TRANSCRANIAL SONOGRAPHY IN PATIENTS WITH MYOTONIC DYSTROPHY TYPE 1 STOJAN PERIC, MD, ALEKSANDRA PAVLOVIC, MD, PhD, VESNA RALIC, MS, VALERIJA DOBRICIC, PhD, IVANA BASTA, MD, PhD, DRAGANA LAVRNIC, MD, PhD, and VIDOSAVA RAKOCEVIC STOJANOVIC, MD, PhD Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, 6 Dr Subotica Street, 11000 Belgrade, Serbia Accepted 31 December 2013 ABSTRACT: Introduction: In this study we analyzed transcranial sonography (TCS) in patients with myotonic dystrophy type 1 (DM1). Methods: This cross-sectional study included 66 DM1 patients and 55 matched healthy controls (HCs). Echogenicity of the brainstem raphe (BR) and substantia nigra (SN) and third ventricle width (DTV) were assessed by TCS. Results: BR hypoechogenicity was more common in DM1 patients than in HCs (37.7% vs. 7.8%, P < 0.01). Patients with depression or fatigue were more likely to have BR hypoechogenicity (80.0% vs. 29.4%, P < 0.01 and 51.9% vs. 24.2%, P < 0.05, respectively). Both hypoechogenicity and hyperechogenicity of SN were more frequent in DM1 patients than in controls (26.2% vs. 10.9% and 13.1% vs. 1.8%, respectively, P < 0.01). DTV was increased in DM1 patients compared with HCs (6.0 6 1.4 vs. 4.9 6 0.9 mm, P < 0.01). Conclusion: TCS can offer new insight into structural changes of several cerebral areas in patients with DM1. Muscle Nerve 50: 278–282, 2014
Myotonic
dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults.1 It is a multisystem disease that affects many organs, including the central nervous system (CNS).1 CNS manifestations in DM1 include cognitive defects, personality changes, mood disorders, fatigue, and sleep disorders.2 Magnetic resonance imaging (MRI) studies in DM1 patients show involvement of both white and gray matter.3–6 Transcranial sonography (TCS) is useful for diagnosis of neurodegenerative and affective disorders by evaluating echogenicity of various midline structures.7,8 TCS can depict abnormalities of the substantia nigra (SN), midbrain raphe, and basal ganglia that are less easily detected by other techniques.7 With the use of current high-end ultrasound systems, image resolution of echogenic deep brain structures by TCS is superior to convenAdditional Supporting Information may be found in the online version of this article. Abbreviations: ANOVA, analysis of variance; BR, brainstem raphe; CNS, central nervous system; DM1, myotonic dystrophy type 1; DSS, Daytime Sleepiness Scale; DTI, diffusion tensor imaging; DTV, width of the third ventricle; EDS, excessive daytime sleepiness; FSS, Krupp’s Fatigue Severity Scale; Ham-D, Hamilton Rating Scale for Depression; HC, healthy control; IPD, idiopathic Parkinson disease; LN, lentiform nucleus; MIRS, Muscular Impairment Rating Scale; MRI, magnetic resonance imaging; RAD, reactive adjustment disorder; RLS, restless legs syndrome; RN, red nucleus; SN, substantia nigra; TCS, transcranial sonography; WD, Wilson disease Key words: brainstem raphe; depression; myotonic dystrophy type 1; substantia nigra; transcranial sonography This study was supported by the Ministry of Science of Serbia (grants 175083 and 175022). Correspondence to: A. Pavlovic; e-mail: [email protected] C 2014 Wiley Periodicals, Inc. V
Published online 3 January 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24162
278
Transcranial Sonography in DM1
tional field-strength magnetic resonance imaging (MRI) under clinical conditions, especially because image resolution is less affected by patient movement or breathing.8 Increased echogenicity of brain structures detected with TCS has been attributed to structural changes such as gliosis and altered concentrations of trace metals and metalbinding proteins in the brain. Thus, TCS can supplement other neuroimaging methods.8 TCS may potentially reveal biomarkers of CNS involvement in DM1 and help us to better understand the structural basis of some functional abnormalities. The aim of this study was to analyze TCS findings in a large cohort of DM1 patients and to define their clinical relevance. METHODS
