|Year : 2008 | Volume
| Issue : 1 | Page : 16-29
Epilepsy and cognition
Joy D Desai
Department of Neurology, The Jaslok Hospital and Research Centre, Mumbai, India
Joy D Desai
1703/B, Lady Ratan Towers, Dainik Shivner Marg, Worli, Mumbai - 400 018
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Epilepsy and cognition have a multi-tiered reciprocal relationship. Alteration in cognitive abilities and performance may occur in tandem with persistent seizures in a patient with epilepsy. Age at onset, type of seizures, frequency of seizures, types of underlying epilepsy syndrome, and the underlying pathological brain substrate driving epilepsy may all have variable and independent effects on cognition. Therapeutic intervention with anti-epileptic drugs (AEDs) variably modulates cognitive abilities in a patient with epilepsy. Pathological substrate specific effects can compound the potential negative effects of AEDs on cognition. In this review all these aspects are addressed with an analysis of relevant evidence from peer-reviewed publications.
Keywords: Epilepsy, cognition, seizure frequency, syndromes, pathological substrate, anti-epileptic drugs
|How to cite this article:|
Desai JD. Epilepsy and cognition. J Pediatr Neurosci 2008;3:16-29
| Introduction|| |
The term 'epilepsy' encompasses a number of different syndromes whose cardinal feature is a predisposition to recurrent unprovoked seizures. The term 'epilepsy' takes its name from the Greek ' lopsis ,' meaning 'a seizure.'
Epilepsy is one of the most common neurological problems in the world, with the likelihood of about 3% of the general population suffering from this disease at some point in their lives.  It is a chronic condition that has complex effects on social, vocational and psychological function. In recent years, important advances have been made in the diagnosis and treatment of seizure disorders. 
Epidemiological studies have shown that the incidence of epilepsy is highest in the first year of life and then drops steadily to a nadir, which persists throughout most of adult life.  The incidence then rises to a peak in people above age 75 years.  Ironically, much more information exists about adults with epilepsy than about those in the two extremes of life, during which epilepsy onset is more frequent.
| Epilepsy and Cognition: Does Cognition Deteriorate Because of Epilepsy?|| |
' Cognitive ' - Pertaining to the mental processes of perceiving, thinking and memory; used loosely to refer to intellectual functions as opposed to physical functions.
Cognitive behavioral problems were recognized in patients with epilepsy in ancient times and documented in the 19 th century neurologic literature. , Gowers found that although most patients demonstrated normal intellect and pattern of behavior, some had interictal abnormalities. 
He recognized that the etiology of this change was multifactorial but hypothesized that epilepsy was the most important cause. Lennox expanded on Gower's work, identifying five potential factors in the cognitive and behavioral decline associated with epilepsy: 
- Brain injury prior to seizure onset
- Epilepsy itself
- Medications for epilepsy
- Psychological handicaps
The insights of Gowers and Lennox remain valid. The study of mental deterioration in epilepsy focuses on their observations and their suggested mechanisms. Studies that track cognitive change in patients with epilepsy over time are among the most important data documenting or refuting mental deterioration. Most longitudinal studies of this type have provided proof that intellectual decline is indeed progressive. ,, However, some such studies showed no deterioration or even improvement, possibly related to therapy with antiepileptic drugs. , In the face of contrasting evidence, it remains unclear whether uncontrolled epilepsy causes mental decline. One study compared change of memory and nonmemory functions in 147 surgically and 102 medically treated patients with temporal lobe epilepsy. All participants were evaluated at baseline (T1) and after 2 to 10 years (T3). Surgical patients underwent additional testing, 1 year postoperatively (T2). Data were analyzed at an individual and group level. Sixty-three percent of the surgical and 12% of the medically treated patients were seizure-free at T3. Fifty percent of the medically treated and 60% of the surgical patients showed significant memory decline at T3 with little change in nonmemory functions. Seizure-free surgical patients showed recovery of nonmemory functions at T2 and of memory functions at T3. In addition, psychosocial outcome was better when seizures were controlled. The study concluded that chronic temporal lobe epilepsy is associated with progressive memory impairment. Surgery, particularly if unsuccessful, accelerates this decline. However, memory decline may be stopped and even reversed if seizures are fully controlled. 
| Cognitive Impairment and Seizures: Do Seizures Cause Brain Damage?|| |
The relationship between seizures and cognitive dysfunction is complex. Several studies have focused on the effects of variables such as etiology, type, severity and laterality of seizures on cognition.  In addition cognitive dysfunction may be corelated with age of onset, frequency and duration of seizures.
Age of onset
Most studies indicate that early age of onset of seizures corelates with poor cognitive function in epilepsy. ,,,,,, Several studies emphasize that age of onset is, in fact, the most important predictor of cognitive outcome in patients with epilepsy. , In a series of 1,141 patients, Strauss et al. demonstrated a linear decline in IQ, from adult onset (mean IQ, 93.4) to age of onset before 1 year (mean IQ, 84.4). 
The question of whether younger patients are at greater risk for cognitive change as compared to adults remains unanswered.
Type of seizures
Absence seizures were traditionally considered benign, but recent studies have shown long-term cognitive and behavioral problems. The cause of these problems in patients with absence epilepsy remains unknown. Pavone et al. studied cognitive deficits in patients with absence seizures. Sixteen children with absence seizures showed lower neuropsychological testing scores in general cognitive functioning and visuo-spatial skills when compared to normal controls. Memory disturbances were also detected in absence epilepsy patients, with selective involvement of nonverbal memory and delayed recall whereas verbal memory and language skills were relatively preserved. Patients whose seizures began at an earlier age were observed to have more severe cognitive deficits. The authors concluded that children with generalized epilepsy demonstrate a more generalized neuro-cognitive dysfunction rather than specific lateralizing deficits. Language skills in such children were relatively well preserved. Patients with absence epilepsy seem to show a similar neuro-cognitive profile, which may be a reflection of the underlying epilepsy syndrome. 
