YEBEH-04098; No of Pages 5 Epilepsy & Behavior xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Review
SPECT findings in autism spectrum disorders and medically refractory seizures Masayuki Sasaki ⁎ Department of Child Neurology, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8551, Japan
a r t i c l e
i n f o
Article history: Revised 26 October 2014 Accepted 28 October 2014 Available online xxxx Keywords: Epilepsy Autism spectrum disorders Neuroimaging
a b s t r a c t A high rate of seizures and electroencephalogram abnormalities has been noted in individuals with autism spectrum disorders (ASDs). Common underlying neurodevelopmental abnormalities may exist in the brains of individuals with both ASDs and epilepsy. Single-photon emission computed tomography (SPECT) studies of the brain have provided sensitive brain function findings. Such studies often reveal not only localized areas of hyperperfusion, which could be related to the seizure-onset zone, but also localized areas of hypoperfusion that may correlate with the focal reductions in function observed in the prefrontal lobes, cingulate gyrus, superior temporal gyrus, and mesial temporal lobes of many individuals with both ASDs and epilepsy. The focal neuronal dysfunction revealed by SPECT could be caused by aberrant neuronal connectivity. This article is part of a Special Issue entitled “Autism and Epilepsy”. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Autism, a developmental disorder, is characterized by a specific pattern of impaired social interaction, verbal and nonverbal communication, and behaviors or interests (DSM-IV-TR) [1]. Autism spectrum disorders (ASDs) are behaviorally heterogeneous, suggesting a disease spectrum with multiple etiologies. Interpatient variations with respect to neurological abnormalities and the range of behavioral manifestations have greatly impeded an elucidation of the neurobiological mechanisms associated with ASDs. A high rate of seizures and electroencephalogram (EEG) abnormalities has long been reported in individuals with ASDs [2–7]. The prevalence of epilepsy in autism ranges from 7% to 46% [8–10]. Therefore, it is widely known that children with ASDs carry a high risk of epilepsy. Epilepsy and ASDs frequently occur concomitantly, and common underlying mechanisms as well as common genetic and environmental risk factors may converge and enhance the understanding of both disorders. Autism spectrum disorders and epilepsy have been conceptualized as large-scale neural network disorders with altered cortical–subcortical connectivity [11]. However, the precise pathophysiological basis of the relationship between ASDs and epilepsy has not yet been well established.
and epilepsy, the foci of paroxysmal discharges are frequently found in the frontal lobes and/or temporal lobes [12–17]. Localization-related epilepsy is more frequent than generalized epilepsy among children with ASDs. Although seizures in some children with ASDs respond relatively well to available antiepileptic drug (AED) therapy, seizures in most children with ASDs are resistant to AED therapy [8–10]. 3. SPECT studies in ASDs In children with both ASDs and medically refractory seizures, several modalities are usually applied to investigate the present condition of the central nervous system and the appropriateness of surgical treatment. Brain magnetic resonance imaging (MRI) usually does not demonstrate apparent structural abnormalities. In addition to EEG, single-photon emission computed tomography (SPECT) is very useful for determining epileptic foci. In localization-related epilepsy, an ictal SPECT study can reveal areas of hyperperfusion that indicate the seizure-onset zone. However, the seizure-onset zone is usually shown as an area of hypoperfusion in interictal SPECT studies (Fig. 1). 3.1. SPECT for the assessment and treatment of epilepsy
2. Epilepsy and EEG abnormalities in ASDs The types of epilepsy observed in children with ASDs vary from generalized to localization-related epilepsy [5]. In children with both ASDs ⁎ Tel.: +81 42 341 2711. E-mail address: [email protected].
Subtraction ictal SPECT coregistered to MRI (SISCOM) [18] frequently reveals epileptic foci (seizure-onset zone) in the cortex even when MRI has not shown any structural abnormalities. Ictal SPECT is a very useful additional tool for determining the areas of epileptic foci [19]. The use of SISCOM would improve the accuracy of such evaluations even in individuals with both ASDs and epilepsy.
http://dx.doi.org/10.1016/j.yebeh.2014.10.033 1525-5050/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Sasaki M, SPECT findings in autism spectrum disorders and medically refractory seizures, Epilepsy Behav (2014), http:// dx.doi.org/10.1016/j.yebeh.2014.10.033
2
M. Sasaki / Epilepsy & Behavior xxx (2014) xxx–xxx
Fig. 1. Brain MRI (a, c) and interictal 99mTc-ECD SPECT (b, d) of a 4-year-old girl with both ASDs and epilepsy. SPECT reveals areas of hypoperfusion in the left temporal lobe (b, d). MRI reveals high intensity areas in the tip of the left temporal lobe (a). The seizures stopped following the resection of this area in this case. The pathological examination confirmed type IIA focal cortical dysplasia.