We performed a cross-sectional study of 66 genetically confirmed DM1 patients (52.5% men, aged 19–64 years) who were recruited consecutively from the outpatient and inpatient units of the Neurology Clinic in Belgrade, from October 2011 to June 2012. Molecular genetic confirmation of CTG repeat expansion was obtained in addition to clinical and electromyographic data.9 Patients with congenital DM1, 2 with structural brain disease (1 stroke and 1 brain tumor), and 2 patients who were using selective serotonin reductase inhibitors, were excluded from the analysis because these factors may affect brain echogenicity. Our study also comprised 55 gender- and age-matched healthy controls (HCs) who had no neurological, psychiatric, or somatic disorders. All participants provided informed consent for the study, which was approved by the ethics review board of the School of Medicine, University of Belgrade. The following measures were used in DM1 patients: the Muscular Impairment Rating Scale (MIRS) was used to rate the severity of muscle involvement in DM110; and depressive symptoms were assessed by a psychiatrist using the Hamilton Rating Scale for Depression (Ham-D).11 A Ham-D score of 17 indicates moderate or severe depression.12 Severity of fatigue was measured by the Krupp Fatigue Severity Scale (FSS)13 (score of 36 indicates the presence of marked fatigue); the Daytime Sleepiness Scale (DSS) was administered to all patients.14 A DSS score of 7 indicates excessive MUSCLE & NERVE
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Table 1. Demographic and clinical features of DM1 patients and HCs. Features Gender (% men) Age, years (mean 6 SD) Age at onset, years (mean 6 SD) Disease duration, years (mean 6 SD) MIRS (%) II III IV V CTG (mean number 6 SD) CTG (%) E1 E2 E3 E4
DM1 (n 5 61)
HCs (n 555)
52.5 41.2 6 10.3 22.3 6 9.9
47.3 44.4 6 12.1 /
18.9 6 8.6
/
13.1 52.5 32.8 1.6 746.8 6 280.1 19.7 68.9 8.2 3.3
/
/
/
DM1, myotonic dystrophy type 1; HCs, healthy controls; MIRS, Muscular Impairment Rating Scale. number of CTG repeats: E1, 100–500; E2, 500–1000; E3, 1000–1500; and E4, >1500. P > 0.05 when comparing gender and age between groups.
daytime sleepiness (EDS). Patients were also interviewed for the presence of the restless legs syndrome (RLS) according to the criteria of the National Institutes of Health.15 TCS was performed in all DM1 patients and HCs through the pre-auricular acoustic bone window using a color-coded, phased-array ultrasound system equipped with a 2.5-MHZ transducer (ProSound Alpha 10; Aloka, Japan). The TCS examination was conducted by a trained examiner blinded to all clinical data and was reanalyzed off-line by another blinded TCS expert. In case of disagreement, consensus conclusion on the finding was reached. Standard ultrasound parameters were used, including penetration depth of 16 cm and dynamic range of 50–55 dB.7 Image brightness, contrast, and time-gain compensation were adjusted to obtain the best image. Low echogenicity of the brainstem raphe (BR) was assumed if the echogenic line of the midbrain raphe was interrupted or not visible when imaged from both sides.7 Echogenic size measurements of SN were performed on axial TCS scans automatically after manually encircling the outer circumference of the SN echogenic area. According to previously published criteria and by our laboratory,7,16 echogenic sizes of 0.19 cm2 were classified as normal, and sizes of >0.19 cm2 as hyperechogenic. SN hypoechogenicity was classified in individuals with total SN echogenic sizes bilaterally below 1 standard deviation of the mean for the general population (90% of patients with idiopathic RLS.17 Clinical manifestations of RLS were rare in the DM1 patients in our study, so the clinical correlates of the SN hypoechogenicity are not clear. Decreased iron content in the SN that correlates with its hypoechogenicity on TCS was demonstrated in RLS, both at autopsy and in MRI studies.32,33 However, data on brain iron content in DM1 patients are lacking. None of the DM1 patients in our study had other conditions associated with symptomatic RLS and SN hypoechogenicity, such as end-stage renal disease, symptomatic peripheral neuropathy, IPD under domapinergic therapy, or spinocerebellar ataxia.34 Hyperechogenicity of the RN and LN was found in approximately 10% of the DM1 patients we studied. It has been suggested