To clarify the diagnosis and treatment of epilepsy with higher brain dysfunction (E-HBD).
To clarify the diagnosis and treatment of epilepsy with higher brain dysfunction (E-HBD).
Using neuropsychological testing we identified three cases.
All three cases showed persistent aphasia, amnesia or attention deficits – possibly connected with epilepsy – and were treated with anti-epileptic drugs (AED). Although the AED proved effective, there were no findings of non-convulsive status epileptics.
The etiology of E-HBD is unclear, but treatment with AED alleviated the higher brain function deficits in our three patients.
Higher brain dysfunctions, such as aphasia and amnesia, are found in cases of head trauma and cerebral vascular disease. Neurodegenerative diseases produce symptoms of progressive higher brain dysfunctions that are hard to distinguish from non-progressive symptoms. Epilepsy might be associated with higher brain dysfunction. Furthermore, ictal aphasia and transient epileptic amnesia (TEA)[2, 3] with temporal lobe epilepsy are also well known.
If an epileptic attack persists or is repeated over a short period, it is regarded as non-convulsive status epilepticus (NCSE). The patient might become comatose.[4, 5] We also know that NCSE might occur with milder disturbances of consciousness, and/or other symptoms.[6-8] Amnesia[2, 9, 10] or aphasia[11-13] can, in rare cases, also occur as NCSE symptoms.
Furthermore, cases of epilepsy with higher brain dysfunction (E-HBD) without electroencephalography (EEG) evidence of NCSE have been clinically identified.[14, 15] Nagayama suggested the use of the descriptive phrase “antiepileptic drug-responsive neurological deficit” for cases where patients respond to use of anti-epileptic drugs (AED). The therapeutic response to AED is thus a key component of establishing E-HBD.
We examined three cases of E-HBD without EEG evidence of NCSE to clarify their symptomatology, and found that AED were successful in alleviating the patients’ dysfunctions.
We examined three patients diagnosed with E-HBD whose symptoms disappeared after use of AED. Other diagnoses, such as cerebral vascular disease or neurodegenerative disease, could not account for their symptoms. All three patients were examined at Showa University Hospital in Tokyo, Japan, in 2011.
A 64-year-old, right-handed man developed difficulty in conversation after a few minutes of generalized attack. He had had an operation for an arteriovenous malformation in the left temporal lobe, and a year earlier had started to use valproic acid (800 mg/day). He regained consciousness after his attack, but 2 days later could not speak.
The patient had paraphasia and could not fully follow instructions (video 1 on day 5). Furthermore, he could neither read nor write. There was no motor paralysis, but a postoperative change in the left parietal lobe was evident with magnetic resonance imaging (MRI).
The patient's difficulty with language comprehension continued; and on day 4, although his EEG was normal, we gave him an intravenous injection of diazepam (10 mg). Immediately after the injection he was able, with a little paraphasia, to follow instructions; but in approximately 1 hour he went back to his previous state. We added levetiracetam (2000 mg/day) to valproic acid (800 mg/day). His language comprehension improved, and on day 42 his speech and auditory comprehension were normal (video 2), aside from mild agraphia and alexia, and construction apraxia. (Fig. 1)
An 84-year-old right-handed woman, with a history of generalized attacks from the age of 33 years, complained of amnesia and was diagnosed with possible temporal lobe epilepsy with automatism. The fronto-parieto-temporal lobes showed small spikes bilaterally. The etiology was unclear. She was already taking phenytoin (150 mg/day), and its blood level was within the therapeutic range. She had not had a generalized attack for 10 years, although automatism occurred every 1–3 months. On MRI, mild bilateral hippocampal sclerosis was suspected (Fig. 2). Her amnesia became severe – according to the patient's own account it had begun 6 months before – and we added lamotrigine to phenytoin and gradually increased the dose to 200 mg/day over 2 months. After starting on lamotrigine, the patient's memory gradually improved and, 3 months later, the amnesia was gone and her automatism stopped. (Fig. 3)
A 74-year-old right-handed woman developed amnesia and difficulty in word finding. Approximately 1 month after appearance of the first symptoms, she could not understand television programs or dress herself. Then she had a generalized attack and was hospitalized. On admission, she had mild disturbance of consciousness, but no paralysis or sensory disturbance. She was prescribed carbamazepine with a blood concentration in the therapeutic range. On day 7 after admission, the patient became disoriented (video 3), but with intravenous injection of diazepam (10 mg) she became alert. We added carbamazepine (400 mg/day) on day 8 and levetiracetam (1000 mg/day) on day 14. On day 16, we reduced the carbamazepine to 200 mg/day because of hepatic dysfunction. On day 8, the patient was alert with normal orientation, but her forward digit span test was 4 and 2 reversed. She was discharged on day 16. She visited us on day 22, and we added levetiracetam (2000 mg/day) to guard against paroxysmal mild consciousness disturbance. On day 62, the patient was alert and had no paroxysmal consciousness disturbance (video 4 on day 88). (Fig. 4)
We assessed the neuropsychological symptoms before and after adjustment of AED. Standardized neuropsychological tests were used. With case 1, who showed aphasia, we used the Mini-Mental State Examination (MMSE) and the Western Aphasia Battery (WAB). With cases 2 and 3, who had memory disturbance or a dementia-like state, we used MMSE and the Wechsler Memory Scale-Revised (WMS-R).
