Case 38-2006 — A 5-Year-Old Boy with Headache and Abdominal Pain
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《新英格兰医药杂志》
Presentation of Case
Dr. Kirsten Zanger (Pediatrics): A 5-year-old boy was admitted to the hospital because of headache, abdominal pain that had increased in severity and frequency, increasing abdominal girth, and a rash.
The patient had been well until 5 months earlier, when severe headaches, occasionally associated with emesis, and episodes of abdominal pain developed. His pediatrician saw him several times during the next month; the results of initial physical examinations were normal, but at the end of that month, papilledema was seen on funduscopic examination. Magnetic resonance imaging (MRI) of the brain the next day showed collections of subdural fluid over both hemispheres. Later that day he was admitted to this hospital through the emergency department.
Vital signs and the results of physical and neurologic examinations were normal, except for the bilateral papilledema. Serum levels of glucose and electrolytes and the results of renal and liver function tests were normal. The results of a complete blood count are shown in Table 1. The next day, the subdural fluid was drained through two frontal burr holes. Cytologic examination of the fluid showed rare monocytes (Table 1). Examination of a dural biopsy specimen revealed a single arteriole partially occluded by intimal proliferation, with no abnormality in other layers of the arteriole and no evidence of a cellular inflammatory reaction. Postoperatively, the headaches resolved, although intermittent abdominal pain occurred; the patient was discharged on the fifth hospital day.
Table 1. Results of Laboratory Tests.
After discharge, the patient continued to have episodes of abdominal pain and a poor appetite. One month later, the headaches recurred, accompanied by projectile vomiting; computed tomographic (CT) scanning showed repeated accumulation of subdural fluid. He was readmitted to the hospital, and a subdural–peritoneal shunt was inserted. Intraoperatively, approximately 50 ml of fluid was noted in the peritoneal cavity. Analysis of subdural and peritoneal fluid showed no evidence of infection; flow cytometry showed no abnormal T-cell or B-cell populations (the results of other tests are shown in Table 1). The patient was seen by consultants from the pediatric neurology, gastroenterology, hematology, and rheumatology services. An abdominal ultrasound examination was normal, except for a small quantity of free peritoneal fluid. An abdominal radiograph showed stool throughout the colon, and a polyethylene–glycol electrolyte solution was administered for constipation. The serum albumin level was 3.2 g per deciliter, and the lactate dehydrogenase level 278 U per liter; levels of glucose, electrolytes, amylase, and lipase and results of liver and renal function tests were normal. Tests for antinuclear antibodies, antineutrophil cytoplasmic antibodies, Epstein–Barr virus, and Lyme disease were negative. The headaches resolved, and the patient was discharged on the fifth hospital day, with a plan for follow-up with a neurologist, a gastroenterologist, and a rheumatologist.
After discharge, he was initially free of headaches but continued to have intermittent abdominal pain. Outpatient evaluation showed lactose malabsorption on a lactose breath test and allergies to strawberries, grapes, apples, and dairy products; the fruits were eliminated from his diet. Six weeks later (2 months before admission), a rotavirus infection developed, and the patient was hospitalized overnight because of dehydration. Subsequently, headaches occurred daily, and episodes of abdominal pain continued. An upper gastrointestinal series with a small-bowel follow-through study performed 2 days after the admission for rotavirus infection showed delayed transit time, with mucosal thickening and irregularities, primarily in the jejunum. Two weeks later, upper endoscopy and colonoscopy showed mild chronic gastric inflammation. Examination of biopsy specimens disclosed no abnormalities. The abdominal pain abated for several weeks after the administration of Lactobacillus acidophilus.
Five weeks before admission, the patient's mother noted that his gait was unsteady. A neurologist found no abnormalities on examination of the joints or on neurologic examination. Propranolol was prescribed in the event that the patient's headaches were migraines, but it was discontinued after 1 week because the headaches persisted. Two weeks later, a nonpruritic macular rash appeared on his lower abdomen and gradually spread to the upper thighs. The headaches and abdominal pain worsened, his appetite decreased, and he lost 0.9 kg. Two days before admission, he saw a rheumatologist, who found approximately 30 macules, 3 mm in diameter, on the lower abdomen and 3 on the upper thighs, which were slightly hyperpigmented and were not ulcerated. Over the next 2 days, episodes of abdominal pain worsened, and abdominal distention developed. He was admitted to this hospital.
The patient's mother reported that the headaches usually occurred early in the day, were often precipitated by exercise, and were occasionally associated with vomiting; they were relieved within 30 to 60 minutes by acetaminophen. The abdominal pain occurred abruptly; the child would cry out and double over, describing pain in the center of his abdomen. The pain typically lasted 30 to 60 minutes and then resolved. It was not accompanied by nausea, vomiting, diarrhea, or a change in bowel habits. He had no fevers, respiratory problems, joint pain, or other problems.
The patient's birth and development had been normal, and before this illness, he had been healthy. His immunizations were up to date. There was no family history of migraines, neurologic diseases, or other inherited diseases. His medications were acetaminophen, polyethylene–glycol electrolyte solution, and lactobacillus. He lived with his parents and a younger brother, all of whom were in good health.
On physical examination, the patient was a thin, pale boy who was not in acute distress. The fluid collection and the shunt were palpable under the scalp on the right side. The abdomen was distended, with a visible fluid wave when the patient was recumbent; it was soft and nontender, without organomegaly. A rash with a centripetal distribution was present, predominantly on the abdomen, the lower portion of the chest, and proximal thighs. The lesions were heterogeneous in appearance. Lesions described by the patient's mother as early were erythematous, slightly raised papules, several millimeters in diameter. Those that were several days old had a central white dot that became umbilicated after a period of a few more days; the skin in the center of the crater had a thin, wrinkled appearance, with faint telangiectasia at the margins. The neurologic examination disclosed a slightly ataxic gait. The remainder of the physical examination was normal. Levels of serum electrolytes, bilirubin, urea nitrogen, creatinine, phosphorus, lipase, C-reactive protein, alkaline phosphatase, and alanine aminotransferase were normal; the total protein level was 5.2 g per deciliter, albumin level 2.7 g per deciliter, calcium level 7.8 mg per deciliter (1.95 mmol per liter), aspartate aminotransferase 39 U per liter, and lactate dehydrogenase 205 U per liter.