that abnormal hyperechogenicity in brain structures is a consequence of trace metal accumulation.7,35 Because the DM1 mutation leads to impairment of a premessenger RNA splicing for various proteins,1 we hypothesize that alternative splicing for certain trace metal transporters and storage proteins may be impaired in DM1. Overexpression of human DMPK in C2C12 myogenic culture induces expression of ferritin heavy chain mRNA.36 Zecca et al.37 scanned postmortem brains from normal individuals and found a positive correlation between the echogenic area of the SN and the concentration of iron and heavy and light ferritins. DTV was increased in DM1 patients compared with HCs, and this finding was related to age. We Transcranial Sonography in DM1
assume that increased DTV reflects loss of gray and white brain matter observed on voxel-based morphometry studies in patients with DM1.3,5,6 This study has limitations due to its crosssectional design and lack of other imaging methods that could provide additional information. Behavioral measures were not assessed in HCs, thus it is possible that the HCs did not reflect the general healthy population. Also, observed associations between behavioral measures and TCS findings in DM1 patients were not assessed in HCs, so we cannot conclude that they were disease-specific. In conclusion, TCS offers new insights into structural changes of several cerebral areas in DM1 patients. It revealed a high percentage of BR hypoechogenicity associated with depression and fatigue. Enlarged DTV reflects cerebral atrophy in midline brain areas. Increased frequency of SN hypoechogenicity was also observed, although its clinical relevance remains unclear. Further studies on larger numbers of patients, incorporating comparisons with other imaging techniques and with histopathology, will be valuable. REFERENCES 1. Harper P. Myotonic dystrophy, 3rd ed. London: W.B. Saunders; 2001. 2. Meola G, Sansone V. Cerebral involvement in myotonic dystrophies. Muscle Nerve 2007;36:294–306. 3. Antonini G, Mainero C, Romano A, Giubilei F, Ceschin V, Gragnani F, et al. Cerebral atrophy in myotonic dystrophy: a voxel based morphometric study. J Neurol Neurosurg Psychiatry 2004;75:1611–1613. 4. Fukuda H, Horiguchi J, Ono C, Ohshita T, Takaba J, Ito K. Diffusion tensor imaging of cerebral white matter in patients with myotonic dystrophy. Acta Radiol 2005;46:104–109. 5. Weber YG, Roebling R, Kassubek J, Hoffmann S, Rosenbohm A, Wolf M, et al. Comparative analysis of brain structure, metabolism, and cognition in myotonic dystrophy 1 and 2. Neurology 2010;74:1108– 1117. 6. Minnerop M, Weber B, Schoene-Bake JC, Roeske S, Mirbach S, Anspach C, et al. The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease. Brain 2011;134:3530–3546. 7. Berg D, Godau J, Walter U. Transcranial sonography in movement disorders. Lancet Neurol 2008;7:1044–1055. 8. Skoloudık D, Walter U. Method and validity of transcranial sonography in movement disorders. Int Rev Neurobiol 2010;90:7–34. 9. Prior TW. Technical standards and guidelines for myotonic dystrophy type 1 testing. Genet Med 2009;11:552–555. 10. Mathieu J, Boivin H, Meunier D, Gaudreault M, B egin P. Assessment of a disease-specific muscular impairment rating scale in myotonic dystrophy. Neurology 2001;56:336–340. 11. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62. 12. Zimmerman M, Martinez JH, Young D, Chelminski I, Dalrymple K. Severity classification on the Hamilton depression rating scale. J Affect Disord 2013;150:384–388. 13. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patienys with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121–1123. 14. Laberge L, Gagnon C, Jean S, Mathieu J. Fatigue and daytime sleepiness rating scales in myotonic dystrophy: a study of reliability. J Neurol Neurosurg Psychiatry 2005;76:1403–1405. 15. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of Health; International Restless Legs Syndrome Study Group. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of Health. Sleep Med 2003;4:101–119. 16. Mijajlovic M, Petrovic I, Stojkovic T, Svetel M, Stefanova E, Kostic VS. Transcranial parenchymal sonography in Parkinson’s disease. Vojnosanit Pregl 2008; 65:601–605.
