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Jing Cai - One of the best experts on this subject based on the ideXlab platform.
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investigation of Sagittal Image acquisition for 4d mri with body area as respiratory surrogate
Medical Physics, 2014Co-Authors: Yilin Liu, F Yin, Z Chang, Brian G Czito, Manisha Palta, Mustafa R Bashir, Y Qin, Jing CaiAbstract:Purpose: The authors have recently developed a novel 4D-MRI technique for imaging organ respiratory motion employing cine acquisition in the axial plane and using body area (BA) as a respiratory surrogate. A potential disadvantage associated with axial Image acquisition is the space-dependent phase shift in the superior–inferior (SI) direction, i.e., different axial slice positions reach the respiratory peak at different respiratory phases. Since respiratory motion occurs mostly in the SI and anterior–posterior (AP) directions, Sagittal Image acquisition, which embeds motion information in these two directions, is expected to be more robust and less affected by phase-shift than axial Image acquisition. This study aims to develop and evaluate a 4D-MRI technique using Sagittal Image acquisition. Methods: The authors evaluated axial BA and Sagittal BA using both 4D-CT Images (11 cancer patients) and cine MR Images (6 healthy volunteers and 1 cancer patient) by comparing their corresponding space-dependent phase-shift in the SI direction ( δ SPS SI ) and in the lateral direction ( δ SPS LAT ) , respectively. To evaluate Sagittal BA 4D-MRI method, a motion phantom study and a digital phantom study were performed. Additionally, six patients who had cancer(s) in the liver were prospectively enrolled in this study. For each patient, multislice Sagittal MR Images were acquired for 4D-MRI reconstruction. 4D retrospective sorting was performed based on respiratory phases. Single-slice cine MRI was also acquired in the axial, coronal, and Sagittal planes across the tumor center from which tumor motion trajectories in the SI, AP, and medial–lateral (ML) directions were extracted and used as references from comparison. All MR Images were acquired in a 1.5 T scanner using a steady-state precession sequence (frame rate ∼ 3 frames/s). Results: 4D-CT scans showed that δ SPS SI was significantly greater than δ SPS LAT (p-value: 0.012); the median phase-shift was 16.9% and 7.7%, respectively. Body surface motion measurement from axial and Sagittal MR cines also showed δ SPS SI was significantly greater than δ SPS LAT . The median δ SPS SI and δ SPS LAT was 11.0% and 9.2% (p-value = 0.008), respectively. Tumor motion trajectories from 4D-MRI matched with those from single-slice cine MRI: the mean (±SD) absolute differences in tumor motion amplitude between the two were 1.5 ± 1.6 mm, 2.1 ± 1.9 mm, and 1.1 ± 1.0 mm in the SI, ML, and AP directions from this patient study. Conclusions: Space-dependent phase shift is less problematic for Sagittal acquisition than for axial acquisition. 4D-MRI using Sagittal acquisition was successfully carried out in patients with hepatic tumors.
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su d 218 02 4d mri based on body area ba surrogate and Sagittal Image acquisition
Medical Physics, 2012Co-Authors: Y Qin, F Yin, Z Chang, W P Segars, Jing CaiAbstract:Purpose: 4D‐MRI based on body area (BA) surrogate using axial Image acquisition has been demonstrated. Since respiratory motion mostly occurs in the superior‐inferior (SI) direction, it is expected that Sagittal acquisition may provide more robust and accurate breathing signal than axial acquisition. The aim of this study was to investigate the feasibility of extracting breathing signals from Sagittal Images using BA surrogate and its application in 4D‐MRI. Methods: 7 human subjects were Imaged continuously in a single (n=5) or multiple (n=2) Sagittal planes using a steady‐state precession sequence. Imaging parameters were: TR/TE, 3.7ms/1.21ms; Matrix, 256×166; FOV, 350×300mm; flip angle, 52°; slice thickness, 5mm; frame rate: ∼3 frames/s. Imaging time per slice is 2 minutes for single slice acquisition and ∼10 seconds for multi‐slice acquisition. Breathing signals were generated for all subjects by tracking the change of BA. The multi‐slice Sagittal acquisition was performed on a MRI‐ compatible motion phantom with a cylindrical gel target and was simulated on a 4D digital human phantom. Breathing signals were extracted from the Sagittal Images using the BA surrogate. Respiratory phases were calculated. 4D‐MRI of both phantoms were retrospectively reconstructed based on the respiratory phases. Results: Breathing signals extracted from both single slice and multi‐slice Sagittal acquisitions showed stable and well‐ characterized patterns. 4D‐MRI of the physical phantom showed clear sinusoidal motion of the gel target in all three planes with minimal artifacts. Simulated ‘4D‐MRI’ of the 4D digital phantom matched well with original Images: the mean absolute difference in motion amplitude of the ‘tumor’ was 0.4±0.3mm. Small artifacts of discontinuity were observed in the SI direction in certain phases. Conclusions: It is feasible to extract breathing signals from Sagittal Images for 4D‐MRI application. Further investigation is needed to test whether Sagittal acquisition is more robust and accurate than axial acquisition for breathing signal extraction.
