- Email: [email protected]
Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex
Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex Hidehiro Ishikawa a,⇑, Atsushi Niwa a, Masaru Asahi a, Keita Matsuura a, Satoshi Masuzugawa b, Yo Niida c, Masayuki Maeda d, Mineo Kondo e, Hidekazu Tomimoto a a
Department of Neurology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan Masuzugawa Neurology Clinic, 817-3 Iinojike, Suzuka, Mie 513-0802, Japan Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku-gun, Ishikawa 920-0293, Japan d Department of Advanced Diagnostic Imaging, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan e Department of Ophthalmology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan b c
a r t i c l e
i n f o
Article history: Received 17 June 2017 Accepted 23 October 2017 Available online xxxx Keywords: Tuberous sclerosis complex Magnetic resonance spectroscopy Diffusion tensor imaging Quadrantanopia TSC2
a b s t r a c t Tuberous sclerosis complex (TSC) 1 or TSC2 is mutated in most TSC patients. TSC2 mutations are more frequently associated with worse outcomes, earlier age at seizure onset, more severe intellectual disability, and higher tuber load than TSC1. The degree of white matter involvement is thought to be associated with the severity of neurological impairment. At present, genotype–phenotype correlations and relationship between tuber burden and neurological disability in TSC are debatable. We presented a 43-year-old patient with TSC2 mutation, whose symptom was only incomplete quadrantic visual field deficit in spite of multiple brain tubers. The visual field deficit was thought to be due to a small lesion in the upper medial part of the optic radiation revealed by diffusion tensor imaging. Her brain tubers showed normal findings in magnetic resonance spectroscopy. Our case suggested that neurological and neuropsychiatric manifestations of TSC are affected by the quality rather than number of the lesions. In addition, MRS may be useful to identify the correlation between brain tubers and neurological disability in TSC patients. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Tuberous sclerosis complex (TSC) is a multisystem genetic disorder that affects almost every organ [1]. The gene responsible for this disorder is on chromosome 9q34 (TSC1) or chromosome 16p13.3 (TSC2). TSC2 mutations are more frequently associated with worse outcomes, earlier age at seizure onset, more severe intellectual disability, and higher tuber load than TSC1 [1]. The degree of white matter involvement is thought to be associated with the severity of neurological impairment [1]. We describe an adult patient with a TSC2 mutation whose only symptom was incomplete quadrantic visual field deficit in spite of multiple brain lesions. 2. Case report A 43-year-old woman presented with right inferior quadrantic visual field deficit. Despite the presence of neoplastic changes in ⇑ Corresponding author. E-mail address: [email protected] (H. Ishikawa).
her retina, the cause of the visual field deficit in her left eye was unknown. Family history was unremarkable. Neurological examination was normal except for the visual field deficit. Routine blood and cerebrospinal fluid test results were normal. The patient’s full intelligence quotient on the Wechsler adult intelligence scale (third edition) was 100. Her electroencephalography (EEG) results were normal. Computed tomography revealed multiple calcified subependymal nodules protruding into the brain ventricle, pulmonary lymphangiomyomatosis, and renal angiomyolipomas (Fig. 1a). Transcatheter arterial embolization was required for an 11 cm right renal angiomyolipoma. Brain magnetic resonance imaging (MRI) revealed radially oriented white matter bands and cortical or subcortical tubers in addition to the subependymal nodules (Fig. 1b). There were no heterogeneous lesions on fluid attenuated inversion recovery (FLAIR). MR spectroscopy (MRS) and diffusion tensor fiber tractography (DT-FT) were performed (Fig. 1c–e). Retinal hamartomas were detected by an ophthalmologist, and perimetry exam indicated partial deficits in the right inferior quadrantic visual field (Fig. 2a, b). No angiofibromas were observed. Genetic testing by CEL nuclease-mediated heteroduplex incision with polyacrylamide gel electrophoresis and silver stain-
https://doi.org/10.1016/j.jocn.2017.10.072 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ishikawa H et al. Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex. J Clin Neurosci (2017), https://doi.org/10.1016/j.jocn.2017.10.072
2
H. Ishikawa et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Fig. 1. Radiological findings of the central nervous system and viscera. (A) Computed tomography revealed multiple calcified subependymal nodules protruding into the brain ventricle, small thin-walled cysts in the lungs, and angiomyolipomas in the kidneys. (B) 3-Tesla double inversion recovery (DIR) magnetic resonance images revealed cortical and subcortical tubers (contentious arrows), radially oriented white matter bands (circles), and subependymal nodules (dashed arrows). (C) Magnetic resonance spectroscopy results were normal. (D) Axial fluid attenuated inversion recovery (FLAIR) with optic radiation tractography indicated that the radial band and high intensity lesions were located on the optic radiation. (E) Comparison of coronal FLAIR with optic radiation tractography and the DIR image indicates that the upper part of the optic radiation was slightly affected by the lesions.
