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Show ORIGINAL CONTRIBUTION Bilateral Isolated Lateral Geniculate Body Lesions in a Patient With Pancreatitis and Microangiopathy Raghu C. Mudumbai, MD and Anuja Bhandari, MD, FRCOphth Abstract: An 18- year- old woman developed pancreatitis and a thrombotic microangiopathy but no electrolyte abnormalities. She required intubation hours after admission and was not able to communicate for 8 days. Upon recovering consciousness, she reported severely impaired vision in both eyes, but ophthalmologic evaluation and neuroimaging were not obtained until several days later. Ophthalmologic examination documented retinal infarcts and profound binocular vision loss with hourglass bilateral homonymous hemianopic visual field loss. MRI showed signal abnormalities restricted to the area of the lateral geniculate bodies ( LGBs) with characteristics most suggestive of hemorrhagic infarction. Very few cases of isolated bilateral LBG lesions have been reported. Damage has been attributed to myelinolysis from osmotic demyelination or to infarction from microvascular occlusion. This case conforms more to microvascular infarction. The vulnerability of the LGB to selective microvascular infarction may be based on a combination of its unique architecture and high metabolic demand. (/ Neuro- Ophthalmol 2007; 27: 169- 175) Acute bilateral lesions of the lateral geniculate bodies ( LGBs) are rarely reported ( 1- 8). Two major etiologies have been proposed: myelinolysis and ischemia. We present a patient who developed acute bilateral visual loss in the setting of acute pancreatitis and pathologically demonstrated renal microangiopathy. Brain imaging disclosed lesions confined to the LGBs with signal characteristics suggesting hemorrhagic infarction. CASE REPORT An 18- year- old woman developed acute pancreatitis and a microangiopathy. She denied alcohol abuse, mumps, Department of Ophthalmology, University of Washington, Seattle, Washington. Address correspondence to Raghu Mudumbai, MD, Department of Ophthalmology, Box 356485, University of Washington, 1959 Pacific Ave. NE, Seattle, WA 98195; E- mail: raghum@ u. washington. edu or use of corticosteroids or other medications. She was taking oral contraceptive pills. She was admitted to a community hospital because of impaired consciousness, pulmonary edema, and hypoxemia and was intubated shortly after admission. Serum calcium and triglyceride levels were normal, and results of abdominal ultrasound, and abdominal CT scans were negative. The serum amylase level was elevated at 4,836 U/ L ( normal 30- 110 U/ L). She had thrombocytopenia with a platelet count of 74,000/ L ( 150,000- 400,000/ L) and anemia with a hematocrit of 28.4% ( 35%- 46%). There was an increase in schistocytes. The lactate dehydrogenase ( LDH) level was elevated at 11,874 U/ L ( 313- 618 U/ L), results of a Coombs test were negative, the D- dimer level was > 6,700 ng/ mL (< 500 ng/ mL), haptoglobin was < 7 mg/ dL ( 37- 308 mg/ dL), and fibrinogen was 252 mg/ dL ( 170- 410 mg/ dL). Thrombin time and prothrombin time were normal. Partial thromboplastin time ( PTT) was mildly elevated at 54 seconds ( 23- 36 seconds). The von Willebrand factor cleaving protease ( ADAMTS- 13) activity was mildly decreased at 59% ( 67%- 177%), and the inhibitor level of 0.4% with subsequent testing revealed an activity level of 83%. An ADAMTS- 13 level of < 5% is consistent with congenital or idiopathic thrombotic thrombocytic purpura ( TTP), but modest decreases, as seen in our patient, are found in a variety of conditions, including disseminated intravascular coagulation ( DIC). Antinuclear antibody and antineutrophilic cytoplasmic antibody levels were normal. Initial renal parameters were elevated with a blood urea nitrogen ( BUN) of 29 mg/ dL and creatinine of 3.8 mg/ dL, both of which steadily rose. The combination of falling platelets, prolonged PTT, minimal schistocytes, and significantly elevated D- dimer led to a provisional diagnosis of DIC due to pancreatitis. Because of renal failure, she was treated with hemodialysis. A renal biopsy showed cortical infarction. There was arteriolar and arterial thrombosis and intimal thickening consistent with microangiopathy. Immunofluorescence revealed fibrin and vascular thrombi. These pathologic findings, together with the laboratory results, were consistent with a diagnosis of thrombotic microangiopathy ( TMA). J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 169 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Mudumbai and Bhandari Eight days into her illness, she was extubated and reported impaired vision such that she could not recognize faces. She was transferred 10 days after onset of initial symptoms to our facility for further evaluation and management of acute pancreatitis accompanied by acute renal failure and DIC. The patient remained anuric and continued to undergo