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17. Godau J, Schweitzer KJ, Liepelt I, Gerloff C, Berg D. Substantia nigra hypoechogenicity: definition and findings in restless legs syndrome. Mov Disord 2007;22:187–192. 18. Huber H. Transcranial sonography—anatomy. Int Rev Neurobiol 2010;90:35–45. 19. Behnke S, Double KL, Duma S, Broe GA, Guenther V, Becker G, et al. Substantia nigra echomorphology in the healthy very old: correlation with motor slowing. Neuroimage 2007;34:1054–1059. 20. Avrahami E, Katz A, Bornstein N, Korczyn AD. Computed tomographic findings of brain and skull in myotonic dystrophy. J Neurol Neurosurg Psychiatry 1987;50:435–438. 21. Berg D, Supprian T, Hofmann E, Zeiler B, Jager A, Lange KW, et al. Depression in Parkinson’s disease: brainstem midline alteration on transcranial sonography and magnetic resonance imaging. J Neurol 1999;246:1186–1193. 22. Becker G, Berg D, Lesch KP, Becker T. Basal limbic system alteration in major depression: a hypothesis supported by transcranial sonography and MRI findings. Int J Neuropsychopharmacol 2001;4:21–31. 23. Ono S, Inoue K, Mannen T, Mitake S, Shirai T, Kanda F, et al. Intracytoplasmic inclusion bodies of the thalamus and the substantia nigra, and Marinesco bodies in myotonic dystrophy: a quantitative morphological study. Acta Neuropathol 1989;77:350–356. 24. Ono S, Takahashi K, Jinnai K, Kanda F, Fukuoka Y, Kurisaki H, et al. Loss of serotonin-containing neurons in the raphe of patients with myotonic dystrophy: a quantitative immunohistochemical study and relation to hypersomnia. Neurology 1998;50:535–538. 25. Ono S, Takahashi K, Jinnai K, Kanda F, Fukuoka Y, Kurisaki H, et al. Loss of catecholaminergic neurons in the medullary reticular formation in myotonic dystrophy. Neurology 1998;51:1121–1124. 26. Oyamada R, Hayashi M, Katoh Y, Tsuchiya K, Mizutani T, Tominaga I, et al. Neurofibrillary tangles and deposition of oxidative products in the brain in cases of myotonic dystrophy. Neuropathology 2006; 26:107–114.
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27. Winblad S, Jensen C, Ma˚nsson JE, Samuelsson L, Lindberg C. Depression in myotonic dystrophy type 1: clinical and neuronal correlates. Behav Brain Funct 2010;6:25. 28. Mijajlovic MD. Transcranial sonography in depression. Int Rev Neurobiol 2010;90:259–272. 29. Walter U, Horowski S, Benecke R, Zettl U. Transcranial brain sonography findings related to neuropsychological impairment in multiple sclerosis. J Neurol 2007;254(suppl 2):49–52. 30. Walter U, Prudente-Morrissey L, Herpertz SC, Benecke R, Hoeppner J. Relationship of brainstem raphe echogenicity and clinical findings in depressive states. Psychiatry Res 2007;155:67–73. 31. Laberge L, Dauvilliers Y, B egin P, Richer L, Jean S, Mathieu J. Fatigue and daytime sleepiness in patients with myotonic dystrophy type 1: to lump or split? Neuromuscul Disord 2009;19:397–402. 32. Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 2003;61:304–309. 33. Godau J, Klose U, Di Santo A, Schweitzer K, Berg D. Multiregional brain iron deficiency in restless legs syndrome. Mov Disord 2008;23: 1184–1187. 34. Godau J, Sojer M. Transcranial sonography in restless legs syndrome. Int Rev Neurobiol 2010;90:199–215. 35. Svetel M, Mijajlovic´ M, Tomic´ A, Kresojevic´ N, Pekmezovic´ T, Kostic´ VS. Transcranial sonography in Wilson’s disease. Parkinsonism Relat Disord 2012;18:234–238. 36. Watanabe T, Sasagawa N, Usuki F, Koike H, Saitoh N, Sorimachi H, et al. Overexpression of myotonic dystrophy protein kinase in C2C12 myogenic culture involved in the expression of ferritin heavy chain and interleukin-1alpha mRNAs. J Neurol Sci 1999;167:26–33. 37. Zecca L, Berg D, Arzberger T, Ruprecht P, Rausch WD, Musicco M, et al. In vivo detection of iron and neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage. Mov Disord 2005;20:1278–1285.