Focal areas of activation are frequently identified through more detailed observations of MRI and SPECT findings, particularly SISCOM (Fig. 2). Individuals with both ASDs and medically refractory seizures found to be surgical candidates can later undergo lesionectomy to treat epilepsy. Single-photon emission computed tomography and magnetoencephalography (MEG) play important roles in seizure-onset zone determinations. Following removal of these zones, the epileptic seizures disappear, and autistic symptom intensity may decrease in some individuals with both ASDs and epilepsy, though not all [20]. Occasionally, pathological analyses of the surgically removed tissues confirm the existence of focal cortical dysplasia type IIA or IIB. 3.2. SPECT for detecting areas of neuronal dysfunction Recently, a new method has been applied to children with ASDs and medically intractable seizures. An easy Z-score imaging system (eZIS) program was developed to analyze the individual perfusion 99mTcethylcysteinate dimer (ECD) SPECT images compared with healthy
controls obtained from a database [21,22]. Each SPECT image is subjected to anatomic standardization using statistical parametric mapping with an original 99mTc-ECD template, followed by isotropic smoothing and comparisons with the means and standard deviations (SDs) of SPECT images obtained from the database [22]. A voxel-by-voxel Zscore analysis is performed after voxel normalization to the global mean values as follows: Z-score = [(control mean) − (individual value)] / (control SD). The Z-score maps are displayed as overlays on the tomographic sections and are projected with average Z-scores to the surfaces of the anatomically standardized MR imaging templates [21]. We used eZIS to analyze 99mTc-ECD SPECT perfusion maps of children with both ASDs and medically intractable seizures [20]. This method revealed a mixed hypoperfusion pattern, particularly in the prefrontal cortex, medial frontal cortex, anterior cingulate cortex, medial parietal cortex, and/or anterior temporal cortex. The areas of hypoperfusion were divided into 2 groups according to the main hypoperfusion patterns observed on eZIS, which were described as the medial cingulate type (Fig. 3) and temporal type (Fig. 4).
Please cite this article as: Sasaki M, SPECT findings in autism spectrum disorders and medically refractory seizures, Epilepsy Behav (2014), http:// dx.doi.org/10.1016/j.yebeh.2014.10.033
M. Sasaki / Epilepsy & Behavior xxx (2014) xxx–xxx
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Fig. 2. Brain MRI (a, d) and interictal (b, e) and ictal 99mTc-ECD SPECT (c, f) of a 3-year-old girl with both ASDs and epilepsy. Ictal SPECT (c, f) reveals areas of hyperperfusion in the left prefrontal lobe. MRI reveals a blurred border between the cortex and the white matter in the left prefrontal lobe, and moderately high intensity areas in the white matter are also seen in the same area. SISCOM reveals hyperperfusion in the left prefrontal lobe during the ictal state. The seizures were not controlled after resection of the left prefrontal lobe in this case. The pathological examination confirmed type IIB focal cortical dysplasia in this area.
