A 2-YEAR-OLD BOY WITH HEMOLYTIC UREMIC SYNDROME AND PNEUMOCEPHALUS

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PATHOLOGICAL FINDINGS
Gross pathologic examination of the brain revealed a large area of intraparenchymal hemorrhage with necrosis and cavitation over the left frontal and parietal lobes.There was extensive midline shift with the left hemisphere being significantly larger than the right.Sequential coronal sections of the cerebrum displayed a 6.5 ¥ 6 ¥ 5.5 cm area of dark brown discoloration with friable tissue and cavitation in the left frontal and parietal lobes, extending down the internal capsule to the midbrain (Figures 2 and 3).There was extensive vacuolization involving the cortex, white matter, basal ganglia, caudate and putamen, most severe in the right parietal lobe.Left uncal herniation was seen (Figure 4).Sequential transverse sections of the brainstem perpendicular to its long axis displayed an area of hemorrhage with cystic spaces and discoloration in the left midbrain, continuing into the left pons (Figure 5).Microscopic examination of the cortex, white matter, deep grey matter, hippocampi, cerebellum and brainstem revealed multiple holes of varying sizes (Figure 6), as well as diffuse colonization with rod-shaped bacteria, but without the expected tissue response (Figures 7-9).
General autopsy revealed a similar diffuse bacterial colonization of the lungs, kidneys, liver, and bowel (Figure 10), without an inflammatory response.The kidneys also showed stigmata of HUS, including numerous occlusive thrombi within the glomerular capillaries (Figure 11).There was also necrotizing colitis (Figure 10) and pneumatosis of the abdominal viscera including the colon, spleen, and retroperitoneal tissues.
What is the diagnosis?

DIAGNOSIS
Pneumocephalus due to Clostridium septicum in association with hemolytic uremic syndrome.

DISCUSSION
Clostridium septicum (C.septicum) is an anerobic, spore-forming, gram-positive bacillus, first isolated by Pasteur and Joubert in 1877.It is found in soil and feces and is a well-known cause of gas gangrene in devitalized tissue (1,2).C. septicum was reportedly responsible for much of the gas gangrene in wounded soldiers during World Wars I and II (1).Whether or not C. septicum is part of the normal human fecal flora is still debated.Studies have reported the presence of the organism in the feces of two to three percent of humans (1), and as many as 63 percent of people may carry the bacterium in the appendix (2).
There is a strong association between C. septicum bacteremia and malignancy, especially colon cancer and leukemia.These patients often have some devitilization of colonic tissue by the presence of tumor or necrosis of the tumor and hemorrhage as complications of therapy (3).C. septicum is an opportunistic pathogen, and this injured ischemic colonic epithelium is the likely portal of entry into the bloodstream.Children with hemolytic uremic syndrome may also develop bowel devitalization, either by direct injury to the bowel by infection with E. coli O157:H7 or devitalization of the bowel by thrombosis of small blood vessels secondary to the HUS (3).The mechanism of spread to distant sites appears to be hematogenous.
Sepsis, in this case from C. septicum, results in damage to the vascular walls in the vessels of the brain.These weakened vessels in combination with the patient's thrombocytopenia likely resulted in the large cerebral hemorrhage in this patient.C. septicum organisms were seen diffusely throughout the brain, but without the expected tissue response.There was, however, antemortem radiologic evidence of infection.Other organs with bacterial invasion also failed to show the expected tissue response.The patient was not known to be immunocompromised, so it is unknown as to why his tissues did not react as expected.Bacteria continue to disseminate during the agonal period, and because C. septicum is an anaerobic organism, it can continue to proliferate after death.
The multiple holes of variable sizes ("swiss-cheese" brain) seen in this patient are secondary to the gas-producing bacterium C. septicum, and are compatible with the patient's history of pneumocephalus.Several holes were seen radiologically premortem, but the process continues after death.
C. septicum infection following HUS is a rare phenomenon, but several cases have been reported in the literature (1-4).In one report summarizing six cases (2), four had C. septicum involvement of the brain (brain abscess, pneumocephalus and meningoen-cephalitis, cerebritis, and cerebritis and meningitis), one had myonecrosis, and one had sepsis and abdominal fasciitis.The mortality rate for C. septicum infections in children with HUS is high, with only two out of the six reported patients surviving.With brain involvement, the mortality rate is even higher at 75 percent, with the one known survivor having a brain abscess rather than diffuse pneumocephalus.Early identification of C. septicum infection in children with HUS is important because prompt antibiotic therapy may alter the course of this otherwise fatal illness (3).