Transient epileptic and global amnesia: Real-life differential diagnosis

Epilepsy & Behavior 88 (2018) 205–211

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Transient epileptic and global amnesia: Real-life differential diagnosis Jacopo Lanzone 1, Lorenzo Ricci ⁎,1, Giovanni Assenza, Martina Ulivi, Vincenzo Di Lazzaro, Mario Tombini Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, University Campus Bio-Medico of Rome, via Álvaro del Portillo, 21, 00128 Rome, Italy

a r t i c l e

i n f o

Article history: Received 11 March 2018 Revised 20 July 2018 Accepted 21 July 2018 Available online xxxx Keywords: Transient amnesia Epileptic amnesia Focal seizure Temporal lobe epilepsy Transient global amnesia

a b s t r a c t Objective: Transient epileptic amnesia (TEA) is an underestimated condition in emergency clinical setting, where most of transient amnesic episodes tend to be classified as transient global amnesia (TGA). We designed this study to evaluate the actual frequency of TEA in a real-life scenario and to highlight the features that can help clinicians distinguishing it from TGA. Methods: We retrospectively collected clinical data of 83 patients who accessed our emergency ward for an abrupt onset of amnesic disorder, initially interpreted as TGA. All patients underwent neurological evaluation, magnetic resonance imaging (MRI) scan, and standard 21-channel scalp electroencephalography (EEG) recording (standard EEG [st-EEG]). Moreover, patients with borderline epileptiform abnormalities on st-EEG or with normal st-EEG but high clinical suspicion for TEA underwent a 16-channel 24-hour ambulatory EEG (24-h EEG). Clinical features, neurophysiological, and neuroimaging data were analyzed and compared in the two groups (TEA and TGA). Results: Diagnosis of TEA, according to Zeman's criteria, was made in 15 patients (18%). From a clinical point of view recurrence (p b .001) and atypical symptoms such as confusion or language disorder (TGA plus manifestations), appear to be key elements in order to discriminate between TEA and TGA (80% of patients with TEA vs 7.8% of patients with TGA; p b .001). In our sample, duration of the episodes did not significantly differ between TGA and TEA, even though it is usually described as shorter for TEA. This result could be related with a prolonged postictal state in these patients. The analysis of st-EEG results evidenced low sensitivity for interictal epileptiform abnormalities (IEAs) detection (52.3%), with not conclusive data in distinguishing TEA from TGA. On the contrary, 24-h EEG showed IEAs in all patients with epilepsy, mostly during sleep, suggesting an essential diagnostic role of long-lasting EEG recording for TEA. Finally, structural abnormalities were more frequent in patients with TEA (26.6%). In the group with TGA, the only imaging alteration found was diffusion weighted imaging (DWI) hippocampal hyperintensity. Conclusion: Our findings show that in a real-life clinical scenario, TEA is frequent but often overlooked. However, simple clinical data and widely available neurophysiological examinations can truly help to effectively distinguish TEA from TGA. © 2018 Elsevier Inc. All rights reserved.

1. Introduction Transient amnesic syndromes are distinct clinical syndromes with impressive features, regularly encountered by neurologists in acute clinical setting. Diagnosis of these syndromes can be difficult, and their nature has been debated for over 50 years [1]. Among the typical examples of acute-onset amnesic syndromes, transient global amnesia (TGA) is without any doubt the most emblematic; TGA is characterized by the sudden onset of dramatic anterograde amnesia lasting up to 24 h. Although the etiology of this specific syndrome is unknown, there is consistent evidence that assigns a causative ⁎ Corresponding author. E-mail addresses: [email protected] (L. Ricci), [email protected] (M. Tombini). 1 The authors equally contributed to the paper.

https://doi.org/10.1016/j.yebeh.2018.07.015 1525-5050/© 2018 Elsevier Inc. All rights reserved.