The eZIS system has been used to assess brain perfusion in children with both ASDs and medically intractable seizures. Because this system is very sensitive, it is useful not only for identifying epileptic foci in ictal studies but also for identifying areas of hypoperfusion [20]. The eZIS system can reveal focal areas of hypoperfusion in children with ASDs and medically intractable seizures. However, brain perfusion SPECT studies
should be carefully interpreted because epilepsy strongly influences brain perfusion. The seizure-onset zone usually exhibits hypoperfusion during interictal studies and hyperperfusion during ictal studies [19]. In general, individuals with both ASDs and epilepsy have been thought to be poor candidates for SPECT studies, given the difficulty associated with distinguishing abnormalities in the regional cerebral
Fig. 3. eZIS from interictal 99mTc-ECD SPECT of a 10-year-old boy with both ASDs and epilepsy. This figure simultaneously indicates the areas of hypoperfusion and hyperperfusion relative to the standard database. Areas of hyperperfusion or hypoperfusion are displayed as orange and yellow or blue and green areas, relatively. The areas of hypoperfusion are visible in the medial prefrontal cortex, cingulate cortex, and parietal cortex. The bar on the right represents the standard deviation (SD). This figure is typical of the medial cingulate-type eZIS pattern. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Please cite this article as: Sasaki M, SPECT findings in autism spectrum disorders and medically refractory seizures, Epilepsy Behav (2014), http:// dx.doi.org/10.1016/j.yebeh.2014.10.033
4
M. Sasaki / Epilepsy & Behavior xxx (2014) xxx–xxx
Fig. 4. eZIS from an interictal 99mTc-ECD SPECT of a 4-year-old girl with both ASDs and epilepsy. The areas of hyperperfusion, which are shown as orange and yellow areas, can be observed in the bilateral prefrontal cortex. The areas of hypoperfusion are visible in the left anterior temporal cortex. This figure is typical of the temporal-type eZIS pattern. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
blood flow (rCBF) due to ASDs caused by seizure-related changes, even in interictal studies [23–26]. Because SPECT with the eZIS system is very sensitive, it may be useful for detecting abnormal brain regions related to the epileptic focus and for assessing regions of low or high rCBF in individuals with ASDs. One study has reported correlations between reduced rCBF and behavioral deficits [25]. Hypoperfusion in the medial cingulate areas, as shown by some studies, correlated strongly with the symptoms of ASDs. The left medial frontal cortex is strongly associated with the theory of mind, the process in which another person's thoughts and intentions are recognized and interpreted [27,28], which is severely disturbed in individuals with ASDs [29]. Healthy individuals exhibit activation of the medial prefrontal cortex during tasks that rely on the ability to attribute mental states to others, whereas individuals with Asperger syndrome do not. Functional MRI studies have also linked activity in the medial frontal cortex to the theory of mind [30]. The relationship between ASDs and epilepsy or EEG abnormalities has become a topic of intense interest because the mechanism of epileptogenesis may correlate with the specific symptoms of ASDs. An iomazenil (123I-IMZ) SPECT study identified dramatic reductions in tracer accumulation in the superior and medial frontal cortices [31]. In addition, IMZ SPECT can be used to indirectly evaluate intracerebral synaptic cleft gamma-aminobutyric acid (GABA)A receptor expression, providing a deeper understanding of GABAergic function in the context of ASDs. Indeed, such studies have shown that disturbances in the GABAergic system contribute to the aggravation of ASD symptoms, a finding consistent with the strong relationship between ASDs and epilepsy [31]. The high prevalence of epileptiform activity in individuals with ASDs is considered secondary to the neuropathological processes common to both disorders [32]. Indeed, SPECT and EEG studies have revealed an overlap between the areas of hypoperfusion or hyperperfusion and EEG paroxysmal discharges [20], indicating common neurodevelopmental deficits in the brains of individuals with ASDs. It is well accepted that epilepsy is not a main causal factor for autism. However, epilepsy most likely occurs in areas of the brain that are functionally or pathologically involved with ASDs. Recently, new genetic and biological studies have been performed, and novel biological markers
such as serotonin and dopamine transporter markers have also been used in SPECT studies [11]. Additional neurobiological studies in individuals with ASDs and epilepsy are needed to elucidate the underlying pathophysiological mechanisms. 4. Limitations of SPECT investigations Single-photon emission computed tomography studies have several limitations [33], many of which are related to the use of radioisotopes. First, it is unethical to expose healthy age-matched controls, particularly children, to these agents. Second, it is often difficult to find amenable individuals with ASDs; therefore, most imaging studies usually involve a relatively small number of subjects. Third, it is difficult to repeat these studies several times in the same individuals to obtain longitudinal series. Furthermore, because children with ASDs are often uncooperative, sedation is needed in most cases; even adults with ASDs, particularly those with retardation, may not remain still during data acquisition. Obviously, objectivity requires cooperation between the separate behavioral and neuroimaging groups. 5. Conclusions Single-photon emission computed tomography studies frequently reveal focal hypoperfusion particularly in the temporal and frontal lobes in individuals with ASDs. However, neuropathological and MRI studies have not revealed consistent morphological abnormalities in individuals with ASDs. The reasons for this discrepancy are not known. One hypothesis suggests that deficient connectivity leads to dysfunctional brain activity in individuals with ASDs, which can be observed via functional MRI. Therefore, even if the local morphological structures are not disorganized, focal neuronal function may be disturbed by aberrant connectivity. As a result, SPECT studies could reveal focal hypoperfusion in areas with normal gross morphology and cellular organization. The colocalization of rCBF and EEG abnormalities (e.g., focal epileptiform activity or interictal paroxysmal discharges) is a strong indicator of local dysfunction at the microcircuit or neuronal levels in individuals with ASDs [20]. Dysfunctional brain activity may be further exacerbated by abnormalities in the regional and long-range cortical connections [33].
