Nonconvulsive status epilepticus in peritoneal dialysis patients

Nonconvulsive Status Epilepticus in Peritoneal Dialysis Patients Kai Ming Chow, MRCP, Angela Yee-Moon Wang, MRCP, Andrew Che-Fai Hui, MRCP, Teresa Yuk-Hwa Wong, MRCP, Cheuk Chun Szeto, MRCP, and Philip Kam-Tao Li, FRCP, FACP ● This report describes nonconvulsive status epilepticus (NCSE) in four patients with end-stage renal disease (ESRD) on peritoneal dialysis therapy. All patients presented with acute confusion or stuporous state without clinical motor seizures. Three patients had active systemic infections and were being administered antibiotics. Diagnoses were confirmed in all cases by electroencephalogram (EEG), which showed characteristic diffuse sharp waves and spikes. The EEG appearance improved after anticonvulsant therapy. All patients had satisfactory control of their electrical seizure activity and made varying degrees of mental recovery. To our knowledge, this is the first reported series of NCSE in patients with ESRD on peritoneal dialysis therapy. It shows NCSE as a differential diagnosis for acute confusion. We emphasize the need for nephrologists to consider NCSE as a differential diagnosis for uremic encephalopathy. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Nonconvulsive status epilepticus (NCSE); renal failure; electroencephalogram (EEG).

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ENAL FAILURE is associated with a wide range of metabolic disturbances. Confusion and altered mental states are commonly encountered in dialysis patients. Metabolic encephalopathy, hypertensive crisis, infection, and dialysis disequilibrium are the common causes. Nonconvulsive status epilepticus (NCSE) is a rare but important differential diagnosis because the condition is potentially reversible with treatment. Here, we report four cases of NCSE in patients with end-stage renal disease (ESRD) on peritoneal dialysis therapy. CASE REPORT

Case 1 A 69-year-old woman on continuous ambulatory peritoneal dialysis (CAPD) therapy since 1997 for ESRD of unknown cause was admitted in February 1999 with fever and productive cough. Chest radiograph showed right midzone consolidation, treated as community-acquired pneumonia with intravenous cefepime, 2 g/d. The patient’s fever settled, and sputum production gradually decreased. However, she developed confusion 6 days after admission. On

examination, she had spontaneous eye opening, no verbal response, and did not obey commands. She could move all four limbs spontaneously, and no motor convulsion or myoclonus was observed. There was no focal neurological sign or meningism. Laboratory tests showed the following values: serum sodium, 132 mmol/L; potassium, 3.3 mmol/L; urea, 46.2 mg/dL; creatinine, 14.2 mg/dL; glucose, 133 mg/dL; calcium, 8.5 mg/dL; bicarbonate, 22 mmol/L; and base excess, 2 mmol/L. Liver function and coagulation profile test results were unremarkable. Contrast computed tomography (CT) of the brain showed no intracranial spaceoccupying lesion. Examination of cerebrospinal fluid (CSF) showed opening pressure of 14 cm H2O; protein, 0.23 g/L (normal, 0.15 to 0.45 g/L); and no white blood cells. An electroencephalogram (EEG) showed generalized continuous spike and sharp waves (Fig 1). A diagnosis of NCSE was made. She was administered diazepam, 10 mg intravenously, and phenytoin, 750 mg intravenously over 1 hour, followed by phenytoin, 100 mg slow intravenous injection every 8 hours. Intravenous cefepime was discontinued. A repeat EEG 6 hours after the initiation of anticonvulsant therapy showed organized background activity with very few spikes and sharp waves (Fig 1). Her mental state also improved dramatically, and she was able to make coherent verbal responses. She became fully alert and was able to walk 3 days later. She was then discharged from the hospital and maintained on oral phenytoin, 300 mg/d.