hemodialysis. Results of the following tests were all normal: activated protein C resistance, antiphospholipid antibody panel, protein S antigen, protein C activity, prothrombin DNA screen, antithrombin III, complement 3, and complement 4. At no time did the patient have hyponatremia or hypernatremia. Brain MRI ( Fig. 1), performed without contrast 11 days after the onset of symptoms and 3 days after the patient was capable of reporting visual impairment, revealed bilateral symmetrical FLAIR signal hyperinten-sities in the posterior thalami in the region of the LGBs. There was increased signal on Tl MRI suggestive of a hemorrhagic lesion. There was no restricted diffusion on diffusion imaging. A gradient echo MRI sequence was not performed. Precontrast brain CT scanning, performed 17 days after onset of symptoms and 9 days after the report of visual loss, showed no abnormalities. ( A repeat scan performed 32 months later revealed the same increased signal on Tl MRI, suggesting a hemorrhagic lesion.) Twelve days after her initial symptoms, our ophthalmologic examination performed in the eye clinic disclosed best- corrected visual acuities of 8/ 200 in both eyes. Color vision with Ishihara plates was 3/ 15 right eye and 0/ 15 left eye. In dim illumination, pupils were measured at 6 mm both eyes and reacted briskly to light. There was no afferent pupillary defect. Anterior segment examination was unremarkable. Dilated fundus examination was normal in the right eye. A few cotton- wool spots and a single retinal hemorrhage were noted along the superior vascular arcade in the left eye ( Fig. 2). Goldmann visual field examination ( Fig. 3) performed 12 days after the report of visual loss showed hourglass visual field defects in both eyes. After our initial examination, the patient was treated with 250 mg intravenous methylprednisolone every 6 hours for 24 hours followed by a tapering dose of 60 mg prednisone with a 10 mg taper per day. During the course of her hospital stay, the pancreatitis improved with a decrease in amylase level to 440 U/ L. At discharge, the platelet count was normal at 172,000/| JLL, hematocrit was normal at 22%, and creatinine was normal at 9.9 mg/ dL. On examination 32 months after illness onset, her best- corrected visual acuities were 20/ 25 right eye and 20/ 20 left eye. Color vision by Ishihara plates was 2/ 11 right eye and 2/ 11 left eye. The pupils reacted briskly. No afferent pupillary defect was present. There was more optic disc pallor in the left eye than in the right eye. Goldmann visual field examination ( Fig. 4) showed slight improvement in the visual field loss. DISCUSSION Bilateral isolated LGB lesions, as seen in our patient, have been described rarely. ( Table 1) The earliest report dates to 1933 when Mackenzie et al ( 1) described a case of syphilitic anterior choroidal arteritis resulting in bilateral LGB infarcts. In 1972, Merren ( 2) provided details of a 37- year- old woman with pancreatitis who was found on autopsy to have well- demarcated coagulative necrosis of both LGBs and hemorrhage of the right basis pontis in association with microangiopathic hemolytic anemia and renal necrosis. The patient was an alcoholic with a disputed history of methanol consumption. In 1995, Donahue et al ( 7) presented a patient with hourglass visual field defects from bilateral LGB lesions attributed to central pontine myelinolysis after liver FIG. 1. Axial FLAIR ( left) and precontrast T1 coronal ( right) MRI performed 3 days after the report of visual loss and 11 days after the onset of symptoms shows high signal in the region of the lateral geniculate bodies bilaterally ( arrows). 170 © 2007 Lippincott Williams & Wilkins Lateral Geniculate Body Lesions J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 FIG. 2. Fundus photo of the left eye shows cotton- wool spots and retinal hemorrhage. transplantation for alcoholic cirrhosis. In 1996, Greenfield et al ( 3) described a woman thought to have a " lateral geniculitis" in association with severe diarrhea. In 2001, Barton ( 6) described a patient with liver failure who underwent a liver transplant and had developed visual loss four months prior to neuro- ophthalmologic examination. She was believed to have extrapontine myelinolysis. In 2002, Moseman and Shelton ( 4) reported a woman with LGB and retinal infarctions from vasoconstriction in severe preeclampsia. In the same year, Imes et al ( 5) reported a patient thought to have intrageniculate myelinolysis affecting selective layers of the LGB ( with sparing of the pons) after near fatal uterine hemorrhage requiring a hysterectomy. In 2004, Lefebvre et al ( 8) reported on a 31- year- old woman who had anaphylactic shock resulting in hemorrhagic infarcts of both LGBs. Our patient, like the patient of Merren ( 2), developed pancreatitis with subsequent DIC, pulmonary edema, and renal failure. She was significantly hypotensive through