Please cite this article as: Sasaki M, SPECT findings in autism spectrum disorders and medically refractory seizures, Epilepsy Behav (2014), http:// dx.doi.org/10.1016/j.yebeh.2014.10.033
M. Sasaki / Epilepsy & Behavior xxx (2014) xxx–xxx
Acknowledgment This review study was supported, in part, by Research Grant (24-7) for Nervous and Mental Disorders from the Ministry of Health, Labor and Welfare of Japan. Conflict of interest The author declares that there are no conflicts of interest. References [1] American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. 2000 [Text Revision, Washington, DC]. [2] Tuchman R, Cuccaro M, Alessandri M. Autism and epilepsy: historical perspective. Brain Dev 2010;32:709–18. [3] Creak M, Pampiglione G. Clinical and EEG studies on a group of 35 psychotic children. Dev Med Child Neurol 1969;11:218–27. [4] Berg AT, Plioplys S. Epilepsy and autism: is there a special relationship? Epilepsy Behav 2012;23:193–8. [5] Tuchman R, Rapin I. Epilepsy in autism. Lancet Neurol 2002;1:352–8. [6] Deonna T, Roulet E. Autistic spectrum disorder: evaluating a possible contributing or causal role of epilepsy. Epilepsia 2006;47(Suppl. 2):79–82. [7] Levisohn PM. The autism–epilepsy connection. Epilepsia 2007;48:33–5. [8] Hara H. Autism and epilepsy: a retrospective follow-up study. Brain Dev 2007;29: 486–90. [9] Danielsson S, Gillberg IC, Billstedt E, Gillberg C, Olsson I. Epilepsy in young adults with autism: a prospective population-based follow-up study of 120 individuals diagnosed in childhood. Epilepsia 2005;46:918–23. [10] Sansa G, Carlson C, Doyle W, Weiner HL, Bluvstein J, Barr W, et al. Medically refractory epilepsy in autism. Epilepsia 2011;52:1071–5. [11] Tuchman R, Hirtz D, Mamounas LA. NINDS epilepsy and autism spectrum disorders workshop report. Neurology 2013;81:1630–6. [12] Kawasaki Y, Yokota K, Shinomiya M, Shimizu Y, Niwa S. Brief report: electroencephalographic paroxysmal activities in the frontal area emerged in middle childhood and during adolescence in a follow-up study of autism. J Autism Dev Disord 1997; 27:605–20. [13] Kawasaki Y, Shinomiya M, Takayanagi M, Niwa SI. Paroxysmal EEG abnormalities and epilepsy in pervasive developmental disorders: follow-up study until adolescence and beyond. Brain Dev 2010;32:769–75. [14] Rossi PG, Parmeggiani A, Bach V, Santucci M, Visconti P. EEG features and epilepsy in patients with autism. Brain Dev 1995;17:169–74. [15] Rossi PG, Posar A, Parmeggiani A. Epilepsy in adolescents and adults with autistic disorder. Brain Dev 2000;22:102–6.