Diagnostic procedures were performed, and additional consultations were obtained.
Differential Diagnosis
Dr. Verne S. Caviness, Jr.: May we review the diagnostic imaging?
Dr. Pallavi Sagar: The MRI scan of the brain obtained during the first admission showed bilateral subdural fluid collections with leptomeningeal and dural enhancement (Figure 1A and 1B). The collections were hyperintense as compared with the cerebrospinal fluid, indicating a high protein content. There was no evidence of hemorrhage or signal abnormalities on diffusion-weighted imaging that might have suggested the presence of subdural hematomas or empyema. These findings suggested an inflammatory meningovascular process.
Figure 1. MRI of the Brain.
An axial susceptibility image from the first admission (Panel A) shows bilateral subdural fluid collections (arrows), which were mildly hyperintense in comparison with cerebrospinal fluid on a fluid-attenuated inversion recovery sequence (not shown), a finding consistent with a high protein content. A T1-weighted image obtained after the administration of contrast material (Panel B) shows leptomeningeal enhancement along the right frontoparietal convexity (arrow). An axial susceptibility image obtained on day 7 of the current admission (Panel C) shows that the bilateral subdural fluid collections have increased despite the presence of drains. There are petechial hemorrhages along the cortical surface and at the junction of gray and white matter (arrows), with an evolving intraparenchymal hematoma in the right temporoparietal lobe (not shown). A T1-weighted image obtained after the administration of contrast material on the seventh day of the current admission (Panel D) shows that the leptomeningeal enhancement has become more diffuse, involving both cerebral hemispheres (arrows) with progressive cerebral atrophy.
Dr. Caviness: When I saw this 5-year-old boy at the time of his second admission for subdural–peritoneal shunt placement, it was apparent that his condition was extremely unusual. He had idiopathic fluid collections, distributed bilaterally throughout the cerebral subdural compartments, which recurred after drainage.
Subdural Hygroma
Typically, a subdural fluid collection, whether hygroma or hematoma, is unilateral, lens-shaped, and confined to the cerebral convexity. The subdural space is actually a virtual space: the inner face of the dura and the outer face of the arachnoid are bound to each other by collagen and other connective tissue elements.1 Subdural fluid collections typically dissect these membranes, and leading the dissection is the tapered edge of the lens-shaped collection. In contrast, the fluid collections in this case were distributed bilaterally and symmetrically to the entire subdural compartment, suggesting that there was little or no resistance to splitting the bond between the dural and arachnoid surfaces. Another very atypical feature of this case is the absence of an antecedent cause for the subdural fluid collections. In well over 80% of subdural hygromas in children, trauma or infection is an identifiable antecedent cause of the fluid collection; neither was seen in this case. Finally, well over half of subdural hygromas in children occur before 2 months of age.
The combination of this patient's young age, the distribution of fluid, and the absence of an antecedent cause would be expected in only about 3% of cases.2 Furthermore, idiopathic subdural collections typically respond to subdural drainage and do not recur.2 Thus, the probability of seeing all the features of this case in a general pediatric neurosurgical population approaches zero.2
The radiologic findings combined with the elevated level of protein in the cerebrospinal fluid suggest an abnormality of the microvasculature. At the time of the first drainage of the subdural collections, Dr. William Butler (Neurosurgery) performed a biopsy of the dura. Dr. Frosch, may we review that specimen?
Dr. Matthew P. Frosch: The dura was of normal thickness; there was no inflammation or evidence of previous hemorrhage. A single dural arteriole had intimal proliferation that did not include macrophages or other elements typically observed in atherosclerotic lesions (Figure 2A). The vessel had an intact elastic lamina (Figure 2B), and although rare lymphocytes were present, there was no evidence of vasculitis. No amyloid was present.
Figure 2. Dural Biopsy Specimen.
An abnormal vessel in the dense connective tissue of the dura (Panel A) shows increased cellularity of the intima (hematoxylin and eosin). The elastic lamina of this vessel is well preserved (Panel B, elastic tissue stain).
Dr. Caviness: The character of this vessel was reminiscent of the pathologic vascular changes in a case of Degos's disease that I saw as an intern in medicine at this hospital in 1963.3 Dr. Frosch and I considered this possibility, but the clinical presentation at the time did not support this diagnosis.
Degos's Disease
Degos's disease was initially described as a cutaneous disease with a morphologically distinctive rash.4,5,6,7 The onset ranges from the first months of life to the seventh decade. Between 20 and 30% of cases are limited to the skin, and these patients have a normal life expectancy. However, in the majority of cases, this is a lethal, multisystem disease. The most common cause of death is microvascular infarctions in the intestines, resulting in perforation and peritonitis. The central nervous system is frequently involved, with a spectrum of vasculopathic lesions. Although subdural fluid collections have been reported in several cases, they occurred in patients with extensive vascular occlusion.8
A brief period of improvement followed placement of the shunt, but then the child became increasingly uncomfortable, with severe abdominal pain and headache. He was seen by a gastroenterologist.
Dr. Esther J. Israel: When I first saw this patient, he had had abdominal pain and headaches for several months, and there was the unusual finding of fluid in both his brain and his abdomen. Rheumatologic and oncologic causes were considered, but the results of these evaluations were negative. We then considered common causes of chronic, recurrent abdominal pain in childhood, including constipation, lactose intolerance, dyspepsia, infection, celiac disease, inflammatory bowel disease, renal disease, neoplasms, and connective-tissue disorders. The abdominal pain was transiently relieved with treatment for constipation, lactose intolerance, and infection. When the pain continued to recur despite these measures, colonoscopy and upper endoscopy were performed, but no abnormalities were revealed.
