Accepted Manuscript Title: Pilomotor seizures: An autonomic semiology of limbic encephalitis? Author: Rodrigo Rocamora Juan L. Becerra Pilar Fossas Mar´ıa Gomez Rosa M. Vivanco-Hidalgo Jos´e A. Mauri Albert Molins PII: DOI: Reference:

S1059-1311(14)00129-0 http://dx.doi.org/doi:10.1016/j.seizure.2014.04.013 YSEIZ 2333

To appear in:

Seizure

Received date: Revised date: Accepted date:

25-2-2014 1-4-2014 28-4-2014

Please cite this article as: Rocamora R, Becerra JL, Fossas P, Gomez M, Vivanco-Hidalgo RM, Mauri JA, Molins A, Pilomotor seizures: An autonomic semiology of limbic encephalitis?, SEIZURE: European Journal of Epilepsy (2014), http://dx.doi.org/10.1016/j.seizure.2014.04.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

*Highlights (for review)

Highlights

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First time a case series of piloerection seizures of autoimmune origin. TLE cases with ictal theta-delta rhythmic activity on VEEG w/o generalization. Also in cases with long-lasting TLE and typical hippocampal sclerosis on MRI. Seizure semiology characterized by highly daily frequency without loss of awareness. 3 cases of anti-LGI1 LE with pilomotor seizures as presenting symptom and not FBDS.

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*Manuscript

Pilomotor seizures: An autonomic semiology of limbic encephalitis? Rodrigo Rocamora1, Juan L. Becerra2, Pilar Fossas3, María Gomez5, Rosa M. Vivanco-Hidalgo1, José A. Mauri4, Albert Molins6. 1

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Epilepsy Monitoring Unit, Hospital del Mar, Barcelona, Epilepsy Monitoring Unit, Hospital Germans 3 4 Trias i Pujol, Barcelona. Department of Neurology, Hospital de Mataró, Barcelona. Department of 5 Neurology, Hospital Clínico Universitario, Zaragoza. Department of Neurology, Hospital San Pedro, 6 Logroño, Department of Neurology, Hospital Dr. Josep Trueta, Girona.

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R. Rocamora M.D., Ph.D. Department of Neurology Hospital del Mar Passeig Maritim 25-29 08003 Barcelona, Spain Phone: (+34) 93-2483235 Fax: (+34) 93-2483236 E-Mail: [email protected]

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*Corresponding author and current address:

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Running title: Pilomotor seizures: An autonomic semiology of limbic encephalitis? Word count: 1632 Text pages: 8

Key words: Seizures, autonomic, pilomotor, autoimmune, limbic encephalitis.

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Abstract Purpose Ictal piloerection is an infrequent seizure semiology that is commonly overlooked as an ictal epileptic manifestation. Piloerection is considered to be principally caused by temporal lobe activity although frontal and hypothalamic seizure origins have been

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reported. The described etiology has shown a wide variety of structural causes such as mesial temporal sclerosis, tumors, posttraumatic, cavernomas and cryptogenic

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epilepsies.

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Methods

We retrospectively reviewed the incidence of ictal piloerection in the clinical records of patients who underwent video-EEG monitoring (VEEGM) between 2007 and 2013

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in a multicenter cooperative study. All patients presented refractory epilepsies and were evaluated with a protocol that included brain MRI, neuropsychology and

Results

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VEEGM.

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A total of 766 patients were evaluated in four tertiary centers in Spain. Five patients

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showed piloerection as principal seizure semiology (prevalence 0.65 %). The mean age at seizure onset was 39.6 years and the average epilepsy duration was 5.2 years (range 2-14) before diagnosis. Four patients were additionally examined with FDG-PET and/or SPECT-SISCOM. All presented temporal lobe epilepsy (TLE), three right-sided and two left-sided. A typical unilateral hippocampal sclerosis was described in 3 cases. The etiology detected in all cases was limbic encephalitis. Three had LGI1, one anti-Hu, and another Ma2 antibodies. Conclusion

Our series describes a so far not well-recognized autoimmune association of pilomotor seizures to limbic encephalitis. This etiology should be ruled out through a comprehensive diagnostic work-up even in cases of long-lasting TLE with typical hippocampal atrophy on MRI.

Key words: Seizures, autonomic, pilomotor, autoimmune, limbic encephalitis.

