Periodic epileptiform discharges in mesial temporal lobe epilepsy with hippocampal sclerosis

Open ArchivePublished:June 19, 2013DOI:https://doi.org/10.1016/j.seizure.2013.05.013

      Abstract

      Purpose

      Periodic epileptiform discharges (PEDs) are an uncommon, abnormal EEG pattern seen usually in patients with acute diseases and less frequently in chronic conditions, such as mesial temporal lobe epilepsy (mTLE). Evaluate the clinical histories, neuroimaging findings, and serial electrophysiological studies prior to the appearance of PEDs in patients with mTLE secondary to hippocampal sclerosis (HS).

      Methods

      We searched 19, 375 EEGs (2006–2012) for the presence of PEDs secondary to mTLE due to HS.

      Results

      12 patients were included. The patients with PEDs had a high prevalence of psychiatric comorbilities, including major depression (50%), interictal psychosis (16%) and dementia (8%). All of the patients had intractable epilepsy with similar clinical findings. We observed a sequential neurophysiological worsening of the EEG patterns prior to the appearance of PEDs. Five patients with PEDs underwent epilepsy surgery and four were seizure free at follow-up 15 (±9) months.

      Conclusions

      PEDs are rare in patients with mTLE and HS and their presence in these cases could reflect clinical severity and neurophysiologic worsening, clinically manifested by intractable epilepsy and severe psychiatric comorbidities. The presence of PEDs in EEGs of patients with mTLE, however, was not associated with poor postsurgical seizure-freedom.

      Keywords

      1. Introduction

      Scalp electroencephalographic (EEG) findings in patients with temporal lobe epilepsy (TLE) commonly contain interictal blunt spikes, sharp waves, or sharp-slow waves complexes with maximal amplitude in basal anterior temporal electrodes (sphenoidal, zygomatic, mandibular notch ≥ T1/2 ≥ F7/8 ≥ T3/4).
      • Blume W.T.
      The necessity for sphenoidal electrodes in the presurgical evaluation of temporal lobe epilepsy: con position.
      These interictal epileptiform abnormalities are usually unilateral and may appear isolated or in short rhythmic trains lasting 1–2 s.
      • Gibbs E.L.
      • Fuster B.
      • Gibbs F.A.
      Peculiar low temporal localization of sleep; induced seizure discharges of psychomotor type.
      Other EEG patterns have also been reported in patients with TLE, such as interictal rhythmic delta activity
      • Di Gennaro G.
      • Quarato P.P.
      • Onorati P.
      • et al.
      Localizing significance of temporal intermittent rhythmic delta activity (TIRDA) in drug-resistant focal epilepsy.
      and frontal midline theta activity,
      • Ciganek L.
      Theta discharges in the middle line EEG symptom of temporal lobe epilepsy.
      but the occurrence of interictal periodic epileptiform discharges (PEDs) in TLE is far less common.
      • Pohlmann-Eden B.
      • Hoch D.B.
      • Cochius J.L.
      • Chiappa K.H.
      Periodic lateralized epileptiform discharges, a critical review.
      Periodic lateralized epileptiform discharges (PLEDs) were described initially by Chatrian et al.
      • Chatrian G.E.
      • Shaw C.M.
      • Leffman H.
      The significance of periodic lateralized epileptiform discharges in EEG: an electrographic, clinical and pathological study.
      and are considered abnormal indicating an increased risk for partial onset seizures.
      • Orta D.S.
      • Chiappa K.H.
      • Quiroz A.Z.
      • Costello D.J.
      • Cole A.J.
      Prognostic implications in periodic epileptiform discharges.
      Most often PEDs are found in patients with acute disease commonly caused by acute or subacute structural lesion of the cerebral cortex that can either diffuse or focal.
      • Kuroiwa Y.
      • Celesia G.G.
      Clinical significance of periodic EEG patterns.
      • Téllez-Zenteno J.F.
      • Pillai S.N.
      • Hill M.D.
      • Pillay N.
      Chronic PLEDs with transitional rhythmic discharges (PLEDs-plus) in remote stroke.
      PEDs can also be observed in patients with static encephalopathy and epilepsy,
      • Chatrian G.E.
      • Shaw C.M.
      • Leffman H.
      The significance of periodic lateralized epileptiform discharges in EEG: an electrographic, clinical and pathological study.
      • Orta D.S.
      • Chiappa K.H.
      • Quiroz A.Z.
      • Costello D.J.
      • Cole A.J.
      Prognostic implications in periodic epileptiform discharges.
      • Téllez-Zenteno J.F.
      • Pillai S.N.
      • Hill M.D.
      • Pillay N.
      Chronic PLEDs with transitional rhythmic discharges (PLEDs-plus) in remote stroke.
      and some authors have postulated that chronic PLEDs may be a different entity than that occuring during acute illness.
      • Westmoreland B.
      • Donald W.
      • Klass M.D.
      • Frank W.
      • Sharbrough M.D.
      Chronic periodic lateralized epileptiform discharges.
      Studies have found PEDs in patients with symptomatic epilepsy,
      • Téllez-Zenteno J.F.
      • Pillai S.N.
      • Hill M.D.
      • Pillay N.
      Chronic PLEDs with transitional rhythmic discharges (PLEDs-plus) in remote stroke.
      • Westmoreland B.
      • Donald W.
      • Klass M.D.
      • Frank W.
      • Sharbrough M.D.
      Chronic periodic lateralized epileptiform discharges.
      • Snodgrass S.M.
      • Tsuburaya K.
      • Ajmone Marsan C.
      Clinical significance of periodic lateralized epileptiform discharges: relationship with status epilepticus.
      • Gurer G.
      • Yeisci M.
      • Saygi S.
      • Ciger A.
      Structural lesion in periodic lateralized epileptiform discharges (PLEDs).
      with substantial controversy over whether PEDs and related discharges represent ictal phenomenon meriting aggressive treatment, or reflect a non-specific, self-remitting marker of brain injury.
      • Téllez-Zenteno J.F.
      • Pillai S.N.
      • Hill M.D.
      • Pillay N.
      Chronic PLEDs with transitional rhythmic discharges (PLEDs-plus) in remote stroke.
      To our knowledge no data has been published on the occurrence of PEDs in patients with mesial TLE (mTLE) with hippocampal sclerosis (HS), which is the most common pharmacoresistant form of human epilepsy observed at surgical epilepsy centers.
      • Engel Jr., J.
      Etiology as a risk factor for medically refractory epilepsy: a case for early surgical intervention.
      The classical pattern of HS is characterized by greater loss of principal neurons in the Sommer sector (CA1 and prosubiculum), CA3, and the hilus of dentate gyrus than CA2 sector and subiculum, and often accompanied by astrogliosis and axonal reorganization.
      • Mathern G.W.
      • Wilson C.L.
      • Beck H.
      Hippocampal sclerosis.
      • Thom M.
      • Eriksson S.
      • Martinian L.
      • et al.
      Temporal lobe sclerosis associated with hippocampal sclerosis in temporal lobe epilepsy: neuropathological features.
      In the present study, we describe the clinical and neuroimaging findings in patients with mTLE and HS, as well as electrophysiological changes prior to the appearance of PEDs.