Another study investigated cognition in juvenile myoclonic epilepsy (JME), focusing on frontal functions. Fifteen patients were administered a battery of tests sensitive to frontal lobe dysfunction. The number of patients with impaired test performance and the frequency of impairment per test were calculated and the results compared with 15 patients with temporal lobe epilepsy (TLE) of matching IQ. Although the performance of the group with JME was not uniform, some patients showed marked impairment whereas others showed little or no deficit. A high frequency of impairment was found on tests of 'concept formation'-'abstract reasoning' and mental flexibility, cognitive speed and planning and organization. Significant differences were found between the group with JME and the group with TLE on tests requiring mental flexibility and 'concept formation'-'abstract reasoning.' The results from this study suggest that JME is not a uniformly benign condition. It also supports the theory that frontal deficits may have maladaptive behavioral consequences suggestive of personality dysfunction, as described anecdotally by previous investigators. 
The thresholds for deleterious seizure-induced sequelae are not well understood. Will repeated brief seizures produce similar changes as a single prolonged seizure? Do permanent alterations of neuronal function result from a single brief seizure? How long can neurons resist damage caused by prolonged seizures? Several studies have found that seizure frequency was negatively corelated with cognitive outcome. ,,, Other researchers found that this was not the case, however. , The long-term effects of repeated brief seizures on spatial memory and hippocampal neuronal populations were assessed in kindled rats. Repeated brief seizures induced progressive, permanent functional and structural abnormalities in the hippocampus, which included spatial memory deficits accompanied by gradually evolving neuronal loss in a pattern resembling human hippocampal sclerosis. The memory deficit progressively increased as a function of the number of seizures and was not observed in controls. Neuronal loss was detected in the hippocampus and was associated with progressive memory dysfunction. These experimental results support the view that hippocampal sclerosis and associated memory dysfunction are induced by repeated seizures and imply that seizure control could prevent adverse long-term consequences of seizures on hippocampal-dependent functions. 
Long duration of epilepsy is another factor associated with cognitive decline. , Jokeit and Ebner separated patients with epilepsy into groups on the basis of seizure duration. Their statistics showed that patients with epilepsy of more than 30 years' duration had significantly lower full-scale IQ scores than patients with a duration of epilepsy of 15 to 30 years or fewer than 15 years.  A statistic derived from duration of seizures is 'years with seizures.' This number is obtained by subtracting the number of 12-month periods in which no seizures occurred from the number of years since onset. Years with seizures showed a stronger negative correlation to intelligence than did simple number of years since onset.  Other researchers have found that years with seizures may be the best way to relate time to neuropsychological functioning in epilepsy, because it combines measurement of frequency of attacks with the length of time over which they occurred. 
Etiology of epilepsy is a factor in determining cognitive function and intellectual changes over time. The main distinction is between symptomatic epilepsy (which has an identified cause such as stroke or cortical dysplasia) and idiopathic epilepsy (which has no identified cause other than genetic factors). Symptomatic epilepsy is more often associated with a severe decline than is idiopathic epilepsy. Lennox recognized that cognitive function was twice as likely to deteriorate in the presence of a known cause of epilepsy even if the idiopathic group had more frequent seizures.  In another study, children with idiopathic epilepsy were more likely to conform to the expected normal distribution of intellectual ability for their age.  More recent work has confirmed the poorer prognosis in patients with symptomatic epilepsy. In a longitudinal study of a group of 72 patients with epilepsy, those with the symptomatic form had a significantly lower IQ (89.1) than those with idiopathic epilepsy (102.5) on initial evaluation.  Certain developmental cortical malformations are also associated with developmental delays and epilepsy syndromes.
Polymicrogyria is a common malformation of cortical development, characterized by an excessive number of small gyri and abnormal cortical lamination. Multiple syndromes of region-specific bilateral symmetric polymicrogyria have been reported. The syndrome is characterized by global developmental delay of at least moderate severity, seizures, dysconjugate gaze and bilateral pyramidal and cerebellar signs. In one study, 19 patients from ten families were studied. In all cases, bilateral frontoparietal polymicrogyria was linked to the chromosome 16q locus. Magnetic resonance imaging demonstrated symmetric polymicrogyria affecting the frontoparietal regions most severely, as well as ventriculomegaly, bilateral white matter signal changes and small brainstem and cerebellar structures. 
One study assessed intellectual functioning (IQ) in 54 children and adolescents with intractable epilepsy, who later underwent cortical resection due to unilateral malformations of cortical development acquired in utero . Lesion type was classified into circumscribed mass lesions and diffuse cortical dysplasia based on histopathologic analysis of surgical tissue. Analyses of covariance revealed that circumscribed lesions had a less deleterious effect on nonverbal IQ than did diffuse cortical dysplasia, after controlling for age at seizure onset and extent of lesion. This effect was also found on verbal IQ measures, but only in subjects with right-sided lesions. Subjects with left-sided lesions performed significantly more poorly on verbal IQ measures than those with right-sided lesions. Additionally, younger age at onset and greater extent of lesion were associated with poorer cognitive outcome. The study concluded that cortical dysplasia and early left-hemisphere lesions have a significantly worse impact on cognitive functioning than do circumscribed lesions or right hemisphere developmental lesions in children with epilepsy. 
Tuberous sclerosis and periventricular heterotopic nodules (PVHN)
Kamuro and Tenokuchi (1993) described periventricular heterotopic nodules in a 13-year-old girl, her 34-year-old mother and her 60-year-old grandmother. The mother had suffered from epileptic seizures since she was 15 years old, but the daughter and grandmother were seizure-free. All three showed multiple uncalcified nodules on the lateral ventricular walls on CT. On magnetic resonance imaging (MRI), the intensity of the nodules was the same as that of the cerebral gray matter, suggesting heterotopia; and no other cerebral abnormalities were observed. Extensive examinations failed to show signs of tuberous sclerosis. 
| Case Study|| |
Dementia associated with cortical dysplasia 
A 47½-year-old man presented with an unusual adult-onset dementia. His initial symptoms were those of depression, memory loss and personality change. He developed progressive cognitive decline with prominent psychiatric symptoms. Seizures began approximately 11 months prior to death, and he died 5½ years after onset of symptoms.
Pathologic examination of the brain at autopsy revealed organizing necrosis of the hippocampi, felt to be the result of his seizures. More significant was the finding of widespread microscopic nodular cortical dysplasia. The dysplastic nodules were composed of clusters of abnormal cells with enlarged, pleomorphic, vesicular nuclei, many of which contained nucleoli and had ballooned cytoplasm. There were no mitoses.
Cortical dysplasia is most commonly associated with childhood-onset seizures and has not been reported as a cause of dementia in literature as per the authors' knowledge. The dysplasia may or may not have been the basis of the patient's dementia, but there are several possible patho-etiologic mechanisms of dementia due to cortical dysplasia.