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[16] Parmeggiani A, Barcia G, Posar A, Raimondi E, Santucci M, Scaduto MC. Epilepsy and EEG paroxysmal abnormalities in autism spectrum disorders. Brain Dev 2010;32: 783–9. [17] Hashimoto T, Sasaki M, Sugai K, Hanaoka S, Fukumizu M, Kato T. Paroxysmal discharges on EEG in young autistic patients are frequent in frontal regions. J Med Invest 2001;48:175–80. [18] O'Brien TJ, So EL, Mullan BP, Hauser MF, Brinkmann BH, Bohnen NI, et al. Subtraction ictal SPECT co-registered to MRI improves clinical usefulness of SPECT in localizing the surgical seizure focus. Neurology 1998;50:445–54. [19] Van Paesschen W. Ictal SPECT. Epilepsia 2004;45(Suppl. 4):35–40. [20] Sasaki M, Nakagawa E, Sugai K, Shimizu Y, Hattori A, Nonoda Y, et al. Brain perfusion SPECT and EEG findings in children with autism spectrum disorders and medically intractable epilepsy. Brain Dev 2010;32:776–82. [21] Matsuda H. Role of neuroimaging in Alzheimer's disease, with emphasis on brain perfusion SPECT. J Nucl Med 2007;48:1289–300. [22] Fukushima A, Kato A, Matsuda H, Sugai K, Sasaki M. Establishment of a brain perfusion single photon emission computed tomography database in children by statistical imaging analysis (in Japanese). No to Hattatsu (in Tokyo) 2005;37:400–4. [23] Zillbovicious M, Garreau B, Samson Y, Remy P, Barthélémy C, Syrota A, et al. Delayed maturation of the frontal cortex in childhood autism. Am J Psychiatry 1995;152: 248–52. [24] Mountz JM, Tolbert LC, Lill DW, Katholi CR, Liu H. Functional deficits in autistic disorder: characterization by technetium-99 m-HMPAO and SPECT. J Nucl Med 1995; 36:1156–62. [25] Ohnishi T, Matsuda H, Hashimoto T, Kunihiro T, Nishikawa M, Uema T, et al. Abnormal regional cerebral blood flow in childhood autism. Brain 2000;123:1838–44. [26] Hashimoto T, Sasaki M, Fukumizu M, Hanaoka S, Sugai K, Matsuda H. Single-photon emission computed tomography of the brain in autism: effect of the developmental level. Pediatr Neurol 2000;23:416–20. [27] Happé F, Ehlers S, Fletcher P, Frith U, Johansson M, Gillberg C, et al. “Theory of mind” in the brain. Evidence from a PET scan study of Asperger syndrome. Neuroreport 1996;8:197–201. [28] Ernst M, Zametkin AJ, Matochik JA, Pascualvaca D, Cohen RM. Low medial prefrontal dopaminergic activity in autistic children. Lancet 1997;350:638. [29] Frith CD, Frith U. Interacting minds — a biological basis. Science 1999;286:1692–5. [30] Völlm BA, Taylor AN, Richardson P, Corcoran R, Stirling J, McKie S, et al. Neuronal correlates of theory of mind and empathy: a functional magnetic resonance imaging study in a nonverbal task. Neuroimage 2006;29:90–8. [31] Mori T, Mori K, Fujii E, Toda Y, Miyazaki M, Harada M, et al. Evaluation of the GABAergic nervous system in autistic brain: 123I-iomazenil SPECT study. Brain Dev 2012;34:648–54. [32] Tuchman R. Epilepsy and electroencephalography in autism spectrum disorders. In: Amaral DG, Dawson G, Geschwind G, editors. Autism spectrum disorders. New York: Oxford University Press; 2011. p. 381–94. [33] Sasaki M. Single-photon emission computed tomography and electroencephalography findings in children with autism spectrum disorders. In: Patel VB, editor. Comprehensive guide to autism. New York: Springer; 2014. p. 929–45.