      2. Methods

      This is a case series study, which was carried out using the printed records of all EEGs and video-EEGs performed from January 1st, 2006 to October 31st, 2012 at the Department of Neurophysiology from the National Institute of Neurology (NIN) in Mexico City. Among 19, 375 EEGs and video-EEGs we found that 12 had PEDs and mTLE with HS.
      For these 12 patients we reviewed and summarized clinical information (age, sex, physical findings, past history of febrile seizures, status epilepticus or perinatal hypoxia, age at onset of epilepsy, time since diagnosis of epilepsy, type of seizures, seizure frequency, psychiatric comorbilities, neuropsychological abnormalities, surgery, outcome, and time of follow-up). We used the Engel scale to describe the outcome in the follow-up.
      • Engel Jr., J.
      • Van Ness P.C.
      • Rasmussen T.B.
      Outcome with respect to epileptic seizures.
      The psychiatry department evaluated all patients with psychiatric comorbidities using a typical approach in the outpatient clinic not exactly during the time of EEG recordings showing PEDs.
      Each patient had a workup that included routine laboratory tests, clinical neurological evaluation, neuroimaging, neuropsychological testing, nuclear medicine studies, interictal EEG and video-EEG. The neuropsychological testing and nuclear medicine studies were not performed simultaneously or on the same day as the EEG recordings showing PEDs. High-resolution 3.0 T MRI (T1, T2 and FLAIR acquisitions) was qualitatively reviewed using a standardized protocol by two neuroradiologists who were blinded to EEG findings. For each patient, seizure semiology was described using the Clinical and Electroencephalographic Classification of Epileptic Seizure, ILAE 1981.
      • Commission on Classification
      Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures.
      Based on these results, all patients in the present study were diagnosed with unilateral mesial TLE with MRI evidence of mesial temporal sclerosis without other lesions. The pathological confirmation of HS was available only in the patients who underwent epilepsy surgery.
      All patients had digital awake routine EEG (30 min) and video-EEGs recordings (6–72 h) with 24 scalp electrodes positioned according to the standard 10–20 system of electrode placement, reformatted to both bipolar and off-head referential montages. The filter setting were 0.3 s (0.53 Hz) and 70 Hz. All of the EEG and video-EEGs recordings (with 30–50% of antiepileptic withdrawals) were performed without sedative drugs. No patients had a seizure cluster within 48 h of the EEG or video-EEGs.