Epilepsy syndromes and cognition
Epilepsy syndromes fall into two broad categories  :
I. Generalized : In generalized epilepsy, the predominant type of seizures begins simultaneously in both cerebral hemispheres. Many forms of generalized epilepsy have a strong genetic component; and in most, neurologic function is normal.
II. Partial (localization-related) : In partial epilepsy, by contrast, seizures originate in one or more localized foci, although they can spread to involve the entire brain. Most partial epilepsy syndromes are believed to be the result of one or more central nervous system insults; but in many cases, the nature of the insult is never identified.
Cognitive impairment is frequently observed in children with epilepsy syndromes. One study (Tromp et al. ) aimed at addressing the extent of cognitive dysfunction in patients affected by paroxysmal epileptiform activity (with or without clinical seizures) or by clinical features characteristic of the epilepsy syndrome. To this purpose, combined electroencephalographic (EEG) recording and cognitive testing (IQ and reaction times) were performed in 28 children. Frequent epileptiform EEG discharges significantly reduced reaction time, as did the occurrence of seizures during cognitive testing. Syndrome-related factors tended to affect cognitive functions as well: children with generalized epilepsy and high average seizure frequency obtained lower scores. Linear regression analysis showed that stable aspects of cognitive function, such as intelligence level, were most closely related to the severity of the epilepsy syndrome (average seizure frequency); whereas transient aspects of cognitive function, such as reaction times, are related to the occurrence of epileptiform EEG discharges. This suggests that seizures have a direct effect on transient cognitive aspects, which can accumulate and result in effects on intelligence level. 
In another study, four children with 'epilepsy and continuous spike-wave sleep' syndrome and mental and behavioral regression were followed prospectively with neuropsychological tests, behavioral questionnaires and sleep EEG performed at regular intervals between 1½ and 4 years of age. The children showed a pattern of behavioral and cognitive disturbances similar to that found not only in some developmental autistic-like disorders, but also in adult frontal syndrome. Deterioration was probably due to an unusually longstanding epileptic dysfunction involving the frontal lobes. The process is potentially reversible and seems to be the same as postulated for acquired epileptic aphasia, but in a different localization. 
| Key Facts|| |
Cognition and epilepsy: Multifactorial relationship
- Seizures are associated with cognitive dysfunction, which may at times be domain-specific.
- Cognitive decline is observed in association with specific epilepsy syndromes, e.g., CSWS.
- Age at onset, frequency and duration of seizures are important determinants of cognitive impairment.
- Epilepsy associated with structural malformations of the brain (cortical dysplasia, polymicrogyria) manifests cognitive decline during the course of the disease.
The successful management of epilepsy requires a thorough and individualized approach that accurately establishes the patient's seizure type(s) and, when appropriate, epilepsy syndrome. The availability of new antiepileptic drugs has broadened the spectrum of medical treatment options in epilepsy. The new agents, together with established drugs, offer substantial choice for doctors treating patients with focal or generalized epilepsy. The newer antiepileptic drugs are not necessarily more effective but usually better tolerated than the traditional agents, mainly because of favorable pharmacokinetic profiles and fewer drug interactions. Today, clinicians are able to take advantage of new treatments to minimize the impact of seizures, treatment side effects and epilepsy-related psycho-social difficulties on their patients, thereby enabling them to function in society at the highest possible level. 
AEDs and cognition
Several 'new' antiepileptic drugs (AEDs), i.e., oxcarbazepine, vigabatrin, lamotrigine, zonisamide, gabapentin, tiagabine, topiramate and levetiracetam have been introduced into clinical practice within the last decade. Most of these new drugs are at least as effective as the 'old' AEDs (phenytoin, phenobarbital, sodium valproate and carbamazepine); and, in general, they seem to be better tolerated than the old drugs.
Studies suggest that many of the available antiepileptic drugs, especially the older ones, can have a negative effect on cognitive function, including memory. Although these effects are usually modest, they can have significant impact when certain populations of patients are involved, such as learning in children or driving ability in adults or when already-vulnerable functions are involved, such as memory in elderly patients. Reducing the dose or switching to one of the newer AEDs may improve quality of life for susceptible individuals.
The new AEDs might have less influence on cognitive functions, but the aspect has not been systematically studied. Neuropsychological testing has been the major method of objectively examining cognitive function related to the use of AEDs, but a number of methodological problems blur the results. Alteration of cognition might reflect a chronic adverse effect of AEDs, but the negative effects of the drugs are only one of several factors that may influence cognition. In addition, subjective complaints about cognitive deficits (e.g., memory problems or attention) may also reflect aspects of adverse effects other than those concerning specific cognitive functions (e.g., mood and anxiety). In general, the new AEDs seem to display no or minor negative cognitive effects. In studies in which new AEDs have been compared with old AEDs, there was a tendency in favor of the new AEDs in some of the studies. 
Effects of individual AEDs
Debate concerning the precise cognitive and behavioral effects of different AEDs is far from resolved. In many studies, differences among drugs may reflect differences among the patients taking them rather than differences in the drugs themselves. Although study groups may appear similar, important intrinsic differences may exist between them that can account for different test scores.
Phenytoin has fallen from favor because side effects are more of a problem than with carbamazepine or valproate.  At the risk of oversimplification, there are two basic problems with phenytoin. Side effects such as hirsutism, gum hypertrophy and aggravation of acne occur during chronic use even in patients whose phenytoin concentration is in the therapeutic range. The second problem is phenytoin intoxication resulting from fluctuating serum levels and individual variations in its metabolism, during dose adjustments.  Phenytoin also impairs memory and cognition, although this impairment resolves on drug withdrawal.  In the Holmfrid study, 100 children with epilepsy were seizure-free for one year on monotherapy with carbamazepine, phenytoin or valproic acid.  The AEDs were withdrawn over a three-month period, and the children were reevaluated three to four months later. Significant improvement attributable to drug withdrawal was noted only on the psychomotor speed test, suggesting a limited role for AEDs on cognitive function. However, this study showed that phenytoin patients experienced greater cognitive impairment on tests of motor and mental speed than did carbamazepine patients.