Dr. Caviness: Progressive disability developed, with increasing abdominal girth, confirming the concern at the time of the shunt placement that there was an abnormal degree of fluid collection in the peritoneal cavity. The emergence of a peculiar rash was noted by the parents approximately 2 weeks before the patient's admission because of increasing abdominal girth. The unique features of the rash, together with the finding in the earlier dural biopsy specimen, convinced me of the diagnosis of Degos's disease in this patient. Dr. Mackool saw the patient shortly after admission.
Dr. Bonnie T. Mackool: This patient's cutaneous lesions were typical of Degos's disease. The lesions consist of crops of papules on the trunk, arms, and legs, generally sparing the face, palms, soles, and scalp. Lesions may also occur on the conjunctiva, sclera, choroids, retina, and optic nerve. Early lesions are erythematous, yellow or gray papules, usually 2 to 5 mm in diameter (Figure 3A); they become umbilicated, with central necrosis that has a porcelain, white atrophic appearance with erythematous or telangiectatic borders (Figure 3B).9
Figure 3. Cutaneous Lesions of Degos's Disease.
A photograph shows early skin lesions that are erythematous, yellow or gray papules, with most 2 to 5 mm in diameter (Panel A). During several days, the lesions become umbilicated, with central necrosis characterized by a porcelain, white atrophic appearance and erythematous or telangiectatic borders (Panel B). A biopsy specimen of a lesion on the knee (Panel C) shows homogenization of the dermal collagen, a finding consistent with the presence of ischemia (hematoxylin and eosin). Dermal mucinosis (Panel D) can be seen as blue material between the collagen bundles (colloidal iron stain). These are nonspecific findings that can be seen in connective-tissue diseases but are also consistent with Degos's disease. Photographs in Panels A and B courtesy of Dr. Kenneth Tsai, Department of Dermatology, Massachusetts General Hospital.
The cutaneous eruption typically precedes the visceral symptoms. The lesions are usually asymptomatic but can cause mild burning or itching. The differential diagnosis of cutaneous lesions in Degos's disease includes systemic lupus erythematosus, atrophie blanche, and allergic necrotizing vasculitis. A biopsy of a lesion on the knee was performed on the third hospital day.
Dr. Verne S. Caviness, Jr.'s Diagnosis
Malignant atrophic papulosis (Degos's disease).
Pathological Discussion
Dr. Frosch: The skin biopsy specimen showed a mild, perivascular inflammatory-cell infiltrate. There was a wedge-shaped area of the dermis in which the collagen had a homogeneous appearance — a finding consistent with ischemia (Figure 3C) — and moderate dermal mucinosis (Figure 3D). Although the classic changes that have been described in Degos's disease (atrophic and hyperkeratotic epidermis and a wedge-shaped infarct of the underlying dermis, with the point of the wedge associated with an abnormal vessel) were not present, the findings in this biopsy specimen were considered to be consistent with a clinical diagnosis of the disease.
The pathological lesion of Degos's disease is a predominantly noninflammatory vascular occlusive process, mainly affecting arterioles.4,5,9,10,11 The blood vessels, like the arteriole seen in the dural biopsy specimen from this patient, exhibit increased intimal cellularity that is due to the proliferation of endothelial cells, sometimes with superimposed thrombus. The arteriolar occlusion results in tissue ischemia and infarction, which are responsible for the clinical manifestations of the disease.6,12,13,14 In the central nervous system, involvement of the leptomeningeal vessels causes ischemia and infarction that reflects the distribution of the affected vessels.3,7,15,16,17,18,19,20 In the gastrointestinal tract,21,22,23 the submucosal arteries are typically affected, causing infarction of the bowel, and in some cases, the arteries of peritoneal surfaces are affected.
It has been suggested that Degos's disease is not a distinct disease entity but rather a pathological pattern associated with vascular injury from a variety of causes, such as connective-tissue disease.24,25 However, the distinctive constellation of cutaneous and systemic features, the absence in most cases of diagnostic features of another disease, and the unusual histopathological findings lead many to believe that it is a specific disease, although of unknown cause.26
Dr. Israel: The current admission was precipitated by the marked increase in ascites as well as the new rash. The differential diagnosis of ascites is broad. In the past, ascites was classified as exudative or transudative, but more recently it has been shown to be more helpful to classify ascites on the basis of the serum–ascites albumin gradient (SAAG).27 High-gradient ascites (SAAG, 1.1) is generally associated with conditions that cause portal hypertension, whereas causes of low-gradient ascites include cancer, tuberculosis, pancreatitis, the nephrotic syndrome, and connective-tissue disease. A specimen of this patient's ascites, taken on the third hospital day, together with the skin biopsy specimen, showed a very low SAAG (0.1). Because the ascitic fluid contained no malignant cells or acid-fast bacilli, the amylase and lipase levels were normal, the patient did not have proteinuria, and a tuberculin skin test was negative, a connective tissue disorder or vasculitis was the most likely cause. Degos's disease, a vasculopathy, should cause a low-gradient ascites.
Gastrointestinal involvement by Degos's disease could account for the abdominal symptoms in this case.28 Endoscopic examination may show infarcts and ulcers throughout the entire gastrointestinal tract; pain, perforation, peritonitis, hemorrhage, obstruction, diarrhea, and constipation may occur. After the skin lesions developed in this patient and the diagnosis of Degos's disease was suspected, the endoscopic biopsy specimens were reexamined, and no vascular abnormalities were found. On laparoscopy or laparotomy, white plaques with red borders may be seen on the serosal surface of the intestine.
