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A proton magnetic resonance spectroscopic study in juvenile absence epilepsy in early stages
european journal of paediatric neurology 14 (2010) 224–228
Official Journal of the European Paediatric Neurology Society
Original article
A proton magnetic resonance spectroscopic study in juvenile absence epilepsy in early stages Sibel Canbaz Kabaya,*, Oguzhan Guven Gumustasb, Handan Ozisik Karamanc, Hilmi Ozdend, Oguz Erdince a
Dumlupinar University, Faculty of Medicine, Department of Neurology, Tavsanli Yolu, 43100 Kutahya, Turkey Burtom – Emar Radiodiagnostic Center, Osmangazi, Bursa, Turkey c Onsekizmart University, Faculty of Medicine, Department of Neurology, Canakkale, Turkey d Osmangazi University, Faculty of Medicine, Department of Anatomy, Eskisehir, Turkey e Osmangazi University, Faculty of Medicine, Department of Neurology, Eskisehir, Turkey b
article info
abstract
Article history:
Purpose: The aim of this study to evaluate the hippocampal, frontal and thalamic lobe
Received 28 February 2009
functions in the early stage of the juvenile absence epilepsy (JAE) by magnetic resonance
Received in revised form
proton spectroscopy (MRS).
20 May 2009
Method: Fourteen patients with juvenile absence epilepsy with typical absence seizures and
Accepted 4 June 2009
10 healthy volunteer controls were included in this study. The diagnosis of the patients was in accordance with EEG findings and seizure semiology. All patients had minimum
Keywords:
twice EEG recordings and all had typical 3-Hz generalized spike and slow-wave discharges
Juvenile absence epilepsy
at least on one EEG. All patients had bilateral MRS of frontal, thalamic and hippocampal
Proton magnetic resonance
regions and NAA, NAA/Cr, NAA/Cho, NAA/Cho þ Cr levels were detected.
spectroscopy
Results: The mean age was 14.9 2.05 and 14.5 1.7 of the JAE patients and control subjects,
Brain
respectively. Mean seizure onset duration were 2.3 0.9 years. In patient group the frontal,
Seizures
thalamic and hippocampal NAA/Cr ratios were 1.65, 1.78, 1.47 in right and 1.75, 1.90, 1.42 in left, respectively. While in the control group NAA/Cr ratios were 1.64, 2.42, 1.57 in right and 1.83, 2.44, 1.47 in left, respectively. There weren’t any difference in frontal and hippocampal regions, but the bilateral thalamic NAA, NAA/Cr ratios of the patients were significantly lower than control group even in early stages of the disease. Conclusion: The observed reductions in NAA levels and NAA/Cr ratios of bilateral thalamic regions are consistent with epilepsy related excitoxicity as a possible underlying mechanism even in early stage of JAE. However, we believe that to generalize the results of our study a prospective multicenter study is required. ª 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: þ90274 2652031; fax: þ90274 2652277. E-mail addresses: [email protected] (S.C. Kabay), [email protected] (H. Ozden). 1090-3798/$ – see front matter ª 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2009.06.004
european journal of paediatric neurology 14 (2010) 224–228
1.
Introduction
Absences are generalized nonconvulsive seizures. The International Classification of Epilepsies (ILAE) proposed the classification of three syndromes of idiopathic generalized epilepsy (IGE) with absence seizures: childhood absence epilepsy, juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy.1 JAE develops furtively in physically and mentally healthy adolescents. Although the frequency of the absences is low, and the symptoms are relatively trivial, the diagnosis can be overlooked until generalized tonic–clonic seizures appear. Age at onset is usually between 10 and 17 years, with a peak between 10 and 12 years.2 The main mechanisms of absence seizures are unknown; however, animal study showed that rhythmic thalamic projections to diffusely epileptogenic cortex produce the characteristic hypersynchronous discharges and that increased inhibitory, as well as excitatory, mechanisms which involved.3,4 Typical absence seizures are characterized by a complete consciousness that may be isolated or associated with motor phenomena. A sudden impairment of consciousness is frequent and associated with bilateral, synchronous, symmetric 3-Hz generalized spike and slow-wave discharges on EEG.5,6 An essential characteristic of all these syndromes is that neurologic examination and neuroimaging results are normal.7 The presence of abnormalities in corticothalamic networks has been showed to be the functional basis of absence seizure generation.8 Magnetic resonance proton spectroscopy (MRS) can been used to detect neuronal dysfunction and subtle changes in neuronal density in patients whose brains are macroscopically normal.9,10 It is a noninvasive sensitive technique which has been used especially for quantification of important metabolic information. MRS is able to suggest metabolic abnormalities that are not apparent to conventional MRI, because these abnormalities may precede structural changes.11 Three major peaks characterize MRS spectra: N-acetylaspartate (NAA) marker of neuronal and axonal viability and density; creatine (Cr) used as internal reference, since it is the most stable cerebral metabolite; choline (Cho) reflecting cellular proliferation.12 A decreased NAA signal reflects neuronal loss or dysfunction, while the increase of the signals taken from Cr and Cho reflects gliosis. NAA/Cr signal ratio can be used as an indicator sensitive to neuronal loss and astrocytosis and can be used to evaluate the neuronal function in several diseases also including epilepsy.13–15 Neuronal dysfunction is present at an early stage of the epileptic process. Although there is an early stage study with MRS in partial epilepsies, in our knowledge there is no study about absence epilepsy in early stage of the disease.16 The aim of the study is to evaluate the frontal, thalamic and hippocampal functions in the early stage of the JAE by MRS.
