surgical resections such as unilateral temporal lobectomy and amygdalo - hippo - campectomy have an established place in the management of carefully selected patients with refractory localisation - related epilepsy .
adverse cognitive sequelae of epilepsy surgery have been well - recognised since the seminal report of scoville and milner in 1957 documenting the dense anterograde amnesia in patient h.m .
such amnesia has been observed on occasion following unilateral surgery , reflecting preoperative damage in the unoperated , contralateral , temporal lobe , a finding which mandates careful preoperative assessment of the non - operated hemisphere , for example using sodium amytal ( wada ) testing and/or functional neuroimaging , to try to ensure cognitive function is preserved post - operatively .
we present a patient with refractory epilepsy who , following initially apparently successful unilateral temporal lobectomy , developed recurrent seizures and profound amnesia , and in whom subsequent investigations unexpectedly suggested an autoimmune aetiology .
a 36-year - old right - handed female was referred to our centre for assessment of epileptic seizures and cognitive impairment . at the age of 33 ,
she had undergone a right ( non - dominant ) temporal lobectomy for refractory complex partial seizures , performed at another neuroscience centre with an established epilepsy surgery programme .
the patient 's seizures began at the age of 15 years ; there was no history of childhood febrile convulsions .
seizures were characterised by dj vu , absence , and automatisms , and were thought to arise in the right temporal lobe .
mr imaging appearances were equivocal , with right temporal lobe changes thought to represent either sclerosis or a possible dysplastic lesion . because of the refractory nature of the seizures , pre - operative workup was undertaken , including fdg - pet which showed reduced uptake of tracer in the right temporal lobe .
intracranial eeg ( subtemporal strips ) confirmed complex partial seizures arising from the lateral right temporal cortex , but there also seemed to be subclinical events arising from the left side .
a sodium amytal test performed prior to surgery confirmed that the patient was left - hemisphere dominant for language and that both hemispheres supported memory function .
however , 34 months post - operatively the patient deteriorated with further frequent complex partial seizures . additionally , she was noted to have symptoms suggestive of both anterograde and retrograde amnesia . by this time
cognitive assessment included administration of cognitive screening instruments which showed impaired performance : on the mini - mental state examination ( mmse ) , she scored 23/30 ; on the addenbrooke 's cognitive examination - revised ( ace - r ) , she scored 74/100 , with 12/26 on the memory components ; and on the montreal cognitive assessment , she scored 23/30 ( normal 26/30 ) . on the repeatable battery for the assessment of neuropsychological status ( rbans ) , her delayed memory scores fell within the extremely low range .
this impairment was for both verbal and visual material , with a subtle indication of slightly higher levels of delayed recall with visual information ( list recall total score = 0 ; story recall total score = 1 ; figure recall total score = 2 ) .
other domains assessed by the rbans showed the immediate memory to be in the borderline range , attention was low average , whilst language and visuospatial / constructional abilities were relatively preserved ( table 1 ; left - hand column ) .
in addition to the evidence of right temporal lobectomy , this also showed a high signal change in the left temporal lobe involving the hippocampus ( fig .
serological testing revealed a very high titre of antibodies directed against glutamic acid decarboxylase ( gad ) . in sum , these investigations suggested a diagnosis of anti - gad limbic encephalitis ( le ) . over the next 2 years , the patient was empirically treated with various immunomodulatory interventions including intravenous methylprednisolone , plasma exchange , and two infusions of rituximab , all without obvious clinical improvement in either seizures or cognitive function .
three years after surgery , prior to embarking on a treatment trial of intravenous immunoglobulin at our centre , the patient was still receiving polytherapy for epileptic seizures ( levetiracetam , pregabalin , clonazepam , and lacosamide ) . on cognitive testing
, she now scored 17/30 on the mmse and 63/100 on the ace - r with 8/26 on the memory components . repeating the rbans ,
the cognitive profile was little changed , with the delayed memory score still being extremely low ( table 1 ; right - hand column ) , again affecting both verbal and visual material , with the latter still at slightly higher levels ( list recall total score = 2 ; story recall total score = 2 ; figure recall total score = 8) .