On the 15th hospital day, the abdominal pain increased, and abdominal tenderness, fever (a temperature as high as 39°C), and pleural effusions resulting in difficulty breathing developed. An exploratory laparotomy was performed by Dr. Daniel Doody (Pediatric Surgery) to rule out intestinal perforation. Innumerable small areas of full-thickness ischemia involved all of the small intestine and colon except for the distal sigmoid and proximal rectum (Figure 4). This finding is typical of Degos's disease involving the bowel. No perforation was found; 1300 ml of ascites was removed and sent for culture, a chest tube was inserted, and the abdomen was irrigated and closed.
Figure 4. Intraoperative Photographs of the Abdomen.
The peritoneum is very slightly thickened but not grossly inflamed. However, there are hundreds if not thousands of small areas of full-thickness ischemia involving all of the small intestine and the colon except for the distal sigmoid and proximal rectum (Panels A and B). There is evidence of neovascularization in several sites (Panel C), suggesting the presence of older but still recent areas of infarction. Photographs courtesy of Dr. Daniel Doody, Department of Pediatric Surgery, Massachusetts General Hospital.
Dr. Sagar: Repeated brain MRI performed on the seventh hospital day (Figure 1C and 1D) showed new petechial hemorrhages centered at the junction of gray and white matter, with intraparenchymal hemorrhages and gyral edema. There was a focus of cystic encephalomalacia in the splenium of the corpus callosum. These findings suggest the presence of microinfarcts resulting from occlusive vasculopathy at the microvasculature level (venules and arterioles). The subdural collections had increased in size, and there was diffuse meningeal enhancement and cerebral atrophy.
Discussion of Management
Dr. Eric F. Grabowski: This child had microvascular infarcts in the central nervous system and gastrointestinal tract that numbered in the hundreds, if not thousands; there were persistent leaks of subdural, subgaleal, and serosal fluid. A diagnosis of Degos's disease had been made on the basis of the characteristic rash, a dural biopsy specimen showing an arteriole with endothelial-cell proliferation, and the appearance of the intestinal lesions. Additional laboratory studies showed elevated levels of vascular endothelial growth factor (VEGF) in both subdural fluid and plasma (196 pg per milliliter; normal value, <31), d-dimer levels of 4000 to 6000 ng per milliliter (normal value, <500), and fibrinogen levels of 600 to 1200 mg per deciliter (normal range, 150 to 400); the results of coagulation studies were consistent with the presence of compensated disseminated intravascular coagulation. We therefore considered the hypothesis that this patient had a dysregulation of vascular remodeling and increased vascular permeability due to increased VEGF production, as well as a prothrombotic process.29,30
There is no known effective treatment for Degos's disease, but drugs that target platelets and the coagulation system have been used, as have immunosuppressive agents.7,31 The patient was initially treated with aspirin and dipyridamole, which inhibit platelet function, and fondaparinux, which inhibits factor Xa, but his condition continued to deteriorate, with increasing ascites, pleural effusions, and tachycardia. A trial of infliximab was also administered without benefit.
Beginning on the 25th hospital day, we elected to treat him with bevacizumab, a recombinant human monoclonal antibody directed against VEGF, and low-molecular-weight heparin. Unfortunately, as this regimen was being started, the patient became difficult to arouse, and MRI showed new intracerebellar hemorrhages with evidence of tonsillar herniation, requiring neurosurgical evacuation (Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). After this event, he remained intubated and unresponsive. Nonetheless, during the ensuing 2 weeks, there was a reduction in his abdominal girth (Figure 2 of the Supplementary Appendix), stabilization of the leptomeningeal fluid leak, a reduction in ventricular tachycardia, and a decline in both the serum level of VEGF (<31 pg per milliliter) and the plasma level of fibrinogen (578 mg per deciliter). These events suggested a response to bevacizumab.
However, during the subsequent 2 weeks, the fluid leaks worsened despite a second dose of bevacizumab. Peritonitis, sepsis, and multiorgan-system failure developed, and the patient died after approximately 8 weeks in the hospital. A request for an autopsy was declined.
Dr. Nancy Lee Harris (Pathology): The patient's mother is here at the conference, and I would like to invite her to give us her thoughts.
Ms. Sandra Clancy: When our son died, we thought that he had a very rare and always fatal disease that had no possibility of cure. During his illness and after his death, we became interested in knowing more about this disease.
In March 2005, I traveled to Berlin to attend the First International Conference on Degos's Disease, hosted by Dr. Christos Zouboulis (Department of Dermatology and Immunology, Dessau Medical Center, Dessau, Germany) and attended by patients and patients' relatives. At this conference, we learned several important things. First, we learned that there is a European registry for Degos's disease and an active research program that has begun to collect epidemiologic data as well as skin biopsy samples and blood samples from patients. We also learned that there are many more patients with the disease than we had realized and that there is an active support group for patients (the Degos Patients' Support Network can be accessed at www.degosdisease.com). Finally, we learned the importance of collecting information and tissue samples from patients and of increasing the interest of researchers in this disease. There are good reasons to study it — little is known about the cause and pathologic processes involved, there are more patients than once thought, and there is a strong network of patients and relatives who support research efforts.
Dr. Harris: Can you tell us why you decided not to give permission for an autopsy?
Ms. Clancy: At the time, I believed that we knew why he had died, and it was not clear to me what would be gained by an autopsy. If I had known then just how much can be learned from an autopsy, I might have made a different choice.
Anatomical Diagnosis
Degos's disease, involving the brain, gastrointestinal tract, and skin.
Dr. Grabowski reports receiving consulting fees from Baxter Pharmaceuticals and a research grant from Novo Nordisk Pharmaceuticals; and Dr. Frosch, consulting fees from Bristol-Myers Squibb and Biogen Idec. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Departments of Neurology (V.S.C.), Radiology (P.S.), Pediatrics (E.J.I., E.F.G.), Dermatology (B.T.M.), and Pathology (M.P.F.), Massachusetts General Hospital; and the Departments of Neurology (V.S.C.), Radiology (P.S.), Pediatrics (E.J.I., E.F.G.), Dermatology (B.T.M.), and Pathology (M.P.F.), Harvard Medical School.