One drug-withdrawal study suggested that phenytoin might be more deleterious to function in higher cognitive tasks than carbamazepine or sodium valproate. These changes were noted in a double-blind, prospective placebo-controlled study of discontinuation of phenytoin (PHT), carbamazepine (CBZ) and valproate (VPA) in 58 patients with active epilepsy, receiving multiple antiepileptic drugs (AEDs). A control group of 25 patients continued with existing therapy. Cognitive assessments were made before and at the end of the period of discontinuation of a drug and four weeks later. Simple motor skills improved equally on discontinuation of all three AEDs, with progressive improvement in the subsequent four weeks. Attention and concentration, however, improved on discontinuation of PHT and did not alter with removal of CBZ or VPA. The improvement in the PHT-discontinuation group was significantly different from that in the control group. 
In another drug withdrawal study involving children treated with carbamazepine, valproate or phenytoin as monotherapy, withdrawal of the AED produced improvement in binary-choice and visual-search tasks, but similar improvements were also noted in the normal control group. The performance of the children taking carbamazepine was similar to that of the children in the control group both before and after drug withdrawal. Children taking phenytoin, however, performed poorly both before and after drug discontinuation. A similar impairment, but to a lesser degree, was noted with the valproate group. 
| Antiepileptic Effect and Clinical Use|| |
PHT is one of the most commonly used first-line or adjunctive treatments for partial and generalized seizures, Lennox-Gastaut syndrome, status epilepticus and childhood epileptic syndromes. It is not indicated for myoclonus and absence seizures. This drug is highly effective and economical for the patient; however, tolerability of the drug is still in dispute.
Carbamazepine is used for patients with partial seizures, generalized tonic-clonic seizures or both.  Provided carbamazepine is introduced gradually, tolerability is relatively good in children and younger adults. If further seizures occur, the dose is titrated upwards until the seizures are controlled or the patient starts to have side effects of unsteadiness or drowsiness that necessitate limiting the dose. The maximum tolerated dose should be determined by the patient's symptoms rather than by monitoring the drug concentration. 
Seidel et al. investigated the cognitive and behavioral effects of carbamazepine in children with Benign Rolandic Epilepsy (BRE). Ten children (6-12 years of age) with BRE were evaluated with and without carbamazepine treatment. Fourteen children with migraine headaches and receiving no medication served as a control group. Children with BRE who did not receive carbamazepine were quicker on a visual-search task and recalled stories better than children who did. Higher carbamazepine serum levels were associated with slower performance on the same visual-search task. Significant changes in memory were seen in two while receiving carbamazepine. Although these findings suggest some effects on memory from carbamazepine, they do not support meaningful dosage-related effects within the recommended range. These findings also suggest that some children might experience particular difficulties while receiving carbamazepine and highlight the need to investigate individual subject responses to treatment. 
Another study compared the cognitive effects of carbamazepine and gabapentin (GBP) in healthy senior adults, using a randomized double-blind crossover design.
Thirty-four senior adults were randomized to receive one of the two drugs followed by a five-week treatment period. A four-week washout phase preceded initiation of the second drug. The AEDs were titrated to target doses of either CBZ (800 mg/day) or GBP (2,400 mg/day). Every participant received cognitive testing at pre-drug baseline, end of first drug phase, end of second drug phase and four weeks after completion of the second drug phase. Primary outcome measures were standardized neuropsychological tests of attention/vigilance, psychomotor speed, motor speed, verbal and visual memory and the Profile of Mood State (POMS).
Fifteen senior adults (59-76 years of age) completed the study. Seniors completing the study did not differ significantly from noncompleting seniors in terms of demographic features or baseline cognitive performances. Fifteen of the 19 seniors not completing the study dropped out while receiving CBZ. Adverse events were frequently reported for both AEDs, although they were more common for CBZ. Mean serum levels for the seniors who completed the study were within mid-range clinical doses (CBZ - 6.8 mg/ml; GBP - 7.1 mg/ml). Mild cognitive effects were found for both AEDs compared with the nondrug average condition. Only modest differences were reported between the two drugs in terms of the magnitude of cognitive side effects observed. However, overall tolerability and side-effect profile of CBZ were poorer than those of GBP in senior adults at doses and titration rates reported in this study.
The study highlighted three points, valid in clinical practice:
- Adverse effects of AEDs are common in the elderly population, particularly with carbamazepine. Many of these effects would improve with chronic treatment but would probably not resolve completely. (Seventy-three percent of seniors who completed the study reported tiredness with this drug, as opposed to 33% with gabapentin.)
- Gabapentin had a favorable profile when compared with carbamazepine in terms of cognition and mood.
- Both drugs were inferior with regard to the nondrug condition.
Although this study was relatively small, its results supported the clinical impression that elderly individuals are more sensitive to the sedative and cognitive effects of AEDs and that gabapentin may be somewhat better tolerated than carbamazepine at the doses studied. 
| Key Facts|| |
- One of the most widely used AEDs in the world
- Highly effective for partial-onset seizures (both cryptogenic and symptomatic)
- Good efficacy in the treatment of generalized tonic-clonic seizures
- Well tolerated
- Major disadvantages of this drug are transient adverse dose-related effects when initiating therapy and occasional toxicity
Valproate is effective in generalized tonic-clonic seizures and partial seizures and can be used to treat a wider range of seizure types than carbamazepine.  It is a drug of choice for absences and myoclonic seizures. Although there is no need to build up gradually to a therapeutic dose, the dosage may need to be titrated upwards according to the patient's response. The upper end of the recommended dosage range is 3 g/day, but patients are likely to complain of unacceptable side effects such as sedation, weight gain or tremor well before this dose is reached. One advantage of valproate is that it does not cause enzyme induction. It is an enzyme inhibitor, an important fact when lamotrigine is used concurrently. Unfortunately, valproate is also teratogenic and is implicated in spina bifida. Valproate is a drug of choice for seizures in elderly people. 