Fig. 2. Ophthalmologic and genetic findings. (A) Retinal hamartomas (arrows) were detected by an ophthalmologist. (B) However, retinal lesions cannot cause a partial deficit in the right inferior quadrantic visual field as was found in the left eye of our patient by Goldmann perimetry. (C) TSC2 analysis revealed a missense mutation: NM_000548.3: c.1832G>A, NP_000539.2:p.Arg611Gln.
ing technology detected a TSC2 missense mutation (p.Arg611Gln) (Fig. 2c) [2]. More than two years after diagnosis, the patient’s MRI and perimetry findings have remained unchanged, and her activities of daily living remain completely self-sustaining.
3. Discussion We present a rare case of sporadic TSC occurring in a middleaged patient, with large life-threatening renal angiomyolipomas but without the classic triad of seizures, intellectual disability, and cutaneous angiofibromas. The right inferior visual field deficit in the left eye was thought to be due to a left temporo-occipital lesion, as MRI including DT-FT revealed an intact lateral geniculate body and optic tracts [3]. Particularly, the upper medial part of the optic radiation is thought to be associated with inferior quadrantic visual fields. The inferior quadrantic visual field defects caused by lesions in the optic radiation are sometimes incongruous, and the magnitude of incongruity has been expressed both as a percentage of field loss and as a spatial estimate. The visual field deficit in our
patient can possibly be explained by a small lesion in the upper medial part of the optic radiation (Fig. 1e). Genotype-phenotype correlation in patients with TSC remains unclear. Previous studies suggest TSC2 mutations are associated with more severe symptoms than TSC1 mutations [4]. The missense mutation p.Arg611Gln in TSC2 found in this patient has been reported as pathogenic [5]. Although the reported patients with the missense mutation p.Arg611Gln in TSC2 had been diagnosed by age 11 and associated with seizures, in our patient the disease was diagnosed at the age of 43 years and was not associated with seizures or EEG abnormalities. Phenotypes may be diverse even for the same TSC mutations. Our patient had no TSC-associated neuropsychiatric disorders in spite of the tuber burden. Patients with numerous tubers usually exhibit a severe neurological phenotype. Phenotypes of TSC may be mostly affected by quality of the brain lesions which possibly depends on micropathological differences. A previous study described three types of tubers (Type A, B, and C) based on the MRI signal intensity of the subcortical white matter component [6]. Type C tubers (hypointense on T1, hyperintense on T2, and heterogeneous on FLAIR images) tended to have additional MRI
Please cite this article in press as: Ishikawa H et al. Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex. J Clin Neurosci (2017), https://doi.org/10.1016/j.jocn.2017.10.072
H. Ishikawa et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
findings such as subependymal giant cell tumors in addition to tubers and a higher probability of causing neuropsychiatric disorders than type A and type B tubers. Although our patient had some type B tubers, lack of type C tubers may be associated with the extremely mild neurological involvement. The use of MRS for evaluation of brain lesions in children with TSC has been reported previously [7]. In this study, a decreased NAA/Cr ratio was correlated with the severity of clinical symptoms in children with TSC. To the best of our knowledge, ours is the first report of an adult TSC patient with numerous brain lesions showing normal neuropsychiatric function and normal MRS findings. Our findings support the hypothesis that neurological and neuropsychiatric manifestations of TSC are affected by the quality rather than number of the lesions. In addition, MRS may be useful to identify the correlation between brain tubers and neurological disability in TSC patients.