explanation to a transient disturbance of specific hippocampal circuits involved in memory processing [2,3]. On the other hand, transient epileptic amnesia (TEA) syndrome is an underdiagnosed clinical entity that can occasionally explain an ictal amnesic disorder [4]; it can be attributable to focal ictal or interictal epileptic discharges, usually within the temporal lobe. The relationship between epilepsy and amnesic disorders has been suspected for over a century, but it was Kapur who first came up with the term TEA in 1993, giving its own dignity to this amnesic syndrome. They described TEA as a clinical entity similar to TGA, distinguished by its brevity and recurrence [5]. It is common knowledge that epilepsy can manifest itself with pure amnesic disorder [6], presenting slight to none typical epileptic manifestations (focal seizures with impaired awareness, focal to secondarily generalized seizures, epileptic aura, etc.), and it is especially now well-known that temporal lobe involvement may influence performance in memory-related tasks [7]. Nevertheless, since the definition

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given by Kapur [5], TEA has struggled to impose its-self as a well-recognized epileptic syndrome, mainly for its subtle manifestations, its overlap with temporal lobe epilepsy (TLE) and the similarity with TGA. This disease appears to present more frequently in the adult life, with a slight predominance in male patients [8]; it happens preferentially upon awakening and tends to recur [9]. In 1998, Zeman et al. proposed the following diagnostic criteria for TEA [10]: (1) a history of recurrent witnessed episodes of transient amnesia; (2) cognitive functions other than memory judged to be intact during typical episodes by a reliable witness; (3) evidence for a diagnosis of epilepsy on the basis of one or more defined characteristics (epileptiform abnormalities on electroencephalography, the concurrent onset of other clinical features of epilepsy such as lip-smacking or olfactory hallucinations, a clearcut response to anticonvulsant therapy). Evidences of this syndrome as described by Zeman et al. [10] can easily pass unrecognized. The majority of patients present negative or nonspecific scalp EEG; the rate of clear epileptiform abnormalities in EEG is reportedly 37% [9]; thus, the high rates of EEG normality often lead to a misdiagnosis in the emergency room, and sometimes even in the neurological ward leading TEA to being mistaken for TGA [11]. It is noteworthy to say that some studies demonstrated how high density EEG could enhance the accuracy in the diagnosis [12]; however, this technique is timeand cost-consuming, and it is not currently included in the common diagnostic work-up for ictal amnesic disorders. The difficulty in making a diagnosis on the basis of Zeman's criteria has been evidenced by Ukai and Watanabe [13], who proposed a new classification for this spectrum of disease: according to these authors patients who meet all of the criteria of Zeman et al. [10] should be regarded as having TEA, while patients who do not experience amnesic attacks despite suffering from accelerated long-term forgetting (ALF) [14,15] and/or autobiographical amnesia could be considered to be suffering from ‘broad TEA’; nevertheless in patients with atypical cognitive impairment and epileptic alterations on scalp EEG an epileptic etiology could be considered even if they never reported ictal amnesia and a TEA like disorder. Finally, it was recently proposed [16] that TEA could be a peculiar form of TLE with specific involvement of circuits deputed to the functioning of declarative memory; however, the borders of TEA still somehow remain still somehow blurred, and its potential overlap with late onset epileptic amnesia and cognitive disorders related to long-standing epilepsy such as temporal mesial sclerosis must be considered [17,18]. The aim of our study was to evaluate the accuracy of diagnosis of TEA and TGA in a real medical practice scenario and to identify the main features differentiating the two disorders. To this purpose, we retrospectively analyzed all clinical and instrumental features of patients who came to our attention for an abrupt occurrence of amnesic disorder that first was diagnosed as TGA; then, we identified those patients who met Zeman's criteria for TEA and thus suffered from epilepsy rather than TGA. In this way, we divided our population into groups with TEA and TGA, and we investigated whether there are distinctive features that can help clinicians to differentiate TEA from TGA with greater sensitivity. We regard this matter of critical relevance because patients with TEA tend to promptly answer to therapy with antiepileptic drugs (AEDs), and a high rate of misdiagnosis means that many among these patients have to cope with recurrent amnesic episodes without a proper pharmacological treatment. 2. Patients and methods 2.1. Study population For the purpose of the study, we retrospectively analyzed files and information regarding all patients, who were referred to our second level facility from a first level emergency department (ED) from 2010 to 2018 because of one or more episodes of transient amnesia that