Case 2 From the Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China. Received November 22, 2000; accepted in revised form March 9, 2001. Supported in part by Chinese University of Hong Kong Research Grant Account 6900570. Address reprint requests to Philip Kam-Tao Li, FRCP, FACP, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3802-0020$35.00/0 doi:10.1053/ajkd.2001.26105 400

A 58-year-old woman with diabetic nephropathy and ESRD had been on CAPD therapy since 1996. She had been under treatment for pulmonary tuberculosis for 5 months when she presented to another hospital in May 2000 with 4-day history of progressive confusion. On examination, she was awake but disorientated to time and place. She was afebrile, and there was no neck rigidity or focal neurological deficit. Laboratory tests showed the following values: serum sodium, 131 mmol/L; potassium, 3.3 mmol/L; urea, 63 mg/dL; creatinine, 10.5 mg/dL; calcium, 9.5 mg/dL; and bicarbonate, 19 mmol/L. She was labeled as having uremic encephalopathy. However, her mental state showed no improvement despite intensified peritoneal dialysis for 4 days. She was then

American Journal of Kidney Diseases, Vol 38, No 2 (August), 2001: pp 400-405

Fig 1. EEG recordings of case 1 (A) before treatment and (2) after treatment with intravenous diazepam and phenytoin.

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transferred to our hospital. At that time, she had spontaneous eye opening, confused verbal response, and did not obey commands. She remained afebrile without papilloedema, meningism, or focal neurological sign. Biochemical tests showed the following values: serum sodium, 136 mmol/L; potassium, 3.6 mmol/L; urea, 77.3 mg/dL; creatinine, 15.0 mg/dL; glucose, 99 mg/dL; bicarbonate, 20 mmol/L; magnesium, 2.1 mg/dL; and calcium, 9.4 mg/dL. There was no hepatic dysfunction or coagulopathy. Blood, urine, and sputum cultures were negative. Cerebral CT showed no intracranial space-occupying lesion. Examination of CSF showed normal chemistry, no white blood cells, and negative gram stain. EEG showed frequent sharp waves and slow waves, especially over both frontal regions. A diagnosis of NCSE was made. She was administered lorazepam, 4 mg intravenously, and phenytoin, 750 mg intravenously over half an hour, followed by phenytoin, 100 mg slow intravenous injection every 8 hours. Her mental state gradually improved, and she became fully alert and orientated 2 days later. An EEG 5 days after the start of anticonvulsant therapy showed very occasional interictal sharps. This case has been reported previously.1

Case 3 A 40-year-old woman with diabetic nephropathy and ESRD was on CAPD therapy since 1992 and underwent cadaveric renal transplantation in October 1999. Her postoperative course was complicated by posttransplant lymphoproliferative disorder 1 week after transplantation. Severe vascular rejection and graft dysfunction ensued shortly after a reduction in immunosuppression. Graft nephrectomy was performed 30 days after the transplantation, and she resumed peritoneal dialysis therapy. Her course was complicated by nosocomial pneumonia 10 days after nephrectomy, for which she was administered intravenous cefepime. Four days later, she became agitated. Her mental state deteriorated rapidly, and she became stuporous the next day. On examination, she had no spontaneous eye opening or verbal response, but only withdrawal response to painful stimuli. Fundi examination was normal, and there was no meningism. She had bilateral upgoing plantar responses, but no focal neurological signs. Urea and electrolyte test results were unremarkable. Results from brain CT were normal. Examination of CSF showed negative gram stain, normal glucose level, and no malignant cells. An EEG showed generalized sharp and spike waves. NCSE was diagnosed. She was administered intravenous lorazepam and phenytoin, similar to case 2. However, there was no clinical improvement. Another EEG showed persistent sharp waves. She then was administered a loading dose of phenobarbitone, 200 mg intravenously, followed by a maintenance dosage. Although a repeat EEG showed a substantial reduction in sharp waves afterward, her mental state remained the same. She died of pneumonia 5 weeks later.