2.
Materials and methods
Fourteen JAE patients with typical absence seizures and 10 healthy volunteer controls were included in this study. The diagnosis of the patients was in accordance with EEG findings and seizure semiology. All patients had typical absence seizures repeated several times daily before diagnosis. All
225
patients had minimum twice EEG recordings and all had typical 3-Hz generalized spike and slow-wave discharges at least on one EEG. Inclusion criteria; Age at onset between 10 and 17 years, normal neurologic state and development, brief (4–20 s, exceptionally longer), and frequent (tens per day) absence seizures with abrupt and severe impairment (loss) of consciousness. Patients with other than typical absence seizures such as generalized tonic–clonic seizures (GTCS), or myoclonic jerk prior to or during the active stage of absences, eyelid myoclonia, perioral myoclonia, rhythmic massive limb jerking, and single or arrhythmic myoclonic jerk of the head, trunk, or limbs excluded from the study. However, mild myoclonic elements of the eyes, eyebrows, and eyelids may be featured, particularly in the first 3 s of the absence seizures. Also patients with mild or no impairment of consciousness during the 3–4-Hz discharges, brief EEG 3–4-Hz spike-wave paroxysms of less than 4 s, multiple spikes (more than three) or ictal discharge fragmentations, visual (photic) and other sensory precipitation of clinical seizures were excluded. Patients with abnormal cranial MRI findings coincidentally like periventricular ischemia or arachnoids cysts were excluded from the study.
2.1.
Magnetic resonance imaging
This study was performed using quadrature transmit receive head coil at GE Signa 1.5 T MRI Excite HD (GE Medical Systems, Milwaukee, WI, USA). Our MRI protocol consisted of SE (spin-echo) T1-weighted axial images; (repetition time) TR/TE (echo time), 500/12 ms; excitations, two; matrix size 256 192; slice thickness, 5 mm; interslice gap, 2 mm; and SE T2weighted axial and coronal images TR/TE, 2500/100 ms; excitations, one; matrix size 256 192; slice thickness, 5 mm; interslice gap, 2.5 mm. Also T1-weighted inversion recovery 3 mm thick images, perpendicular to long axis of hippocampus and T2-weighted coronal fluid attenuated inversion recovery (FLAIR) images were used. We used both T2-weighted axial and coronal images to guide us in locating voxels for proton magnetic resonance spectroscopy (MRS) studies.
2.2.
Magnetic resonance spectroscopy
All the Spectroscopy imaging was performed on GE Signa 1.5 T MRI Excite HD (GE Medical Systems, Milwaukee, WI, USA). All the imaging was performed with transmit receive head coil, using 2D Probe (software of GE) PRESS (point resolved surface coil spectroscopy) CSI (chemical shift imaging) multivoxel spectroscopy sequence. The probe (software of GE) offers single voxel and multivoxel proton spectroscopy with automated water suppression and gradient shimming. Probe expands the clinical utility of MR by providing a chemical analysis of the brain. Multivoxel probe enables analysis of larger volumes of interest while maintaining the ability to breakdown the analysis to smaller areas of interest. Also this technique is acquired in a short scan time, with the ability to acquire spectroscopy data from both pathology and normal regions (control spectrum) in single acquisition. Advanced function software by GE Healthcare was used for post
226
european journal of paediatric neurology 14 (2010) 224–228
processing. This programmed, enables data processing including metabolic color maps, metabolic ratios, retrospective voxel shifting, baseline correction and phase correction. Consequently, CSI techniques are considered versatile thus have greatly improved the quality of clinical MR spectroscopy on epilepsy imaging. For the spectra SE sequence containing 144 ms echo time was used. TR was obtained as 1000 ms and the mean signal to noise ratio 100 and number of excitations (NEX) ¼ 1 respectively. Acquisition ¼ 1; acquisition time ¼ 5.28 min; frequency ¼ 18; field of view (FOV) ¼ 24 cm; voxel thickness ¼ 13.2 mm. In both thalamic and hippocampal areas volume of interest (VOI) has been defined as 5 ml in the examination of multivoxel proton MR spectroscopy. VOI has been performed to both thalami and hippocampus separately as a multivoxel proton MR spectroscopy. The most important cause of working separately both thalami and both hippocampus may be disrupting on the spectrum depending upon vascular structures, pulsations and cerebrospinal fluid between and around the anatomic structure. In both frontal areas VOI has been defined as 15 ml in the examination of multivoxel proton MR spectroscopy. VOI has been performed to both frontal areas together as a multivoxel proton MR spectroscopy. Again; taking advantages of from these properties the ROIs were placed exactly at the frontal regions (both frontal areas) localized at white-gray nuclei composition. ROI values for both thalami and hippocampus are on an average 50 mm2 (1 pixel). ROI values for both frontal areas are on an average 110 mm2 (2 pixels). At the end of the study; spectrum and absolute values of N-acetylaspartate (NAA), creatine (Cr) were obtained from ROI areas. NAA and Cr are the crucial metabolites supporting information neurochemically.
2.3.
Statistical analysis
All statistical analysis was performed with the SPSS for Windows (SPSS Inc. Standard Version, Release 11.5) statistical software package for social sciences. The baseline demographic and clinical features such as age, gender, and the duration seizures of the JAE were evaluated with the analysis of variance test (ANOVA). The measurements MRS parameters were used with t-test, independent samples test, paired samples test both JAE patients and control subjects for the statistical analysis. p < 0.05 was considered statistically significant.