Conflicts of interest The authors declare that they have no conflicts of interest.
Acknowledgement We are grateful to the doctors in department of urology and radiology for performing transcatheter arterial embolization. We are also thank Ms. Kana Matsuda for performing the WAIS III test.
3
Ethical standards For this type of study, formal consent is not required because it is a case report, so all diagnostic tests and treatments were performed according to routine clinical practice. Informed consent Informed consent and permission to publish the case report anonymously was obtained from the patient. References [1] Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 2015;14:733–45. [2] Niida Y, Kuroda M, Mitani Y, Okumura A, Yokoi A. Applying and testing the conveniently optimized enzyme mismatch cleavage method to clinical DNA diagnosis. Mol Genet Metab 2012;107:580–5. [3] Mandelstam SA. Challenges of the anatomy and diffusion tensor tractography of the Meyer loop. AJNR Am J Neuroradiol 2012;33:1204–10. [4] Kothare SV, Singh K, Chalifoux JR, et al. Severity of manifestations in tuberous sclerosis complex in relation to genotype. Epilepsia 2014;55:1025–9. [5] Ali M, Girimaji SC, Markandaya M, Shukla AK, Sacchidanand S, Kumar A. Mutation and polymorphism analysis of TSC1 and TSC2 genes in Indian patients with tuberous sclerosis complex. Acta Neurol Scand 2005;111:54–63. [6] Gallagher A, Grant EP, Madan N, Jarrett DY, Lyczkowski DA, Thiele EA. MRI findings reveal three different types of tubers in patients with tuberous sclerosis complex. J Neurol 2010;257:1373–81. [7] Matsuo N, Imamura A, Ito R, Sugawara K, Takahashi Y, Kondo N. The correlation between 1H-MR spectroscopy and clinical manifestation with tuberous sclerosis complex. Neuropediatrics 2007;38:126–9.
Please cite this article in press as: Ishikawa H et al. Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex. J Clin Neurosci (2017), https://doi.org/10.1016/j.jocn.2017.10.072
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex Hidehiro Ishikawa a,⇑, Atsushi Niwa a, Masaru Asahi a, Keita Matsuura a, Satoshi Masuzugawa b, Yo Niida c, Masayuki Maeda d, Mineo Kondo e, Hidekazu Tomimoto a a
Department of Neurology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan Masuzugawa Neurology Clinic, 817-3 Iinojike, Suzuka, Mie 513-0802, Japan Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Kahoku-gun, Ishikawa 920-0293, Japan d Department of Advanced Diagnostic Imaging, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan e Department of Ophthalmology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan b c
a r t i c l e
i n f o
Article history: Received 17 June 2017 Accepted 23 October 2017 Available online xxxx Keywords: Tuberous sclerosis complex Magnetic resonance spectroscopy Diffusion tensor imaging Quadrantanopia TSC2
a b s t r a c t Tuberous sclerosis complex (TSC) 1 or TSC2 is mutated in most TSC patients. TSC2 mutations are more frequently associated with worse outcomes, earlier age at seizure onset, more severe intellectual disability, and higher tuber load than TSC1. The degree of white matter involvement is thought to be associated with the severity of neurological impairment. At present, genotype–phenotype correlations and relationship between tuber burden and neurological disability in TSC are debatable. We presented a 43-year-old patient with TSC2 mutation, whose symptom was only incomplete quadrantic visual field deficit in spite of multiple brain tubers. The visual field deficit was thought to be due to a small lesion in the upper medial part of the optic radiation revealed by diffusion tensor imaging. Her brain tubers showed normal findings in magnetic resonance spectroscopy. Our case suggested that neurological and neuropsychiatric manifestations of TSC are affected by the quality rather than number of the lesions. In addition, MRS may be useful to identify the correlation between brain tubers and neurological disability in TSC patients. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Tuberous sclerosis complex (TSC) is a multisystem genetic disorder that affects almost every organ [1]. The gene responsible for this disorder is on chromosome 9q34 (TSC1) or chromosome 16p13.3 (TSC2). TSC2 mutations are more frequently associated with worse outcomes, earlier age at seizure onset, more severe intellectual disability, and higher tuber load than TSC1 [1]. The degree of white matter involvement is thought to be associated with the severity of neurological impairment [1]. We describe an adult patient with a TSC2 mutation whose only symptom was incomplete quadrantic visual field deficit in spite of multiple brain lesions. 2. Case report A 43-year-old woman presented with right inferior quadrantic visual field deficit. Despite the presence of neoplastic changes in ⇑ Corresponding author. E-mail address: [email protected] (H. Ishikawa).