required admission in the ED. The exclusion criteria were as follows: psychiatric comorbidities, dementia, and diagnosis of secondary cause for acute amnestic syndrome (transient ischemic attack, metabolic encephalopathy, intoxication, psychogenic fugue, dissociative disorders, hypoglycemia) (Fig. 1). Thus, we identified 91 patients admitted for a sudden onset amnesic disorder of which 8 patients were excluded since they met exclusion criteria (1 mild ischemic stroke, 4 patients with confusion in the context of dementia, 2 patients with psychiatric comorbidities, 1 patient with hepatic encephalopathy). Finally, we identified 83 patients who matched the established criteria. All patients were admitted in our ward within 24 h from the symptoms onset. At first evaluation in ED, all 83 patients were diagnosed as TGA on the basis of clinical history collected by ED medical doctors and first level examinations (routine blood tests, electrocardiogram [EKG], and brain computed tomography [CT] scan) (Fig. 1). Thus, for all patients clinical characteristics of attacks, context of occurrence, possible triggering factors, and cognitive problems were assessed by experienced neurologists with the aid of witnesses if available. We gave particular attention in asking for the following: duration of the event, recurrence, happening upon awakening, and presence of symptoms that are not typical for TGA (staring, automatisms, olfactory hallucinations, language disorder, tremor, ataxia, spatial disorientation, severe confusion as reported in the clinical records, transient facial palsy, etc.); from now on, we will refer to such symptoms as ‘TGA plus’. The term confusion, even if we are accustomed to its use in clinical practice, can be misleading; we specify that in this paper we use it with the meaning of severe attention impairment. All patients underwent a full neurological examination and waking standard electroencephalography (EEG) (st-EEG) recording with 21-channel scalp EEG system (international 10–20 system, sampling rate 256 Hz, 0.3-Hz to 70-Hz band pass filter; Micromed Brain Quick System). The EEG recording was performed in the laboratory in eyes closed, resting condition, for the duration of 10–15 min including hyperventilation and intermittent photic stimulation. Moreover, patients with borderline epileptiform abnormalities on st-EEG or with normal st-EEG but high clinical suspicion for TEA underwent 16-channel 24-hour ambulatory EEG (24-h EEG, sampling rate 256 Hz, 0.3-Hz to 70-Hz band pass filter; Micromed Brain Spy System), which allowed us to record even nocturnal sleep in all subjects studied. For the purpose of this study, we considered EEG to be abnormal if focal or diffuse interictal epileptiform transients (spike, sharp wave, or spike-and-wave discharges) or focal theta waves with spiky morphology were found. Finally, all patients performed cerebral MRI (1.5-T MRI, T1, T2, DWI, apparent diffusion coefficient (ADC), fluid attenuation inversion recovery (FLAIR) brain sequences). Moreover, due to the retrospective nature of the study although some of the patients with TEA complained mild memory impairment, neuropsychological evaluation was not performed since it was not part of our routine work-up. According to Zeman's criteria [10] evidence of epilepsy was supported through any combination of epileptiform interictal abnormalities on EEG, reports of simultaneous classically epileptic features (‘TGA plus’ symptoms), and/or a positive treatment response to antiepileptic drugs (AEDs). Thus, 15 patients out of 83 (18%) resulted as affected by focal epilepsy and were diagnosed as TEA; their features were summarized in the Table 1. In detail, all patients fulfilled at least 2 supportive criteria as specified at point 3 of the Zeman's criteria: 10 out of 15 patients had all 3 criteria (epileptiform abnormalities, ‘TGA plus’ symptoms and clearcut response to anticonvulsant therapy), 2 out of 15 had epileptiform abnormalities and ‘TGA plus’ symptoms (their outcome was not known as they were lost at follow-up) and 3 out of 15 patients had epileptiform abnormalities and clearcut response to anticonvulsant therapy (they were all seizure-free). Differences in demographics, clinical features, and on investigation findings were compared in patients with TGA and TEA in order to highlight distinguishing characteristics between the two groups (Table 2). Our study was approved by local Ethics Committee.

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Fig. 1. Flow chart of the study design: MRI = magnetic resonance imaging; st-EEG = 21-channel standard scalp EEG recording; EEG 24H = 16-channel 24-hour ambulatory EEG; IEAs = interictal epileptiform abnormalities.