Case 4 A 46-year-old woman who had underlying focal glomerulosclerosis progressed to ESRD in 1993 and underwent

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CAPD. In February 2000, she had Pseudomonas aeruginosa peritonitis treated by intravenous ciprofloxacin, amikacin, ceftazidime, and Tenckhoff catheter removal. However, she failed to respond to antibiotic therapy and developed progressive confusion with automatic behavior. Neurological examination was unremarkable. Brain CT and lumbar puncture results were normal. An EEG showed generalized theta waves and occasional triphasic waves. The diagnosis of NCSE was made. She was treated with intravenous diazepam and phenytoin, as in case 1. A repeat EEG 4 days later showed satisfactory control of seizure activity. Despite subsequent improvement in mental state, she finally died of nosocomial pneumonia.

DISCUSSION

NCSE is an uncommon neurological condition characterized by persistent seizure activity on EEG, but minimal clinical motor phenomena.2 The true incidence of NCSE is unknown3 because it is frequently underdiagnosed.4,5 Contrary to convulsive status epilepticus, NCSE has been regarded as a relatively benign condition.6,7 It occurs in two forms: absence status epilepticus and complex partial status epilepticus, defined by Porter and Penry8 and Treiman and DelgadoEscueta,9 respectively. In both cases, there should be ictal EEG abnormality that improves promptly after intravenous antiepileptic drug administration, together with observable effects on clinical manifestation of the status. A range of EEG abnormalities has been reported, from the presence of periodic lateralizing epileptiform discharges to continuous diffuse spike waves. Two basic patterns are recognized: cyclic or continuous ictal EEG activity. In patients with cyclic changes, the EEG may evolve; such epileptiform discharges as polyspike discharges, rhythmic slow waves, or irregular spikes or sharps are initially confined to one region, become more widespread, and subsequently spread to both hemispheres. Our series suggests that NCSE is not uncommon in patients with ESRD. It is also possible that our finding simply reflects a better recognition of the condition, with early application of electrophysiological investigations. Bergen et al10 reported an estimated incidence of seizure of approximately 10% in patients with chronic renal failure. Plum and Posner11 also noted that convulsions occurred in one third of patients with ESRD and was frequently a preterminal event. Most seizures in that series were generalized tonic-clonic type. Searching through the published literature, we only identified four

F/69

F/58

F/40

F/46

NA

Patient No.

1

2

3

4

Scholtes et al,13 1996 Dixit et al,14 2000

M/41

Krumoholz et al,12 1995 Unknown

8.7 on HD

5.8 on HD

NA

12.5 on PD

15.0 on PD 11.9 on PD

14.2 on PD

Serum Creatinine (mg/dL)

Memory, cognitive loss

Confusion

Confusion, obtundation

Confusion

Confusion

Stupor

Confusion

Confusion

Clinical Features

Pancreatitis, HIV

Chronic dialysis Pneumonia post–lung transplant Nil

Diabetes, tuberculosis Diabetes, PTLD, pneumonia Pseudomonas aeruginosa peritonitis

Pneumonia

Other Concurrent Condition

Unknown

Nil of significance

Nil of significance Cefepime

Ceftazidime, ciprofloxacin

Isoniazid, rifampicin Ceftazidime

Cefepime

Drugs

Generalized sharp-wave/slow-wave activity at 2.5-3 Hz Continuous generalized spike and wave discharge at 2-3 Hz Generalized 3-6 Hz slow activity

Slow background activity, continuous polymorphic theta and delta waves, frequent bilateral frontal sharp waves NA

Frequent sharp and slow waves over frontal area Generalized sharp and spike wave discharges at 3-4 Hz

Generalized continuous sharp waves

EEG

Immediate resolution of confusion Confusion improved after benzodiazepine, no recurrence

⬎72 h

Recurrence

NA

Seizure activity under control on EEG but mental and cognitive impairment

Improved EEG appearance mainly

EEG improvement followed by mental recovery Full recovery within 2 d

Outcome

12 h

2d

NA

8d

4d

8d

3d

Duration of Status*

Abbreviations: PTLD, posttransplant lymphoproliferative disorder; PD, peritoneal dialysis; HD, hemodialysis; HIV, human immunodeficiency virus; NA, not available. *Duration is defined as the time from the onset of neurological symptoms to the disappearance of ictal activity in the EEG.