Table 1 – Correlation of NAA values and NAA/Cr ratio of the JAE patient and control groups. MRS results
JAE
Control subjects
p values*
Thalamic NAA
Right 1144.3 598.2 Left 1140.7 644.6
2211.2 1412.5 2265.3 1226.0
0.019 0.008
Frontal NAA
Right 1096.8 698.3 Left 1242.0 691.2
1126.2 412.8 1354.3 387.8
0.907 0.648
Hippocampus NAA
Right 1509.5 1558.5 1150.8 499.2 Left 1470.9 1595.02 1036 448
0.492 0.413
Thalamic NAA/Cr
Right Left
1.78 0.38 1.90 0.42
2.42 0.49 2.44 0.58
0.002 0.016
Frontal NAA/Cr
Right Left
1.65 0.43 1.75 0.43
1.64 0.40 1.83 0.39
0.970 0.669
Hippocampus NAA/Cr
Right Left
1.47 0.35 1.42 0.32
1.57 0.35 1.47 0.44
0.500 0.745
three had generalized seizures 1–3 per year, two had 3–5 absences per week, one used her antiepileptic irregularly and had 5–7 absences per day before control. All patients were seizure free for at least 1 day before MRS imaging, the patient whom used her antiepileptic irregularly, advised for regular pill taking and underwent MRS after 1 week seizure free period. Nine patients had mono therapy [valproic acid (VPA), lamotrigine (LMT), levetiracetam (LEV)], five had poly therapy (LMT þ VPA or VPA þ LEV). The NAA and NAA/Cr ratios were decreased significantly in bilateral thalamic regions of the patients ( p < 0.05). But there weren’t any differences in frontal and temporal regions (Table 1, Figs. 1 and 2). 2400 R.frontal NAA 2200
L.frontal NAA R.thalamic NAA
2000
L.thalamic NAA R.hippocampus NAA L.hippocampus NAA
1800
1600
3.
Results 1400
The mean ages were 14.9 2.05 (range 11–19) and 14.5 1.7 (range 12–17) of the JAE patients and control subjects, respectively. The mean age seizure onset was 12.6 2.09 (range 10–16). Mean seizure onset duration was 2.3 0.9 (range 1–4) years. Their female/male ratios were 9/5 and 6/4 in the JAE patients and control subjects, respectively. Of the patients who had generalized seizures the mean duration between last seizure and the MR spectroscopic imaging was 6.7 7.1 (range 1–24) months. Of these patients seven had only absence seizures, four had absence and generalized seizures and three had also rare myoclonic jerks. Mean seizure free period of the patients was 13.2 9.6 months (range 1–24),
1200
1000
800
Control Subject
JAE
Fig. 1 – Right and left frontal, thalamic and hippocampal NAA values of the JAE patient and control groups.
european journal of paediatric neurology 14 (2010) 224–228
2,6 R.frontal NAA/Cr L.frontal NAA/Cr 2,4
R.thalamic NAA/Cr L.thalamic NAA/Cr
2,2
R.hippocampus NAA/Cr L.hippocampus NAA/Cr
2,0
1,8
1,6
1,4
1,2
Control Subject
JAE
Fig. 2 – Right and left frontal, thalamic and hippocampal NAA/Cr ratios of the JAE patient and control groups.
4.
Discussion
Absence seizures in JAE are characterized by abrupt onset and termination of marked impairment of consciousness with or without other signs. Severe impairment of consciousness is the essential feature of the absence seizure in JAE. There is complete loss of awareness and responsiveness and cessation of on-going activities.17 Several clinical and experimental studies showed that epileptic discharges generated from the thalamic and thalamo-cortical networks especially shown by animal and deep EEG studies in absence seizures.18–21 Recently, neuronal metabolism and function are demonstrated by noninvasive imaging techniques using such as MRS, 15 FDG PET, and functional MRI. MRS has been used in neurological disease to characterize gross structural lesions and to detect neuronal dysfunction in patients with epilepsies.22 Although its function is unknown, NAA exists only in neurons and the decreases in NAA levels are found in diseases of the brain.23,24 Cr is found in both neurons and glial cells.9 Its level remains relatively stable even during disease and therefore MRS results are often expressed as a ratio of NAA/Cr and this value is taken to reflect neuronal dysfunction or changes in neuronal density.22 Cho is bound to cell membranes, myelin and complex brain lipids. It is also used as a marker for background cellular density and so the ratio NA/
227
Cho is used as another indicator of neuronal dysfunction.9 Labate et al. suggested that both thalamus and cortex at the time of the absence seizures are involved by demonstrating highly significant blood-oxygenation level-dependent (BOLD) activation of the thalamus during short absence seizures in a child at 7 years old with newly diagnosed, untreated IGE, using fMRI/EEG.17 Negative BOLD response reflects the hemodynamic and metabolic down-regulation accompanying neuronal inhibition.25 Bernasconi et al showed the progressive thalamic neuronal dysfunction in patients with idiopathic generalized epilepsy. They showed the reduction of mean thalamic NAA/Cr ratio in patients with IGE when compared with normal controls. There were no differences in NAA/Cr between patients whose seizures were well controlled and those in whom seizures were not controlled. There was no correlation between thalamic NAA/Cr and mean number of spike and wave complexes. They mentioned to the progressive thalamic neuronal dysfunction in patients with IGE supporting the notion of abnormal thalamo-cortical circuitry as a