      2.1 Patients with PEDs and mTLE with HS

      All EEGs or video-EEGs that had been reported as repetitive or periodic discharges, PLEDs, PEDs or periodic epileptiform abnormalities were included in the present study. The following inclusion criteria were considered: (1) EEGs or video-EEGs that meet the criteria of PLEDs, bilateral independent PLEDS (BIPLEDs) or generalized periodic epileptiform discharge (GPEDs), (2) Both male and female patients aged more than 16 years and (3) complete clinical records and a follow-up until death or for at least one year. Patients with reports of triphasic sharp waves, status epilepticus, incomplete clinical records or with a follow-up of less than one year were excluded from the study. For each patient, we identified the first EEG or video-EEG study showing evidence of PEDs and then reviewed all previous EEG studies to evaluate changes in the previous EEGs done on the same patient.
      For the purpose of this study, we classified PEDs as PLEDs, BIPLEDs or GPEDs, using strictly adhered-to definitions. PLEDs were characterized as lateralized or focal; periodic or near periodic; or spike, spike-wave, or sharp-wave complex presentations throughout most or all of the recording.
      • Chatrian G.E.
      • Shaw C.M.
      • Leffman H.
      The significance of periodic lateralized epileptiform discharges in EEG: an electrographic, clinical and pathological study.
      GPEDs were defined as the occurrence of periodic complexes occupying at least 50% of a standard 30-minute EEG over both hemispheres in a symmetric, diffuse, and synchronized manner
      • Orta D.S.
      • Chiappa K.H.
      • Quiroz A.Z.
      • Costello D.J.
      • Cole A.J.
      Prognostic implications in periodic epileptiform discharges.
      • Kuroiwa Y.
      • Celesia G.G.
      Clinical significance of periodic EEG patterns.
      • Brenner R.P.
      • Schaul N.
      • Periodic EEG
      patterns: classification, clinical correlation, and pathophysiology.
      and BIPLEDs were defined as bilateral independent periodic lateralized epileptiform discharges.
      • Orta D.S.
      • Chiappa K.H.
      • Quiroz A.Z.
      • Costello D.J.
      • Cole A.J.
      Prognostic implications in periodic epileptiform discharges.
      • de la Paz D.
      • Brenner R.P.
      Bilateral independent periodic lateralized epileptiform discharges: clinical significance.
      • Kalamangalam G.P.
      • Diehl B.
      • Burgess R.C.
      Neuroimaging and neurophysiology of periodic lateralized epileptiform discharges: observations and hypotheses.

      2.2 Statistics analysis

      We used descriptive statistics, all the values are expressed in mean, percents and standard deviations.