F/40

Tanimu et al,15 1998

M/44

Sex/Age (y)

Table 1. Summary of Clinical and Electroencephalographic Features of Uremic Patients With NCSE in our Series and Reported Cases

NONCONVULSIVE STATUS EPILEPTICUS IN PD 403

404

isolated reports of NCSE in patients with renal failure.12-15 One patient had human immunodeficiency virus infection,12 one patient had aluminum encephalopathy,13 and two patients were on chronic hemodialysis therapy.14,15 Two of four patients had underlying infection, which is consistent with the reported association among the nonuremic population. According to previous epidemiological studies and reports of NCSE, possible precipitating events included alcohol,16 drug withdrawal,4,13,17 infection,4,18 hypoxia,4 cerebrovascular accident,4 menstruation,19 electroconvulsive therapy,20,21 malignancy,22,23 cyclosporine A therapy,24 metrizamide during myelography,25 and antibiotic neurotoxicity.14,26-28 The mechanism of reduced seizure threshold in renal failure is unknown. In vitro data showed the presence of proconvulsive metabolites, including guanidinosuccinic acid, creatinine, and creatine, in plasma and CSF of uremic patients.29 The epileptogenic potency of these compounds was further supported by behavioral studies in animals.30 To hypothesize the link between NCSE and ESRD, we tabulated the clinical features of uremic patients with NCSE from our series and the literature (Table 1). Of all uremic patients with NCSE, the vast majority were documented to have underlying infection requiring antimicrobial therapy. Three of four patients from our series were administered antibiotic therapy before the onset of NCSE. However, rechallenge was not attempted in our patients, and a causal relationship was difficult to prove. Antibiotic dosages had been adjusted according to standard guidelines. Previous studies found permeability changes in the blood-brain barrier,31 which may explain the increased risk for drug-related neurotoxicity in uremic patients. Penicillins, cephalosporins, imipenem/cilastatin, and quinolones have been reported to cause seizure in uremic patients,14,26,27,32-34 presumably because of competitive antagonism of inhibitory ␥-aminobutyric acid receptor in the nervous system.35 These observations indicate an association between neurotoxicity and parenteral administration of large doses of medication in patients with renal insufficiency. It should be noted that all our patients had underlying infection before NCSE. Whether infection per se or subsequent antibiotic treatment precipitated NCSE is not clear, but it is

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reasonable to presume both mechanisms contribute. Our data showed an increased incidence of preceding infection in the dialysis population compared with nonuremic patients with NCSE. As in previous series, intercurrent systemic infection was cited in 8%13 to 15%6 of NCSE cases among the latter. The possibility of a reduced seizure threshold caused by systemic infection and excess susceptibility in the uremic state deserves further study. Cerebrovascular accident was found to be the second most common cause of NCSE in a population-based study of nonuremic patients.4 Despite a high prevalence of hypertensive and atherosclerotic cerebral vascular diseases in patients with ESRD, none of our patients had preceding cerebrovascular events (Table 1). The outcome of NCSE is unclear given the limited number of large series.4,5,12,36 Among nonuremic patients, sequelae including progression to chronic epilepsy, recurrent NCSE, longterm intellectual deficit, and death have been reported.3,12,36 In one series of 10 patients, three deaths were directly or indirectly attributable to NCSE.36 In our series, three patients (cases 1, 2, and 4) manifested both clinical and electrophysiological evidence of improvement after treatment. The other patient (case 3) did not recover and died within 2 months after the onset of NCSE despite satisfactory control of seizure activity by early anticonvulsant therapy. This suggests that development of NCSE may reflect the severity of the underlying medical condition, such as systemic infection. Further study is needed to determine whether the development of NCSE signifies a worse outcome in uremic patients. In summary, our report shows NCSE as an important differential diagnosis of confusion in uremic patients. Attention should be drawn particularly to early recognition of this potentially reversible condition, which might be associated with significant mortality and morbidity. Nephrologists need to consider the possibility of NCSE and arrange an early EEG when uremic patients show acute confusion or altered mental state. REFERENCES 1. Chow KM, Hui AC, Szeto CC, Wang AY, Li PK: A confused uraemic lady. Lancet 357:278, 2001 2. Williamson PD: Complex partial status epilepticus, in