Desai et al. presented a paper on their experience with valproate toxicity at the 25 th International Epilepsy Congress held at Lisbon.  He reported that 18 out of 67 patients being treated with valproate reported a weight gain of over 5 kg, while 26 patients reported severe hair loss. Five patients developed symptomatic Parkinsonism More Details that reversed after stopping therapy, and three of these patients also reported cognitive impairment. One patient presented with physical signs suggestive of multiple-system atrophy and bilateral hearing loss. A syndrome mimicking progressive supranuclear palsy developed after nine months of valproate therapy. The withdrawal of valproate led to a catastrophic, malignant, neuroleptic syndrome, requiring therapy with dantrolene in this patient. Additionally, three patients suffered progressive worsening of symptoms on addition of topiramate to valproate, associated with a rise in serum ammonia. One patient lapsed into a hyperammonemic coma, with normal hepatic functions after a single loading dose of valproate. His serum carnitine levels were low. Substitution of lamotrigine by valproate resulted in complete recovery.
| Case Report 1|| |
Reversible valproic acid-induced dementia 
Reversible valproic acid-induced dementia was documented in a 21-year-old man with epilepsy who had a 3-year history of insidious progressive decline in global cognitive abilities documented by serial neuropsychological studies. Repeat neuropsychological testing seven weeks after discontinuation of the drug revealed dramatic improvement in IQ, memory, naming and other tasks commensurate with clinical recovery in his intellectual capacity. Possible pathophysiological mechanisms which may have been operative in this case include:
- A direct central nervous system (CNS) toxic effect of valproic acid
- A paradoxical epileptogenic effect secondary to the drug
- An indirect CNS toxic effect mediated through valproic acid-induced hyperammonemia
| Case Report 2|| |
Reversible dementia and apparent brain atrophy during valproate therapy 
Two children developed severe cognitive and behavioral deterioration, suggestive of a degenerative disease while being treated with sodium valproate for idiopathic, localization-related epilepsy with centro-temporal spikes. Magnetic resonance imaging revealed marked central and generalized cortical and cerebellar atrophy. In both patients, clinical symptoms and signs cleared in a few weeks following valproate withdrawal. The magnetic resonance imaging appearance improved within three months in one of the patients and normalized in both after 6 and 12 months. No metabolic changes were associated with the clinical or imaging abnormalities. Although the mechanism of this rare idiosyncratic complication of valproate therapy is unknown, we advocate discontinuing valproate therapy in all epileptic patients with neuro-mental deterioration or brain atrophy of unknown etiology.
| Case Report 3|| |
Reversible parkinsonism and cognitive impairment with chronic valproate use 
Following an initial report of the insidious development of reversible valproate-induced hearing, motor and cognitive dysfunction in two patients, the authors evaluated 36 patients in an epilepsy clinic who had been taking therapeutic levels of valproate for at least 12 months. Twenty-nine of these patients were examined according to a prospective protocol. They observed varying degrees of parkinsonism and cognitive impairment, from none to severe. Discontinuation of valproate in 32 affected patients led to subjective and objective improvement on follow-up testing at least three months later. Improvement was greatest in patients who were affected most. The authors concluded that a syndrome of reversible parkinsonism and cognitive impairment may develop insidiously in patients who have been treated with valproate for more than 12 months. The association with valproate may be overlooked due to the insidious onset.
A recent study investigated the effect of carbamazepine and valproate on intelligence in pre-natally exposed children of mothers with epilepsy. The intelligence of 182 children of mothers with epilepsy and 141 control children was tested in a blinded setting at pre-school or school age. One hundred seven children were exposed to AED monotherapy, 86 to carbamazepine and 13 to valproate. Thirty children were exposed to polytherapy, 23 combinations included carbamazepine and 17 included valproate. The median maternal doses and blood levels during the second half of pregnancy were 600 mg and 26 micromol/L for carbamazepine and 950 mg and 300 micromol/L for valproate. The mean verbal and nonverbal IQ scores in the children exposed in utero to carbamazepine monotherapy were 96 and 103. They did not differ from those of control subjects, whose mean verbal and nonverbal IQ scores were 95 and 102. However, significantly reduced verbal IQ scores were found in children exposed to valproate (mean, 82; 78-87) and to polytherapy (mean, 85; 80-90) compared with those of the carbamazepine group and controls. The study concluded that carbamazepine monotherapy with maternal serum levels within the reference range does not impair intelligence in pre-natally exposed offspring. Exposures to polytherapy and to valproate during pregnancy were associated with significantly reduced verbal intelligence. The independent effects of valproate remain unconfirmed because low maternal education and polytherapy confounded the results. 
The newer AEDs
The past decade has brought many advances to the treatment of epilepsy, including many new pharmacological agents. Eight new antiepileptic drugs have been approved for use in the past decade. Each new antiepileptic drug is well tolerated and demonstrates statistically significant reductions in seizure frequency over baseline. Although there is no evidence to suggest that the newer medications are more efficacious, several studies have demonstrated broader spectrum of activity, fewer drug interactions and overall better tolerability of the new agents. New antiepileptic drugs offer many options in the treatment of epilepsy, each with unique mechanisms of action as well as adverse-effect profiles. No randomized controlled trials have compared the new antiepileptic drugs with each other or against the traditional antiepileptic drugs.  That is not to say that experienced epilepsy specialists regard them as pretty much the same. Brodie has produced a 'star rating system' covering the new drugs and also the older treatments. 
Lamotrigine has been on the market for about seven years. ,, One of the main advantages of lamotrigine is that it causes little cognitive impairment or overt sedation compared with other treatments. , It sometimes has an arousing or alerting effect, which in elderly people may manifest as unwanted agitation. Lamotrigine has a wide spectrum of activity. The chief drawback is the risk of allergic reactions. These occur less often than is the case with carbamazepine, but they are more often severe and can be life threatening; although this is rare. Introducing lamotrigine gradually is one of the keys to reducing the frequency and severity of allergic reactions. Patients on valproate therapy should receive lower doses of lamotrigine than those receiving carbamazepine, phenytoin or lamotrigine monotherapy, as valproate inhibits lamotrigine metabolism. There often seems to be synergy between lamotrigine and valproate, over and above that expected from the pharmacokinetic interaction. However, lamotrigine is also effective as monotherapy. 
In a recently completed double-blind comparison of lamotrigine and carbamazepine in 260 patients with newly diagnosed partial or generalized tonic-clonic seizures, the efficacy of the two drugs was similar; but lamotrigine was better tolerated. 
Another study compared the cognitive and behavioral effects of lamotrigine and carbamazepine. Twenty-five healthy adults were randomized to receive either lamotrigine (150-200 mg/day) or carbamazepine (600-800 mg/day) adjusted to achieve mid-range standard therapeutic blood levels. Patients were tested at the end of each AED treatment period and in three drug-free conditions (two pre-treatment baselines and a final post-treatment period [one month after last AED]. The neuropsychological test battery included 19 measures yielding 40 total variables. Direct comparison of the two AEDs revealed significantly better performance on 19 (48%) variables for lamotrigine but none for carbamazepine. Differences spanned both objective cognitive and subjective behavioral measures, including cognitive speed, memory, graphomotor coding, neurotoxic symptoms, mood factors, sedation, perception of cognitive performance and other quality-of-life perceptions. Comparison of lamotrigine with nondrug average revealed better performance on one (2.5%) variable for nondrug average and on one (2.5%) variable for lamotrigine. The study concluded that lamotrigine produces significantly fewer untoward cognitive and behavioral effects than does carbamazepine at the dosages used in this study. 
