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Brain & Development 28 (2006) 610–613

Case report

Zonisamide eradicated paroxysmal headache with EEG abnormalitiestriggered by hypertensive encephalopathy due

to purpura nephritic syndrome

Yuki Anzai a,b,*, Masaharu Hayashi c, Tatsuo Ohya a

a Department of Pediatrics, St. Luke’s International Hospital, Tokyo, Japanb Department of Pediatrics, National Rehabilitation Center for Disabled Children, Tokyo, Japan

c Department of Clinical Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan

Received 20 June 2005; received in revised form 16 December 2005; accepted 10 April 2006

Abstract

Generally, prognosis of hypertensive encephalopathy in childhood is favorable. We reported a 5-year-old girl who presented witha headache attack and EEG abnormalities after hypertensive encephalopathy due to purpura nephritis. The patient had sufferedfrom hypertensive encephalopathy due to purpura nephritis, which soon ameliorated. Five months later, she developed attacksof headache, vomiting and disturbed consciousness with left side-predominant EEG abnormalities. Although carbamazepine andsodium valproate failed to improve her condition, zonisamide eradicated both the symptoms and EEG abnormalities, and an attackhas not reoccurred for 5 years since completion of her treatment. It is noteworthy that delayed-onset complications can occur inchild hypertensive encephalopathy, cases of which should be followed up prudently. Zonisamide should be considered for treatmentof attacks of headaches with an epileptic character.� 2006 Elsevier B.V. All rights reserved.

Keywords: Purpura nephritis; Hypertensive encephalopathy; Headache attack; EEG abnormalities; Zonisamide

1. Introduction

Recent reductions of the frequency of acute glomeru-lonephritis have led to only rare occurrences of childhypertensive encephalopathy, except for that occurringduring renal transplantation [1]. Generally, the long-term prognosis is favorable, given that appropriatetreatments are implemented at the acute phase. Here,we reported a 5-year-old female patient, who developedintractable attacks of headache and vomiting associatedwith EEG abnormalities after hypertensive encephalop-athy caused by purpura nephritis. We stress the

0387-7604/$ - see front matter � 2006 Elsevier B.V. All rights reserved.

doi:10.1016/j.braindev.2006.04.005

* Corresponding author. Tel.: +81 3 3974 2146; fax: +81 3 3554E-mail address: y-annzai@ryouiku.or.jp (Y. Anzai).

delayed-onset complication of hypertensive encephalop-athy, and discussed the importance of zonisamide fortreatment of headache attacks, as this treatment eradicatedboth attacks and EEG abnormalities in our patient.

2. Case report

The girl was born to healthy non-consanguineousparents after an uneventful pregnancy. There was noperinatal asphyxia and psychomotor development wasnormal. Neither was there a family history of neuromus-cular disorders including migraine and epilepsy. Nohabitual headache occurred until after the episode ofpurpura nephritis. At the age of 5 years, 1 week aftera common cold, she developed abdominal and leg pains

Y. Anzai et al. / Brain & Development 28 (2006) 610–613 611

in addition to purpura and was admitted to the DoaiMemorial Hospital. She revealed purpura and abdomi-nal tenderness but not hypertension or edema. Bloodand urine tests were normal, and she was diagnosed withvascular purpura. Two weeks later, she showed subtleproteinuria that rapidly progressed, and subsequentlyhypoalbuminemia and hypercholesterolemia occurred.Under a diagnosis of nephrotic syndrome, treatmentwith adrenocortical steroids was initiated. Althoughproteinuria vanished, during the period when the ste-roids were being tapered, she suddenly showed hyper-tensive encephalopathy, which was composed ofhypertension (150–180 mmHg/ 100–110 mmHg), head-ache, vomiting, unconsciousness and the repetitiveoccurrence of generalized tonic–clonic convulsions.Antihypertensive drugs, diuretics and dexamethasonewith diazepam injection quickly controlled the hyperten-sion and convulsions, consciousness disturbance disap-peared gradually, but headache and vomiting lastedfor 4 days. She did not exhibit fever, leukocytosis or ahigh titer of CRP in the blood, whereas pressureincreased to 227 mmH2O without pleocytosis on cere-brospinal fluid examination. Brain CT demonstratedmild edema (data not shown); brain MRI could not bedone because of her unstable condition. EEG revealedhigh voltage slow wave activities and/or sporadic sharpwaves predominantly on the left side (Fig. 1A). The anti-hypertensive drugs with a diuretic were discontinued.Five months after the onset of hypertensive encephalop-athy, she developed frequent bouts of headache andvomiting sometimes with transient consciousness distur-bances. The headache attack was not accompanied withaura or cause, repetitively appeared five to six times aday and lasted for 30 min at its severest. The headachesper se were characterized by an unbearable feeling of