      3. Results

      3.1 Patients with PEDs and mTLE with HS

      From 2006 to 2012, we recorded 19, 375 EEGs and video-EEGs in inpatients and outpatients. We identified twelve patients who had EEGs that contained PEDs, and all had mTLE with HS based on EEG, neuroimaging and epileptic semiology. In these twelve patients, BIPLEDs, GPEDs, PLEDs or PLED-like activity were captured on at least 1 available EEG or video-EEG, which represents a prevalence of 0.061% among the inpatient and outpatient EEG and video-EEG recordings. Complete clinical information, EEGs, video-EEGs and neuroimaging findings were available in all the patients. Table 1, Table 2 show the clinical, neurophysiological and neuroimaging findings of these patients. All the patients with hypoperfusion in the SPECT study were concordant with the PEDs localization, ictal onset recorded in the video-EEG and the HS side indicated by brain MRI, except two patient with PLEDs that showed bi-temporal hypometabolism in the SPECT.
      Table 1Clinical and neuroimaging findings of patients with periodic epileptiform discharges and mesial temporal epilepsy secondary to hippocampal sclerosis.
      No. of patientsAge/sexPED typePast medical historySide mTLE with HS (MRI)Type of seizures (ILAE)Frequency (mo)Psychiatric comorbilitiesNeuro-psychological deficitsInterictal SPECTSurgeryEngel scaleFollow-up (months)
      Febrile seizuresPerinatal hypoxiaAge at onset of epilepsy (years)Diagnosis of epilepsy (years)
      143/FPLEDYes1726RB1b,C25Recurrent major depressive disorder, frequents postictal psychosisModerate verbal and visual memory deficits. Short-term memory deficit and long-term memory episodic dysfunctionBilteral mesial temporal hypoperfusionR AH and temporal anterior lobectomyIA27
      233/FPLEDYes132LB1b,C210Major depressive disorder, generalized anxiety disorderModerate verbal and visual memory deficitsLeft temporal hypoperfusionL AHIA11
      330/MPLEDYes217RB1b,C24Major depressive disorderModerate verbal and visual memory deficitsBilteral R > L mesial temporal hypoperfusionR AH and temporal anterior lobectomyIA22
      433/MPLEDYes284LB1b53Major depressive disorderSemantic language,mild shortmemory verbal and visual deficitsLeft fronto-temporal hypoperfusionL AH and temporal anterior lobectomyII7
      541/FPLED1823RB1b,C24Postictal psychosis, Interictal dysphoric disorderModerate verbal and visual memory deficities.
      Major depressive disorderMini-mental Folstein 20/30
      642/MPLEDYes141RB1b,C24Interictal psychosisMini-mental Folstein 24/30
      772/FPLEDYes665RB1b4Interictal psychosisApraxias, agnosias, severe visual and verbal memory deficities
      Dementia
      838/FPLEDYes532RB1b,C210Interictal dysphoric disorderModerate verbal and visual memory deficities
      925/MPLED1015LC2,D8
      1027/FPLED1215RA4b,C320Major depressive disorderMild verbal and visual memory deficitiesR AH and temporal anterior lobectomyIA8
      1140/MBiPLED2020LA4b, B1b,C215Interictal dysphoric disorderMild verbal memory deficitsLeft temporal hypoperfusion
      1247/MBiPLED442LB2b16Moderate verbal and mild visual memory deficities
      Table 2Neurophysiological evolution of the previous electroencephalographic patterns of periodic epileptiform discharges in patients with mesial temporal epilepsy secondary to hippocampal sclerosis.
      No. of patients-19 years-18 years-11 years-8 years-6 years-5 years-3 years-2 years-1 yearOnset PEDs
      13–4 Hz right focal temporal background slowing and sharp waves.3–4 Hz right focal temporal background slowing and sharp waves.3–4 Hz right focal temporal background slowing.3–4 Hz right focal temporal background slowing and sharp waves.3–4 Hz right focal temporal background slowing and sharp waves.5–7 Hz generalized background slowing and 3–4 Hz right focal temporal paroxysmal slowing and sharp waves.5–7 Hz generalized background slowing and 3–4 Hz right focal temporal background slowing and sharp waves.√√5–7 Hz generalized background slowing and 3–4 Hz right focal temporal background slowing and PLEDs