2.2. Statistical analysis Descriptive statistics is presented as mean ± standard deviation or median ± range, depending on data distribution. Data distribution was assessed by means of Kolmogorov–Smirnov test. We compared each variable between the groups with TEA and TGA using Chi-squared testing for categorical data and Mann–Whitney U test for continuous data, as no continuous data were normally distributed (except for age showing normal distribution; thus, t-test for independent samples was used in this case). A p value b .05 was considered statistically significant. Data were analyzed using SPSS, version 23 (Chicago, IL). Variables that were found to be statistically significant were further analyzed using a multivariate regression model. Variables were added in a backwards stepwise procedure. For all clinical features, apart from 24-hour EEG results, logistic regression was used with associations assessed by odds ratios (OR) and their Wald CIs.

3. Results Fifteen out of 83 patients (age: 67.2 ± 5.2 years; females/males: 11/4) responded to Zeman's criteria and thus were diagnosed as TEA, while 64 patients (age: 62.8 ± 9.4 years, females/males: 37/ 27) were diagnosed as TGA. Finally, the remaining 4 patients fulfilling all Zeman's criteria except seizures recurrence were considered affected by suspected focal epilepsy. Patients with TEA were significantly older than those with TGA (t-test; F = 5192; t = − 2523; df = 39,640, p = .016). No significant differences in age and sex (Mann–Whitney U test = 394, p = .280) were evident in the two groups. The clinical and instrumental features of patients with TEA are displayed in Table 1. In detail, 13 patients suffered from TLE, 2 from structural focal epilepsy (thalamic cavernome and cerebral post-traumatic malacic lesion). Two patients showed at MRI cerebral alterations (left temporal venous ectasia and pinealome) not linked to

epileptogenic focus. Lateralization was left hemispheric in 8 patients, right in 4, and bilateral in 3. All patients with TEA underwent st-EEG. Clear, recurrent interictal epileptiform abnormalities (IEAs) were present only in 8 (53.3%) out of 15 patients and were consistently over temporal or frontotemporal regions. Moreover, 12 patients underwent 24-h EEG, and they all (100%) had IEAs. In detail, all patients who performed the 24-h EEG showed IEAs during sleep, and in 4 patients IEAs were present only during sleep. The median duration of the amnestic attacks was 3 h (ranging from 15 min to 24 h), and only 1 (6.6%) out of 15 patients typically experienced episodes lasting less than 1 h. Amnesia was the only feature of all attacks in 3 patients (20%) while the other ones complained further symptoms: language disorder (1 patient), headache (2 patients), spatial disorientation (3 patients), mild confusion (9 patients), and aphasia (1 patient). The attacks were characterized by a mixed anterograde and retrograde amnesia, sometimes with repetitive questioning showing a clinical picture hardly distinguishable from TGA. Most patients presented recurrent episodes (median 2, range 2–5, 44 overall recurrences). Attacks occurred upon awaking in 40% of patients. No specific triggers were identified. Finally, most patients had a good response to antiepileptic therapy: 8 (53.3%) out 15 patients were seizure-free, 5 patients had less than 1 seizure per year, and the other ones were lost at follow-up. However, as in our sample there are several patients with two or a few attacks, a ‘clear cut’ response is difficult to determine. 3.1. Clinical anamnestic findings Clinical features of the two groups (TEA and TGA) were displayed in Table 1 and Fig. 2. Considering all clinical findings, we did not find any significant difference between the two groups except for episodes recurrence (group with TEA: median = 2; range = 2–5; group with TGA: median = 0, range = 0–4; p = b .001) and the occurrence of other symptoms in addition to anterograde amnesia (80% of patients with TEA vs 14.3% of patients with TGA; p b .001), in particular confusion (73.3% of patients with TEA vs 6.2% of patients with TGA; p b

5

2

2

6

T left

63 F TLE normal

4

3

0.4

T left

60 M TLE normal

5

2

1

T right

64 F TLE normal

6

5

1

T left

67 F TLE normal

7

CBZ Less than1/y

LVT SF

LVT SF

LTG SF

LVT SF

LTG SF

LVT Less than 1/y

Morning Morning Morning Afternoon Morning Morning (awakening) (awakening) Confusion Confusion Confusion Headache – – Language disturbance, confusion