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Dr. Kirsten Zanger (Pediatrics): A 5-year-old boy was admitted to the hospital because of headache, abdominal pain that had increased in severity and frequency, increasing abdominal girth, and a rash.
The patient had been well until 5 months earlier, when severe headaches, occasionally associated with emesis, and episodes of abdominal pain developed. His pediatrician saw him several times during the next month; the results of initial physical examinations were normal, but at the end of that month, papilledema was seen on funduscopic examination. Magnetic resonance imaging (MRI) of the brain the next day showed collections of subdural fluid over both hemispheres. Later that day he was admitted to this hospital through the emergency department.
Vital signs and the results of physical and neurologic examinations were normal, except for the bilateral papilledema. Serum levels of glucose and electrolytes and the results of renal and liver function tests were normal. The results of a complete blood count are shown in Table 1. The next day, the subdural fluid was drained through two frontal burr holes. Cytologic examination of the fluid showed rare monocytes (Table 1). Examination of a dural biopsy specimen revealed a single arteriole partially occluded by intimal proliferation, with no abnormality in other layers of the arteriole and no evidence of a cellular inflammatory reaction. Postoperatively, the headaches resolved, although intermittent abdominal pain occurred; the patient was discharged on the fifth hospital day.
Table 1. Results of Laboratory Tests.
After discharge, the patient continued to have episodes of abdominal pain and a poor appetite. One month later, the headaches recurred, accompanied by projectile vomiting; computed tomographic (CT) scanning showed repeated accumulation of subdural fluid. He was readmitted to the hospital, and a subdural–peritoneal shunt was inserted. Intraoperatively, approximately 50 ml of fluid was noted in the peritoneal cavity. Analysis of subdural and peritoneal fluid showed no evidence of infection; flow cytometry showed no abnormal T-cell or B-cell populations (the results of other tests are shown in Table 1). The patient was seen by consultants from the pediatric neurology, gastroenterology, hematology, and rheumatology services. An abdominal ultrasound examination was normal, except for a small quantity of free peritoneal fluid. An abdominal radiograph showed stool throughout the colon, and a polyethylene–glycol electrolyte solution was administered for constipation. The serum albumin level was 3.2 g per deciliter, and the lactate dehydrogenase level 278 U per liter; levels of glucose, electrolytes, amylase, and lipase and results of liver and renal function tests were normal. Tests for antinuclear antibodies, antineutrophil cytoplasmic antibodies, Epstein–Barr virus, and Lyme disease were negative. The headaches resolved, and the patient was discharged on the fifth hospital day, with a plan for follow-up with a neurologist, a gastroenterologist, and a rheumatologist.
After discharge, he was initially free of headaches but continued to have intermittent abdominal pain. Outpatient evaluation showed lactose malabsorption on a lactose breath test and allergies to strawberries, grapes, apples, and dairy products; the fruits were eliminated from his diet. Six weeks later (2 months before admission), a rotavirus infection developed, and the patient was hospitalized overnight because of dehydration. Subsequently, headaches occurred daily, and episodes of abdominal pain continued. An upper gastrointestinal series with a small-bowel follow-through study performed 2 days after the admission for rotavirus infection showed delayed transit time, with mucosal thickening and irregularities, primarily in the jejunum. Two weeks later, upper endoscopy and colonoscopy showed mild chronic gastric inflammation. Examination of biopsy specimens disclosed no abnormalities. The abdominal pain abated for several weeks after the administration of Lactobacillus acidophilus.
Five weeks before admission, the patient's mother noted that his gait was unsteady. A neurologist found no abnormalities on examination of the joints or on neurologic examination. Propranolol was prescribed in the event that the patient's headaches were migraines, but it was discontinued after 1 week because the headaches persisted. Two weeks later, a nonpruritic macular rash appeared on his lower abdomen and gradually spread to the upper thighs. The headaches and abdominal pain worsened, his appetite decreased, and he lost 0.9 kg. Two days before admission, he saw a rheumatologist, who found approximately 30 macules, 3 mm in diameter, on the lower abdomen and 3 on the upper thighs, which were slightly hyperpigmented and were not ulcerated. Over the next 2 days, episodes of abdominal pain worsened, and abdominal distention developed. He was admitted to this hospital.
The patient's mother reported that the headaches usually occurred early in the day, were often precipitated by exercise, and were occasionally associated with vomiting; they were relieved within 30 to 60 minutes by acetaminophen. The abdominal pain occurred abruptly; the child would cry out and double over, describing pain in the center of his abdomen. The pain typically lasted 30 to 60 minutes and then resolved. It was not accompanied by nausea, vomiting, diarrhea, or a change in bowel habits. He had no fevers, respiratory problems, joint pain, or other problems.
The patient's birth and development had been normal, and before this illness, he had been healthy. His immunizations were up to date. There was no family history of migraines, neurologic diseases, or other inherited diseases. His medications were acetaminophen, polyethylene–glycol electrolyte solution, and lactobacillus. He lived with his parents and a younger brother, all of whom were in good health.
On physical examination, the patient was a thin, pale boy who was not in acute distress. The fluid collection and the shunt were palpable under the scalp on the right side. The abdomen was distended, with a visible fluid wave when the patient was recumbent; it was soft and nontender, without organomegaly. A rash with a centripetal distribution was present, predominantly on the abdomen, the lower portion of the chest, and proximal thighs. The lesions were heterogeneous in appearance. Lesions described by the patient's mother as early were erythematous, slightly raised papules, several millimeters in diameter. Those that were several days old had a central white dot that became umbilicated after a period of a few more days; the skin in the center of the crater had a thin, wrinkled appearance, with faint telangiectasia at the margins. The neurologic examination disclosed a slightly ataxic gait. The remainder of the physical examination was normal. Levels of serum electrolytes, bilirubin, urea nitrogen, creatinine, phosphorus, lipase, C-reactive protein, alkaline phosphatase, and alanine aminotransferase were normal; the total protein level was 5.2 g per deciliter, albumin level 2.7 g per deciliter, calcium level 7.8 mg per deciliter (1.95 mmol per liter), aspartate aminotransferase 39 U per liter, and lactate dehydrogenase 205 U per liter.