      23–5 Hz left temporal focal background slowingLeft fronto- temporal sharp waves7–8 Hz generalized background slowing and 3–4 Hz left fronto- temporal focal background slowing and sharp waves.7–8 Hz generalized background slowing and 3–4 Hz left fronto- temporal focal background slowing and sharp waves.7–8 Hz generalized background slowing and 3–4 Hz left fronto- temporal focal background slowing and sharp waves.√√7-8 Hz generalized background slowing and 3–4 Hz left fronto-background temporal focal slowing and PLEDs
      3Right fronto-temporal sharp waves3–4 Hz right temporal paroxysmal focal slowing.Right fronto-temporal sharp waves.√√Right PLEDs
      47–8 Hz generalized background slowing and 3–4 Hz left focal temporal background slowing and PLEDs√√7-8 Hz generalized background slowing and 3–4 Hz focal left temporal background slowing and PLEDs
      5Right temporal sharp waves.7–8 Hz generalized background slowing and 3–4 Hz right temporal focal background slowing and PLEDs
      6Right temporal sharp wavesRight PLEDs
      74–6 Hz generalized background slowing and 3–4 Hz right temporal focal background slowing and sharp waves4–6 Hz generalized background slowing and 3–4 Hz right temporal focal background slowing and PLEDs
      84–6 Hz generalized slowing and 3–4 Hz right temporal focal slowing and sharp waves4–6 Hz generalized slowing and 3–4 Hz right temporal focal slowing and PLEDs
      95–6 Hz bi-temporal sharp waves and left PLEDsLeft PLEDs
      10Bi-frontal sharp waves√√7–8 Hz generalized background slowing, 5–6 Hz bi-temporal background slowing and right temporal PLEDs
      11√√3-4 Hz bi-temporal background slowing and sharp waves.√√6–7 Hz generalized, 5–6 Hz bi-temporal background slowing and left temporal PLEDs and right temporal sharp waves√√4-6 Hz generalized background slowing and BiPLEDs
      12Bi-temporal sharp waves√√7–8 Hz generalized background slowing and BiPLEDs
      √√Inpatient video-EEG.
      The mean age of the patients was 39 (±12) year-old and 50% (6/12) were female. All patients were righthanded and 58% (7/12) of them had right mTLE. One patient with BIPLEDs had a past history of status epilepticus. The mean of the age at onset of epilepsy was 12 (±9) years old and the mean frequency of seizures monthly was 13 (±14). Also, all the patients had pharmacoresistant epilepsy and were taking 3 or more antiepileptics drugs, had normal physical and general neurological exams, but had moderate-to-severe neuropsychological deficits and were diagnosed with severe psychiatric diseases that included major depression 50% (6/12) or interictal psychosis 16% (2/12). Five patients underwent epilepsy surgery and four were seizure free at follow-up 15 (±9) months. The pathological analysis showed HS in these patients. Of the seven patients that had not had surgical treatment at the time of this study, two had interictal psychosis and dementia and their guardians declined surgical treatment, one patient refused the surgery, while the remaining four patients are scheduled for epilepsy surgery.
      Fig. 1, illustrates the evolution of the EEG abnormalities before BiPLEDs were first observed. Table 2 shows the progression for an increase from slowing focal to generalized disturbances in the EEG of 5/12 patients. No patient had status epilepticus during the EEG recording. Among the 12 patients we had prior EEG or video-EEG recordings, which dated back to a median of 3 years (range 1–19 years). The PLEDs disappears in the postsurgical EEGs in patients who underwent epilepsy surgery.
      Figure thumbnail gr1
      Fig. 1Forty year-old male (Patient No. 11) with left mesial temporal epilepsy and hippocampal sclerosis. His video-EEG performed one year ago (A) showed 6–7 Hz generalized and 5–6 Hz bi-temporal slowing with periodic lateralized epileptiform discharges on the left temporal region and often sharp waves on the right temporal region. (B) In the follow-up the video-EEG shows Bi-PLEDs. These patterns were noted throughout or most of the total duration of the video-EEG recordings both during awake and sleep states. Low and high cut filters: 1–70 Hz. Notch: 60 Hz. Sensitivity: 100 μVp-p. (C) Cerebral MRI 3 T, (1) coronal T2 FLAIR and (2) STIR sequences showing left mesial temporal sclerosis. It's was perfomed the same year of the (A) video-EEG.