Fig. 1. Electroencephalograms. During the acute phase (A), background actsharp waves. During the intermittent phase at the time when headache and vo9–10 Hz alpha activity in the occipital area, but intermingled with sharp wa

heaviness but not of pulsation. She showed no autonom-ic abnormalities, and brain MRI, magnetic resonanceangiography (MRA), a test for orthostatic dysregulationand fiber gastroscopy failed to demonstrate any abnor-malities (Fig. 2). However, spikes and/or sharp waveswere found in the left frontal, temporal and central areason EEG (Fig. 1B). As epileptic abnormalities were sus-pected to be involved in her headache attacks, anticon-vulsant therapy was started (Fig. 3). Three months’administration of carbamazepine did not alleviate eitherheadache or vomiting, and so carbamazepine was chan-ged to sodium valproate, which was also ineffective. Atthe age of 7 years she attended our hospital and zonisa-mide was added to sodium valproate. The frequency ofher headache attacks then dramatically decreased, andsodium valproate was terminated. At the age of 8 years,clonazepam was transiently combined with zonisamidebecause of the persistence of EEG abnormalities, butthis was suspended due to exacerbated drowsiness(Fig. 3) even though paroxysmal activities were reducedon EEG. Five years after onset, at the age 10 years, bothher headache attacks and EEG abnormalities complete-ly vanished (data not shown). Six months after the dis-appearance of the headache attack, zonisamide wastapered and terminated. Presently, she is 16 years old,shows no neurological abnormalities, and intelligencequotient (IQ) is 90 (verbal IQ, 86; performance IQ, 97)on Wechsler–Bellevue intelligence for children III.

3. Discussion

There has been a recent transition in the etiology ofchild hypertensive encephalopathy, with renal trans-plantation taking the place of acute glomerulonephritis

ivity is composed of diffuse slow delta activity and left side-dominantmiting attacks occurred repetitively (B), background activity containedves predominantly on the left hemisphere.

Fig. 2. Magnetic resonance imagings (MRI) and angiography (MRA).All T1-weighted (A) and T2-weighted (B) images on MRI, and MRA(C) showed no abnormalities.

612 Y. Anzai et al. / Brain & Development 28 (2006) 610–613

as the main cause [1]. Our patient suggested that purpu-ra nephritis, a common child renal disease, can lead tohypertensive encephalopathy, which is characterized byheadache, vomiting, visual disturbances and seizures,and is relatively acute at onset [2]. Recently, reversibleposterior leukoencephalopathy has frequently beenassociated with hypertensive encephalopathy [3]; andthough not confirmed in our patient, hypertensiveencephalopathy was ameliorated only by conservativetherapy. However, 5 months later our patient devel-oped headache attacks, vomiting and consciousness

disturbances associated with EEG abnormalities,regardless of the absence of changes on MRI andMRA. Her attacks are speculated to reflect epilepsy,migraine with EEG abnormalities, or epileptic headacheand other paroxysmal events. Epilepsy may fit betterthan migraine because of the absence of a family history,the characteristics of the headaches and that there wasno relapse after the termination of zonisamide. Howev-er, it is known that epilepsy and migraine are linked bytheir symptom profiles, co-morbidity and treatment, andthe exact relationship between the two entities has beenmuch discussed [4]. Similarly, our patient’s attacks arehard to definitively diagnose. Although an attack canbe expected as an accidental coincidence, it is morelikely that the attacks were a delayed-onset complicationof hypertensive encephalopathy, because EEG abnor-malities during both the hypertensive encephalopathyand the repetitions of the attacks showed a similar lefthemisphere predominance. Further, in hypertensiveencephalopathy, the left hemisphere predominanceshould also be noted, whereas a parieto-occipital prefer-ence is usually stressed in reversible leukoencephalopa-thy. Generally, hypertensive encephalopathy does notcause a severe sequel in the absence of structural chang-es, and the attacks occurred in our patient almost half ayear after hypertensive encephalopathy. The pathogene-sis of hypertensive encephalopathy remains unclear, butbreakdown in cerebral autoregulation is speculated to beinvolved in the generation of encephalopathy [1]. Theoccurrence of a headache attack might be related to adisturbed nociceptive system regulation in the acutephase. Delayed-onset complication should therefore beconsidered in child hypertensive encephalopathy.

Zonisamide is a widely used anticonvulsant drug inJapan, and was extremely effective in alleviating theheadache attacks and vomiting with EEG abnormali-ties in our patient. Generally, various anticonvulsantshave been applied to migraine prophylaxis [5]. Zonisa-mide has recently also been used as a preventive treat-ment for migraines, and has been shown to be welltolerated in many subjects [6,7]. Zonisamide may playa role in both headache and epilepsy, especially inrespect to localization-related seizures, via neuronalstabilization by altering the functions of ion channelsand modifying the metabolism of neuropeptides andneurotransmitters [7]. Carbamazepine has traditionallybeen recommended for headache attacks in which epi-leptic or migrainous characteristics cannot be well dif-ferentiated; and more recently, sodium valproate hasbeen taking the place of carbamazepine [6]. It is pos-sible that zonisamide was effective for the epilepticcharacteristics of our patient’s attacks. Nevertheless,the rapid improvement in the attacks after the startof zonisamide treatment may be suggestive that zon-isamide can also be an option for the treatment ofsuch an attack.

Fig. 3. Clinical course. Asterisk and arrow denote the onset of hypertensive encephalopathy and headache attack, respectively. Abbreviations: CBZ,carbamazepine; VPA, sodium valproate; ZNS, zonisamide; CZP, clonazepam.

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