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Myotonic
dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults.1 It is a multisystem disease that affects many organs, including the central nervous system (CNS).1 CNS manifestations in DM1 include cognitive defects, personality changes, mood disorders, fatigue, and sleep disorders.2 Magnetic resonance imaging (MRI) studies in DM1 patients show involvement of both white and gray matter.3–6 Transcranial sonography (TCS) is useful for diagnosis of neurodegenerative and affective disorders by evaluating echogenicity of various midline structures.7,8 TCS can depict abnormalities of the substantia nigra (SN), midbrain raphe, and basal ganglia that are less easily detected by other techniques.7 With the use of current high-end ultrasound systems, image resolution of echogenic deep brain structures by TCS is superior to convenAdditional Supporting Information may be found in the online version of this article. Abbreviations: ANOVA, analysis of variance; BR, brainstem raphe; CNS, central nervous system; DM1, myotonic dystrophy type 1; DSS, Daytime Sleepiness Scale; DTI, diffusion tensor imaging; DTV, width of the third ventricle; EDS, excessive daytime sleepiness; FSS, Krupp’s Fatigue Severity Scale; Ham-D, Hamilton Rating Scale for Depression; HC, healthy control; IPD, idiopathic Parkinson disease; LN, lentiform nucleus; MIRS, Muscular Impairment Rating Scale; MRI, magnetic resonance imaging; RAD, reactive adjustment disorder; RLS, restless legs syndrome; RN, red nucleus; SN, substantia nigra; TCS, transcranial sonography; WD, Wilson disease Key words: brainstem raphe; depression; myotonic dystrophy type 1; substantia nigra; transcranial sonography This study was supported by the Ministry of Science of Serbia (grants 175083 and 175022). Correspondence to: A. Pavlovic; e-mail: [email protected] C 2014 Wiley Periodicals, Inc. V
Published online 3 January 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24162
278
Transcranial Sonography in DM1
tional field-strength magnetic resonance imaging (MRI) under clinical conditions, especially because image resolution is less affected by patient movement or breathing.8 Increased echogenicity of brain structures detected with TCS has been attributed to structural changes such as gliosis and altered concentrations of trace metals and metalbinding proteins in the brain. Thus, TCS can supplement other neuroimaging methods.8 TCS may potentially reveal biomarkers of CNS involvement in DM1 and help us to better understand the structural basis of some functional abnormalities. The aim of this study was to analyze TCS findings in a large cohort of DM1 patients and to define their clinical relevance. METHODS
We performed a cross-sectional study of 66 genetically confirmed DM1 patients (52.5% men, aged 19–64 years) who were recruited consecutively from the outpatient and inpatient units of the Neurology Clinic in Belgrade, from October 2011 to June 2012. Molecular genetic confirmation of CTG repeat expansion was obtained in addition to clinical and electromyographic data.9 Patients with congenital DM1, 2 with structural brain disease (1 stroke and 1 brain tumor), and 2 patients who were using selective serotonin reductase inhibitors, were excluded from the analysis because these factors may affect brain echogenicity. Our study also comprised 55 gender- and age-matched healthy controls (HCs) who had no neurological, psychiatric, or somatic disorders. All participants provided informed consent for the study, which was approved by the ethics review board of the School of Medicine, University of Belgrade. The following measures were used in DM1 patients: the Muscular Impairment Rating Scale (MIRS) was used to rate the severity of muscle involvement in DM110; and depressive symptoms were assessed by a psychiatrist using the Hamilton Rating Scale for Depression (Ham-D).11 A Ham-D score of 17 indicates moderate or severe depression.12 Severity of fatigue was measured by the Krupp Fatigue Severity Scale (FSS)13 (score of 36 indicates the presence of marked fatigue); the Daytime Sleepiness Scale (DSS) was administered to all patients.14 A DSS score of 7 indicates excessive MUSCLE & NERVE
August 2014
Table 1. Demographic and clinical features of DM1 patients and HCs. Features Gender (% men) Age, years (mean 6 SD) Age at onset, years (mean 6 SD) Disease duration, years (mean 6 SD) MIRS (%) II III IV V CTG (mean number 6 SD) CTG (%) E1 E2 E3 E4
DM1 (n 5 61)
HCs (n 555)
52.5 41.2 6 10.3 22.3 6 9.9
47.3 44.4 6 12.1 /
18.9 6 8.6
/
13.1 52.5 32.8 1.6 746.8 6 280.1 19.7 68.9 8.2 3.3
/
/
/
DM1, myotonic dystrophy type 1; HCs, healthy controls; MIRS, Muscular Impairment Rating Scale. number of CTG repeats: E1, 100–500; E2, 500–1000; E3, 1000–1500; and E4, >1500. P > 0.05 when comparing gender and age between groups.