      4. Discussion

      Our results shows a prevalence of 0.061% of PLEDs due to mTLE and HS among the inpatient and outpatient EEG and video-EEG recoding in a neurological third level center. Their presence in these cases could reflect clinical severity and neurophysiologic worsening, clinically manifested by intractable epilepsy and severe psychiatric comorbidities. The presence of PEDs in EEGs of patients with mTLE, however, was not associated with poor postsurgical seizure-freedom.
      Periodic epileptiform discharges are a rare EEG pattern. PLEDs prevalence varies from 0.1 to 1% in EEG laboratories.
      • Chatrian G.E.
      • Shaw C.M.
      • Leffman H.
      The significance of periodic lateralized epileptiform discharges in EEG: an electrographic, clinical and pathological study.
      • Orta D.S.
      • Chiappa K.H.
      • Quiroz A.Z.
      • Costello D.J.
      • Cole A.J.
      Prognostic implications in periodic epileptiform discharges.
      • Kuroiwa Y.
      • Celesia G.G.
      Clinical significance of periodic EEG patterns.
      • Schraeder P.L.
      • Snigh N.
      Seizure disorders following periodic lateralized epileptiform discharges.
      • Terzano M.G.
      • Parrino L.
      • Mazzucchi A.
      • Moretti G.
      Confusional states with periodic lateralized epileptiform discharges (PLEDs). A peculiar epileptic syndrome in the elderly.
      • Walsh J.M.
      • Brenner R.P.
      Periodic lateralized epileptiform discharges long-term outcome in adults.
      • Raroque Jr., H.G.
      • Wagner W.
      • Gonzalez P.C.
      • et al.
      Reassessment of the clinical significance of periodic lateralized epileptiform discharges in pediatric patients.
      • García-Morales I.
      • García M.T.
      • Galán-Dávila L.
      • et al.
      Periodic lateralized epileptiform discharges: etiology, clinical aspect, seizure and evolution in 130 patients.
      • Fitzpatrick W.
      • Lowry N.
      PLEDs: clinical correlates.
      However, the true incidence is likely higher as many patients with PLEDs may not undergo EEG, particularly those without a recent seizure or altered mental status.
      • Fitzpatrick W.
      • Lowry N.
      PLEDs: clinical correlates.
      Similarly, the true prevalence and incidence of BIPLEDs and GPEDs are also unknown, although studies report an incidence between 4% and 22% of BIPLEDs in patients in the intensive care unit
      • Chatrian G.E.
      • Shaw C.M.
      • Leffman H.
      The significance of periodic lateralized epileptiform discharges in EEG: an electrographic, clinical and pathological study.
      • Kalamangalam G.P.
      • Diehl B.
      • Burgess R.C.
      Neuroimaging and neurophysiology of periodic lateralized epileptiform discharges: observations and hypotheses.
      • Fitzpatrick W.
      • Lowry N.
      PLEDs: clinical correlates.
      and a prevalence of 0.1% in routine EEG.
      • Fitzpatrick W.
      • Lowry N.
      PLEDs: clinical correlates.
      We did not found any patient with GPEDs and mTLE and HS. One possible reason is that GPEDS are usually seen in multifocal or diffuse cerebral injuries as anoxia, and herald a less favorable prognosis with higher mortality, though chronic GPEDs are now well recognized.
      • Orta D.S.
      • Chiappa K.H.
      • Quiroz A.Z.
      • Costello D.J.
      • Cole A.J.
      Prognostic implications in periodic epileptiform discharges.
      The prevalence of the PED in patients with mTLE and HS based in the criteria of clinical diagnosis is unknown.
      • Verma A.
      • Radtke R.
      EEG of partial seizures.
      The present study describes the clinical characteristics and outcome of patients with PEDs and mTLE with HS. We found that our patients had the risk factors and natural history of patients with mTLE due to HS,
      • Berg A.T.
      The natural history of mesial temporal lobe epilepsy.
      and all had intractable epilepsy with complex partial seizures sometimes with secondary generalization. Also, all of our patients had normal physical and neurological exams, but had moderate-to- severe neuropsychological deficits, which has been previously described in patients with mTLE and HS.
      • Berg A.T.
      The natural history of mesial temporal lobe epilepsy.
      All had severe psychiatric comorbilities, including major depression, dementia or interictal psychosis with a prevalence higher than expected compared with patients with mTLE and HS without PEDs reported in other similar clinical case series.
      • Caramelli P.
      • Castro L.H.
      Dementia associated with epilepsy.
      • Nadkarni S.
      • Arnedo V.
      • Devinsky O.
      Psychosis in epilepsy patients.
      One possible risk factor for this high prevalence is focus laterality in temporal lobe, our patients showed PLEDs more often on the right (66%). Currently, the type of affective disorder in relation to focus laterality in temporal lobe epilepsy is controversial.
      • Kalinin V.V.
      • Polyanskiy D.A.
      Focus laterality and interictal psychiatric disorder in temporal lobe epilepsy.
      Other predictors for development of interictal psychosis such as earlier age at onset of epilepsy, complex partial seizures or generalized tonic clonic seizures, and borderline intellectual functioning were similar to other studies.
      • Adachi N.
      • Matsuura M.
      • Okubo Y.
      • Oana Y.
      • Takei N.
      • Kato M.
      • Hara T.
      • Onuma T.
      Predictive variables of interictal psychosis in epilepsy.
      Our descriptive study doesn’t allow establishment of physiopathological or etiological associations between the cognitive dysfunctions and psychiatric conditions and the PEDs in mTLE with HS. Another limitation is the lack of serial neuropsychological evaluations during the follow-up.
      Neuroimaging abnormalities occur in 90 to 100% of patients with PLEDs.
      • Gurer G.
      • Yeisci M.
      • Saygi S.
      • Ciger A.
      Structural lesion in periodic lateralized epileptiform discharges (PLEDs).
      However, only one patient with chronic BIPLEDs and bilateral hippocampal injury has been published,
      • Fushimi M.
      • Matsubuchi N.
      • Sekine A.
      • Shimizu T.