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Introduction Ictal piloerection (“goose bumps”) is an infrequent form of autonomic seizures and is commonly overlooked as an ictal epileptic manifestation. Piloerection is principally considered to be an expression of ictal temporal lobe activity1 although other seizure

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origins such as frontal or hypothalamic have been reported.2 The described etiology has shown a wide variety of structural causes such as mesial temporal sclerosis,

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tumors, posttraumatic, cavernomas, and cryptogenic epilepsies.1

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Limbic encephalitis (LE) is an autoimmune disorder clinically characterized by the presence of impaired memory, behavioral/psychiatric abnormalities, and epileptic

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seizures. LE is often associated with antibodies against intracellular/nuclear antigens (mainly paraneoplastic), being small-cell lung cancer (SCLC) the most commonly

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associated. LE associated with antibodies against surface antigens (mainly non-

immunotherapy.

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paraneoplastic) is less frequent and presents a better prognosis of recovery after

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We report here a series of five patients who debuted with pilomotor seizures of autoimmune origin that led to the diagnosis of limbic encephalitis.

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Material and methods Patients with pilomotor seizures were selected from databases in four tertiary neurology centers in Spain. We retrospectively reviewed the incidence of ictal piloerection in the clinical files of patients who underwent VEEGM between 2007 and

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2013. All patients were examined routinely with a protocol that included 1.5 or 3 T head MRI, neuropsychological evaluation, and VEEGM (Table 1). Due to the atypical

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autonomic seizure semiology and/or disease-course all patients underwent a

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comprehensive evaluation for autoimmune and paraneoplastic diseases in the same centralized laboratory.

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We also reviewed the files of patients with diagnosis of LE with or without epilepsy

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during the same period of time (6-year period).

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Results A total of 766 patients between December 2007 and June 2013 were evaluated. Five patients were detected with piloerection as the main seizure semiology (prevalence 0.65 %). All of them presented refractory temporal lobe epilepsy (TLE). The mean

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age at seizure onset was 39.6 years and the average epilepsy duration was 5.2 years (range 2-14).

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Three were right-sided and two left-sided. Head MRI examination revealed unilateral

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hippocampal atrophy with hyperintensity in 3 patients and uni- or bilateral mesial temporal swelling in the other 2 patients. Four patients were additionally examined

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with FDG-PET and/or SISCOM. Ictal SPECT displayed ipsilateral temporal hyperperfusion but FDG-PET could show either hyper- or hypometabolism. VEEG

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recorded in all cases episodes of ictal piloerection usually with preservation of awareness, electroencephalographically characterized by temporal theta-delta

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rhythmic activity without generalization. The etiology detected in all cases was limbic

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encephalitis. Three had LGI1 (leucine-rich glioma-inactivated 1), one anti-Hu, and another Ma2 antibodies (Table 1).

Case 1: 40-year-old left-handed patient with epilepsy since the age of 26. His seizures were characterized by episodes of ictal piloerection without loss of awareness followed by sweating on hands. Only twice did he experience focal seizures evolving to generalized tonic-clonic components. A central hypersomnia had been diagnosed years ago. The brain MRI showed a right temporal hippocampal sclerosis. SISCOM revealed a hyperperfusion mesial temporal right. VEEGM showed seizures with a right-sided anterior temporal lobe onset. Neuropsychology revealed a reduction in visual and figurative memory as well as a dysexecutive syndrome. CSF analysis showed Ma2 antibodies. Tumor screening revealed an intratubular germ cell

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neoplasia that was resected. He was treated with corticosteroids in bolus, IVIg, cyclophosphamide and posteriorly rituximab. However, despite complete excision of the primary tumor, the patient has remained with refractory seizures, excessive daily sleepiness and significant memory impairment.

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Case 2: 39-year-old right-handed computer technician with refractory epilepsy for three years. Focal seizures consisted of episodes of left-sided piloerection

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accompanied by body paresthesias without loss of awareness (Fig. 1). A single, focal

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evolving to generalized tonic-clonic seizure had been reported in the past. MRI showed a right-sided hippocampal sclerosis. The neuropsychological evaluation

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revealed mild executive dysfunctions. Seizure-onset was temporal right posterior. SISCOM revealed hyperperfusion posterior temporal right, and FDG-PET a

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hypometabolism right temporal. Serum and CSF analysis showed LGI1 antibodies.

symptoms after 6 months.

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Therapy with intravenous corticosteroids was initiated with resolution of the

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Case 3: 35-year-old right-handed female patient with refractory epilepsy for the last two years. The semiology consisted of seizures with widespread piloerection followed by speech arrest without loss of awareness with multiple episodes during the day. Far less frequently, she had dyscognitive seizures with oral automatisms. Head MRI showed swelling of the left amygdala and hippocampus. VEEGM revealed a seizure onset localized temporal left anterior. The neuropsychological evaluation revealed a dysexecutive syndrome. Serum analysis showed LGI1 antibodies. Intravenous corticosteroids were initiated with complete suppression of the symptoms after few weeks of treatment. She remained free of seizure with normalization of all cognitive functions until last evaluation in December 2013.