much of her hospital course ( low blood pressure of 89/ 41 mm Hg). Renal biopsy was consistent with a microangiopathy and renal thrombosis. ADAMTS- 13 activity was only mildly low. ( Severely decreased ADAMTS- 13 activity is thought to be a marker for TTR) A complaint of blurred vision led to our examination, which showed fresh retinal infarcts in one eye, hourglass bilateral homonymous hemianopia, and MRI revealing a normal- appearing brain except for FLAIR signal hyper-intensities in LGBs with increased signal on Tl suggestive of blood products within the lesion. This clinical presentation led us to believe that the patient had bilateral hemorrhagic infarctions of the LGBs. The LGB ( 9) is a cap- like structure on the posterior end of the thalamus. It has a very high metabolic rate and a dual blood supply, consisting of the anterior choroidal artery that arises from the internal carotid artery and supplies the anterior hilus and the lateral choroidal artery, a branch of the posterior cerebral artery that supplies the rest of the nucleus including the macular zone. The LGB has multiple layers of tightly connected, criss- crossing white and gray matter. Myelinolysis, or osmotic demyelination, has been proposed in three reports ( 5- 7) as the cause of bilateral LGB damage ( Table 1). Myelinolysis usually occurs in individuals with chronic debilitating conditions such as alcoholism and liver disease after chronic hyponatremia has been rapidly reversed. Affected structures include the pons and various extrapontine sites such as the cerebellum, thalamus, caudate, putamen, and LGB. In the acute phase, MRI discloses symmetric hypointense signal on Tl and hyperintense signal on T2/ FLAIR and may acutely show enhancement with contrast ( 10). The LGB is thought to be affected because it shares the same grid arrangement of white and gray matter as the FIG. 3. Goldmann visual field examination performed 12 days after the report of visual loss shows hourglass homonymous hemianopic defects. 171 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Mudumbai and Bhandari FIG. 4. Goldmann visual field examination performed 32 months after the first report of visual loss shows some improvement relative to initial Goldmann visual field values. pons, where there is tight meshing between neurons and ohgodendroglia that makes these tissues sensitive to osmotic forces ( 11). Because of their compact relationship with surrounding neurons, the oligodendrocytes in the LGB and pons have a limited capacity to swell as a means of maintaining iso- osmolality with the extracellular space. They are then forced to actively extrude osmolytes, a process that leads to cell shrinkage. TABLE 1. Prior Study Mackenzie et al1 1933 Merren2 1972 Donahue et al7 1995 Greenfield et al3 1996 Imes et al5 2002 reports Moseman and Shelton4 2002 Lefebvre et al8 2004 of bilateral lateral geniculate body lesions Age N/ A 37 37 28 33 21 31 Sex F F F F F F F Visual field defects Incongruous symmetric superior Altitudinal hemianopia and lower nasal quadrant defect OD Unable - Light perception vision Bilateral congruous hourglass defects Left homonymous wedge- shaped defects and incongruous right homonymous hemianopia Bilateral, highly incongruous sectoranopc defects Unable ( Light perception only) Incongruous binasal and bitemporal defects improving over time MRI N/ A N/ A Initial: Increased T2 signal in central pons with sparing of peripheral pons; F/ U: T2 high signal of LGBs 6 months later Increased T2 signal of LGBs and left optic tract. Minimal enhancement Symmetrically decreased Tl signal with enhancement, increased T2/ FLAIR signal of LGBs and optic tracts Symmetric, bilateral decreased Tl signal, increased FLAIR/ T2 signal in LGBs Symmetric lesions of LGBs and parahippocampal regions seen on FLAIR as high signal intensity suggestive of hemorrhagic ischemia. Normal Tl without enhancement. Hemosiderin on gradient echo imaging N/ A, not available. 172 © 2007 Lippincott Williams & Wilkins Lateral Geniculate Body Lesions J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Of the three patients in whom LGB lesions were attributed to myelinolysis, the patient reported by Donahue et al ( 7) presents the most convincing scenario. This was a young woman with alcoholic cirrhosis and chronic hyponatremia who was undergoing liver transplantation. She underwent overcorrection of serum sodium to hyper-natremia; she did not have hypotension or severe blood loss. Increased T2 MRI signal was present in the central pons with sparing of the peripheral pons. Repeat MRI months later, using Horton's ( 12) protocol for imaging the LGB, disclosed hyperintense lesions in both LGBs on T2 MRI. The patient of Imes et al ( 5) had a clinical course complicated by massive hemorrhage and hypotension requiring hysterectomy; there was no hypematremia. The patient of Barton et al ( 6) had mild hyponatremia before hepatic transplant and mild