daytime sleepiness (EDS). Patients were also interviewed for the presence of the restless legs syndrome (RLS) according to the criteria of the National Institutes of Health.15 TCS was performed in all DM1 patients and HCs through the pre-auricular acoustic bone window using a color-coded, phased-array ultrasound system equipped with a 2.5-MHZ transducer (ProSound Alpha 10; Aloka, Japan). The TCS examination was conducted by a trained examiner blinded to all clinical data and was reanalyzed off-line by another blinded TCS expert. In case of disagreement, consensus conclusion on the finding was reached. Standard ultrasound parameters were used, including penetration depth of 16 cm and dynamic range of 50–55 dB.7 Image brightness, contrast, and time-gain compensation were adjusted to obtain the best image. Low echogenicity of the brainstem raphe (BR) was assumed if the echogenic line of the midbrain raphe was interrupted or not visible when imaged from both sides.7 Echogenic size measurements of SN were performed on axial TCS scans automatically after manually encircling the outer circumference of the SN echogenic area. According to previously published criteria and by our laboratory,7,16 echogenic sizes of 0.19 cm2 were classified as normal, and sizes of >0.19 cm2 as hyperechogenic. SN hypoechogenicity was classified in individuals with total SN echogenic sizes bilaterally below 1 standard deviation of the mean for the general population (90% of patients with idiopathic RLS.17 Clinical manifestations of RLS were rare in the DM1 patients in our study, so the clinical correlates of the SN hypoechogenicity are not clear. Decreased iron content in the SN that correlates with its hypoechogenicity on TCS was demonstrated in RLS, both at autopsy and in MRI studies.32,33 However, data on brain iron content in DM1 patients are lacking. None of the DM1 patients in our study had other conditions associated with symptomatic RLS and SN hypoechogenicity, such as end-stage renal disease, symptomatic peripheral neuropathy, IPD under domapinergic therapy, or spinocerebellar ataxia.34 Hyperechogenicity of the RN and LN was found in approximately 10% of the DM1 patients we studied. It has been suggested that abnormal hyperechogenicity in brain structures is a consequence of trace metal accumulation.7,35 Because the DM1 mutation leads to impairment of a premessenger RNA splicing for various proteins,1 we hypothesize that alternative splicing for certain trace metal transporters and storage proteins may be impaired in DM1. Overexpression of human DMPK in C2C12 myogenic culture induces expression of ferritin heavy chain mRNA.36 Zecca et al.37 scanned postmortem brains from normal individuals and found a positive correlation between the echogenic area of the SN and the concentration of iron and heavy and light ferritins. DTV was increased in DM1 patients compared with HCs, and this finding was related to age. We Transcranial Sonography in DM1
assume that increased DTV reflects loss of gray and white brain matter observed on voxel-based morphometry studies in patients with DM1.3,5,6 This study has limitations due to its crosssectional design and lack of other imaging methods that could provide additional information. Behavioral measures were not assessed in HCs, thus it is possible that the HCs did not reflect the general healthy population. Also, observed associations between behavioral measures and TCS findings in DM1 patients were not assessed in HCs, so we cannot conclude that they were disease-specific. In conclusion, TCS offers new insights into structural changes of several cerebral areas in DM1 patients. It revealed a high percentage of BR hypoechogenicity associated with depression and fatigue. Enlarged DTV reflects cerebral atrophy in midline brain areas. Increased frequency of SN hypoechogenicity was also observed, although its clinical relevance remains unclear. Further studies on larger numbers of patients, incorporating comparisons with other imaging techniques and with histopathology, will be valuable. REFERENCES 1. Harper P. Myotonic dystrophy, 3rd ed. London: W.B. Saunders; 2001. 2. Meola G, Sansone V. Cerebral involvement in myotonic dystrophies. Muscle Nerve 2007;36:294–306. 