The role of seizures in reversible posterior leukoencephalopathy

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1 Seizure 2004; 13: doi: /s (03) CASE REPORT The role of seizures in reversible posterior leukoencephalopathy T. OBEID, A. SHAMI & S. KARSOU Departments of Medicine and Diagnostic Imaging, King Khalid National Guard Hospital, Jeddah, Saudi Arabia Correspondence to: Dr Tahir Obeid, M.R.C.P., Section Head, Neurology, Department of Medicine, King Khalid National Guard Hospital, P.O. Box 9515, Jeddah 21423, Saudi Arabia. We report two hypertensive females, one suffering from chronic renal failure and on regular dialysis, the other with eclampsia. Both developed new onset seizures. The patients MRI of brain showed signals consistent with the reversible posterior leukoencephalopathy syndrome (RPLES), but with the signals seen only in the hemisphere where the seizures predominated. The anatomic correlation of the clinical and imaging findings supports the notion that seizures have a major role in the genesis and evolution of RPLES BEA Trading Ltd. Published by Elsevier Ltd. All rights reserved. Key words: leukoencephalopathy; seizures; autoregulation; MRI. INTRODUCTION Reversible posterior leukoencephalopathy syndrome (RPLES) is a recently described entity, which clinically manifests with headache, nausea, vomiting, disturbed level of consciousness, seizures, visual disturbances, and occasionally focal neurologic deficits 7. The hallmark of this syndrome is the presence of reversible lesions, best visualised with T2-weighted MRI imaging especially on FLAIR sequencing. This mainly involves the posterior regions of the brain and is most prominent in the white matter although grey matter may be affected also 6, 7. These lesions are most likely vasogenic oedema and are usually bilateral. The syndrome is commonly described in hypertensive encephalopathy, eclampsia, renal failure and in patients on immunosuppressive therapy 6, 7. An abrupt rise of blood pressure (BP) is incriminated as the main factor in the pathogenesis of this syndrome, although it has been described in absence of severe hypertension 6, 7. Some authors believe that the encephalopathy is, in fact, a seizure-related phenomenon in a brain whose autoregulatory mechanisms are impaired. Hence, it is speculated that RPLES is not a specific syndrome or disease 11, 12. The purpose of our report is to describe two atypical cases that, we believe, illustrate the significant role seizures have in this syndrome. PATIENT 1 A 50-year female patient with chronic renal failure on regular haemodialysis was admitted to King Abdulaziz Medical City (KAAMC), Jeddah, with a disturbed level of consciousness and seizures. The family found the patient in a drowsy state with occasional left-sided motor seizures onset after her dialysis. There was no history of previous seizures. When seen in the Emergency Department, she was drowsy with normal vital signs except for BP of 150/95 mmhg and a left-sided flaccid hemiplegia. She was treated with i.v. diazepam and phenytoin, following which her level of consciousness improved dramatically although the hemiplegia persisted. FBC, including RBC morphology and coagulation profile, were normal apart from a Hb of 9.8 g/dl. Biochemistry results were normal except for /$ BEA Trading Ltd. Published by Elsevier Ltd. All rights reserved.

2 278 T. Obeid et al. Fig. 1: (a) FLAIR imaging showing high signal intensity lesions in the right posterior parietal area. (b) Disappearance of the signals 6 days later. a glucose of 13.4 mm/l. The ECG and echocardiogram showed evidence of left ventricular hypertrophy only. Screening for infection, including CSF examination, was negative. The EEG done 24 hours after admission showed generalised theta activity more prominent on the right side while the admission CT scan of the brain was normal. The MRI which was performed 48 hours later showed high signal intensity lesions in the right parietal region on T2 images, best visualised with FLAIR (Fig. 1(a)). The lesions were non-enhancing and the concomitant MRA was normal. The hemiplegia resolved within 48 hours and a repeat MRI of the brain 6 days later was normal (Fig. 1(b)). Phenytoin therapy was discontinued after 4 weeks and over a follow-up period of 8 months she remained well. PATIENT 2 A 36 years old woman, gravida VII, in the 37th week of gestation was admitted to KAAMC with an antepartum uterine haemorrhage. She was found to have a BP of 170/98 mmhg, oedema of the legs and proteinuria. She was diagnosed as having pre-eclamptic toxaemia with placenta previa. Treatment was started with magnesium sulphate and captopril and the patient was booked for an urgent Caesarean section (CS). Three hours later the patient complained of a severe headache and had visual hallucinations. She then had a generalised tonic clonic seizure lasting less than a minute and was treated with i.v. diazepam. There was no prior history of seizures. Investigations were as