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Case 4: 32-year-old right-handed woman diagnosed with TLE at the age of 30. MRI revealed a swelling left temporo-mesial that evolved over one year into a hippocampal sclerosis. FDG-PET showed hypermetabolism in the same localization. The neuropsychological test revealed a marked reduction in memory span and

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nomination. VEEGM registered focal seizures with piloerection localized over the right arm and epigastric sensation followed by loss of awareness. The EEG ictal-

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onset was left temporal anterior. CSF examination was positive for anti-Hu

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antibodies, however no primary tumor was found in the screening, which has been repeated two times. The patient was treated with corticosteroids in bolus followed by

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monthly IVIg. In the follow-up she displayed an improvement in psychiatric symptoms although seizures remained pharmacoresistant.

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Case 5: 52-year-old right-handed man with TLE characterized by multiple daily episodes of ictal piloerection. The epileptic etiology of piloerection remained

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undiagnosed 4 years being considered a psychiatric symptom until a comprehensive

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neurological workup in 2011 confirmed an anti-LGI1 LE with positive serum antibodies. The initial head MRI showed a hyperintensity in both temporal lobes. The neuropsychological evaluation revealed verbal and visual memory impairments. He was treated with IV corticosteroids showing only mild improvement and posteriorly with IVIg. A VEEG detected a right temporal seizure with theta-delta rhythmic activity associated to generalized piloerection. Seizures remained medically refractory although with lower frequency.

In the same time period, in our institutions were diagnosed 15 patients with LE, all but 2 confirmed by positive antibodies. Of them, 8 had epilepsy as clinical manifestation and 5 pilomotor seizures. Three patients presented focal seizures without piloerection (LE with CASPR2, LGI1 and anti-NMDAR antibodies).

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Discussion Ictal piloerection is an infrequent autonomic semiology of focal seizures, so that, diagnosis of epilepsy may be delayed or missed. We report here a case series of 5

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patients with pharmacoresistant TLE with pilomotor seizures of autoimmune origin and postulate a distinctive etiologic association between this form of autonomic

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seizures and limbic encephalitis.

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Pilomotor seizures have been mainly associated with an origin in the temporal lobe, which suggests a functional relationship between limbic circuits, autonomic

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responses and an associated cutaneous reaction to the parietal lobe. Nonetheless,

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piloerection can be electrically stimulated in different structures related to the central autonomic network outside the temporal lobe. In our series they characteristically

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occurred in at a high daily frequency (Table 1) with a duration ranging from seconds

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to less than two minutes and were normally not followed by loss of awareness. Skin reaction may be localized on one extremity, lateralized to one body side, or generalized from the beginning.3 Unilateral piloerection has been associated with ipsilateral seizure onset,4 although in our series all patients had either bilateral or contralateral skin involvement. Considering the evolution of the disease, it is important to point out the long duration of the epilepsy before the etiologic diagnosis could be established (average 5.2 years). This suggests that when autonomic manifestations are the main manifestation of focal seizures diagnosis may be delayed or missed. In the retrospective analysis of the specificity of this semiology, 5 out of 8 patients with LE and epilepsy showed ictal piloerection. However, not all patients with LE were examined with VEEGM. Therefore, the main value of our study lies in the analysis of its possible sensitivity in which all those who had pilomotor

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seizures also presented LE. In fact, it was the diagnostic work-up of the semiology that led us to the diagnosis of LE in all cases. There are several individual reports on brain tumors associated with pilomotor seizures.5 Indeed, almost half of all cases corresponds to a neoplastic cause. In

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other reports, inflammatory causes were suspected but could not be finally

demonstrated.6 As far we know, there exists only one case reported in the literature

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of ictal piloerection as a clinical presentation form of limbic encephalitis. 7 Particularly,

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in none of the anti-LGI1 LEs (cases 2, 3 and 5) were observed facio-brachial dystonic seizures (FBDS), previously described as typical for this etiology.8

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Our cases exhibited either typical images of unilateral hippocampal sclerosis or

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T2/FLAIR signal increase with hippocampal swelling (Table 1). In LE the hippocampal atrophy with signal increase is indistinguishable from typical

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hippocampal sclerosis.9 Otherwise, patients who show hippocampal swelling with

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signal increase on T2/FLAIR provide a radiological hint to an autoimmune process. When available, ictal SPECT showed a temporal lobe hyperperfusion, also undistinguishable from lesional cases. The FDG-PET, performed in 2 cases showed either temporal hypometabolism that correlated with a hippocampal atrophy or hypermetabolism associated with swelling on MRI (cases 4 and 5). The ictal recordings were characterized by unilateral temporal theta-delta rhythmic activity that tended to remain localized without generalization. There was no preference in lateralization of the TLE. Our study has limitations. It is a retrospective study and therefore we cannot exclude the possibility that pilomotor seizures with other etiologies were not detected. Although three of five cases had anti-LGI1 LE, our casuistic is too small to suggest a particular association. Therefore our findings need to be replicated in larger series. 9

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Conclusions Our series describes a so far not well-recognized possible autoimmune association of pilomotor seizures to limbic encephalitis. A comprehensive diagnostic work-up

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involving this etiology could be relevant even in cases of long-lasting TLE with typical

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hippocampal sclerosis on MRI.