3

12

T left

75 M TLE normal

3

CBZ Less than 1/y

Morning (awakening) Headache upon awakening

4

5

T left

59 F TLE normal

8

LVT *

Spatial disorientation, confusion

Morning

2

2

T left

61 F SFE Thalamic cavernoma

9

ZNS Less than 1/y

Temporal and spatial disorientation, confusion

Morning

5

24

T right

68 F TLE Cystic pinealoma

10

Morning (awakening) Waxing and waning symptoms, spatial disorientation LVT *

3

1

T right

74 F TLE normal

11

2

4

T bil

70 F TLE normal

13

2

5

T left

75 F SFE Bifrontal post-traumatic malacic lesion

14

LVT SF

LVT Less than 1/y

LVT SF

Evening Morning Afternoon (awakening) (awakening) – Postictal Confusion, confusion Aphasia (2 days)

2

3

T left

66 F TLE normal

12

LVT SF

Confusion

–

2

2

67 M TLE Left temporal venous ectasia T bil

15

TLE (temporal lobe epilepsy), SFE (symptomatic focal epilepsy), FT (frontotemporal), T (temporal), Bil (bilateral), CBZ (carbamazepine), LVT (levetiracetam), LTG (lamotrigine), ZNS (zonisamide), SF (seizure-free), (* = lost at follow-up).

Therapy Outcome

Symptom PLUS

3

2.5

Morning

T right

T bil

Epileptic focus Duration of amnestic episode (hours) Recurrence (times) Onset

70 M TLE normal

69 F TLE normal

Age at onset Gender Epilepsy MRI

2

1

Patient

Table 1 Clinical Findings of 15 patients with TEA.

208 J. Lanzone et al. / Epilepsy & Behavior 88 (2018) 205–211

J. Lanzone et al. / Epilepsy & Behavior 88 (2018) 205–211

3.2. EEG

Table 2 Comparison between patients with TEA and TGA on clinical findings.

Clinical findings Recurrence Duration, median (h) Onset on awakening Stress Effort TGA+ Confusion

TEA (15 patients)

TGA (64 patients)

p value

44 recurrences (15/15) 3 6 (40%) 1 (6.7%) 0 12 (80%) 11 (73.3%)

27 recurrences (14/52a) 4 4 (6.2%) 17 (26.6%) 15 (23.4%) 5 (7.8%) 4 (6.2%)

b.001 n.s. .003 n.s. .035 b.001 b.001

5 (7.8%) 1 (6.2%)

n.s. .005

5/64 7/22 5/22

b.001 b.001 b.001

Neuroradiological findings DWI+ (hippocampus) 0 Structural 4 (26.6%) Abnormalities Electroencephalographic findings EEG 8/15 EEG 24H 12/12 IEAs during wake 11/15

209

EEG 24H = 16-channel 24-hour ambulatory EEG; IEAs = interictal epileptiform abnormalities. a Twelve patients with TGA were lost at follow-up.

.001). Moreover, in the group with TEA, the amnesic events happened more often on awakening (40% of patients with TEA vs 6.2% of patients with TGA; p = .003), while TGA events are more frequently triggered by physical effort (24.2% of patients with TGA vs 0% of patients with TEA; p = .026). Surprisingly, contrary to that described in previous papers [11], the duration of the episodes did not significantly differ between the two groups (group with TEA: median = 3 h, range = 23; group with TGA: median = 4 h, range = 24; p = .846). In a multivariate regression model using clinical features that were found to be statistically significative on univariate regression analysis as covariate (number of recurrences, symptoms in addition to anterograde amnesia, presence of MRI structural abnormalities, presence of symptoms at awakening, history of amnesia after emotional stress or physical effort), only clinical history of additional symptoms in addition to amnesia independently predicted the diagnosis of TEA (OR, 21.74; 95% CI, 500–1.06; p = .045).