substrate of seizure generation in this form of epilepsy.26 Bilateral thalamic activation was shown by Salek-Haddadi et al. during prolonged absences in an adult with intractable juvenile absence epilepsy with frequent absences.27 Aghakhani et al. showed the thalamic signal change using fMRI in 80% of patients included in a series of adults with refractory IGE.28 Prevett et al. showed diffusely increased glucose metabolism using PET FDG without predominance of any cerebral areas, while PET H2 15O indicated thalamic blood flow changes.29 Recently, in a SPECT study during a prolonged absence seizure, Nehlig et al. detected the diffuse decrease in cortical blood flow, with relative sparing of the thalamus.30 The activation in the motor cortex bilaterally may reflect the motor component of the absence seizure, whereas the activation in the white matter tracts may be involved in the rapid propagation of the electrical activity. Areas of deactivation were found in the right middle frontal gyrus and bilateral in the retrosplenial areas. The middle frontal gyrus is involved in working memory processes and the retrosplenial areas in maintaining awareness. The deactivation in these two brain areas may indicate relative inhibition during generalized discharges, as previously discussed.31 Patients with IGE may compliance about memory deficits; especially they suffer from poor performance on recall of everyday items. Although no structural abnormalities were shown on histopathologically, or on MRI in IGEs, it is thought that epileptic activity itself may cause dysfunction in the temporal lobes which leads to memory impairment.32,33 Dickson et al. showed that IGE patients perform worse than age matched controls on a range of memory tests that correlated with MRS measures of neuronal dysfunction in the temporal lobes. This result supports the hypothesis that memory deficits in epilepsy may be due to neuronal dysfunction secondary to epileptic activity itself.22 Despite those studies we showed no frontal and temporal functional abnormality in the early stages of the disease, there were not any differences for the frontal and hippocampal NAA/Cr ratios between patients and the control group. We found bilateral thalamic dysfunction also in early stages in absence epilepsy. We think that this finding reflects the early thalamic neuronal functional dysfunction even in early stages of the disease. We think that this result might be
228
european journal of paediatric neurology 14 (2010) 224–228
for the reason of early stage of the disease and no frontal functional disorder has been seen yet. In late stages, either the disease duration or the propagation of the epileptiform activity may lead to temporal and frontal neuronal dysfunction. In conclusion: Quantitative MRS provides further evidence for involvement of the thalamus in JAE. The observed reductions in NAA levels and NAA/Cr ratios of bilateral thalamic regions are consistent with epilepsy related excitoxicity as a possible underlying mechanism even in early stage of JAE. Additional prospective studies of larger numbers of patients are, however, necessary to further elucidate the cause–effect relationship between epileptic seizures and their subsequent effect on the thalamus in JAE.
references
1. Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389–99. 2. Wolf P. Juvenile absence epilepsy. In: Roger J, Bureau M, Dravet C, Dreifuss FE, Perret A, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence. 2nd ed. London: John Libbey; 1992. p. 307–12. 3. Gloor P, Fariello RG. Generalized epilepsy: some of its cellular mechanisms differ from those of focal epilepsy. Trends Neurosci 1988;11:63–8. 4. Futatsugi Y, Riviello JJ. Mechanisms of generalized absence epilepsy. Brain 1998;20:75–9. 5. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981;22:489–501. 6. Porter RJ. The absence epilepsies. Epilepsia 1993;34:42–8. 7. Mattson R. Overview: idiopathic generalised epilepsies. Epilepsia 2003;44:2–6. 8. Chan CH, Briellmann RS, Pell GS, et al. Thalamic atrophy in childhood absence epilepsy. Epilepsia 2006;47:399–405. 9. Hammen T, Stefan H, Ederhardt K, W-Huk BH, Tomandl BF. Clinical applications of 1H-MR spectroscopy in the evaluation of epilepsiesdwhat do pathological spectra stand for with regard to current results and what answers do they give to common clinical questions concerning the treatment of epilepsies? Acta Neurol Scand 2003;108:223–38. 10. Connelly A, Paesschen WV, Porter D, et al. Proton magnetic resonance spectroscopy in MRI-negative temporal lobe epilepsy. Neurology 1998;51:61–6. 11. Fojtikova´ D, Bra´zdil M, Horky´ J, et al. Magnetic resonance spectroscopy of the thalamus in patients with typical absence epilepsy. Seizure 2006;15:533–40. 12. Branddao LA, Doningues RC. MR spectroscopy of the brain. New York: Lippincott Williams & Wilkins; 2003. 13. Cendes F, Knowlton RC, Novotny E. Magnetic resonance spectroscopy in epilepsy: clinical issues. Epilepsia 2002;43:32–9. 14. Cendes F, Stanley JA, Dubeau F. Proton magnetic resonance imaging for discrimination of absence and complex partial seizures. Ann Neurol 1997;41:74–80.