hypematremia postoperatively and did not have " excessive hypotension or blood loss." LGB lesions were alleged on the basis of hourglass visual field defects, but MRI performed 5 months after the transplant showed only a small left lateral thalamic T2 hyperintensity CT scanning performed 13 days after transplantation was normal, and there is no mention of MRI performed at that time. The patient of Barton et al ( 6), although not having clear vasculopathic confounders, does require postulation of purely extrapontine myelinolysis with relatively minor sodium osmolality shifts and without radiologic support of bilateral LGB involvement. The patient of Imes et al ( 5) may have had LGB infarction related to the severe hemorrhage and hypotension instead of the proposed myelinolysis. As an alternative to myelinolysis, vascular compromise by a variety of mechanisms has been proposed as the mechanism of bilateral LGB lesions ( 1,2,4,8). Mackenzie et al ( 1) provided histopathologic evidence of syphilitic gumma and arteritis of the anterior choroidal arteries in a single case of bilateral LGB damage. In discussing why Timing of MRI from presentation Associated findings Proposed etiology Pathology N/ A N/ A Prior right hemiparesis and left hemibody paresthesias that resolved completely Pancreatitis; renal failure 2 weeks 1 week Not stated 1 day 1 day Alcoholic cirrhosis; chronic hyponatremia; post- operative encephalopathy Diarrhea Hypotensive Respiratory distress Retinal ischemia Anaphylactic shock; Syphilitic arteritis Microangiopathy; ? methanol toxicity Central pontine myelinolysis; hyponatremia corrected; no systemic hypotension " Lateral geniculitis" temporally related to infectious etiology of diarrhea " Intrageniculate myelinolysis" after near fatal uterine hemorrhage and hysterectomy Preeclampsia, eclampsia, vasoconstriction Ischemia of LGB LGBs infiltrated by syphilitic gummas, also present in thalamus LGB: coagulative necrosis; Kidney: patchy areas of coagulative necrosis + reactive glomerulus Blood: schistocytes c/ w microangiopathic hemolytic anemia None None None None None Systemic hypotension 173 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Mudumbai and Bhandari the anterior choroidal arteries should be affected in isolation, he stated that syphilis can symmetrically affect any part of the body, including the hands, iris, and choroid. The patient of Merren ( 2), like ours, had pancreatitis and a microangiopathy that led to renal failure. Despite the fact that the LGB has a dual arterial circulation, Merren ( 2) postulated that if acute arterial compromise occurred quickly, necrosis would occur before anastomoses could become effective. He also noted that the microangiopathic process led to occlusion of small arterioles that could cause infarction in the kidneys and the LGBs. His theory was supported by pathologic evidence of liquefactive necrosis in the LGBs. In refuting the notion that myelinolysis accounted for LGB damage in their patient, Lefebvre et al ( 8) pointed out that the hemorrhage seen on MRI, which had not been noted in any reported cases of myelinolysis, probably resulted from disruption of the blood- brain barrier in the distribution of the anterior and lateral posterior choroidal arteries. They attributed the lack of restricted diffusion to the fact that 16 days had elapsed between the onset of visual loss and performance of MRI. In their patient, the low signal of hemosiderin deposits was still seen on gradient echo MRI 1 year later. They hypothesized that hemorrhagic infarction had damaged the LGBs and suggested that the LGBs lay in watershed zones. The mechanism of LGB damage in our patient is also more likely to have been small vessel occlusive disease with hemorrhagic infarction than myelinolysis. There was strong evidence of a thrombotic microangiopathy and no evidence of rapid osmotic shifts. We acknowledge that if these were fresh hemorrhagic infarctions, we would have expected to find restricted diffusion on diffusion imaging and high signal attenuation on brain CT scanning. Like Lefebvre et al ( 8), we attribute the lack of restricted diffusion on diffusion imaging to the fact that the MRI was performed 11 days after our patient's coma began. Given that the patient's consciousness had been impaired we do not know how long the LGB damage was present before she was even able to notice visual loss. Restricted diffusion is known to dissipate within 10- 14 days of vascular compromise ( 13). The absence of signal attenuation of fresh blood on the brain CT could be explained by the even greater delay from the first report of visual loss to the performance of the CT scan and the fact that the area of the putative hemorrhage is very small. As further support for the mechanism of vascular occlusion in our patient, she had features of TTP and hemolytic uremic syndrome ( HUS), two microangiopathies that lead to platelet microthrombi, which