      Benign bilateral independent periodic lateralized epileptiform discharges.
      a 64 year-old man with bilateral hippocampal strokes with recurrent BIPLEDs. With respect to PLEDs and chronic subcortical lesions the prevalence reported in two separate studies had a range between 11 and 15%.
      • Orta D.S.
      • Chiappa K.H.
      • Quiroz A.Z.
      • Costello D.J.
      • Cole A.J.
      Prognostic implications in periodic epileptiform discharges.
      • Kalamangalam G.P.
      • Diehl B.
      • Burgess R.C.
      Neuroimaging and neurophysiology of periodic lateralized epileptiform discharges: observations and hypotheses.
      Whether PEDs are an interictal or ictal activity remains unclear, despite reports of regional increases in cerebral blood flow, oxygen use, or hypermetabolism associated with PLEDs.
      • Fushimi M.
      • Matsubuchi N.
      • Sekine A.
      • Shimizu T.
      Benign bilateral independent periodic lateralized epileptiform discharges.
      • Handforth A.
      • Cheng J.T.
      • Mandelkern M.A.
      • Treiman D.M.
      Markedly increased mesiotemporal lobe metabolism in a case with PLEDs: further evidence that PLEDs are a manifestation of partial status epilepticus.
      • Ergün E.L.
      • Salanci B.V.
      • Erbas B.
      • Saygi S.
      SPECTin periodic lateralized epileptiform discharges (PLEDs): a case report on PLEDs.
      In contrast to previous studies, patients in the current study who had interictal SPECT studies showed mesial temporal hypometabolism, which was similar to a case that described a patient with chronic BIPLEDs with a benign prognosis who had bilateral hypoperfusion in the mesial temporal structures during the BIPLEDs recordings.
      • Fushimi M.
      • Matsubuchi N.
      • Sekine A.
      • Shimizu T.
      Benign bilateral independent periodic lateralized epileptiform discharges.
      A possible explanation for the discrepancies among studies could be related to the stage of the underlying neurological condition. Our patients and the patient with benign BiPLEDs mentioned previously
      • Fushimi M.
      • Matsubuchi N.
      • Sekine A.
      • Shimizu T.
      Benign bilateral independent periodic lateralized epileptiform discharges.
      had underlying chronic neurological conditions compared with the acute or subacute neurological conditions with PLEDs published elsewhere.
      • Fitzpatrick W.
      • Lowry N.
      PLEDs: clinical correlates.
      • Gross D.W.
      • Wiebe S.
      • Blume W.T.
      The periodicity of lateralized epileptiform discharges.
      PLEDs may be observed for a prolonged period without the occurrence of either clinical seizures or electrographic evolution.
      • Pohlmann-Eden B.
      • Hoch D.B.
      • Cochius J.L.
      • Chiappa K.H.
      Periodic lateralized epileptiform discharges, a critical review.
      • Snodgrass S.M.
      • Tsuburaya K.
      • Ajmone Marsan C.
      Clinical significance of periodic lateralized epileptiform discharges: relationship with status epilepticus.
      Positron emission tomographic studies have been undertaken in an attempt to clarify the ictal or interictal nature of PLEDs.
      • Fushimi M.
      • Matsubuchi N.
      • Sekine A.
      • Shimizu T.
      Benign bilateral independent periodic lateralized epileptiform discharges.
      In some, increased local cerebral glucose metabolism could be found.
      • Handforth A.
      • Cheng J.T.
      • Mandelkern M.A.
      • Treiman D.M.
      Markedly increased mesiotemporal lobe metabolism in a case with PLEDs: further evidence that PLEDs are a manifestation of partial status epilepticus.
      In contrast to the latter observation, other studies did not find an increase in either glucose metabolism or cerebral blood flow.
      • Fushimi M.
      • Matsubuchi N.
      • Sekine A.
      • Shimizu T.
      Benign bilateral independent periodic lateralized epileptiform discharges.
      • Hisada K.
      • Morioka T.
      • Nishio S.
      • et al.
      Magnetoencephalographic analysis of periodic lateralized epileptiform discharges (PLEDs).
      We consider in the present patients with mTLE and HS that PEDs are a marker of subcortical injury and not an ictal phenomena. Furthermore, the observation that the periodic discharges described resemble those found at a smaller scale when cortical dysplasias are invasively sampled and TLE PLEDs may arise in instances when the temporal neocortex is dysplastic,
      • Fitzpatrick W.
      • Lowry N.
      PLEDs: clinical correlates.
      is contradicted in our study because the histopathological findings in the neocortical sampled tissue were nonspecific. No patient was considered to have dual pathology, whereas the histopathological diagnosis of HS was evidenced in all cases submitted to surgery. The patient who underwent a left amigdalohippocampectomy (no neocortical resection) was also seizure free after surgery. Further, subsequent postsurgical EEGs showed no evidence of PEDS.
      The pathophysiology associated with PEDs remains uncertain. For example, PLEDs can be generated from an acute or chronic cerebral injury and the location could be cortical, subcortical or both, although the most common substrate in PLEDs is an acute cerebral cortical and subcortical lesion.
      • Orta D.S.
      • Chiappa K.H.
      • Quiroz A.Z.
      • Costello D.J.
      • Cole A.J.
      Prognostic implications in periodic epileptiform discharges.
      • Snodgrass S.M.
      • Tsuburaya K.
      • Ajmone Marsan C.
      Clinical significance of periodic lateralized epileptiform discharges: relationship with status epilepticus.
      • Kalamangalam G.P.
      • Diehl B.
      • Burgess R.C.
      Neuroimaging and neurophysiology of periodic lateralized epileptiform discharges: observations and hypotheses.
      However, some patients have normal neuroimaging studies when the PEDs are found.
      • Orta D.S.
      • Chiappa K.H.
      • Quiroz A.Z.
      • Costello D.J.
      • Cole A.J.
      Prognostic implications in periodic epileptiform discharges.
      • Raroque Jr., H.G.
      • Wagner W.
      • Gonzalez P.C.
      • et al.
      Reassessment of the clinical significance of periodic lateralized epileptiform discharges in pediatric patients.