15. Gadian D. N-Acetylaspartate and epilepsy. Magn Reson Imaging 1995;13:1193–5. 16. Li LM, Dubeau F, Andermann F, Arnold DL. Proton magnetic resonance spectroscopic imaging studies in patients with newly diagnosed partial epilepsy. Epilepsia 2000;41:825–31. 17. Labate A, Briellmann RS, Abbott DF, Waites AB, Graeme D. Jackson typical childhood absence seizures are associated with thalamic activation. Epileptic Disord 2005;7:373–7. 18. Gloor P. Generalized cortico-reticular epilepsies: some considerations on the pathophysiology of generalized bilaterally synchronous spike and wave discharge. Epilepsia 1968;9:249–63. 19. Steriade M, Contreras D. Spike-wave complexes and fast components of cortically generated seizures, I: role of neocortex and thalamus. J Neurophysiol 1998;80:1439–55. 20. McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol 2001;63:815–46. 21. McCormick D. Cortical and subcortical generators of normal and abnormal rhythmicity. Int Rev Neurobiol 2002;49:99–114. 22. Dickson JM, Wilkinson ID, Howell SJ, Griffiths PD, Gru¨newald RA. Idiopathic generalised epilepsy: a pilot study of memory and neuronal dysfunction in the temporal lobes, assessed by magnetic resonance spectroscopy. J Neurol Neurosurg Psychiatry 2006;77:834–40. 23. Urenjak J, Williams S, Gadian D, Noble B. Specific expression of N-acetylaspartate in neurons, oligodendrocyte-type-2 a, oligodendrocyte-type-2 astrocyte progenitors, and immature oligodendrocytes in vitro. J Neurochem 1992;59:55–61. 24. Howe F, Maxwell R, Saunders S, Brown MM, Griffiths JR. Proton spectroscopy in vivo. Magn Reson Q 1993;9:31–59. 25. Stefanovic B, Warnking JM, Pike GB. Hemodynamic and metabolic responses to neuronal inhibition. Neuroimage 2004; 22:771–8. 26. Bernasconi A, Bernasconi N, Natsume J, Antel SB, Andermann F, Arnold DL. Magnetic resonance spectroscopy and imaging of the thalamus in idiopathic generalized epilepsy. Brain 2003;126:2447–54. 27. Salek-Haddadi A, Lemieux L, Merschhemke M, et al. Functional magnetic resonance imaging of human absence seizures. Ann Neurol 2003;53:663–7. 28. Aghakhani Y, Bagshaw AP, Benar CG, et al. fMRI activation during spike and wave discharges in idiopathic generalized epilepsy. Brain 2004;127:1127–44. 29. Prevett MC, Duncan JS, Jones T, Fish DR, Brooks DJ. Demonstration of thalamic activation during typical absence seizures using H2 (15) O and PET. Neurology 1995;45: 1396–402. 30. Nehlig A, Valenti MP, Thiriaux A, et al. Ictal and interictal perfusion variations measured by SISCOM analysis in typical childhood absence seizures. Epileptic Disord 2004;6: 247–53. 31. Archer JS, Abbott DF, Waites AB, Jackson GD. fMRI ‘‘deactivation’’ of the posterior cingulate during generalised spike and wave. Neuroimage 2003;20:1915–29. 32. Meencke H. Neuron density in the molecular layer of the frontal cortex in primary generalised epilepsy. Epilepsia 1985; 26:450. 33. Woermann F, Free S, Koepp M, Sisodiya SM, Duncan JS. Abnormal cerebral structure in juvenile myoclonic epilepsy demonstrated with voxel-based analysis of MRI. Brain 1999; 122:2101–8.
Official Journal of the European Paediatric Neurology Society
Original article
A proton magnetic resonance spectroscopic study in juvenile absence epilepsy in early stages Sibel Canbaz Kabaya,*, Oguzhan Guven Gumustasb, Handan Ozisik Karamanc, Hilmi Ozdend, Oguz Erdince a
Dumlupinar University, Faculty of Medicine, Department of Neurology, Tavsanli Yolu, 43100 Kutahya, Turkey Burtom – Emar Radiodiagnostic Center, Osmangazi, Bursa, Turkey c Onsekizmart University, Faculty of Medicine, Department of Neurology, Canakkale, Turkey d Osmangazi University, Faculty of Medicine, Department of Anatomy, Eskisehir, Turkey e Osmangazi University, Faculty of Medicine, Department of Neurology, Eskisehir, Turkey b
article info
abstract
Article history:
Purpose: The aim of this study to evaluate the hippocampal, frontal and thalamic lobe
Received 28 February 2009
functions in the early stage of the juvenile absence epilepsy (JAE) by magnetic resonance
Received in revised form
proton spectroscopy (MRS).
20 May 2009
Method: Fourteen patients with juvenile absence epilepsy with typical absence seizures and
Accepted 4 June 2009
10 healthy volunteer controls were included in this study. The diagnosis of the patients was in accordance with EEG findings and seizure semiology. All patients had minimum
Keywords:
twice EEG recordings and all had typical 3-Hz generalized spike and slow-wave discharges
Juvenile absence epilepsy
at least on one EEG. All patients had bilateral MRS of frontal, thalamic and hippocampal
Proton magnetic resonance
regions and NAA, NAA/Cr, NAA/Cho, NAA/Cho þ Cr levels were detected.
spectroscopy
Results: The mean age was 14.9 2.05 and 14.5 1.7 of the JAE patients and control subjects,
Brain
respectively. Mean seizure onset duration were 2.3 0.9 years. In patient group the frontal,
Seizures
thalamic and hippocampal NAA/Cr ratios were 1.65, 1.78, 1.47 in right and 1.75, 1.90, 1.42 in left, respectively. While in the control group NAA/Cr ratios were 1.64, 2.42, 1.57 in right and 1.83, 2.44, 1.47 in left, respectively. There weren’t any difference in frontal and hippocampal regions, but the bilateral thalamic NAA, NAA/Cr ratios of the patients were significantly lower than control group even in early stages of the disease. Conclusion: The observed reductions in NAA levels and NAA/Cr ratios of bilateral thalamic regions are consistent with epilepsy related excitoxicity as a possible underlying mechanism even in early stage of JAE. However, we believe that to generalize the results of our study a prospective multicenter study is required. ª 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: þ90274 2652031; fax: þ90274 2652277. E-mail addresses: [email protected] (S.C. Kabay), [email protected] (H. Ozden). 1090-3798/$ – see front matter ª 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2009.06.004
european journal of paediatric neurology 14 (2010) 224–228
1.