Please cite this article as: Sasaki M, SPECT findings in autism spectrum disorders and medically refractory seizures, Epilepsy Behav (2014), http:// dx.doi.org/10.1016/j.yebeh.2014.10.033
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Review
SPECT findings in autism spectrum disorders and medically refractory seizures Masayuki Sasaki ⁎ Department of Child Neurology, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8551, Japan
a r t i c l e
i n f o
Article history: Revised 26 October 2014 Accepted 28 October 2014 Available online xxxx Keywords: Epilepsy Autism spectrum disorders Neuroimaging
a b s t r a c t A high rate of seizures and electroencephalogram abnormalities has been noted in individuals with autism spectrum disorders (ASDs). Common underlying neurodevelopmental abnormalities may exist in the brains of individuals with both ASDs and epilepsy. Single-photon emission computed tomography (SPECT) studies of the brain have provided sensitive brain function findings. Such studies often reveal not only localized areas of hyperperfusion, which could be related to the seizure-onset zone, but also localized areas of hypoperfusion that may correlate with the focal reductions in function observed in the prefrontal lobes, cingulate gyrus, superior temporal gyrus, and mesial temporal lobes of many individuals with both ASDs and epilepsy. The focal neuronal dysfunction revealed by SPECT could be caused by aberrant neuronal connectivity. This article is part of a Special Issue entitled “Autism and Epilepsy”. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Autism, a developmental disorder, is characterized by a specific pattern of impaired social interaction, verbal and nonverbal communication, and behaviors or interests (DSM-IV-TR) [1]. Autism spectrum disorders (ASDs) are behaviorally heterogeneous, suggesting a disease spectrum with multiple etiologies. Interpatient variations with respect to neurological abnormalities and the range of behavioral manifestations have greatly impeded an elucidation of the neurobiological mechanisms associated with ASDs. A high rate of seizures and electroencephalogram (EEG) abnormalities has long been reported in individuals with ASDs [2–7]. The prevalence of epilepsy in autism ranges from 7% to 46% [8–10]. Therefore, it is widely known that children with ASDs carry a high risk of epilepsy. Epilepsy and ASDs frequently occur concomitantly, and common underlying mechanisms as well as common genetic and environmental risk factors may converge and enhance the understanding of both disorders. Autism spectrum disorders and epilepsy have been conceptualized as large-scale neural network disorders with altered cortical–subcortical connectivity [11]. However, the precise pathophysiological basis of the relationship between ASDs and epilepsy has not yet been well established.
and epilepsy, the foci of paroxysmal discharges are frequently found in the frontal lobes and/or temporal lobes [12–17]. Localization-related epilepsy is more frequent than generalized epilepsy among children with ASDs. Although seizures in some children with ASDs respond relatively well to available antiepileptic drug (AED) therapy, seizures in most children with ASDs are resistant to AED therapy [8–10]. 3. SPECT studies in ASDs In children with both ASDs and medically refractory seizures, several modalities are usually applied to investigate the present condition of the central nervous system and the appropriateness of surgical treatment. Brain magnetic resonance imaging (MRI) usually does not demonstrate apparent structural abnormalities. In addition to EEG, single-photon emission computed tomography (SPECT) is very useful for determining epileptic foci. In localization-related epilepsy, an ictal SPECT study can reveal areas of hyperperfusion that indicate the seizure-onset zone. However, the seizure-onset zone is usually shown as an area of hypoperfusion in interictal SPECT studies (Fig. 1). 3.1. SPECT for the assessment and treatment of epilepsy
2. Epilepsy and EEG abnormalities in ASDs The types of epilepsy observed in children with ASDs vary from generalized to localization-related epilepsy [5]. In children with both ASDs ⁎ Tel.: +81 42 341 2711. E-mail address: [email protected].
Subtraction ictal SPECT coregistered to MRI (SISCOM) [18] frequently reveals epileptic foci (seizure-onset zone) in the cortex even when MRI has not shown any structural abnormalities. Ictal SPECT is a very useful additional tool for determining the areas of epileptic foci [19]. The use of SISCOM would improve the accuracy of such evaluations even in individuals with both ASDs and epilepsy.
http://dx.doi.org/10.1016/j.yebeh.2014.10.033 1525-5050/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Sasaki M, SPECT findings in autism spectrum disorders and medically refractory seizures, Epilepsy Behav (2014), http:// dx.doi.org/10.1016/j.yebeh.2014.10.033
2
M. Sasaki / Epilepsy & Behavior xxx (2014) xxx–xxx
Fig. 1. Brain MRI (a, c) and interictal 99mTc-ECD SPECT (b, d) of a 4-year-old girl with both ASDs and epilepsy. SPECT reveals areas of hypoperfusion in the left temporal lobe (b, d). MRI reveals high intensity areas in the tip of the left temporal lobe (a). The seizures stopped following the resection of this area in this case. The pathological examination confirmed type IIA focal cortical dysplasia.