Diagnostic procedures were performed, and additional consultations were obtained.
Differential Diagnosis
Dr. Verne S. Caviness, Jr.: May we review the diagnostic imaging?
Dr. Pallavi Sagar: The MRI scan of the brain obtained during the first admission showed bilateral subdural fluid collections with leptomeningeal and dural enhancement (Figure 1A and 1B). The collections were hyperintense as compared with the cerebrospinal fluid, indicating a high protein content. There was no evidence of hemorrhage or signal abnormalities on diffusion-weighted imaging that might have suggested the presence of subdural hematomas or empyema. These findings suggested an inflammatory meningovascular process.
Figure 1. MRI of the Brain.
An axial susceptibility image from the first admission (Panel A) shows bilateral subdural fluid collections (arrows), which were mildly hyperintense in comparison with cerebrospinal fluid on a fluid-attenuated inversion recovery sequence (not shown), a finding consistent with a high protein content. A T1-weighted image obtained after the administration of contrast material (Panel B) shows leptomeningeal enhancement along the right frontoparietal convexity (arrow). An axial susceptibility image obtained on day 7 of the current admission (Panel C) shows that the bilateral subdural fluid collections have increased despite the presence of drains. There are petechial hemorrhages along the cortical surface and at the junction of gray and white matter (arrows), with an evolving intraparenchymal hematoma in the right temporoparietal lobe (not shown). A T1-weighted image obtained after the administration of contrast material on the seventh day of the current admission (Panel D) shows that the leptomeningeal enhancement has become more diffuse, involving both cerebral hemispheres (arrows) with progressive cerebral atrophy.
Dr. Caviness: When I saw this 5-year-old boy at the time of his second admission for subdural–peritoneal shunt placement, it was apparent that his condition was extremely unusual. He had idiopathic fluid collections, distributed bilaterally throughout the cerebral subdural compartments, which recurred after drainage.
Subdural Hygroma
Typically, a subdural fluid collection, whether hygroma or hematoma, is unilateral, lens-shaped, and confined to the cerebral convexity. The subdural space is actually a virtual space: the inner face of the dura and the outer face of the arachnoid are bound to each other by collagen and other connective tissue elements.1 Subdural fluid collections typically dissect these membranes, and leading the dissection is the tapered edge of the lens-shaped collection. In contrast, the fluid collections in this case were distributed bilaterally and symmetrically to the entire subdural compartment, suggesting that there was little or no resistance to splitting the bond between the dural and arachnoid surfaces. Another very atypical feature of this case is the absence of an antecedent cause for the subdural fluid collections. In well over 80% of subdural hygromas in children, trauma or infection is an identifiable antecedent cause of the fluid collection; neither was seen in this case. Finally, well over half of subdural hygromas in children occur before 2 months of age.
The combination of this patient's young age, the distribution of fluid, and the absence of an antecedent cause would be expected in only about 3% of cases.2 Furthermore, idiopathic subdural collections typically respond to subdural drainage and do not recur.2 Thus, the probability of seeing all the features of this case in a general pediatric neurosurgical population approaches zero.2
The radiologic findings combined with the elevated level of protein in the cerebrospinal fluid suggest an abnormality of the microvasculature. At the time of the first drainage of the subdural collections, Dr. William Butler (Neurosurgery) performed a biopsy of the dura. Dr. Frosch, may we review that specimen?
Dr. Matthew P. Frosch: The dura was of normal thickness; there was no inflammation or evidence of previous hemorrhage. A single dural arteriole had intimal proliferation that did not include macrophages or other elements typically observed in atherosclerotic lesions (Figure 2A). The vessel had an intact elastic lamina (Figure 2B), and although rare lymphocytes were present, there was no evidence of vasculitis. No amyloid was present.
Figure 2. Dural Biopsy Specimen.
An abnormal vessel in the dense connective tissue of the dura (Panel A) shows increased cellularity of the intima (hematoxylin and eosin). The elastic lamina of this vessel is well preserved (Panel B, elastic tissue stain).
Dr. Caviness: The character of this vessel was reminiscent of the pathologic vascular changes in a case of Degos's disease that I saw as an intern in medicine at this hospital in 1963.3 Dr. Frosch and I considered this possibility, but the clinical presentation at the time did not support this diagnosis.
Degos's Disease
Degos's disease was initially described as a cutaneous disease with a morphologically distinctive rash.4,5,6,7 The onset ranges from the first months of life to the seventh decade. Between 20 and 30% of cases are limited to the skin, and these patients have a normal life expectancy. However, in the majority of cases, this is a lethal, multisystem disease. The most common cause of death is microvascular infarctions in the intestines, resulting in perforation and peritonitis. The central nervous system is frequently involved, with a spectrum of vasculopathic lesions. Although subdural fluid collections have been reported in several cases, they occurred in patients with extensive vascular occlusion.8
A brief period of improvement followed placement of the shunt, but then the child became increasingly uncomfortable, with severe abdominal pain and headache. He was seen by a gastroenterologist.
Dr. Esther J. Israel: When I first saw this patient, he had had abdominal pain and headaches for several months, and there was the unusual finding of fluid in both his brain and his abdomen. Rheumatologic and oncologic causes were considered, but the results of these evaluations were negative. We then considered common causes of chronic, recurrent abdominal pain in childhood, including constipation, lactose intolerance, dyspepsia, infection, celiac disease, inflammatory bowel disease, renal disease, neoplasms, and connective-tissue disorders. The abdominal pain was transiently relieved with treatment for constipation, lactose intolerance, and infection. When the pain continued to recur despite these measures, colonoscopy and upper endoscopy were performed, but no abnormalities were revealed.