A few single-blind and open studies suggest efficacy in children with multiple types of seizures, including those with the Lennox-Gastaut syndrome. ,
Antiepileptic effect and clinical use
Lamotrigine is effective in partial-onset and secondarily generalized tonic-clonic seizures, primary generalized seizures (i.e., absence seizures and primary generalized tonic-clonic seizures), atypical absence seizures, tonic/ atonic seizures and Lennox-Gastaut syndrome. It is sometimes effective for myoclonic seizures but can cause worsening of myoclonic seizures in some patients with juvenile myoclonic epilepsy or myoclonic epilepsy of infancy. It currently is approved in the United States for adjunctive therapy for partial-onset and secondarily generalized tonic-clonic seizures, crossover to monotherapy and Lennox-Gastaut syndrome.
Topiramate has now been on the market for a few years, and its effects seem to be more potent and more toxic than those of older AEDs. ,, This is another drug where gradual introduction over some months helps to reduce side effects. Nevertheless, many patients are unable to tolerate an effective dose of topiramate. The main problems are psychological or cognitive changes, sometimes accompanied by difficulty in finding words, which may be devastating for the patient's self-confidence. In addition, topiramate has to be stopped in some patients who are otherwise tolerating it well, because of weight loss. For the foreseeable future, topiramate remains a treatment to be prescribed by the experienced specialist.
Several randomized controlled trials have demonstrated the drug's efficacy in the management of intractable seizures. ,, More recent studies have shown high levels of adverse effects.  Cognitive complaints are prominent among the untoward effects reported and include impaired concentration and memory, slowed thinking and word-finding difficulties. ,, There have been few investigations, however, measuring cognitive changes more systematically, with the use of neuropsychological tests.
Existing studies suggest undesirable cognitive changes, which corroborate subjective complaints. Martin et al.  assessed the cognitive impact of up to 5.7 mg/kg daily of topiramate in healthy volunteers who remained on the drug for four weeks. Performance was assessed in the acute phase of treatment and again at two and four weeks. Volunteers were given up to 5.7 mg/kg daily. Other subjects were assessed at the same time intervals on gabapentin and lamotrigine treatment. Impaired cognitive functioning was recorded in the topiramate group in the acute phase and at four weeks, which was not apparent in the other two groups. Statistically significant declines were recorded on measures of attention, verbal fluency and verbal memory. At the two- and four-week test periods, only the topiramate subjects continued to display neuro-cognitive effects from drug administration. The study results demonstrated potential acute and steady-state adverse cognitive effects for topiramate when compared to gabapentin or lamotrigine in young healthy adults.  However, the authors received a lot of feedback suggesting that their findings might have not been duplicated with slow titration of the topiramate dose used.
Another study by Thompson et al. noted cognitive difficulties in several patients treated with topiramate that were consistent with subjective complaints described by other authors. As intellectual decline may occur in some patients with intractable epilepsy, the authors were anxious not to wrongly attribute the cognitive change to a medication which had improved seizure control in several patients. The study aimed to explore further whether cognitive changes in their patients were indeed a consequence of topiramate and to assess whether certain cognitive processes, in particular measures involving verbal processing, were selectively affected. 
The authors compared the neuropsychological test scores of 18 epileptics on topiramate with those of comparable control subjects. Patients had been taking topiramate for a median of 11 months, with a range of 3-37 months. All patients were receiving at least one other antiepileptic drug. Topiramate dosage ranged from 125 mg to 600 mg, with a median of 300 mg. Neuropsychological tests were performed using the WAIS-R tests of verbal and nonverbal memory, language and perceptual processing.
A statistically significant reduction in seizures was recorded for the topiramate-treated group for both generalized tonic-clonic and complex partial seizures. No patient experienced deterioration in seizure control when treated with topiramate. However, topiramate treatment was associated with impairments on tests of cognitive functioning, which were not seen in patients who were not taking this drug and assessed on two occasions at similar intervals. Tests requiring verbal output were particularly vulnerable to topiramate treatment. Reduced verbal fluency was a particularly striking finding and one of word-finding difficulties, which is in keeping with subjective complaints by patients and families. The significant changes in verbal IQ recorded were surprising as such measures have been considered by some to be insensitive to antiepileptic-drug effects.
The changes did not seem likely to be confounded by seizure control as the patients treated with topiramate experienced fewer seizures in the three months before the second assessment session. All patients had been taking the drug for a minimum of three months, and so the cognitive changes cannot be attributed to an acute effect expected to diminish over time, nor could they be a consequence of too rapid introduction of the drug.
By contrast, on tests of nonverbal learning and recall and perceptual analysis, which are cognitively demanding, the changes on the drug were much less marked.
The results were in keeping with those described by Sziklas et al. ,  who reported improvements in digit span, language comprehension and fluency, 10 to 14 days after the reduction of topiramate.
A recent randomized clinical trial, however, has reported less marked cognitive effects of topiramate given as an add-on treatment, in comparison with those of sodium valproate.  The maximum dose used in this study was 200 mg, which contrasts with the median dose of 300 mg used in this study. This has been postulated as one reason for the difference in the size of the cognitive effects between the studies.
The findings from this study have clinical implications. In recent years, reviews of the literature on antiepileptic drugs have concluded that adverse effects are small  or have emphasized positive psychotropic effects.  In such a climate, there is a risk that the negative impact of drugs may be underestimated and declines in functioning on topiramate misinterpreted as deterioration secondary to intractable epilepsy.  Cognitive changes of the magnitude reported in this study are sufficient to have an impact on everyday life and to reduce a person's efficiency at school, at work and in social settings. Furthermore, the authors have recent experience of patients undergoing evaluation for right temporal lobe surgery being wrongly deemed poor candidates due to impaired performance on tests of verbal memory and other verbal tasks, which subsequently improved when topiramate was withdrawn.