Introduction
Absences are generalized nonconvulsive seizures. The International Classification of Epilepsies (ILAE) proposed the classification of three syndromes of idiopathic generalized epilepsy (IGE) with absence seizures: childhood absence epilepsy, juvenile absence epilepsy (JAE), and juvenile myoclonic epilepsy.1 JAE develops furtively in physically and mentally healthy adolescents. Although the frequency of the absences is low, and the symptoms are relatively trivial, the diagnosis can be overlooked until generalized tonic–clonic seizures appear. Age at onset is usually between 10 and 17 years, with a peak between 10 and 12 years.2 The main mechanisms of absence seizures are unknown; however, animal study showed that rhythmic thalamic projections to diffusely epileptogenic cortex produce the characteristic hypersynchronous discharges and that increased inhibitory, as well as excitatory, mechanisms which involved.3,4 Typical absence seizures are characterized by a complete consciousness that may be isolated or associated with motor phenomena. A sudden impairment of consciousness is frequent and associated with bilateral, synchronous, symmetric 3-Hz generalized spike and slow-wave discharges on EEG.5,6 An essential characteristic of all these syndromes is that neurologic examination and neuroimaging results are normal.7 The presence of abnormalities in corticothalamic networks has been showed to be the functional basis of absence seizure generation.8 Magnetic resonance proton spectroscopy (MRS) can been used to detect neuronal dysfunction and subtle changes in neuronal density in patients whose brains are macroscopically normal.9,10 It is a noninvasive sensitive technique which has been used especially for quantification of important metabolic information. MRS is able to suggest metabolic abnormalities that are not apparent to conventional MRI, because these abnormalities may precede structural changes.11 Three major peaks characterize MRS spectra: N-acetylaspartate (NAA) marker of neuronal and axonal viability and density; creatine (Cr) used as internal reference, since it is the most stable cerebral metabolite; choline (Cho) reflecting cellular proliferation.12 A decreased NAA signal reflects neuronal loss or dysfunction, while the increase of the signals taken from Cr and Cho reflects gliosis. NAA/Cr signal ratio can be used as an indicator sensitive to neuronal loss and astrocytosis and can be used to evaluate the neuronal function in several diseases also including epilepsy.13–15 Neuronal dysfunction is present at an early stage of the epileptic process. Although there is an early stage study with MRS in partial epilepsies, in our knowledge there is no study about absence epilepsy in early stage of the disease.16 The aim of the study is to evaluate the frontal, thalamic and hippocampal functions in the early stage of the JAE by MRS.
2.
Materials and methods
Fourteen JAE patients with typical absence seizures and 10 healthy volunteer controls were included in this study. The diagnosis of the patients was in accordance with EEG findings and seizure semiology. All patients had typical absence seizures repeated several times daily before diagnosis. All
225
patients had minimum twice EEG recordings and all had typical 3-Hz generalized spike and slow-wave discharges at least on one EEG. Inclusion criteria; Age at onset between 10 and 17 years, normal neurologic state and development, brief (4–20 s, exceptionally longer), and frequent (tens per day) absence seizures with abrupt and severe impairment (loss) of consciousness. Patients with other than typical absence seizures such as generalized tonic–clonic seizures (GTCS), or myoclonic jerk prior to or during the active stage of absences, eyelid myoclonia, perioral myoclonia, rhythmic massive limb jerking, and single or arrhythmic myoclonic jerk of the head, trunk, or limbs excluded from the study. However, mild myoclonic elements of the eyes, eyebrows, and eyelids may be featured, particularly in the first 3 s of the absence seizures. Also patients with mild or no impairment of consciousness during the 3–4-Hz discharges, brief EEG 3–4-Hz spike-wave paroxysms of less than 4 s, multiple spikes (more than three) or ictal discharge fragmentations, visual (photic) and other sensory precipitation of clinical seizures were excluded. Patients with abnormal cranial MRI findings coincidentally like periventricular ischemia or arachnoids cysts were excluded from the study.
2.1.
Magnetic resonance imaging
This study was performed using quadrature transmit receive head coil at GE Signa 1.5 T MRI Excite HD (GE Medical Systems, Milwaukee, WI, USA). Our MRI protocol consisted of SE (spin-echo) T1-weighted axial images; (repetition time) TR/TE (echo time), 500/12 ms; excitations, two; matrix size 256 192; slice thickness, 5 mm; interslice gap, 2 mm; and SE T2weighted axial and coronal images TR/TE, 2500/100 ms; excitations, one; matrix size 256 192; slice thickness, 5 mm; interslice gap, 2.5 mm. Also T1-weighted inversion recovery 3 mm thick images, perpendicular to long axis of hippocampus and T2-weighted coronal fluid attenuated inversion recovery (FLAIR) images were used. We used both T2-weighted axial and coronal images to guide us in locating voxels for proton magnetic resonance spectroscopy (MRS) studies.
2.2.
