Seizure: European Journal of Epilepsy
Volume 19, Issue 7 , Pages 446-449, September 2010

Non-paraneoplastic limbic encephalitis characterized by mesio-temporal seizures and extratemporal lesions: A case report

  • Vittoria Cianci

      Affiliations

    • Institute of Neurology, Magna Græcia University of Catanzaro, Italy
    • Magna Græcia University of Catanzaro; Regional Epilepsy Center, Italy
    • ,
  • Angelo Labate

      Affiliations

    • Institute of Neurology, Magna Græcia University of Catanzaro, Italy
    • ,
  • Pierluigi Lanza

      Affiliations

    • National Research Council, Piano Lago–Mangone, Cosenza, Italy
    • ,
  • Angela Vincent

      Affiliations

    • Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Department of Clinical Neurology, England, United Kingdom
    • ,
  • Antonio Gambardella

      Affiliations

    • Institute of Neurology, Magna Græcia University of Catanzaro, Italy
    • National Research Council, Piano Lago–Mangone, Cosenza, Italy
    • ,
  • Damiano Branca

      Affiliations

    • Neurological Unit, “Riuniti” Hospital of Reggio Calabria, Italy
    • ,
  • Luciano Arcudi

      Affiliations

    • Neurological Unit, “Riuniti” Hospital of Reggio Calabria, Italy
    • ,
  • Umberto Aguglia

      Affiliations

    • Institute of Neurology, Magna Græcia University of Catanzaro, Italy
    • Magna Græcia University of Catanzaro; Regional Epilepsy Center, Italy
    • Corresponding Author InformationCorresponding author at: Centro Regionale Epilessie, Presidio Riuniti, Via Melacrino, 89100, Reggio Cal., Italy. Tel.: +39 333 3167327; fax: +39 0965 397973.

Received 12 December 2009; received in revised form 21 May 2010; accepted 4 June 2010. published online 02 July 2010.

Article Outline

Abstract 

Limbic encephalitis (LE) can be either paraneoplastic or a non-paraneoplastic autoimmune disorder. Magnetic resonance imaging (MRI) of the brain on T2-weighted fluid-attenuated inversion recovery (FLAIR) classically shows hyperintensities of the temporal structures, but multifocal involvement of extratemporal cortex has also been described in paraneoplastic LE. Here we describe a 27-year-old woman whose idiopathic autoimmune (glutamic acid decarboxylase-antibody positive) LE debuted with multiple daily mesio-temporal seizures, amnesia and multifocal extratemporal cortical MRI abnormalities. Mesio-temporal MRI signal increase was found after 20 days. This case report highlights that early diagnosis of non-paraneoplastic LE may be considered in patients with multiple daily mesio-temporal seizures and amnesia even in the absence of early typical MRI abnormalities.

Keywords: Antibodies, Epilepsy, GAD, Limbic encephalitis, Magnetic resonance imaging, Seizures

 

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1. Introduction 

It is now accepted that limbic encephalitis (LE) can be paraneoplastic or non-paraneoplastic.1, 2, 3 In non-paraneoplastic cases, high serum levels of voltage-gated potassium channels (VGKC) antibodies (Abs)2, 3 have been found, as well as Abs directed against glutamic acid decarboxylase (GAD),4 N-methyl-D-aspartate (NMDA) receptor/channel or to unknown antigens.5 The typical clinical presentation of idiopathic LE is a subacute onset of confusion, anterograde amnesia, temporal lobe seizures and behavioral changes. Magnetic resonance imaging (MRI) of the brain on T2-weighted fluid-attenuated inversion recovery (FLAIR) shows hyperintensities with swelling usually restricted to the mesio-temporal cortex, with late atrophy and occasional involvement of other temporal structures.6, 7 Extratemporal cortical involvement has been reported only in patients with paraneoplastic LE.8, 9, 10, 11 Here we describe a young woman whose idiopathic autoimmune LE debuted with mesio-temporal seizures associated with multifocal cortical extratemporal abnormalities.