Topiramate is clearly an effective antiepileptic agent, but some patients seem susceptible to cognitive decline. Further prospective investigations of mediating factors such as serum concentrations, co-medication and other potential risk factors are needed to enable appropriate targeting of treatment. In the meantime, the authors recommend that patients and their families be given explicit advice on potential adverse cognitive effects in the same way that candidates for epilepsy surgery are counseled on possible cognitive sequelae. We also suggest that patients are assessed neuropsychologically to monitor changes before and after treatment.
| Key Facts|| |
- Marked antiepileptic effect
- Minimal drug interactions
- Moderately high incidence of cognitive and affective side effects
- Effective in drug-resistant generalized epilepsies
- FDA-approved in:.
1. Partial-onset and secondarily generalized tonic-clonic seizures
2. Primary generalized tonic-clonic seizures
3. Lennox-Gastaut syndrome
There are few reports in the literature regarding the association of topiramate (TPM) with psychotic disorders. , The majority of the psychotic symptoms reported in scientific meetings lack in details. ,, Patients with history of prior psychotic or depressive symptoms had a tendency to develop the same type of mood disorder when put on TPM.  Clinicians should be aware of the possibility of development of acute psychotic symptoms in patients undergoing TPM treatment. Stella et al. reported two cases of topiramate-induced psychosis. 
| Case 1|| |
A 42-year-old married male, engineer, with two children, had been treated for epileptic seizures since the age of two when he had his first episode of febrile seizures. Throughout his infancy, he had several febrile seizures and later on developed partial complex seizures, in the absence of fever, with secondary generalization, once a week. He had no family or personal history of psychiatric disorders. Between 1997 and 2000, he had ten electroencephalograms performed, five of which showed epileptiform activity in the right fronto-temporal region, one in the left fronto-temporal region, two showed intermittent slow waves in right temporal region, one showed a similar pattern in the left temporal region and one was normal. Interictal brain Single Photon Emission Computerized Tomography (SPECT) (1997) suggested hypo-perfusion in the right temporal region. The MRI displayed bilateral hippocampal atrophy with left-sided predominance and a small lesion in the corpus callosum.
He was treated with several AEDs in monotherapy and polytherapy but was never seizure free. As he had been on carbamazepine CR 1,600 mg/day over a year without much improvement, he was put on TPM 50 mg/day. This dose was gradually increased to 300 mg daily. There were no significant side effects but a mild difficulty in recollecting recent facts. As the seizures did not improve, the TPM dosage was increased from 300 mg/day to 350 mg/day. Only one day after being on 350 mg/day, he presented with a full-blown psychotic episode. He awoke at 3 a.m. with severe psychomotor agitation and was verbally and physically aggressive. He was severely disoriented in time, space and self, saying that a serious bus accident with a great number of fatal victims was bound to happen and that he had received a mission from God to save people. He also had visual and persecutory auditory hallucinations and severe paranoid ideas of being haunted by the police. He was taken to a psychiatric outpatient facility, where he became more agitated, broke objects and damaged cars parked in the vicinity. He had to be stopped by the police and taken to a psychiatric hospital, where he was put on diazepam. Carbamazepine was maintained and TPM was withdrawn. Total remission of the psychotic symptoms took place within 48 hours after TPM was completely taken off. This episode was unrelated to epileptic seizures. He was kept on diazepam for several days because of his high anxiety, and carbamazepine CR 1,600 mg/day was maintained. There was no need for anti-psychotic medication, and stopping TPM did not affect the frequency or the clinical features of the epileptic seizures.
| Case 2|| |
A 41-year-old divorced female, with two children, who worked as a nanny, was being treated for temporal lobe epilepsy. She had complex partial seizures with secondary generalization since the age of 12. From 1997 to 2000, five EEGs were done, out of which one displayed bilateral epileptiform activity in frontal regions, two in the right temporal region and two were normal. The CAT scan revealed mild cerebellar atrophy, and an MRI showed mild diffuse cerebellar atrophy, without abnormalities in brain structures. She underwent monotherapy and polytherapy with several AEDs, which failed to bring the seizures under control. Over a period of two years, she was treated with valproic acid twice daily in a total of 1,000 mg/day. Then TPM 50 mg/day was introduced and gradually increased to 100 mg/day taken twice. As the seizures were not controlled, the dosage of TPM was increased to 150 mg/day; and on this very same day, the patient reported a 'strong strange feeling' in relation to her environment - de-personalization, de-realization, severe anxiety, fear, restlessness and psychomotor agitation. She shouted phrases like "I'm going mad," "I'm losing my memory" and "nobody believes in me." She was taken to the casualty room and medicated with diazepam. TPM was reduced from 150 mg/day to 50 mg/day, which alleviated psychomotor agitation and other symptoms. There was no need for anti-psychotic medication. Again this psychotic episode was unrelated to the patient's epileptic seizures, and she had no previous history of psychiatric disorders.
| Discussion|| |
According to ICD-10 criteria,  the two reported cases were diagnosed as acute psychotic disorder. The clinical features appeared suddenly and within a few days after increasing the TPM dosage. However, they quickly remitted after TPM was taken off or reduced.
The frequency of psychotic episodes related to TPM is low, and the most common symptoms were delusions, visual and auditory hallucinations. Data on the adverse effects of TPM report only few cases of psychotic symptoms, such as visual and auditory hallucinations and paranoid delusions, and these patients eventually warranted hospitalization. , Although topiramate has been reported to be associated with various adverse effects like dizziness, giddiness, tiredness, psychomotor slowness, difficulty in attention and concentration, memory impairment, loss of weight and nephrolithiasis, it is considered a safe drug, with good tolerance and favorable pharmacokinetics. , Despite the fact that drugs that induce hepatic metabolism lower its plasma level, TPM has relatively few adverse reactions and very few drug interactions.  When administered with carbamazepine, a potent enzymatic Cytochrome P450 inducer, , TPM undergoes 40% reduction of its plasmatic levels and clearance.  On the other hand, plasma levels of carbamazepine or its epoxide metabolite do not change significantly when TPM is added.  The simultaneous use of TPM and valproate increases the plasma levels of the first by 15%. This has to be taken into account if valproate is eventually withdrawn. TPM, on the other hand, increases valproate clearance, thus reducing its plasma levels. 