Dr. Caviness: Progressive disability developed, with increasing abdominal girth, confirming the concern at the time of the shunt placement that there was an abnormal degree of fluid collection in the peritoneal cavity. The emergence of a peculiar rash was noted by the parents approximately 2 weeks before the patient's admission because of increasing abdominal girth. The unique features of the rash, together with the finding in the earlier dural biopsy specimen, convinced me of the diagnosis of Degos's disease in this patient. Dr. Mackool saw the patient shortly after admission.
Dr. Bonnie T. Mackool: This patient's cutaneous lesions were typical of Degos's disease. The lesions consist of crops of papules on the trunk, arms, and legs, generally sparing the face, palms, soles, and scalp. Lesions may also occur on the conjunctiva, sclera, choroids, retina, and optic nerve. Early lesions are erythematous, yellow or gray papules, usually 2 to 5 mm in diameter (Figure 3A); they become umbilicated, with central necrosis that has a porcelain, white atrophic appearance with erythematous or telangiectatic borders (Figure 3B).9
Figure 3. Cutaneous Lesions of Degos's Disease.
A photograph shows early skin lesions that are erythematous, yellow or gray papules, with most 2 to 5 mm in diameter (Panel A). During several days, the lesions become umbilicated, with central necrosis characterized by a porcelain, white atrophic appearance and erythematous or telangiectatic borders (Panel B). A biopsy specimen of a lesion on the knee (Panel C) shows homogenization of the dermal collagen, a finding consistent with the presence of ischemia (hematoxylin and eosin). Dermal mucinosis (Panel D) can be seen as blue material between the collagen bundles (colloidal iron stain). These are nonspecific findings that can be seen in connective-tissue diseases but are also consistent with Degos's disease. Photographs in Panels A and B courtesy of Dr. Kenneth Tsai, Department of Dermatology, Massachusetts General Hospital.
The cutaneous eruption typically precedes the visceral symptoms. The lesions are usually asymptomatic but can cause mild burning or itching. The differential diagnosis of cutaneous lesions in Degos's disease includes systemic lupus erythematosus, atrophie blanche, and allergic necrotizing vasculitis. A biopsy of a lesion on the knee was performed on the third hospital day.
Dr. Verne S. Caviness, Jr.'s Diagnosis
Malignant atrophic papulosis (Degos's disease).
Pathological Discussion
Dr. Frosch: The skin biopsy specimen showed a mild, perivascular inflammatory-cell infiltrate. There was a wedge-shaped area of the dermis in which the collagen had a homogeneous appearance — a finding consistent with ischemia (Figure 3C) — and moderate dermal mucinosis (Figure 3D). Although the classic changes that have been described in Degos's disease (atrophic and hyperkeratotic epidermis and a wedge-shaped infarct of the underlying dermis, with the point of the wedge associated with an abnormal vessel) were not present, the findings in this biopsy specimen were considered to be consistent with a clinical diagnosis of the disease.
The pathological lesion of Degos's disease is a predominantly noninflammatory vascular occlusive process, mainly affecting arterioles.4,5,9,10,11 The blood vessels, like the arteriole seen in the dural biopsy specimen from this patient, exhibit increased intimal cellularity that is due to the proliferation of endothelial cells, sometimes with superimposed thrombus. The arteriolar occlusion results in tissue ischemia and infarction, which are responsible for the clinical manifestations of the disease.6,12,13,14 In the central nervous system, involvement of the leptomeningeal vessels causes ischemia and infarction that reflects the distribution of the affected vessels.3,7,15,16,17,18,19,20 In the gastrointestinal tract,21,22,23 the submucosal arteries are typically affected, causing infarction of the bowel, and in some cases, the arteries of peritoneal surfaces are affected.
It has been suggested that Degos's disease is not a distinct disease entity but rather a pathological pattern associated with vascular injury from a variety of causes, such as connective-tissue disease.24,25 However, the distinctive constellation of cutaneous and systemic features, the absence in most cases of diagnostic features of another disease, and the unusual histopathological findings lead many to believe that it is a specific disease, although of unknown cause.26
Dr. Israel: The current admission was precipitated by the marked increase in ascites as well as the new rash. The differential diagnosis of ascites is broad. In the past, ascites was classified as exudative or transudative, but more recently it has been shown to be more helpful to classify ascites on the basis of the serum–ascites albumin gradient (SAAG).27 High-gradient ascites (SAAG, 1.1) is generally associated with conditions that cause portal hypertension, whereas causes of low-gradient ascites include cancer, tuberculosis, pancreatitis, the nephrotic syndrome, and connective-tissue disease. A specimen of this patient's ascites, taken on the third hospital day, together with the skin biopsy specimen, showed a very low SAAG (0.1). Because the ascitic fluid contained no malignant cells or acid-fast bacilli, the amylase and lipase levels were normal, the patient did not have proteinuria, and a tuberculin skin test was negative, a connective tissue disorder or vasculitis was the most likely cause. Degos's disease, a vasculopathy, should cause a low-gradient ascites.
Gastrointestinal involvement by Degos's disease could account for the abdominal symptoms in this case.28 Endoscopic examination may show infarcts and ulcers throughout the entire gastrointestinal tract; pain, perforation, peritonitis, hemorrhage, obstruction, diarrhea, and constipation may occur. After the skin lesions developed in this patient and the diagnosis of Degos's disease was suspected, the endoscopic biopsy specimens were reexamined, and no vascular abnormalities were found. On laparoscopy or laparotomy, white plaques with red borders may be seen on the serosal surface of the intestine.
On the 15th hospital day, the abdominal pain increased, and abdominal tenderness, fever (a temperature as high as 39°C), and pleural effusions resulting in difficulty breathing developed. An exploratory laparotomy was performed by Dr. Daniel Doody (Pediatric Surgery) to rule out intestinal perforation. Innumerable small areas of full-thickness ischemia involved all of the small intestine and colon except for the distal sigmoid and proximal rectum (Figure 4). This finding is typical of Degos's disease involving the bowel. No perforation was found; 1300 ml of ascites was removed and sent for culture, a chest tube was inserted, and the abdomen was irrigated and closed.