Magnetic resonance spectroscopy
All the Spectroscopy imaging was performed on GE Signa 1.5 T MRI Excite HD (GE Medical Systems, Milwaukee, WI, USA). All the imaging was performed with transmit receive head coil, using 2D Probe (software of GE) PRESS (point resolved surface coil spectroscopy) CSI (chemical shift imaging) multivoxel spectroscopy sequence. The probe (software of GE) offers single voxel and multivoxel proton spectroscopy with automated water suppression and gradient shimming. Probe expands the clinical utility of MR by providing a chemical analysis of the brain. Multivoxel probe enables analysis of larger volumes of interest while maintaining the ability to breakdown the analysis to smaller areas of interest. Also this technique is acquired in a short scan time, with the ability to acquire spectroscopy data from both pathology and normal regions (control spectrum) in single acquisition. Advanced function software by GE Healthcare was used for post
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processing. This programmed, enables data processing including metabolic color maps, metabolic ratios, retrospective voxel shifting, baseline correction and phase correction. Consequently, CSI techniques are considered versatile thus have greatly improved the quality of clinical MR spectroscopy on epilepsy imaging. For the spectra SE sequence containing 144 ms echo time was used. TR was obtained as 1000 ms and the mean signal to noise ratio 100 and number of excitations (NEX) ¼ 1 respectively. Acquisition ¼ 1; acquisition time ¼ 5.28 min; frequency ¼ 18; field of view (FOV) ¼ 24 cm; voxel thickness ¼ 13.2 mm. In both thalamic and hippocampal areas volume of interest (VOI) has been defined as 5 ml in the examination of multivoxel proton MR spectroscopy. VOI has been performed to both thalami and hippocampus separately as a multivoxel proton MR spectroscopy. The most important cause of working separately both thalami and both hippocampus may be disrupting on the spectrum depending upon vascular structures, pulsations and cerebrospinal fluid between and around the anatomic structure. In both frontal areas VOI has been defined as 15 ml in the examination of multivoxel proton MR spectroscopy. VOI has been performed to both frontal areas together as a multivoxel proton MR spectroscopy. Again; taking advantages of from these properties the ROIs were placed exactly at the frontal regions (both frontal areas) localized at white-gray nuclei composition. ROI values for both thalami and hippocampus are on an average 50 mm2 (1 pixel). ROI values for both frontal areas are on an average 110 mm2 (2 pixels). At the end of the study; spectrum and absolute values of N-acetylaspartate (NAA), creatine (Cr) were obtained from ROI areas. NAA and Cr are the crucial metabolites supporting information neurochemically.
2.3.
Statistical analysis
All statistical analysis was performed with the SPSS for Windows (SPSS Inc. Standard Version, Release 11.5) statistical software package for social sciences. The baseline demographic and clinical features such as age, gender, and the duration seizures of the JAE were evaluated with the analysis of variance test (ANOVA). The measurements MRS parameters were used with t-test, independent samples test, paired samples test both JAE patients and control subjects for the statistical analysis. p < 0.05 was considered statistically significant.
Table 1 – Correlation of NAA values and NAA/Cr ratio of the JAE patient and control groups. MRS results
JAE
Control subjects
p values*
Thalamic NAA
Right 1144.3 598.2 Left 1140.7 644.6
2211.2 1412.5 2265.3 1226.0
0.019 0.008
Frontal NAA
Right 1096.8 698.3 Left 1242.0 691.2
1126.2 412.8 1354.3 387.8
0.907 0.648
Hippocampus NAA
Right 1509.5 1558.5 1150.8 499.2 Left 1470.9 1595.02 1036 448
0.492 0.413
Thalamic NAA/Cr
Right Left
1.78 0.38 1.90 0.42
2.42 0.49 2.44 0.58
0.002 0.016
Frontal NAA/Cr
Right Left
1.65 0.43 1.75 0.43
1.64 0.40 1.83 0.39
0.970 0.669
Hippocampus NAA/Cr
Right Left
1.47 0.35 1.42 0.32
1.57 0.35 1.47 0.44
0.500 0.745
three had generalized seizures 1–3 per year, two had 3–5 absences per week, one used her antiepileptic irregularly and had 5–7 absences per day before control. All patients were seizure free for at least 1 day before MRS imaging, the patient whom used her antiepileptic irregularly, advised for regular pill taking and underwent MRS after 1 week seizure free period. Nine patients had mono therapy [valproic acid (VPA), lamotrigine (LMT), levetiracetam (LEV)], five had poly therapy (LMT þ VPA or VPA þ LEV). The NAA and NAA/Cr ratios were decreased significantly in bilateral thalamic regions of the patients ( p < 0.05). But there weren’t any differences in frontal and temporal regions (Table 1, Figs. 1 and 2). 2400 R.frontal NAA 2200
L.frontal NAA R.thalamic NAA
2000
L.thalamic NAA R.hippocampus NAA L.hippocampus NAA
1800
1600
3.
Results 1400
The mean ages were 14.9 2.05 (range 11–19) and 14.5 1.7 (range 12–17) of the JAE patients and control subjects, respectively. The mean age seizure onset was 12.6 2.09 (range 10–16). Mean seizure onset duration was 2.3 0.9 (range 1–4) years. Their female/male ratios were 9/5 and 6/4 in the JAE patients and control subjects, respectively. Of the patients who had generalized seizures the mean duration between last seizure and the MR spectroscopic imaging was 6.7 7.1 (range 1–24) months. Of these patients seven had only absence seizures, four had absence and generalized seizures and three had also rare myoclonic jerks. Mean seizure free period of the patients was 13.2 9.6 months (range 1–24),
1200
1000
800
Control Subject
JAE
Fig. 1 – Right and left frontal, thalamic and hippocampal NAA values of the JAE patient and control groups.