All patients of both groups underwent st-EEG: as expected the groups with TEA and TGA differed significantly for occurrence of IEAs during st-EEG (p b .001, Chi-squared test of Pearson). Considering the group with TEA, we observed clear IEAs only in 8 (53.3%) out of 15 patients, while in the group with TGA 57 (89.1%) patients had normal EEG; however, 5 (7.8%) out of 64 patients belonging to the group with TGA showed at st-EEG mild focal epileptiform transients. Patients who presented EEGs with borderline epileptiform abnormalities or had normal st-EEG but high clinical suspicion for TEA underwent 24-h EEG. Once again, the two groups differed significantly (p b .001, Chi-squared test). In detail, in the group with TEA, 12 patients underwent 24-h EEG, and they all (100%) had IEA. All 12 patients who underwent 24-h EEG presented IEAs during nonrapid eye movement (NREM) sleep (Table 1, Fig. 2). Thus, 7 (46.7%) out of 15 patients showed normal results at st-EEG, and the occurrence of IEAs during 24-h EEG recording was crucial in order to reach diagnosis of epilepsy; in particular, in 4 out of 12 patients who underwent 24-h EEG, IEAs were present only during sleep. In the group with TGA, 7 (31.8%) out of 22 patients were proved to have mild focal epileptiform transients at 24-h EEG, although epilepsy is very unlikely as they did not fulfill other supportive Zeman's criteria (Table 2, Fig. 2). 3.3. MRI All the patients in the study had an MRI scan. In the population with TGA, 5 patients had hippocampal hyperintensity in DWI sequence, while no DWI hyperintensities were detected in the group with TEA. On the contrary, in the group with TEA, 4 patients showed structural abnormalities, respectively: thalamic cavernome, pinealome, post-traumatic malacic lesion, and temporal venous ectasia. We checked for statistical significance using Chi-squared test for nonparametric parameters, testing evidenced significant differences in the populations for the presence of structural abnormalities (p b .005). 4. Discussion Our data clearly demonstrated that TEA diagnosis is challenging and underestimated in the Emergency clinical setting, where most of the transient amnesic episodes tend to be classified as TGA. In our sample,

Fig. 2. Clinical features distribution among patients with TEA vs TGA. Structural = Discovery of structural abnormalities on MRI of the brain; EEG = 21-channel standard scalp EEG recording; EEG 24H = 16-channel 24-hour ambulatory EEG; TGA+: TGA plus symptoms.