Figure 4. Intraoperative Photographs of the Abdomen.
The peritoneum is very slightly thickened but not grossly inflamed. However, there are hundreds if not thousands of small areas of full-thickness ischemia involving all of the small intestine and the colon except for the distal sigmoid and proximal rectum (Panels A and B). There is evidence of neovascularization in several sites (Panel C), suggesting the presence of older but still recent areas of infarction. Photographs courtesy of Dr. Daniel Doody, Department of Pediatric Surgery, Massachusetts General Hospital.
Dr. Sagar: Repeated brain MRI performed on the seventh hospital day (Figure 1C and 1D) showed new petechial hemorrhages centered at the junction of gray and white matter, with intraparenchymal hemorrhages and gyral edema. There was a focus of cystic encephalomalacia in the splenium of the corpus callosum. These findings suggest the presence of microinfarcts resulting from occlusive vasculopathy at the microvasculature level (venules and arterioles). The subdural collections had increased in size, and there was diffuse meningeal enhancement and cerebral atrophy.
Discussion of Management
Dr. Eric F. Grabowski: This child had microvascular infarcts in the central nervous system and gastrointestinal tract that numbered in the hundreds, if not thousands; there were persistent leaks of subdural, subgaleal, and serosal fluid. A diagnosis of Degos's disease had been made on the basis of the characteristic rash, a dural biopsy specimen showing an arteriole with endothelial-cell proliferation, and the appearance of the intestinal lesions. Additional laboratory studies showed elevated levels of vascular endothelial growth factor (VEGF) in both subdural fluid and plasma (196 pg per milliliter; normal value, <31), d-dimer levels of 4000 to 6000 ng per milliliter (normal value, <500), and fibrinogen levels of 600 to 1200 mg per deciliter (normal range, 150 to 400); the results of coagulation studies were consistent with the presence of compensated disseminated intravascular coagulation. We therefore considered the hypothesis that this patient had a dysregulation of vascular remodeling and increased vascular permeability due to increased VEGF production, as well as a prothrombotic process.29,30
There is no known effective treatment for Degos's disease, but drugs that target platelets and the coagulation system have been used, as have immunosuppressive agents.7,31 The patient was initially treated with aspirin and dipyridamole, which inhibit platelet function, and fondaparinux, which inhibits factor Xa, but his condition continued to deteriorate, with increasing ascites, pleural effusions, and tachycardia. A trial of infliximab was also administered without benefit.
Beginning on the 25th hospital day, we elected to treat him with bevacizumab, a recombinant human monoclonal antibody directed against VEGF, and low-molecular-weight heparin. Unfortunately, as this regimen was being started, the patient became difficult to arouse, and MRI showed new intracerebellar hemorrhages with evidence of tonsillar herniation, requiring neurosurgical evacuation (Figure 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). After this event, he remained intubated and unresponsive. Nonetheless, during the ensuing 2 weeks, there was a reduction in his abdominal girth (Figure 2 of the Supplementary Appendix), stabilization of the leptomeningeal fluid leak, a reduction in ventricular tachycardia, and a decline in both the serum level of VEGF (<31 pg per milliliter) and the plasma level of fibrinogen (578 mg per deciliter). These events suggested a response to bevacizumab.
However, during the subsequent 2 weeks, the fluid leaks worsened despite a second dose of bevacizumab. Peritonitis, sepsis, and multiorgan-system failure developed, and the patient died after approximately 8 weeks in the hospital. A request for an autopsy was declined.
Dr. Nancy Lee Harris (Pathology): The patient's mother is here at the conference, and I would like to invite her to give us her thoughts.
Ms. Sandra Clancy: When our son died, we thought that he had a very rare and always fatal disease that had no possibility of cure. During his illness and after his death, we became interested in knowing more about this disease.
In March 2005, I traveled to Berlin to attend the First International Conference on Degos's Disease, hosted by Dr. Christos Zouboulis (Department of Dermatology and Immunology, Dessau Medical Center, Dessau, Germany) and attended by patients and patients' relatives. At this conference, we learned several important things. First, we learned that there is a European registry for Degos's disease and an active research program that has begun to collect epidemiologic data as well as skin biopsy samples and blood samples from patients. We also learned that there are many more patients with the disease than we had realized and that there is an active support group for patients (the Degos Patients' Support Network can be accessed at www.degosdisease.com). Finally, we learned the importance of collecting information and tissue samples from patients and of increasing the interest of researchers in this disease. There are good reasons to study it — little is known about the cause and pathologic processes involved, there are more patients than once thought, and there is a strong network of patients and relatives who support research efforts.
Dr. Harris: Can you tell us why you decided not to give permission for an autopsy?
Ms. Clancy: At the time, I believed that we knew why he had died, and it was not clear to me what would be gained by an autopsy. If I had known then just how much can be learned from an autopsy, I might have made a different choice.
Anatomical Diagnosis
Degos's disease, involving the brain, gastrointestinal tract, and skin.
Dr. Grabowski reports receiving consulting fees from Baxter Pharmaceuticals and a research grant from Novo Nordisk Pharmaceuticals; and Dr. Frosch, consulting fees from Bristol-Myers Squibb and Biogen Idec. No other potential conflict of interest relevant to this article was reported.
Source Information
From the Departments of Neurology (V.S.C.), Radiology (P.S.), Pediatrics (E.J.I., E.F.G.), Dermatology (B.T.M.), and Pathology (M.P.F.), Massachusetts General Hospital; and the Departments of Neurology (V.S.C.), Radiology (P.S.), Pediatrics (E.J.I., E.F.G.), Dermatology (B.T.M.), and Pathology (M.P.F.), Harvard Medical School.
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