      One theory considers the spatially variable nature of brain lesions and proposes PLEDs can arise from different sites of the cortical-subcortical system prone to synchronous oscillations resulting from perturbation (i.e., lesion) of one or more sites.
      • Kalamangalam G.P.
      • Diehl B.
      • Burgess R.C.
      Neuroimaging and neurophysiology of periodic lateralized epileptiform discharges: observations and hypotheses.
      Furthermore, changes in morphology and spatial patterns of PLEDs could arise from different sites within the network that generate different oscillations. Acute epilepsy animal models induced by bicuculline placed in the hippocampal-parahippocampal region of the isolated guinea pig brain found interictal and ictal epileptiform activities with variability of spatial propagation and time course in the olfactory-temporal region. In this model, arterial perfusion of bicuculline-induced periodic interictal spikes that originate in the piriform cortex, propagated to the entorrinal cortex and then sometimes spread to the CA1 region in the hippocampus.
      • Uva L.
      • Librizzi L.
      • Wendling F.
      • de Curtis M.
      Propagation dynamics of epileptiform activity acutely induced by bicuculline in the hippocampal-parahippocampal region of the isolated Guinea pig brain.
      However, ictal discharges are characterized by a peculiar pattern of fast activity that originates from the entorhinal/hippocampal region and only secondarily propagates to the perirhinal cortex. The results suggest that reiteration of ictal events may promote changes in the propagation pattern of epileptiform discharges that could act as trigger elements in the development of temporal lobe epilepsy.
      • Uva L.
      • Librizzi L.
      • Wendling F.
      • de Curtis M.
      Propagation dynamics of epileptiform activity acutely induced by bicuculline in the hippocampal-parahippocampal region of the isolated Guinea pig brain.
      Another interesting finding is that epileptiform ictal discharges are prevented by periodic interictal spiking in the piriform cortex
      • Uva L.
      • Librizzi L.
      • Wendling F.
      • de Curtis M.
      Propagation dynamics of epileptiform activity acutely induced by bicuculline in the hippocampal-parahippocampal region of the isolated Guinea pig brain.
      and olfactory cortex.
      • Librizzi L.
      • de Curtis M.
      Epileptiform ictal discharges are prevented by periodic interictal spiking in the olfactory cortex.
      Invasive electroencephalography in patients with mesial temporal lobe epilepsy shows that the presence of periodic spikes before seizure onset has a significant correlation with reduced CA1 cell counts. This phenomenon is followed, in spontaneous seizures, by 13–25 Hz discharges in medial temporal lobe structures. Although hippocampus or entorhinal cortex are involved to a variable degree in mesial temporal epilepsy, the periodic spikes are more consistently seen in hippocampus.
      • King D.
      • Spencer S.
      Invasive electroencephalography in mesial temporal lobe epilepsy.
      Mesial temporal lobe epilepsy with HS is a group of chronic disorders characterized by prominent neuronal loss and gliosis in the hippocampus and amygdala,
      • Yang T.
      • Zhou D.
      • Stefan H.
      Why mesial temporal lobe epilepsy with hippocampal sclerosis is progressive: uncontrolled inflammation drives disease progression?.
      yet little is known about its ‘natural’ history from initial onset.
      • Berg A.T.
      The natural history of mesial temporal lobe epilepsy.
      The course of the disorder is complex and may appear relatively benign at first with intractable seizures emerging only later.
      • Berg A.T.
      The natural history of mesial temporal lobe epilepsy.
      Newly published data indicate that it may be a progressive disease, but the mechanism underlying the progressive nature remains unknown.
      • Yang T.
      • Zhou D.
      • Stefan H.
      Why mesial temporal lobe epilepsy with hippocampal sclerosis is progressive: uncontrolled inflammation drives disease progression?.
      Ictal or inter-ictal chronic animal models of PEDS in temporal lobe epilepsy are lacking and the clinical evidence of chronic PLEDS in epileptic patients is rare.
      • Téllez-Zenteno J.F.
      • Pillai S.N.
      • Hill M.D.
      • Pillay N.
      Chronic PLEDs with transitional rhythmic discharges (PLEDs-plus) in remote stroke.
      • Westmoreland B.
      • Donald W.
      • Klass M.D.
      • Frank W.
      • Sharbrough M.D.
      Chronic periodic lateralized epileptiform discharges.
      • Gurer G.
      • Yeisci M.
      • Saygi S.
      • Ciger A.
      Structural lesion in periodic lateralized epileptiform discharges (PLEDs).
      • Gross D.W.
      • Wiebe S.
      • Blume W.T.
      The periodicity of lateralized epileptiform discharges.
      Our patients are unique because PEDs are inter-ictal markers of subcortical injury, specifically in HS and provide a clinical opportunity to study the role of the inter-ictal PEDs in mesial temporal epilepsy with HS. The neurophysiological findings from previous EEGs of the same patients that later developed PEDs provides support that mTLE is a progressive disease.
      • Yang T.
      • Zhou D.
      • Stefan H.
      Why mesial temporal lobe epilepsy with hippocampal sclerosis is progressive: uncontrolled inflammation drives disease progression?.
      Other limitations of our study are the sample size, generalizability of our findings due to the potential sampling and selection bias of the referral patterns to our third level neurological center and the known limitations of retrospective studies.

      5. Conclusion

      In our study, PEDs were potential markers of clinical severity and neurophysiologic progression in patients with mTLE due to HS, clinically manifested by intractable epilepsy and severe psychiatric comorbilities, however, they did not impact the outcome after the epilepsy surgery. More studies with higher number of patients are needed to confirm these findings.

      Conflict of interest statement

      None.

      Acknowledgements

      None.

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