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15 (18%) out of 83 patients, first considered as affected by TGA, were eventually diagnosed as TEA. Among clinical findings, the episode recurrence, which is one of the core diagnostic Zeman's criteria (point 1), and the presence of the other symptoms other than amnesia (TGA plus) seem to be the most useful clinical aspects for the identification of TEA syndrome, while the duration of the clinical episodes failed to discriminate between the two disorders leading to a misdiagnosis. Finally, the frequent occurrence of TEA upon awakening and the presence of IEAs during sleep in all patients with TEA appear as key features of this disorder and let us hypothesize the existence of a strong link between TEA and sleep. The clinical and instrumental features of the patients with epilepsy in our series are consistent with TEA syndrome as previously described [11,16,19]: TLE that begins in late-middle to old age, with recurrent amnesic episodes, characterized by a mixed anterograde and retrograde amnesia, and sometimes with repetitive questioning; the attacks occur commonly on waking and show a good response to AEDs. It is well-known that the diagnosis of TEA is challenging, and there is not much data about the exact frequency of TEA in the real clinical scenario. Recently, Butler and Zeman described the clinical, neuropsychological, and radiological features of 50 patients with TEA as part of the UK-wide TIME (The Impairment of Memory in Epilepsy) [21]; this population counts for one of the most complete descriptions of TEA spectrum disease. As in our experience, TEA is typically misdiagnosed at presentation; in their case series, epilepsy was the first specialist diagnosis in only 12 out of 50 (24%) patients. In our study, we focused on all those features that are at the clinician's disposal in most of clinical scenarios and may help in differential diagnosis between TEA and TGA. It is interesting to see how TEA and TGA differ in many ways one from the other in these simple yet fundamental features. Being an epileptic disorder, TEA has by definition the tendency to recur, and, as already described in literature [21], also in our sample, recurrence was shown to be significantly different between the two groups. Among 15 patients with an episode of TEA, all patients presented at least two episodes and 44 overall recurrences, while among the 64 patients diagnosed with TGA, we counted only 27 recurrent events (Table 2). Moreover, considering clinical features a significant difference in the two populations was found for TGA plus manifestations (ataxia, language disorder, spatial disorientation, aphasia, transient facial palsy), particularly for confusion. These findings are consistent with the idea that since TEA is part of the TLE spectrum, both ictal (ataxia, aphasia), postictal (transient facial palsy, spatial disorientation, confusion), and ictal/postictal symptoms (aphasia, confusion, ataxia) could be added to pure amnesic manifestation. It is to be noted that the presence of TGA plus manifestations was the only factor that independently predicted the diagnosis of TEA in our multivariate regression model, enlightening the significance of this anamnestic finding in the differential diagnosis between TEA and TGA, being also a core component of the Zeman's diagnostic criteria for TEA. It is mandatory to evidence that in our population, ictal automatisms and olfactory hallucinations were not reported; they might have been undetected by witnesses, since a significant part of the episodes happened at awakening. In addition, as the clinical history was collected by general neurologists it is likely that some very specific question might be missed during clinical history collection. Moreover, in our sample, there were 3 patients (20%) who presented a pure amnesic syndrome very similar to typical TGA with reiterative questioning and anterograde amnesia. From a clinical point of view, TGA is often reported as having a strong correlation with physical effort and emotional stress [3]; our data were consistent with this finding. In the group with TGA, 17 patients reported emotional stress and 15 committed physical effort before the occurrence of the clinical event, while only one patient in the group with TEA reported emotional stress. Surprisingly, taking into account the duration of the episodes, no significant difference was found between the two groups. A possible

explanation of this finding could be linked to the high prevalence of postictal symptoms, in particular confusion, in our patients with TEA sample. We hypothesize that the duration of symptoms referred by the patients in the group with TEA comprises ictal activity and, for the most part, postictal state; conversely, TGA onset and conclusion are more gradual and blurred. Thus, patients and caregivers could perceive and report the episode as shorter than it actually is. Moreover, in the group with TEA the episodes tend to occur more often upon awakening with respect to the group with TGA, thus making the ictal manifestations not recognizable, while postictal symptoms (amnesic disorder and confusion) may last even for hours. In fact, it is well-known that epilepsy tends to occur during the shifts between sleep and wakefulness [22], and in our population, 6 (40%) out of 15 patients with TEA reported that the amnesic event happened upon awakening; in contrast, in the group with TGA, only 4 (6.2%) out of 64 experienced post-awakening amnesic episodes. As already described by other authors [11], seizures are known to have a close relation with circadian rhythms and with sleep instability patterns [22,23]. Finally, as we have selected cases previously observed in ED and then sent to our department as second level center, we cannot rule out a bias toward more dramatic or prolonged episodes of amnesia, while the less severe and shorter ones are usually met in different settings (outpatient clinic, general practice, etc.). Taking into account instrumental findings, st-EEG evaluation showed a good specificity (91.7%) but a very low sensitivity in detecting clear IEAs (53.3%). On the contrary, the 24-h EEG performed in 37 patients with unclear clinical features and/or electrophysiological patterns revealed clear IEAs in all patients with TEA. In particular, through this exam, we were able to identify 12 patients affected by focal epilepsy (6 of which showed normal results at st-EEG). Interestingly, the IEAs were recognized during nighttime in all patients who underwent 24-h EEG. To our knowledge, there are no standardized protocols of recommended diagnostic exams for patients with suspected episode of TEA. On the basis of our findings, we strongly suggest the inclusion of the 24-h EEG or EEG monitoring during sleep time for every patient with amnestic episode and additional elements that could raise suspicion for an epileptic phenomenon. Moreover, we observed a meaningful prevalence of IEAs also in patients with a more classical TGA presentation (7.8% with st-EEG). Despite these EEG abnormalities, diagnosis of epilepsy was unlikely in this subgroup of patients, according to both Zeman's criteria [10] and the International League Against Epilepsy guidelines for the diagnosis and management of epilepsy, which also emphasize the importance of clinical features rather than EEG findings [24]. Moreover, taking into account the point 3 of diagnostic Zeman's criteria [10] (epileptiform abnormalities, ‘TGA plus’ symptoms, and clearcut response to anticonvulsant therapy), while patients with TGA showed only EEG abnormalities; all patients with TEA fulfilled at least 2 supportive criteria (Table 2). Regarding cerebral MRI studies, structural abnormalities were more frequent in patients with TEA, while DWI hippocampal hyperintensity is suggestive of TGA. However, in our sample the frequency of this finding is very low (7.8%). Recent data from studies that used high-resolution MRI have shown that focal hyperintense lesions correlating to restricted diffusion in the lateral hippocampus can be reliably detected with a detection rate up to 85% with optimized MRI parameters and by acknowledging the time course of the lesion [25]. In particular, the maximum level of detection occurs within 48–72 h after onset of symptoms, and can be detected for up to 7–10 days, so early imaging might not detect these lesions [26]. Thus, the low occurrence of DWI hippocampal hyperintensities in our patients with TGA could be due to the use of standard 1.5-T MRI and/or not optimal timing of imaging. Anyway, in a substantial number of patients with TGA, however, there are no discernible DWI lesions despite typical symptomatology; this probably suggests a threshold-dependent phenomenon of the pathophysiological mechanisms, leading to functional deficits in CA1 but not to signal changes detectable with MRI.