can occlude arterioles and capillaries ( 14). The overlap between TTP and HUS has led to their being considered forms of TMA. Renal failure and neurologic abnormalities are common features. Cerebral microthrombi can be seen in 50% of HUS cases going to autopsy with evidence that cerebral and renal endothelial cells may share susceptibility to apoptosis from TTP/ HUS ( 15,16). DIC, a known complication of severe pancreatitis, could easily have accounted for the microvascular occlusions ( 17,18). Moreover, both acute pancreatitis and DIC have been associated with acute bilateral renal necrosis ( 19). Our patient is strikingly similar to the patient of Merren ( 2), who also had pancreatitis and developed abnormalities of coagulation that led to TMA and LGB lesions. Pathologic evaluation of the LGBs in the Merren's patient ( 2) showed clear evidence of ischemic necrosis rather than myelinolysis. Myelinolysis and ischemia each provide adequate pathophysiologic mechanisms for LGB damage, but they do not provide a satisfying explanation as to why the LGBs should be have been compromised without apparent damage to other parts of the central nervous system. The hypothesis of Lefebvre et al ( 8) that the LGB is part of a watershed zone is tenuous because of the infrequent involvement of the LGB in other watershed infarcts. Myelinolysis most typically involves the pons with less frequent involvement of other structures like the LGB. The high metabolic demand of the LBGs may make them vulnerable to myelinolysis or ischemic damage. Myelinolysis usually requires hypernatremia from rapid correction of chronic hyponatremia leading to extravasation of intracellular fluid to the intravascular space, which results in rapid dehydration of the oligodendrocytes. If isotonicity is not established before inorganic ion shifts occur, cells must synthesize organic osmoles to prevent further cell shrinkage. If the metabolic rate is high enough, patients with poor nutrition become at risk for the development of demyelination because they cannot easily generate the compensatory organic osmoles ( 11). The vulnerability of the LGB to infarction might also be based on its vascular architecture. Fujino ( 20) found that blood vessels ran vertically through the LGB, from which short transverse vessels branched off. Each vertical vessel gave branches to corresponding laminae. Importantly, there were no anastomoses between the cellular layers of the LGB and between the LGB and optic radiations. The most vascular areas of the LGB were the intermediate quadrant ( macula) and the caudal portion. The blood supply to the medial and lateral quadrants was relatively poor. The small clusters of terminal capillaries did not have overlap in their vascular supply. Fujino ( 20) concluded that " this rich vascularity points to the active metabolism which must be taking place in this important structure." Also, " with the rich vascularity of the macular region of the LGB, it would be difficult for a small vascular accident to affect macular function severely. Because each vertical vessel sends branches 174 © 2007 Lippincott Williams & Wilkins Lateral Geniculate Body Lesions J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 to corresponding areas of adjoining laminae, an occlusion of one of these vessels would result in a homonymous field defect. And because of the lesser vascularity of the quadrants representing peripheral visual fields, occlusion of these vessels would result in a relatively large field defect." It is interesting that every reported case of bilateral LGB lesions has involved women, particularly during pregnancy. TTP/ HUS is associated with pregnancy and has a preponderance in women. A meta- analysis of 2,229 patients with TTP/ HUS showed that 66% were women and that 13% of837 women with TTP/ HUS were pregnant ( 21). Acknowledgments We thank Drs. Kenneth Maravilla ( Radiology) and John Harlan ( Hematology) at the University of Washington, Dr. Louis Sokoloff at the National Institute of Health, and Dr. Marcus Raichle at Washington University for their comments regarding metabolism in the brain and lateral geniculate bodies, and Dr. Phillip P. Chen at the University of Washington for his review of the manuscript. REFERENCES 1. Mackenzie I, Meighan S, Pollock EN. On the projection of the retinal quadrants on the lateral geniculate bodies, and the relationship of the quadrants to the optic radiations. Trans OphthalmolSoc UK 1933; 53: 142- 69. 2. Merren MD. Bilateral lateral geniculate body necrosis as a cause of amblyopia. Neurology 1972; 22: 263- 8. 3. Greenfield DS, Siatkowski RM, Schatz NJ, et al. Bilateral lateral geniculitis associated with severe diarrhea. Am J Ophthalmol 1996; 122: 280- 1. 4. Moseman CP, Shelton S. Permanent blindness as a complication of pregnancy- induced hypertension. Obstet Gynecol 2002; 100: 943- 5. 5. 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