Focal areas of activation are frequently identified through more detailed observations of MRI and SPECT findings, particularly SISCOM (Fig. 2). Individuals with both ASDs and medically refractory seizures found to be surgical candidates can later undergo lesionectomy to treat epilepsy. Single-photon emission computed tomography and magnetoencephalography (MEG) play important roles in seizure-onset zone determinations. Following removal of these zones, the epileptic seizures disappear, and autistic symptom intensity may decrease in some individuals with both ASDs and epilepsy, though not all [20]. Occasionally, pathological analyses of the surgically removed tissues confirm the existence of focal cortical dysplasia type IIA or IIB. 3.2. SPECT for detecting areas of neuronal dysfunction Recently, a new method has been applied to children with ASDs and medically intractable seizures. An easy Z-score imaging system (eZIS) program was developed to analyze the individual perfusion 99mTcethylcysteinate dimer (ECD) SPECT images compared with healthy
controls obtained from a database [21,22]. Each SPECT image is subjected to anatomic standardization using statistical parametric mapping with an original 99mTc-ECD template, followed by isotropic smoothing and comparisons with the means and standard deviations (SDs) of SPECT images obtained from the database [22]. A voxel-by-voxel Zscore analysis is performed after voxel normalization to the global mean values as follows: Z-score = [(control mean) − (individual value)] / (control SD). The Z-score maps are displayed as overlays on the tomographic sections and are projected with average Z-scores to the surfaces of the anatomically standardized MR imaging templates [21]. We used eZIS to analyze 99mTc-ECD SPECT perfusion maps of children with both ASDs and medically intractable seizures [20]. This method revealed a mixed hypoperfusion pattern, particularly in the prefrontal cortex, medial frontal cortex, anterior cingulate cortex, medial parietal cortex, and/or anterior temporal cortex. The areas of hypoperfusion were divided into 2 groups according to the main hypoperfusion patterns observed on eZIS, which were described as the medial cingulate type (Fig. 3) and temporal type (Fig. 4).
Please cite this article as: Sasaki M, SPECT findings in autism spectrum disorders and medically refractory seizures, Epilepsy Behav (2014), http:// dx.doi.org/10.1016/j.yebeh.2014.10.033
M. Sasaki / Epilepsy & Behavior xxx (2014) xxx–xxx
3
Fig. 2. Brain MRI (a, d) and interictal (b, e) and ictal 99mTc-ECD SPECT (c, f) of a 3-year-old girl with both ASDs and epilepsy. Ictal SPECT (c, f) reveals areas of hyperperfusion in the left prefrontal lobe. MRI reveals a blurred border between the cortex and the white matter in the left prefrontal lobe, and moderately high intensity areas in the white matter are also seen in the same area. SISCOM reveals hyperperfusion in the left prefrontal lobe during the ictal state. The seizures were not controlled after resection of the left prefrontal lobe in this case. The pathological examination confirmed type IIB focal cortical dysplasia in this area.
The eZIS system has been used to assess brain perfusion in children with both ASDs and medically intractable seizures. Because this system is very sensitive, it is useful not only for identifying epileptic foci in ictal studies but also for identifying areas of hypoperfusion [20]. The eZIS system can reveal focal areas of hypoperfusion in children with ASDs and medically intractable seizures. However, brain perfusion SPECT studies
should be carefully interpreted because epilepsy strongly influences brain perfusion. The seizure-onset zone usually exhibits hypoperfusion during interictal studies and hyperperfusion during ictal studies [19]. In general, individuals with both ASDs and epilepsy have been thought to be poor candidates for SPECT studies, given the difficulty associated with distinguishing abnormalities in the regional cerebral
Fig. 3. eZIS from interictal 99mTc-ECD SPECT of a 10-year-old boy with both ASDs and epilepsy. This figure simultaneously indicates the areas of hypoperfusion and hyperperfusion relative to the standard database. Areas of hyperperfusion or hypoperfusion are displayed as orange and yellow or blue and green areas, relatively. The areas of hypoperfusion are visible in the medial prefrontal cortex, cingulate cortex, and parietal cortex. The bar on the right represents the standard deviation (SD). This figure is typical of the medial cingulate-type eZIS pattern. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Please cite this article as: Sasaki M, SPECT findings in autism spectrum disorders and medically refractory seizures, Epilepsy Behav (2014), http:// dx.doi.org/10.1016/j.yebeh.2014.10.033
4
M. Sasaki / Epilepsy & Behavior xxx (2014) xxx–xxx
Fig. 4. eZIS from an interictal 99mTc-ECD SPECT of a 4-year-old girl with both ASDs and epilepsy. The areas of hyperperfusion, which are shown as orange and yellow areas, can be observed in the bilateral prefrontal cortex. The areas of hypoperfusion are visible in the left anterior temporal cortex. This figure is typical of the temporal-type eZIS pattern. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