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2. Case report 

A 27-year-old woman with no family or personal history of epilepsy or febrile convulsions presented at the emergency room because of daily episodes of funny feelings four days after a febrile episode. At admission to neurology department, she was diagnosed of mesio-temporal lobe epilepsy with multiple daily seizures. In the past history, she had depression, anxiety treated with antidepressants, and autoimmune Hashimoto's thyroiditis diagnosed at the age of 24 and treated for 11 months with corticosteroids that were stopped 18 months before. Her interictal neurological examination was normal. The neuropsychological examination included Raven's coloured progressive matrices [score=23.5, normal value (n.v.)>17.5], immediate and delayed recall of a short story (score=4, n.v.>6.5), thirty paired word associates (score=4, n.v. >6.5), semantic verbal fluency test (score=36, n.v.>17), phonemic verbal fluency test (score=31, n.v.>25), and revealed severe impairment of recent memory, with preservation of language functions. The interictal EEG showed spike-waves over the right temporal lobe (Fig. 1a). Ictal video-EEG monitoring showed seizure pattern consisting of temporo-parietal, rhythmic theta waves followed by epigastric aura (Fig. 1b), and spiking activity and diffuse fast rhythms associated with fear, flushing, diaphoresis and déjà-vu without loss of consciousness or language disorders (Fig. 1c–e). Temporo-spatial disorientation and sometimes amnesia followed the seizures. Visual and somatosensory evoked potentials were normal. Routine laboratory analyses were normal (including glucose), but the sodium level was low 126mEq/L (n.v. 135–145). Cerebrospinal fluid (CSF) analysis showed the presence of oligoclonal bands, with normal protein and cellular content. No serum antibodies against onconeural antigens were found. PCR amplification for herpes simplex virus (HSV) on CSF, serum antibodies to herpes simplex virus (HSV), human herpes virus (HHV)-6 and HHV-7, extensive serum tests for viral, bacterial and fungal infections, neoplastic serum markers (Carcinoembryonic antigen, alpha-fetoprotein, Ca125, Ca19-9, Ca15-3), Anti-Nuclear-Abs, antibodies to Extractable-Nuclear-Antigen, cytoplasmic-Antineutrophil Cytoplasmic-Abs (cANCA), perinuclear-ANCA, anti-transglutaminase-Abs and anti-gliadin-Abs were negative or normal. At that time, no serum reactivity to VGKC-Abs or to the NR1/NR2 heteromers of the NMDA receptor/channel was detected (A.V.), whereas a radioimmunoprecipitation assay evaluation of stored serum and CSF collected at entry demonstrated very high levels of anti-GAD-Abs in the serum (6000U/ml normal value<1.0U/ml) and in CSF (120U/ml, normal value:<1U/ml). The anti-GAD intrathecal synthesis index [CSF anti-GAD IgG value/serum anti-GAD value]/[CSF albumin/serum albumin], (positive value>1) was positive (value: 7.7). Thyroid hormones were also normal, while high serum titer of both antithyroid microsomal (424IU/ml, n.v.<50) and antithyroid peroxidase (3334IU/ml: n.v.<60) antibodies were at lower levels than 30 months previously (anti-microsomal-Abs: 800IU/ml; anti-peroxidase-Abs: 4585IU/ml). Whole-body CT, including brain, did not show any abnormality. On admission, 2 days after the onset of illness, T2, FLAIR, and diffusion-weighted brain MRI sequences showed two small hyperintensity areas localized in the parietal cortex of the right hemisphere and in the fronto-basal cortex of the left hemisphere, with no contrast enhancement. Surprisingly, no abnormalities were observed in the temporal lobes (Fig. 2a–c) at this time, but a second MRI performed 20 days later showed typical bilateral swelling with hyperintensity (with no contrast enhancement) of the mesial temporal lobes bilaterally, but more evident on the right side, as well as persistence of the extratemporal lesions (Fig. 2d–f). The patient was treated with anti-epileptic medication (topiramate 200mg/day) and i.v. methylprednisolone (1g/day for five consecutive days). One week after steroid treatment, the seizures were reduced in frequency and duration, the interictal EEG was normal and MRI showed only the persistence of hyperintensity over the right mesial temporal lobe (Fig. 2g–i). The patient was discharged with anticonvulsant therapy only. However, at follow-up (1, 2 and 3 months after the end of immunotherapy) she still had severe impairment of the recent memory and her temporal lobe seizures had become resistant to anti-epileptic treatment, but she refused treatment with i.v. immunoglobulins or oral steroids. Six months after onset, a repeated MRI was unchanged (showing only right temporal lobe signal abnormality, without hippocampal atrophy) and whole-body PET scan was normal. Treatment with oral prednisone (50mg/day) was then accepted. Six months after onset of oral prednisone, neurological and psychometric evaluations were unchanged.