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2,6 R.frontal NAA/Cr L.frontal NAA/Cr 2,4
R.thalamic NAA/Cr L.thalamic NAA/Cr
2,2
R.hippocampus NAA/Cr L.hippocampus NAA/Cr
2,0
1,8
1,6
1,4
1,2
Control Subject
JAE
Fig. 2 – Right and left frontal, thalamic and hippocampal NAA/Cr ratios of the JAE patient and control groups.
4.
Discussion
Absence seizures in JAE are characterized by abrupt onset and termination of marked impairment of consciousness with or without other signs. Severe impairment of consciousness is the essential feature of the absence seizure in JAE. There is complete loss of awareness and responsiveness and cessation of on-going activities.17 Several clinical and experimental studies showed that epileptic discharges generated from the thalamic and thalamo-cortical networks especially shown by animal and deep EEG studies in absence seizures.18–21 Recently, neuronal metabolism and function are demonstrated by noninvasive imaging techniques using such as MRS, 15 FDG PET, and functional MRI. MRS has been used in neurological disease to characterize gross structural lesions and to detect neuronal dysfunction in patients with epilepsies.22 Although its function is unknown, NAA exists only in neurons and the decreases in NAA levels are found in diseases of the brain.23,24 Cr is found in both neurons and glial cells.9 Its level remains relatively stable even during disease and therefore MRS results are often expressed as a ratio of NAA/Cr and this value is taken to reflect neuronal dysfunction or changes in neuronal density.22 Cho is bound to cell membranes, myelin and complex brain lipids. It is also used as a marker for background cellular density and so the ratio NA/
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Cho is used as another indicator of neuronal dysfunction.9 Labate et al. suggested that both thalamus and cortex at the time of the absence seizures are involved by demonstrating highly significant blood-oxygenation level-dependent (BOLD) activation of the thalamus during short absence seizures in a child at 7 years old with newly diagnosed, untreated IGE, using fMRI/EEG.17 Negative BOLD response reflects the hemodynamic and metabolic down-regulation accompanying neuronal inhibition.25 Bernasconi et al showed the progressive thalamic neuronal dysfunction in patients with idiopathic generalized epilepsy. They showed the reduction of mean thalamic NAA/Cr ratio in patients with IGE when compared with normal controls. There were no differences in NAA/Cr between patients whose seizures were well controlled and those in whom seizures were not controlled. There was no correlation between thalamic NAA/Cr and mean number of spike and wave complexes. They mentioned to the progressive thalamic neuronal dysfunction in patients with IGE supporting the notion of abnormal thalamo-cortical circuitry as a substrate of seizure generation in this form of epilepsy.26 Bilateral thalamic activation was shown by Salek-Haddadi et al. during prolonged absences in an adult with intractable juvenile absence epilepsy with frequent absences.27 Aghakhani et al. showed the thalamic signal change using fMRI in 80% of patients included in a series of adults with refractory IGE.28 Prevett et al. showed diffusely increased glucose metabolism using PET FDG without predominance of any cerebral areas, while PET H2 15O indicated thalamic blood flow changes.29 Recently, in a SPECT study during a prolonged absence seizure, Nehlig et al. detected the diffuse decrease in cortical blood flow, with relative sparing of the thalamus.30 The activation in the motor cortex bilaterally may reflect the motor component of the absence seizure, whereas the activation in the white matter tracts may be involved in the rapid propagation of the electrical activity. Areas of deactivation were found in the right middle frontal gyrus and bilateral in the retrosplenial areas. The middle frontal gyrus is involved in working memory processes and the retrosplenial areas in maintaining awareness. The deactivation in these two brain areas may indicate relative inhibition during generalized discharges, as previously discussed.31 Patients with IGE may compliance about memory deficits; especially they suffer from poor performance on recall of everyday items. Although no structural abnormalities were shown on histopathologically, or on MRI in IGEs, it is thought that epileptic activity itself may cause dysfunction in the temporal lobes which leads to memory impairment.32,33 Dickson et al. showed that IGE patients perform worse than age matched controls on a range of memory tests that correlated with MRS measures of neuronal dysfunction in the temporal lobes. This result supports the hypothesis that memory deficits in epilepsy may be due to neuronal dysfunction secondary to epileptic activity itself.22 Despite those studies we showed no frontal and temporal functional abnormality in the early stages of the disease, there were not any differences for the frontal and hippocampal NAA/Cr ratios between patients and the control group. We found bilateral thalamic dysfunction also in early stages in absence epilepsy. We think that this finding reflects the early thalamic neuronal functional dysfunction even in early stages of the disease. We think that this result might be
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for the reason of early stage of the disease and no frontal functional disorder has been seen yet. In late stages, either the disease duration or the propagation of the epileptiform activity may lead to temporal and frontal neuronal dysfunction. In conclusion: Quantitative MRS provides further evidence for involvement of the thalamus in JAE. The observed reductions in NAA levels and NAA/Cr ratios of bilateral thalamic regions are consistent with epilepsy related excitoxicity as a possible underlying mechanism even in early stage of JAE. Additional prospective studies of larger numbers of patients are, however, necessary to further elucidate the cause–effect relationship between epileptic seizures and their subsequent effect on the thalamus in JAE.
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