Meador et al.  compared the occurrence of cognitive effects during topiramate (TPM) and valproate (VPA) add-on therapy in adults with partial seizures on carbamazepine (CBZ). A comprehensive neuropsychological test battery including cognitive, mood and quality-of-life measures was used in this multi-center randomized double-blind study. After a four-week baseline, the study drug was titrated over 8 weeks to target dosages of TPM - 400 mg/day, VPA - 2,250 mg/day or placebo and then maintained for an additional 12 weeks. The neuropsychological test battery was administered at baseline and at the end of titration and maintenance periods.
| Results|| |
Slightly more patients on TPM dropped out of the study.
At the end of maintenance, effects of TPM and VPA were comparable, except for two variables (Symbol Digit Modalities Test and Controlled Oral Word Association Test), in which TPM had greater negative effects relative to VPA.
Cognitive effects of TPM were greater than those of VPA at the end of titration than at the end of maintenance.
The study concluded that with adjunctive therapy at moderate dose escalation rate, the cognitive effects of TPM were slightly worse than those of VPA in patients who tolerated therapy over several months.
Mula et al.  studied the role of hippocampal sclerosis (HS) in developing psychiatric and cognitive adverse events during therapy with topiramate (TPM), in patients with temporal lobe epilepsy (TLE). They analyzed data from 70 patients with TLE and HS and 128 patients with cryptogenic TLE matched for age, sex, starting dose and titration schedule of TPM.
| Results|| |
The study results showed that patients with TLE and HS were more prone to develop cognitive side effects and depression as compared to patients with cryptogenic TLE, during TPM therapy, despite the same titration schedule. Regression analysis demonstrated that only HS and not duration of epilepsy or polytherapy regimen represented the main risk factor for the occurrence of cognitive adverse effects and depression.
While these reports may sound alarming, it must be emphasized that adverse effects of topiramate like those of other AEDs serve to warn physicians of possible problems in specific susceptible patient populations. Also, the use of other anticonvulsants in patients with structural abnormalities of the temporal lobe, e.g., mesial sclerosis, may also predispose to the occurrence of cognitive problems, e.g., levetiracetam. The early trials of topiramate used large dosing schedules in significant number of patients, besides adopting a rapid titration schedule. It is perceived by many that slower titration and a lower ceiling of its dosage would reduce the occurrence of cognitive problems. Therefore, the occurrence of cognitive deficits is not a barrier to its judicious use as it has a robust efficacy in all seizure types. There are no reports of cognitive deficits occurring in patients on lower total doses of topiramate - as for example, in the therapy for migraine prophylaxis. It remains for the next decade of its use to elucidate its place in the therapeutic armamentarium against epilepsy and migraine.
| Key Facts|| |
- Most first-line AEDs may potentially produce impairment of cognition, especially in susceptible epileptics: syndrome, substrate, etc.
- Phenobarbitone (PHB), Phenytoin (PHT), Carbamazepine (CBZ) and Valproic Acid (VPA) have a negative effect on cognition, perhaps, in descending frequency.
- VPA, thought to produce minimal cognitive impairment, may not be as benign as perceived.
- Lamotrigine has a negligible cognitive adeverse effects.
- TPM produces language and behavioral adverse effects, especially when rapidly titrated and in higher doses. This effect may be compounded in specific substrate settings, e.g., Mesial Temporal Sclerosis.
The evidence base for the most effective use of some of the new antiepileptic drugs (lamotrigine, gabapentin, topiramate and oxcarbazepine) in newly treated patients with epilepsy will improve significantly when the results of the study of Standard And New Antiepileptic Drugs (SANAD) are analyzed in 2005. This randomized controlled trial compares the longer-term clinical outcomes and cost-effectiveness of treatment with carbamazepine or valproate with those of new drugs in around 3,000 patients. Two further antiepileptic drugs will become available in some European countries and the UK in the near future - zonisamide and pregabalin. It is likely that they will initially be licensed as adjunctive treatments in focal epilepsy. Although a number of other substances are currently under pre-clinical evaluation, it is likely that zonisamide and pregabalin will be the last new antiepileptic drugs to enter clinical use for some time.
| Summary|| |
The development of new antiepileptic drugs has not changed the basic principles of the medical therapy of epilepsy, but it has substantially increased treatment choice. So far, it does not appear that the new drugs have greater anticonvulsant potency than conventional agents. However, the new drugs have a more favorable side effect profile, which may represent a significant advantage in the treatment of a chronic disorder. It remains to be demonstrated that this potential advantage outweighs the disadvantage of considerably greater costs of 'modern' antiepileptic therapy. Moreover, long-term side effects may only become apparent with continuing use of these new drugs. The choice of treatments now available enables physicians to take account of their patients' particular wishes and circumstances. Most of the new agents have better pharmacokinetic properties than conventional antiepileptic drugs, including fewer interactions with other drugs. This facilitates combination therapy when two or more drugs are necessary. On the other hand, knowledge on the safety of the new antiepileptic drugs in pregnancy remains deficient (with the possible exception of lamotrigine), so that patients cannot really be informed about the risk of malformations associated with most of the new drugs. Some of the new antiepileptic drugs (especially lamotrigine and gabapentin) have fewer negative cognitive effects than standard anticonvulsants. The dose of several of the new drugs can be increased relatively quickly, at least during monotherapy, providing rapid anticonvulsant protection. Their broad spectrum of action allows them to be used in focal as well as idiopathic generalized epilepsies (lamotrigine, topiramate, levetiracetam). There is an urgent need for appropriately powered prospective studies to guide the clinical use of the new antiepileptic drugs and to enable physicians to choose between conventional and new drugs.
| Key Facts|| |
Principles of medical treatment of epilepsy
- Determine the need for antiepileptic treatment (consider antiepileptic drugs after more than one unprovoked seizure, a single seizure in the presence of identifiable intracranial lesion, presentation with status epilepticus).
- Determine seizure type and epilepsy syndrome (focal/ generalized/ unclassifiable) and choose appropriate first-line antiepileptic drug (broad-spectrum in unclassifiable epilepsies).
- Increase antiepileptic drug to an appropriate dose.
- If ineffectual, consider further treatment options:
• Increase to fully effective/maximum tolerated dose.
• Switch to alternative monotherapy.
• Choose appropriate add-on antiepileptic drugs.
- If ineffectual, consider nonmedical treatment options (especially epilepsy surgery for refractory focal epilepsies).
- If combination antiepileptic drug therapy fails to achieve full seizure control, consider reverting to most effective monotherapy.
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