3. Antonini G, Mainero C, Romano A, Giubilei F, Ceschin V, Gragnani F, et al. Cerebral atrophy in myotonic dystrophy: a voxel based morphometric study. J Neurol Neurosurg Psychiatry 2004;75:1611–1613. 4. Fukuda H, Horiguchi J, Ono C, Ohshita T, Takaba J, Ito K. Diffusion tensor imaging of cerebral white matter in patients with myotonic dystrophy. Acta Radiol 2005;46:104–109. 5. Weber YG, Roebling R, Kassubek J, Hoffmann S, Rosenbohm A, Wolf M, et al. Comparative analysis of brain structure, metabolism, and cognition in myotonic dystrophy 1 and 2. Neurology 2010;74:1108– 1117. 6. Minnerop M, Weber B, Schoene-Bake JC, Roeske S, Mirbach S, Anspach C, et al. The brain in myotonic dystrophy 1 and 2: evidence for a predominant white matter disease. Brain 2011;134:3530–3546. 7. Berg D, Godau J, Walter U. Transcranial sonography in movement disorders. Lancet Neurol 2008;7:1044–1055. 8. Skoloudık D, Walter U. Method and validity of transcranial sonography in movement disorders. Int Rev Neurobiol 2010;90:7–34. 9. Prior TW. Technical standards and guidelines for myotonic dystrophy type 1 testing. Genet Med 2009;11:552–555. 10. Mathieu J, Boivin H, Meunier D, Gaudreault M, B egin P. Assessment of a disease-specific muscular impairment rating scale in myotonic dystrophy. Neurology 2001;56:336–340. 11. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62. 12. Zimmerman M, Martinez JH, Young D, Chelminski I, Dalrymple K. Severity classification on the Hamilton depression rating scale. J Affect Disord 2013;150:384–388. 13. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patienys with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121–1123. 14. Laberge L, Gagnon C, Jean S, Mathieu J. Fatigue and daytime sleepiness rating scales in myotonic dystrophy: a study of reliability. J Neurol Neurosurg Psychiatry 2005;76:1403–1405. 15. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of Health; International Restless Legs Syndrome Study Group. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of Health. Sleep Med 2003;4:101–119. 16. Mijajlovic M, Petrovic I, Stojkovic T, Svetel M, Stefanova E, Kostic VS. Transcranial parenchymal sonography in Parkinson’s disease. Vojnosanit Pregl 2008; 65:601–605.
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17. Godau J, Schweitzer KJ, Liepelt I, Gerloff C, Berg D. Substantia nigra hypoechogenicity: definition and findings in restless legs syndrome. Mov Disord 2007;22:187–192. 18. Huber H. Transcranial sonography—anatomy. Int Rev Neurobiol 2010;90:35–45. 19. Behnke S, Double KL, Duma S, Broe GA, Guenther V, Becker G, et al. Substantia nigra echomorphology in the healthy very old: correlation with motor slowing. Neuroimage 2007;34:1054–1059. 20. Avrahami E, Katz A, Bornstein N, Korczyn AD. Computed tomographic findings of brain and skull in myotonic dystrophy. J Neurol Neurosurg Psychiatry 1987;50:435–438. 21. Berg D, Supprian T, Hofmann E, Zeiler B, Jager A, Lange KW, et al. Depression in Parkinson’s disease: brainstem midline alteration on transcranial sonography and magnetic resonance imaging. J Neurol 1999;246:1186–1193. 22. Becker G, Berg D, Lesch KP, Becker T. Basal limbic system alteration in major depression: a hypothesis supported by transcranial sonography and MRI findings. Int J Neuropsychopharmacol 2001;4:21–31. 23. Ono S, Inoue K, Mannen T, Mitake S, Shirai T, Kanda F, et al. Intracytoplasmic inclusion bodies of the thalamus and the substantia nigra, and Marinesco bodies in myotonic dystrophy: a quantitative morphological study. Acta Neuropathol 1989;77:350–356. 24. Ono S, Takahashi K, Jinnai K, Kanda F, Fukuoka Y, Kurisaki H, et al. Loss of serotonin-containing neurons in the raphe of patients with myotonic dystrophy: a quantitative immunohistochemical study and relation to hypersomnia. Neurology 1998;50:535–538. 25. Ono S, Takahashi K, Jinnai K, Kanda F, Fukuoka Y, Kurisaki H, et al. Loss of catecholaminergic neurons in the medullary reticular formation in myotonic dystrophy. Neurology 1998;51:1121–1124. 26. Oyamada R, Hayashi M, Katoh Y, Tsuchiya K, Mizutani T, Tominaga I, et al. Neurofibrillary tangles and deposition of oxidative products in the brain in cases of myotonic dystrophy. Neuropathology 2006; 26:107–114.
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Transcranial Sonography in DM1
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MUSCLE & NERVE
August 2014