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This study is not free from limitations. Patients classified as to having TEA do not always meet all the supportive Zeman's criteria [10] as detailed at point 3. In particular, in our population, some patients did not present typical symptoms of TLE (automatisms and olfactory hallucinations). Even if data were faithfully collected by experienced neurologists some faint symptoms might have been lost. Moreover, 2 patients were lost at follow-up, thus the response to antiepileptic therapy has not been defined. In addition, as we previously stated, our facility is a second level center, and we cannot rule out a selection bias in favor of more severe and prolonged amnesic episodes, thus leading to a slightly higher incidence of TEA. Since the study is retrospective, we could not guarantee to have all the patients undergo 24-h EEG, but only patients with abnormal EEG patterns or high clinical suspicion underwent 24-h EEG. Thus, this datum was not considered in our multivariate analysis because of this bias. Finally, as previously elucidated [14,15], patients with TEA very often have persistent interictal complaints of ALF, autobiographical, and topographical amnesia. Unfortunately, in our department, neuropsychological evaluation is not part of the routine workup for this kind of patients, thus we were not able to collect these data in order to confirm previous observations and possibly to compare both groups (TEA and TGA). Further studies will be needed to address this interesting topic. In conclusion, our study is, to our knowledge, the first real-life observational evaluation of patients with ictal amnesia in which patients were systematically screened for a differential diagnosis with TEA in basis of accurate clinical and instrumental characteristics. According to previous studies [11], our data confirmed that TEA is focal epilepsy of temporal origin, mostly with unknown etiology, tendency to recur, and with good prognosis and response to AEDs. From a clinical point of view, the presence of several symptoms other than amnesia (‘TGA plus’ manifestations), in particular confusion, is the key feature that is able to discriminate between TEA and TGA events. As a new finding, in our sample, duration of the symptoms did not significantly differ between TGA and TEA episodes, typically shorter in the last ones. This result could raise the suspicion for a long postictal state in these patients. Moreover, the high frequency of TEA onset at awakening and the observance of high prevalence of interictal EEG abnormalities during sleep seem to suggest a possible link between TEA and sleep. Finally, the low sensitivity of st-EEG in IEAs identification could lead a wrong diagnosis in several patients, determining the TEA prevalence lower than it actually is; thus, in our opinion the execution of 24-h EEG or EEG monitoring of sleep could be crucial in the diagnostic work-up and follow-up of patients with ictal amnesia episodes. Ethical publication statement We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Disclosure of conflict of interest None of the authors has any conflict of interest to disclose. References [1] Croft PB, Heathfield KWG, Swash M. Differential diagnosis of transient amnesia. Br Med J 1973;4:593–6.

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