behaviourally , she used external memory aids to record daily events since she had no recall of these after only a brief period of time .
antibodies to gad have been associated with various neurological syndromes , including stiff person syndrome , cerebellar ataxia , epilepsy , paraneoplastic syndromes ( encephalomyelitis , cerebellar ataxia , and le ) , idiopathic le , and myasthenia gravis . from the epilepsy perspective , in a cohort of 253 epilepsy patients , liimatainen et al .   detected anti - gad antibodies in 15 patients ( 5.9 vs. 1.5% in 200 controls ) , most of them ( 90% ) with temporal lobe epilepsy . in a study of patients with adult - onset ( > 30 years ) temporal lobe epilepsy , anti - gad antibodies
were found in 5 out of 42 , with evidence for pharmacoresistant epilepsy with associated memory impairment and other autoimmune diseases .
temporal lobe epilepsy with anti - gad antibodies may not therefore be a rare condition , especially amongst the treatment - refractory patients referred for surgical evaluation .
the precise pathogenic sequence of events in our patient remains uncertain ; a number of potential explanations exist .
it is possible that she had two separate problems , namely mesial temporal sclerosis followed by adult - onset anti - gad antibody le .
if this is so , it might be speculated whether her temporal lobectomy surgery might have unmasked epitopes which initiated an autoimmune response that produced anti - gad antibodies and hence le .
another possibility is that the entire syndrome was due to anti - gad le , albeit very long - lived .
defined non - paraneoplastic anti - gad le as a chronic non - remitting disorder , with antibody titres remaining high after intravenous methylprednisolone . moreover , none of their patients became seizure free despite intense anti - epileptic drug therapy , unlike the situation in le associated with voltage - gated potassium channel ( vgkc / lgi1 ) antibodies [ 10 , 11 ] .
furthermore , cognitive impairments did not improve after treatment in anti - gad le . in this context , it is of note that the neuropathological examination of our patient 's temporal lobectomy specimen found evidence of chronic inflammatory change consisting almost exclusively of t cells with associated microglial activation , suggesting a chronic encephalitic process in addition to hippocampal sclerosis .
to date there is little information on the efficacy of intravenous immunoglobulin in anti - gad le .
response has been reported in new - onset focal epilepsy , but the chances of success must be doubtful in chronic epilepsy , as in our patient . this case may illustrate that autoimmune processes , rather than surgery , may cause bilateral hippocampal pathology resulting in profound amnesia , behaviourally akin to that seen in the classic amnesic patient h.m .
[ 14 , 15 ] . following bilateral anterior temporal lobectomy for intractable seizures with partial hippocampal removal , h.m . developed a profound anterograde amnesia for episodic autobiographical material but with preserved general intelligence , attention , working memory , language and perceptual skills .
in contrast , the neuropsychological outcome following unilateral non - dominant hemisphere temporal lobectomy , as undergone by our patient , is usually confined to material - specific ( i.e. visual rather than verbal ) memory impairments .
we recommend that the possibility of anti - gad le needs to be considered in all patients with refractory epilepsy of presumed temporal lobe origin , including those being considered for epilepsy surgery , especially those whose clinical course is not typical for mesial temporal sclerosis .
 we describe a patient who developed significant cognitive decline with profound amnesia following non - dominant temporal lobectomy for refractory seizures , in whom the original suspicion of structural pathology was revised following the discovery of clinical and neuropathological markers of inflammation , neuropsychological evidence of bilateral involvement , and high titres of antibodies directed against glutamic acid decarboxylase ( gad ) . 
 this case adds to the evidence that the diagnosis of non - paraneoplastic anti - gad limbic encephalitis merits consideration in any patient with a refractory seizure disorder and cognitive decline . 
Introduction
Case Report
Discussion