her retina, the cause of the visual field deficit in her left eye was unknown. Family history was unremarkable. Neurological examination was normal except for the visual field deficit. Routine blood and cerebrospinal fluid test results were normal. The patient’s full intelligence quotient on the Wechsler adult intelligence scale (third edition) was 100. Her electroencephalography (EEG) results were normal. Computed tomography revealed multiple calcified subependymal nodules protruding into the brain ventricle, pulmonary lymphangiomyomatosis, and renal angiomyolipomas (Fig. 1a). Transcatheter arterial embolization was required for an 11 cm right renal angiomyolipoma. Brain magnetic resonance imaging (MRI) revealed radially oriented white matter bands and cortical or subcortical tubers in addition to the subependymal nodules (Fig. 1b). There were no heterogeneous lesions on fluid attenuated inversion recovery (FLAIR). MR spectroscopy (MRS) and diffusion tensor fiber tractography (DT-FT) were performed (Fig. 1c–e). Retinal hamartomas were detected by an ophthalmologist, and perimetry exam indicated partial deficits in the right inferior quadrantic visual field (Fig. 2a, b). No angiofibromas were observed. Genetic testing by CEL nuclease-mediated heteroduplex incision with polyacrylamide gel electrophoresis and silver stain-
https://doi.org/10.1016/j.jocn.2017.10.072 0967-5868/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ishikawa H et al. Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex. J Clin Neurosci (2017), https://doi.org/10.1016/j.jocn.2017.10.072
2
H. Ishikawa et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
Fig. 1. Radiological findings of the central nervous system and viscera. (A) Computed tomography revealed multiple calcified subependymal nodules protruding into the brain ventricle, small thin-walled cysts in the lungs, and angiomyolipomas in the kidneys. (B) 3-Tesla double inversion recovery (DIR) magnetic resonance images revealed cortical and subcortical tubers (contentious arrows), radially oriented white matter bands (circles), and subependymal nodules (dashed arrows). (C) Magnetic resonance spectroscopy results were normal. (D) Axial fluid attenuated inversion recovery (FLAIR) with optic radiation tractography indicated that the radial band and high intensity lesions were located on the optic radiation. (E) Comparison of coronal FLAIR with optic radiation tractography and the DIR image indicates that the upper part of the optic radiation was slightly affected by the lesions.
Fig. 2. Ophthalmologic and genetic findings. (A) Retinal hamartomas (arrows) were detected by an ophthalmologist. (B) However, retinal lesions cannot cause a partial deficit in the right inferior quadrantic visual field as was found in the left eye of our patient by Goldmann perimetry. (C) TSC2 analysis revealed a missense mutation: NM_000548.3: c.1832G>A, NP_000539.2:p.Arg611Gln.
ing technology detected a TSC2 missense mutation (p.Arg611Gln) (Fig. 2c) [2]. More than two years after diagnosis, the patient’s MRI and perimetry findings have remained unchanged, and her activities of daily living remain completely self-sustaining.