Patients were also examined using EEG, MRI and single photon emission computed tomography (SPECT) with 123I-IMP.
Video 1 shows the patient's aphasia on day 5: spontaneous speech was fluent, naming was paraphasic, and comprehension and repetition were severely disturbed. He could neither read nor write. There was no anosognosia, and he was able to say: “I can't understand what you are saying” and “Here is bad” (while pointing to his head).
On day 4 we added levetiracetam (2000 mg/day) to valproic acid (800 mg/day) and the patient's aphasia disappeared over a few days. Table 1 shows the Western Aphasia battery results on days 18 and 43. He recovered normal speaking ability, but mild alexia with agraphia continued.
|Case 1||Case 2||Case 3|
|Day 18||Day 43||6 months||9 months||Day 8||Day 62|
|General memory||–||–||Under 50||77||56||94|
|Visual memory||–||–||Under 50||77||Under 50||75|
|Digit span (forward/backward)||–||–||–||–||5/4||8/5|
The patient's amnesia only came to our notice 6 months after it first appeared, and at that point, her MMSE score was 26/30 with errors on orientation, calculation and recall. However, the patient clearly had long-term retrograde amnesia, because she could not remember when and where she had married or had a baby. She also showed anterograde amnesia in failing to keep a subsequent appointment at the hospital. WMS-R showed severe memory dysfunction with preserved attention/concentration.
We added lamotrigine to phenytoin, and 3 months later–9 months after first complaining of amnesia–her MMSE score was the same at 26/30 with errors on orientation, calculation and recall. On the WMS-R test, the patient showed recovery of memory function with almost the same attention/concentration score (Table 1).
On day 8 of hospitalization, taking carbamazepine (200 mg/day), the patient's consciousness level was E4V5M6/Glasgow Coma Scale, with no orientation disturbance. Her MMSE was 28/30 with errors on calculation and recall. On WMS-R, she showed attention/concentration deficit (Table 1).
She was discharged on day 16 with suspicion of paroxysmal mild consciousness disturbance, and we added levetiracetam (2000 mg/day) on day 22. After taking levetiracetam, the patient had no attention/concentration deficit or memory disturbance.
We examined EEG before dose adjustment of AED. Case 1 (day 4) showed normal EEG, and there were no localized slow waves. Case 2 showed small sharp spikes, frontal to central, with left dominancy. In addition, case 2 showed right temporal slow waves (Fig. 5). With other montages, there were no small sharp spikes. Case 3 on days 2 and 8 (Fig. 6) had high-amplitude slow waves with left frontal and bilateral temporal dominancy.
Cases 2 and 3 were examined with123I-IMP SPECT: case 2 was examined 6 months after onset, and case 3 (5 hours after injection of diazepam) on day 7. Case 2 had decreased blood flow in the bilateral frontal lobes, right temporal lobe and left posterior lobe. Case 3 had decreased blood flow in the right temporal lobe and bilateral parietal lobes.