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Engel J, Pedley TA (eds): Epilepsy: A Comprehensive Textbook. Philadelphia, PA, Lippinocott-Raven, 1997, pp 681699 3. Fountain NB. Status epilepticus: Risk factors and complications. Epilepsia 41:S23-S30, 2000 (suppl 2) 4. Towne AR, Waterhouse EJ, Boggs JG, Garnett LK, Brown AJ, Smith JR, DeLorenzo RJ: Prevalence of nonconvulsive status epilepticus in comatose patients. Neurology 54:340-345, 2000 5. Kaplan PW: Assessing the outcomes in patients with nonconvulsive status epilepticus: Nonconvulsive status epilepticus is underdiagnosed, potentially overtreated, and confounded by comorbidity. J Clin Neurophysiol 16:341-352, 1999 6. Guberman A, Cantu-Reyna G, Stuss D, Broughton R: Nonconvulsive generalized status epilepticus: Clinical features, neuropsychological testing, and long-term follow-up. Neurology 36:1284-1291, 1986 7. Cockerell OC, Walker MC, Sander JWAS, Shorvon SD: Complex partial status epilepticus: A recurrent problem. J Neurol Neurosurg Psychiatry 57:835-837, 1994 8. Porter RJ, Penry JK: Petit mal status, in DelgadoEscueta AV, Wasterlain CG, Treiman DM, Porter RJ (eds): Status Epilepticus, vol 34. New York, NY, Raven, 1983, pp 61-67 9. Treiman DM, Delgado-Escueta AV: Complex partial status epilepticus, in Delgado-Escueta AV, Wasterlain CG, Treiman DM, Porter RJ (eds): Status Epilepticus, vol 34. New York, NY, Raven, 1983, pp 69-80 10. Bergen DC, Ristanovic R, Gorelick PB, Kathipalia S: Seizures and renal failures. Int J Artif Organs 17:247-251, 1994 11. Plum F, Posner JB: Metabolic brain diseases causing coma, in Plum F, Posner JB (eds): The Diagnosis of Stupor and Coma (ed 2). Philadelphia, PA, Davis, 1972 12. Krumholz A, Sung GY, Fisher RS, Barry E, Bergery GK, Grattan LM: Complex partial status epilepticus accompanied by serious morbidity and mortality. Neurology 45: 1499-1504, 1995 13. Scholtes FB, Renier WO, Meinardi H: Non-convulsive status epilepticus: Causes, treatment, and outcome in 65 patients. J Neurol Neurosurg Psychiatry 61:93-95, 1996 14. Dixit S, Kurle P, Buyan-Dent L, Sheth RD: Status epilepticus associated with cefepime. Neurology 54:21532155, 2000 15. Tanimu DZ, Obeid T, Awada A, Huraib S, Iqbal A: Absence status: An overlooked cause of acute confusion in hemodialysis patients. J Nephrol 11:146-47, 1998 16. Fujiwara T, Watanabe M, Matauda K, Senbongi M, Yagi K, Seino M: Complex partial status epilepticus caused by ingestion of alcohol: A case report. Epilepsia 32:650-656, 1991 17. Engel J, Ludwig BL, Fetell M: Prolonged partial complex status epilepticus: EEG and behavioural observations. Neurology 28:863-869, 1978 18. Dunne JW, Summers QA, Stewart-Wynne EG: Nonconvulsive status epilepticus: A prospective study in an adult general hospital. Q J Med 62:117-126, 1987

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