3 The role of seizures in reversible posterior leukoencephalopathy 279 Fig. 2: (a) FLAIR imaging showing high signal intensity lesions in the occipital and parietal area. (b) FLAIR images showing resolution of the signals 3 weeks later. follows: a normal FBC, including RBC morphology and coagulation profile, apart from Hb of 10.2 g/dl. The biochemical screening was normal except for an albumin of 25 g/dl (N = 34 48) and mildly elevated liver enzymes. Autoimmune and hepatitis screens were negative. An emergency CS was performed. Postoperatively, she continued to complain of headaches and visual blurring. She subsequently had six, right-sided partial motor seizures all lasting less than 10 minutes, following which the patient was given 1.5 g of i.v. phenytoin. At that time a bedside visual field assessment was normal, her reflexes were brisk with power of grade 4 (MRC grading) and a Babinski s sign on the right. The BP increased to 180/110 mmhg and was treated with captopril and hydralazine. The CT scan of brain showed a hypodense area in left parieto-occipital region. An MRI of the brain performed 48 hours later showed signals on the T2-weighted images and FLAIR in the right parieto-occipital region which was non-enhancing (Fig. 2(a)). A concomitant MRA was normal. The postictal EEG showed increased theta/delta activity in the left hemisphere with no epileptogenic foci. The neurological findings resolved in 5 days although she complained of visual blurring which lasted for 2 weeks. A repeat MRI 10 days later showed reduction in the size of the signals and had normalised 3 weeks later (Fig. 2(b)). The patient s phenytoin was stopped after 3 weeks and she reported no further seizures over a follow-up period of 6 months. DISCUSSION These two cases qualify for the diagnosis of RPLES, as they both had the etiologic, clinical and radiological features of RPLES. Other diagnostic considerations, such as ischemic stroke, sinus thrombosis, infection and autoimmune diseases, are unlikely because of the clinical course and lack of supportive evidence. What is unusual is the fact that the transient signal changes

4 280 T. Obeid et al. were unilateral, which makes our cases formes fruste of RPLES. The unilaterality of the MRI high signal intensity lesions corresponding to the side of the brain where the convulsive activity appears to have dominated, suggests that seizures must have a major role in the evolution of these MRI lesions. One may argue that the MRI signals in these cases are the well-known transient seizure-related shadows well described in the literature 1, 3 5, 8 10, It is interesting to note that in reviewing such cases, the lesions are usually seen only in protracted partial status epilepticus. These two cases had no history of epilepsy and their seizures were short-lived. The previously described shadows in status epilepticus whether partial or generalised differ in many aspects from the MRI signal changes described in RPLES and seen in these two cases. With status the signals are usually cortical although subcortical extension may occur 3 5, 8 10, 13. Not infrequently they are associated with swelling of the gyri with a mass effect 3 5, 8, 10, 13. As well, they are usually seen in the maximally discharging regions as documented in functional MRI, SPECT and video-eeg studies 1, 4, 5, 8, 10. There is a suggestion that the changes in the grey matter result from hypoxia or release of excitatory amines 4. In the majority of RPLES cases tonic clonic or occipital lobe seizures precede the other manifestations of the syndrome, although status epilepticus is not described 2, 7, 14. Some authors believe that in patients with RPLES, as in these two cases, the seizures, which are not protracted, cause unilateral vasogenic oedema in vulnerable regions of the brain 11, 12. These are usually the posterior regions where the paucity of sympathetic innervation of this region is hypothesised to predispose to this vulnerability 2. Most RPLES patients have severe metabolic abnormalities which are believed to disturb the integrity of distal brain vascularity or interfere with sympathetic activity, leading to a breakdown of the blood brain barrier (BBB) 6, 7. The abrupt rise of BP relative to baseline may play a major role in disrupting this autoregulatory mechanism 6. Seizures themselves may contribute to an abrupt rise in BP. There are as yet no prospective studies of RPLES making under reporting of seizures a real possibility. This is especially so in the situation when RPLES patients have associated serious medical problems which may make subtle seizures difficult to recognise. The lack of enhancement on MRI in these two patients suggests that the breakdown of BBB was transient as the imaging was done 2 days after the ictus. The magnitude and extent of the lesions depend mainly on the water content of the brain as well as the type and severity of seizures. Occipital lobe seizures have been described as a major clinical manifestation of RPLES This suggests that occipital lobe seizures may play a significant role in the anatomical location of the signal changes, offering an alternative explanation for the posterior location of the lesions instead of the hypothesis that a paucity of sympathetic innervation in that region is the reason for this location 2. The abrupt development of RPLES and its quick response to the lowering of BP and control of seizures, despite of the signal changes outlasting the clinical features of the syndrome by several days or weeks, imply that the shadows have no significant role in the symptology of the syndrome except for the visual disturbances. Shortcomings of these case studies include a lack of utilisation of DWI, functional MRI and video-eeg monitoring. Despite these limitations the anatomic correlation of the clinical and imaging finding supports the notion that seizures play a major significant role in the genesis and evolution of RPLES 11. ACKNOWLEDGEMENTS We would like to thank Professor Hisham Arab for allowing us to include case 2 in the study, Dr Thomas Austin for reviewing the manuscript and Ms Maria Belen L. Almoro for her secretarial support. REFERENCES 1. Bauer, J., Stefan, H., Huk, W. J., Feistel, H. et al. CT, MRI and SPECT neuroimaging in status epilepticus with simple, partial and complex partial seizures: case report. Journal of Neurology 1989; 236: Bakshi, R., Bates, V. E., Mechtler, L. L., Kinkel, P. R. and Kinkel, R. W. Occipital lobe seizures as the major clinical manifestation of reversible posterior leukoencephalopathy syndrome: magnetic resonance imaging findings. Epilepsia 1998; 39: De Carolis, P., Crisci, M., Laudadio, S., Baldrati, A. and Sacquegna, T. 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