3. Discussion We present a rare case of sporadic TSC occurring in a middleaged patient, with large life-threatening renal angiomyolipomas but without the classic triad of seizures, intellectual disability, and cutaneous angiofibromas. The right inferior visual field deficit in the left eye was thought to be due to a left temporo-occipital lesion, as MRI including DT-FT revealed an intact lateral geniculate body and optic tracts [3]. Particularly, the upper medial part of the optic radiation is thought to be associated with inferior quadrantic visual fields. The inferior quadrantic visual field defects caused by lesions in the optic radiation are sometimes incongruous, and the magnitude of incongruity has been expressed both as a percentage of field loss and as a spatial estimate. The visual field deficit in our
patient can possibly be explained by a small lesion in the upper medial part of the optic radiation (Fig. 1e). Genotype-phenotype correlation in patients with TSC remains unclear. Previous studies suggest TSC2 mutations are associated with more severe symptoms than TSC1 mutations [4]. The missense mutation p.Arg611Gln in TSC2 found in this patient has been reported as pathogenic [5]. Although the reported patients with the missense mutation p.Arg611Gln in TSC2 had been diagnosed by age 11 and associated with seizures, in our patient the disease was diagnosed at the age of 43 years and was not associated with seizures or EEG abnormalities. Phenotypes may be diverse even for the same TSC mutations. Our patient had no TSC-associated neuropsychiatric disorders in spite of the tuber burden. Patients with numerous tubers usually exhibit a severe neurological phenotype. Phenotypes of TSC may be mostly affected by quality of the brain lesions which possibly depends on micropathological differences. A previous study described three types of tubers (Type A, B, and C) based on the MRI signal intensity of the subcortical white matter component [6]. Type C tubers (hypointense on T1, hyperintense on T2, and heterogeneous on FLAIR images) tended to have additional MRI
Please cite this article in press as: Ishikawa H et al. Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex. J Clin Neurosci (2017), https://doi.org/10.1016/j.jocn.2017.10.072
H. Ishikawa et al. / Journal of Clinical Neuroscience xxx (2017) xxx–xxx
findings such as subependymal giant cell tumors in addition to tubers and a higher probability of causing neuropsychiatric disorders than type A and type B tubers. Although our patient had some type B tubers, lack of type C tubers may be associated with the extremely mild neurological involvement. The use of MRS for evaluation of brain lesions in children with TSC has been reported previously [7]. In this study, a decreased NAA/Cr ratio was correlated with the severity of clinical symptoms in children with TSC. To the best of our knowledge, ours is the first report of an adult TSC patient with numerous brain lesions showing normal neuropsychiatric function and normal MRS findings. Our findings support the hypothesis that neurological and neuropsychiatric manifestations of TSC are affected by the quality rather than number of the lesions. In addition, MRS may be useful to identify the correlation between brain tubers and neurological disability in TSC patients.
Conflicts of interest The authors declare that they have no conflicts of interest.
Acknowledgement We are grateful to the doctors in department of urology and radiology for performing transcatheter arterial embolization. We are also thank Ms. Kana Matsuda for performing the WAIS III test.
3
Ethical standards For this type of study, formal consent is not required because it is a case report, so all diagnostic tests and treatments were performed according to routine clinical practice. Informed consent Informed consent and permission to publish the case report anonymously was obtained from the patient. References [1] Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 2015;14:733–45. [2] Niida Y, Kuroda M, Mitani Y, Okumura A, Yokoi A. Applying and testing the conveniently optimized enzyme mismatch cleavage method to clinical DNA diagnosis. Mol Genet Metab 2012;107:580–5. [3] Mandelstam SA. Challenges of the anatomy and diffusion tensor tractography of the Meyer loop. AJNR Am J Neuroradiol 2012;33:1204–10. [4] Kothare SV, Singh K, Chalifoux JR, et al. Severity of manifestations in tuberous sclerosis complex in relation to genotype. Epilepsia 2014;55:1025–9. [5] Ali M, Girimaji SC, Markandaya M, Shukla AK, Sacchidanand S, Kumar A. Mutation and polymorphism analysis of TSC1 and TSC2 genes in Indian patients with tuberous sclerosis complex. Acta Neurol Scand 2005;111:54–63. [6] Gallagher A, Grant EP, Madan N, Jarrett DY, Lyczkowski DA, Thiele EA. MRI findings reveal three different types of tubers in patients with tuberous sclerosis complex. J Neurol 2010;257:1373–81. [7] Matsuo N, Imamura A, Ito R, Sugawara K, Takahashi Y, Kondo N. The correlation between 1H-MR spectroscopy and clinical manifestation with tuberous sclerosis complex. Neuropediatrics 2007;38:126–9.
Please cite this article in press as: Ishikawa H et al. Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex. J Clin Neurosci (2017), https://doi.org/10.1016/j.jocn.2017.10.072