a year, clearly setting her apart from the more common patient who has night-time enuresis.
The first thing that I did was to place a catheter into her bladder so as to decompress it. When that was accomplished, we demonstrated with an ultrasound that her hydronephrosis disappeared and her creatinine improved to 1.7 mg/dL. This tells us that her problem originates from the bladder.
Dr. Listernick: What is the pathogenesis of her problem?
Dr. Cheng: We call this a "nonneurogenic neurogenic bladder," or Hinman syndrome. As it turns out, she had seen a urologist when her symptoms first began years ago; a renal ultrasound and VCUG at that time were normal. This tells us that both her present reflux and encopresis were secondary to pelvic floor dysfunction, a phenomenon over which, at the moment, she had no control.
Dr. Lane: When I first saw her, she had significant pyuria and a positive urine culture, despite the absence of symptoms aside from wetting. I suspect that she had had numerous such infections in the past, contributing, in part, to her renal insufficiency.
Dr. Listernick: How can she be treated?
Dr. Cheng: I placed her on a regimen of intermittent catheterization which cured her of her wetting. She no longer is having urinary tract infections.
Dr. Lane: We performed a renal scan, which showed significant bilateral renal scarring. I would expect that her renal function will most likely slowly deteriorate over time and that she wili require dialysis.
Dr. Cheng: Early on, behavior modification for treatment of dysfunctional voiding would have been possible. Her bladder dysfunction is irreversible at this point. Her bladder is like an old piece of worn out leather that no longer stretches.
Dr. Listernick: Should this have been discovered sooner?
Dr. Lane: Part of the problem was that the family never had any follow-up visits with the urologist that they had seen 7 years ago.
Dr. Sentongo: I expect children with severe encopresis to improve within several months and to be weaned off of stool softeners at the end of 1 year. If this doesn't occur, one must look at potential reasons for this failure, such as non-compliance, psychosocial stresses, or underlying medical problems.
Dr. Listernick: Thank you, everybody.