MRI findings are shown in Table 2. None of the three cases had a high intensity area on diffusion weighted imaging. Magnetic resonance angiography was normal except for case 1 as a result of postoperative change.
|Case 1||Day 3 after the attack||Postoperative change in left temporal lobe|
|Case 2||6 months after first noticing problem|| |
Bilateral hippocampal sclerosis was suspected
Chronic ischemic change in bilateral basal ganglia area
|Case 3||Day 2||No abnormal findings|
All three patients had higher brain dysfunction. Case 1 had aphasia, case 2 had amnesia and case 3 had attention deficit. The symptoms differed from those seen in cases of cerebral vascular disease or neurodegenerative disease. The aphasia of case 1 was of the fluent type, but differed from Wernicke's or semantic aphasia. He was aware of his deficits, and that is not typical of Wernicke's aphasia. Patients with semantic aphasia are occasionally aware of the problem, but they have preserved ability of repetition. Progressive aphasia as part of neurodegenerative disease proceeds in a subtle way, whereas the symptoms of case 1 were acute onset.
Epileptic aphasia appears in childhood as Landau–Kleffner syndrome, but its etiology and pathology are not well understood. The main symptom is auditory agnosia. In adults, ictal aphasia is best known for the language deficits of epileptic attack.
Lüders et al. identified four language areas: Wernicke's, Broca's, the basal temporal area (anterior fusiform area) and a supplemental motor area. Variations in aphasia from word finding difficulty to total aphasia, on stimulation of the basal temporal language area, have been reported, though electrical stimulus strength was not uniform. In a case of NCSE, epileptic aphasia occurred gradually and improved slowly over many months.
In case 1, the aphasia was acute onset, endured for many days and disappeared with AED. The patient's residual alexia with agraphia might have been as a result of postoperative change. Furthermore, the symptoms cannot be ascribed to cerebrovascular or neurodegenerative disease.
Case 2 had long-term retrograde amnesia and anterograde amnesia. Amnesia with epilepsy was defined by Kapur et al. as TEA, and is both long-term and circumscribed in focus. Manes et al. proposed a decades long form of retrograde amnesia. It has also been suggested that recurrent attacks disturb memory fixation and erase cortical memory traces. Thus, micro-anatomical changes in the temporal lobe are a possible background cause of pathological change. The WMS-R score of case 2, 6 months after first onset, is attributable to memory fixation, TEA and long-term amnesia.
The symptoms of case 3 resembled progression of dementia. However, the digit span test and WMS-R showed attention deficit. Mild consciousness disturbance occurs with epileptic attacks, especially with temporal epilepsy. Persistent or repeated short-term consciousness disturbance might be caused by NCSE, but this patient did not show NCSE symptoms as described later.
None of the cases had EEG findings consistent with NCSE. Cases 2 and 3 were examined with 123I-IMP SPECT, but there were no hyperperfusion areas to indicate epilepsy. In contrast, disappearance of symptoms with AED does suggest epileptic higher brain dysfunction. The preceding convulsive attacks and automatism also suggest E-HBD. There was nothing on MRI to indicate the cause of the symptoms.
We believe our three cases support Nagayama's concept of an “antiepileptic drug-responsive neurological deficit”, and there is a recent report of mild cognitive impairment with levetiracetam linked to relief of hippocampal hyperactivity. Focal hyperactivity without EEG evidence or hyper blood flow is a possibility for all three cases.
As to lesions: in case 1 the left temporal lobe might have been the focus of epileptic change because of the patient's fluent aphasia and postoperative change in the same lobe. In case 2, bilateral mesial temporal lobe was a possibility because of the patient's amnesia and MRI findings of hippocampal sclerosis.
The aphasia of case 1 might be unique, because there was no compensatory process or connection with vascular supply. Case 2, in contrast, had insidious amnesia and there might be compensation. However, the patient's amnesia was not like Alzheimer's disease. She showed significant retrograde amnesia with regard to her autobiography, and this is typical of epileptic amnesia. We believe that E-HBD indicates distinctive higher brain dysfunction in relation to lesions, compensatory processes, repetitive attacks and other factors.
Our basic understanding of E-HBD is incomplete, but on the basis of the three case studies described here, its symptoms might be reversible with AED, although such symptoms must be carefully separated from those of vascular disease of acute onset, and from generative disease of long-term onset. With the present three patients, their histories of convulsion or automatism helped us make this separation, clearly diagnose their E-HBD and treat them successfully with AED.
This study was supported by the Tamagawa University Center of Excellence under the Ministry of Education, Culture, Sports, Science, and Technology (MEXT); a Grant-in-Aid for Scientific Research on Innovative Areas, ‘Face Perception and Recognition’, (MEXT, 23119720), and a Grant-in-Aid for Scientific Research (MEXT, 23591283).