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Bibliography: Stefan H, Pauli E, Kerling F, Schwarz A, Koebnick C. Autonomic auras: left hemispheric predominance of epileptic generators of cold shivers and goose bumps? Epilepsia. 2002;43(1):41–5.

2.

Seo DW, Lee HS, Hong SB, Hong SC, Lee EK. Pilomotor seizures in frontal lobe epilepsy: case report. Seizure. Elsevier; 2003;12(4):241–4.

3.

Masnou P, Gagnepain J-P, Fouad A, Ducreux D, Adams D. Pilomotor seizures associated with sequential changes in magnetic resonance imaging. Epileptic Disord. 2006 Sep;8(3):232–7.

4.

Loddenkemper T. Localising and lateralising value of ictal piloerection. J Neurol Neurosurg Psychiatr. 2004 Jun 1;75(6):879–83.

5.

Fisch L, Megevand P, Badoud A, Seeck M, Burkhard PR. Pilomotor seizure: When paroxysmal gooseflesh heralds brain tumor. Neurology. 2012 Apr 9;78(15):1189–9.

6.

Lam EM, Worrell GA, Laughlin RS. Semiology of the rare seizure subtype piloerection. Arch Neurol. 2010 Dec;67(12):1524–7.

7.

Wieser S, Kelemen A, Barsi P, Vincent A, Borbely C, Rasonyi G, et al. Pilomotor seizures and status in non-paraneoplastic limbic encephalitis. Epileptic Disord. 2005 Sep;7(3):205–11.

8.

Irani SR, Michell AW, Lang B, Pettingill P, Waters P, Johnson MR, et al. Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol. 2011 Mar 17;69(5):892–900.

9.

Bien CG, Elger CE. Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life. Epilepsy Behav. 2007 Jun;10(4):529–38.

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Appendices Figure legend Fig. 1: VEEG monitoring of patient 2: Ictal piloerection on the left side of the body

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during a right temporal seizure.

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Tables Table 1: VEEG characteristics, neuroimaging and demographics of patients. TLE,

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temporal lobe epilepsy; n/a, not available.

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Table

Patient 2

Patient 4

Patient 5

Age, y/gender

40/M

39/M

35/F

32/F

52/M

Epilepsy type

TLE

TLE

TLE

TLE

TLE

Side

Right

Right

Left

Left

Right

Epilepsy duration

14 y

3y

2y

3y

4y

Follow-up since diagnosis

2y

1.8 y

2y

1.5 y

2.4 y

Seizure type,

Pilomotor/ GTCSs

Pilomotor/ acoustic;

Pilomotor/ epigastric

Pilomotor/ epigastric

Pilomotor

GTCGs

aura

aura

Hippocampal sclerosis

Hippocampal

Hypertrophy and

Hyperintensity left

Hyperintensity bilateral

right

sclerosis

hyperintensity left

temporo mesial >>

temporo mesial

right

temporo mesial

hippocampal sclerosis

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ep te

MRI

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primary/secondary

Patient 3

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Patient 1

Ictal VEEG

Right delta rythmic

Right theta rythmic

Left theta rhytmic

Left theta rhythmic

Right theta-delta

activity temporal ant.

activity, temporal

activity, temporal ant.

activity, temporal ant.

rhythmic activity

post.

1-10/day

5-20/day

10-15/day

5-20/day

1-3/day

SPECT

Hyperperfusion right

Hyperperfusion right

n/a

n/a

n/a

temporal mesial

temporal lateral

n/a

Hypometabolism

n/a

Hypermetabolism left

Hypometabolism

temporal

bilateral

Depression

Anxiety, depression

Delusions

Executive dysfunction

Verbal memory deficit

Verbal and visual

PET

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Seizure frequency

Psychiatric symptoms

Cognition

Antibodies

Anxiety, depression

right temporal Acoustic hallucinations

Memory defect;

Executive

Executive dysfunction

dysfunction

Ma2

LGI1

memory dysfunction LGI1

Anti-Hu

LGI1

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Figure

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Pilomotor seizures: an autonomic semiology of limbic encephalitis?

Ictal piloerection is an infrequent seizure semiology that is commonly overlooked as an ictal epileptic manifestation. Piloerection is considered to b...
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