blood flow (rCBF) due to ASDs caused by seizure-related changes, even in interictal studies [23–26]. Because SPECT with the eZIS system is very sensitive, it may be useful for detecting abnormal brain regions related to the epileptic focus and for assessing regions of low or high rCBF in individuals with ASDs. One study has reported correlations between reduced rCBF and behavioral deficits [25]. Hypoperfusion in the medial cingulate areas, as shown by some studies, correlated strongly with the symptoms of ASDs. The left medial frontal cortex is strongly associated with the theory of mind, the process in which another person's thoughts and intentions are recognized and interpreted [27,28], which is severely disturbed in individuals with ASDs [29]. Healthy individuals exhibit activation of the medial prefrontal cortex during tasks that rely on the ability to attribute mental states to others, whereas individuals with Asperger syndrome do not. Functional MRI studies have also linked activity in the medial frontal cortex to the theory of mind [30]. The relationship between ASDs and epilepsy or EEG abnormalities has become a topic of intense interest because the mechanism of epileptogenesis may correlate with the specific symptoms of ASDs. An iomazenil (123I-IMZ) SPECT study identified dramatic reductions in tracer accumulation in the superior and medial frontal cortices [31]. In addition, IMZ SPECT can be used to indirectly evaluate intracerebral synaptic cleft gamma-aminobutyric acid (GABA)A receptor expression, providing a deeper understanding of GABAergic function in the context of ASDs. Indeed, such studies have shown that disturbances in the GABAergic system contribute to the aggravation of ASD symptoms, a finding consistent with the strong relationship between ASDs and epilepsy [31]. The high prevalence of epileptiform activity in individuals with ASDs is considered secondary to the neuropathological processes common to both disorders [32]. Indeed, SPECT and EEG studies have revealed an overlap between the areas of hypoperfusion or hyperperfusion and EEG paroxysmal discharges [20], indicating common neurodevelopmental deficits in the brains of individuals with ASDs. It is well accepted that epilepsy is not a main causal factor for autism. However, epilepsy most likely occurs in areas of the brain that are functionally or pathologically involved with ASDs. Recently, new genetic and biological studies have been performed, and novel biological markers
such as serotonin and dopamine transporter markers have also been used in SPECT studies [11]. Additional neurobiological studies in individuals with ASDs and epilepsy are needed to elucidate the underlying pathophysiological mechanisms. 4. Limitations of SPECT investigations Single-photon emission computed tomography studies have several limitations [33], many of which are related to the use of radioisotopes. First, it is unethical to expose healthy age-matched controls, particularly children, to these agents. Second, it is often difficult to find amenable individuals with ASDs; therefore, most imaging studies usually involve a relatively small number of subjects. Third, it is difficult to repeat these studies several times in the same individuals to obtain longitudinal series. Furthermore, because children with ASDs are often uncooperative, sedation is needed in most cases; even adults with ASDs, particularly those with retardation, may not remain still during data acquisition. Obviously, objectivity requires cooperation between the separate behavioral and neuroimaging groups. 5. Conclusions Single-photon emission computed tomography studies frequently reveal focal hypoperfusion particularly in the temporal and frontal lobes in individuals with ASDs. However, neuropathological and MRI studies have not revealed consistent morphological abnormalities in individuals with ASDs. The reasons for this discrepancy are not known. One hypothesis suggests that deficient connectivity leads to dysfunctional brain activity in individuals with ASDs, which can be observed via functional MRI. Therefore, even if the local morphological structures are not disorganized, focal neuronal function may be disturbed by aberrant connectivity. As a result, SPECT studies could reveal focal hypoperfusion in areas with normal gross morphology and cellular organization. The colocalization of rCBF and EEG abnormalities (e.g., focal epileptiform activity or interictal paroxysmal discharges) is a strong indicator of local dysfunction at the microcircuit or neuronal levels in individuals with ASDs [20]. Dysfunctional brain activity may be further exacerbated by abnormalities in the regional and long-range cortical connections [33].
Please cite this article as: Sasaki M, SPECT findings in autism spectrum disorders and medically refractory seizures, Epilepsy Behav (2014), http:// dx.doi.org/10.1016/j.yebeh.2014.10.033
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Please cite this article as: Sasaki M, SPECT findings in autism spectrum disorders and medically refractory seizures, Epilepsy Behav (2014), http:// dx.doi.org/10.1016/j.yebeh.2014.10.033
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