48 YEAR OLD MALE WITH SUDDEN ONSET OF RIGHT SIDED WEAKNESS

CLINICAL HISTORY AND RADIOLOGY

This 48 year‐old male presented in October 2000 with sudden (<12 hours) right‐sided weakness. His admission blood pressure was 178/107. Nervous system examination found reduced visual acuity but no double vision or visual field defects. Right‐sided power was reduced to 0/5 (right arm) and 3/5 (right leg), with normal tone, reduced bulk and increased reflexes. Plantars were bilaterally up‐going with ankle clonus. Admission CT scan showed a 3 cm × 2 cm deep left intracerebral hematoma with surrounding edema. The occipital horns of the lateral ventricles were compressed by bilateral hypointense white matter lesions (Figure 1). The next day he developed uncal herniation and repeat CT scan showed expansion of the hemorrhage. The bilateral white matter hypointensities were unchanged. He expired later that day. In 1995 he underwent liver transplantation for end stage cirrhosis from ethanol and hepatitis C, and was placed on cyclosporin. Hepatic artery stenosis developed and warfarin was commenced in 1999. In 1996 type 1 diabetes mellitus was diagnosed and treated with insulin. In June 2000 he developed microangiopathic hemolytic anemia with thrombocytopenia, secondary to thrombotic thrombocytopenic purpura (TTP), attributed to cyclosporin. In July 2000, acute renal failure led to dialysis and a kidney biopsy showed membranoproliferative glomerulonephritis superimposed on diabetic nephropathy with focal arteritis. From August 2000 significant hypertension developed (clinic values: 181–200/100–118) which was resistant to drug therapy. The patient had failing vision for several months, attributed to diabetic retinopathy.

Figure 1.

PATHOLOGY

From the general autopsy, the kidneys showed a thrombotic microangiopathy superimposed on end‐stage diabetic nephropathy. The transplanted liver showed no rejection. The formalin fixed brain weighed 1675 g. There was bilateral hemispheric swelling and expansion of the left uncus. Coronal sections revealed a left sided hemispheric hematoma, extending from the frontal pole to the hippocampus. Beginning at the caudal limit of the calcarine sulcus, diffuse softening and grey‐green discoloration of white matter was found in the occipital lobes bilaterally, extending to the occipital poles. This spared subcortical regions. Scattered petechial hemorrhages (up to 5 mm) were noted in the occipital cortex overlying these regions (Figure 2). Microscopy showed an acute left frontal hematoma with early tissue infarction. Hypertensive arteriopathy was absent in the basal ganglia. The occipital white matter showed zones of diffuse pallor that spared the subcortical zones. Bielschowsky and Luxol fast blue (Figure 3) showed reduced density of both axons and myelin with no loss of oligodendrocytes. Focal acute hemorrhages were noted in the parenchyma and around small arterioles, but vessels were structurally normal. In addition, perivascular spaces were expanded with small parenchymal cysts (Figure 3). Cortical lesions consisted of scattered parenchymal hemorrhages associated with intraluminal microvascular thrombi and perivascular fibrin exudates (Figure 4). A single cortical microinfarct was found, aged over 1 week. These cortical changes were confined to the occipital lobes.

Figure 2.

Figure 3.

Figure 4.

DIAGNOSIS AND DISCUSSION

Diagnoses

• 1Posterior leukoencephalopathy
• 2Thrombotic microangiopathy related to thrombotic thrombocytopenic purpura (TTP)
• 3Hypertensive hemorrhage.

Discussion

This report details the neuropathology of the ‘reversible posterior leukoencephalopathy syndrome’(6). A previous brain biopsy found ‘edematous white matter’(8). The pathology of these cases is rarely examined, because the syndrome is usually transient and non‐fatal. In this case, the patient died of intracerebral hemorrhage, a complication of hypertension, while posterior leukoencephalopathy was present, and therefore came to autopsy.

The reversible posterior leukoencephalopathy syndrome (PLS) was initially described in 15 cases, 12 with acute hypertension; 7 on immunosuppressants. Imaging showed bilateral posterior white matter changes suggesting edema. In all cases, drugs were withdrawn or hypertension treated, resulting in reversal of clinical and imaging abnormalities (6). In a minority of cases, PLS is not associated with hypertension (3), and the imaging changes can become permanent 2, 3. Cyclosporin itself can play a role in the syndrome by contributing to hypertension through TTP/HUS leading to renal microangiopathy, as was seen in this case (4). Other reports suggest that cyclosporin is a direct cause of the syndrome, both in the absence of hypertension (5), and when co‐administered with chemotherapy (9).

The pathology supports the notion that PLS reflects cerebral edema. The generalized pallor of white matter on stains for axons and myelin, and the formation of cystic spaces (parenchymal and perivascular) suggest increased fluid with separation of myelinated axons. Acute hemorrhages were seen, in keeping with acute hypertension, which can disrupt the blood‐brain barrier and so generate vasogenic cerebral edema (7). The overlying lesions of TTP may have contributed to the pathogenesis of PLS through altered vascular dynamics or ischemia. They have been described as consisting of petechial hemorrhages, microthrombus formation and cortical microinfarcts (1). These were conspicuously confined to the occipital lobes. Why this should be the case is unknown, but it may account for the association between TTP and PLS in this case. This would imply that cerebral TTP is a predisposing factor for PLS that requires the superimposed effect of acute hypertension.