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  • Fig. 1. 

    EEG at admission to neurology department; (a) interictal EEG. Note spike-waves over the right temporal lobe; (b)–(d) ictal EEG. Note disappearance of the alpha activity and presence of rhythmic theta waves on leads P4, T4 and T6. Epigastric aura occurred six sec after onset (b). Spikes and spiking activity on leads T6, P4, F8 and T4 and diffuse fast (13–16Hz) rhythms were associated with fear, flushing, diaphoresis and déjà-vu (c) and (d); (e) end of the seizure (40s after (d)). There was no loss of consciousness during the seizure.

  • View full-size image.
  • Fig. 2. 

    MRI (FLAIR-sequences). At entry (a)–(c): note two small intracortical lesions localized in the parietal cortex of the right hemisphere (10mm: (a) and (b)) and in the fronto-basal cortex of the left hemisphere (6mm: (c)). No abnormalities were observed in the temporal lobes. Twenty days after admission (d)–(f): persistence of the extratemporal cortical lesions (d) and (e) with bilateral hyperintensity and swelling of the mesial temporal lobes (more evident on the right side: (e) and (f). Seven days after immunotherapy (g)–(i) persistence of hyperintensity of the mesial temporal lobe on the right side and disappearance of the other lesions.

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3. Discussion 

Here, we have described a patient with clinical, laboratory and imaging features of LE, including a subacute amnesic syndrome with mesio-temporal seizures, hyponatremia, high levels of anti-GAD-Abs and temporomedial T2/FLAIR signal increase. The failure to demonstrate an occult tumor on whole-body PET and the absence of any clinical and laboratory evidence of paraneoplastic antibodies suggested a non-paraneoplastic, idiopathic condition.2, 3, 7 The patient's serum was negative for VGKC-Abs but strongly positive for GAD-Abs; antibodies to GAD are typically found in stiff-person syndrome, but are increasingly recognized as a marker for other autoimmune CNS conditions such as cerebellar ataxia, palatal tremor, focal epilepsy and occasionally LE.4 LE patients with GAD-Abs may evolve into a refractory temporal lobe epilepsy.12, 13, 14 Temporomedial T2/FLAIR signal increase is usually considered the MRI hallmark of both idiopathic and paraneoplastic LE1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and may be associated with extratemporal signal abnormalities in paraneoplastic LE.8, 9, 10, 11 In non-paraneoplastic LE, however, extratemporal lesions are rare although they have been reported in the subcortical white matter15 or the basal ganglia16 at the same time as the temporomesial lesions. Normal MRI has also been reported in patients with non-paraneoplastic anti-GAD LE4.

EEG is a sensitive investigation in paraneoplastic LE: slow-wave abnormalities are seen in most cases, and focal epileptiform abnormalities are documented in about 50% of the patients17. Focal epileptiform abnormalities were recorded in our patient at onset of LE. Interestingly, ictal clinical manifestations suggested a restricted (temporomesial) symptomatogenic zone,18 while ictal EEG recordings documented a wide (fronto-temporo-parietal) seizure-onset zone18 over the right hemisphere. These findings, along with imaging data, demonstrated that the cortical damage was more diffuse than expected by clinical symptomatology.

In conclusion, the interesting feature of this young woman with high GAD-Abs is that her symptoms followed a flu-like episode and were initially associated with frequent mesio-temporal seizures and multifocal extratemporal cortical abnormalities, in the absence of typical limbic lesions seen on MRI at onset of disease. Besides in patients with LE with classic MRI features, GAD-Abs should also be assayed in patients with subacute onset of amnesic syndrome, temporomesial seizures and extratemporal MRI abnormalities.

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PII: S1059-1311(10)00116-0

doi:10.1016/j.seizure.2010.06.002

Seizure: European Journal of Epilepsy
Volume 19, Issue 7 , Pages 446-449, September 2010

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