Tarique Hussain - One of the best experts on this subject based on the ideXlab platform.
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aortic length measurements for pulse wave velocity calculation manual 2d vs automated 3d centreline extraction
Journal of Cardiovascular Magnetic Resonance, 2017Co-Authors: Arna Van Engelen, Miguel Silva Vieira, Isma Rafiq, Marina Cecelja, Hubrecht De Bliek, Alberto C Figueroa, Tarique Hussain, Torben SchneiderAbstract:Pulse wave velocity (PWV) is a biomarker for the intrinsic stiffness of the aortic wall, and has been shown to be predictive for cardiovascular events. It can be assessed using cardiovascular magnetic resonance (CMR) from the delay between phase-contrast flow waveforms at two or more locations in the aorta, and the distance on CMR Images between those locations. This study aimed to investigate the impact of different distance measurement methods on PWV. We present and evaluate an algorithm for automated centreline tracking in 3D Images, and compare PWV calculations using distances derived from 3D Images to those obtained from a conventional 2D oblique-Sagittal Image of the aorta. We included 35 patients from a twin cohort, and 20 post-coarctation repair patients. Phase-contrast flow was acquired in the ascending, descending and diaphragmatic aorta. A 3D centreline tracking algorithm is presented and evaluated on a subset of 30 subjects, on three CMR sequences: balanced steady-state free precession (SSFP), black-blood double inversion recovery turbo spin echo, and contrast-enhanced CMR angiography. Aortic lengths are subsequently compared between measurements from a 2D oblique-Sagittal plane, and a 3D geometry. The error in length of automated 3D centreline tracking compared with manual annotations ranged from 2.4 [1.8-4.3] mm (mean [IQR], black-blood) to 6.4 [4.7-8.9] mm (SSFP). The impact on PWV was below 0.5m/s (<5%). Differences between 2D and 3D centreline length were significant for the majority of our experiments (p < 0.05). Individual differences in PWV were larger than 0.5m/s in 15% of all cases (thoracic aorta) and 37% when studying the aortic arch only. Finally, the difference between end-diastolic and end-systolic 2D centreline lengths was statistically significant (p < 0.01), but resulted in small differences in PWV (0.08 [0.04 - 0.10]m/s). Automatic aortic centreline tracking in three commonly used CMR sequences is possible with good accuracy. The 3D length obtained from such sequences can differ considerably from lengths obtained from a 2D oblique-Sagittal plane, depending on aortic curvature, adequate planning of the oblique-Sagittal plane, and patient motion between acquisitions. For accurate PWV measurements we recommend using 3D centrelines.
Massachusetts General Hospital - One of the best experts on this subject based on the ideXlab platform.
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Progressive External Ophthalmoplegia
Spencer S. Eccles Health Sciences Library University of Utah, 1996Co-Authors: Shirley H. Wray, Professor Of Neurology Harvard Medical School, Unit For Neurovisual Disorders, Massachusetts General HospitalAbstract:Bilateral Ptosis; Facial Weakness; Complete External Ophthalmoplegia; Normal Pupils; Absent ConvergencePowerPoint Presentations: Progressive External Ophthalmoplegia: http://library.med.utah.edu/NOVEL/Wray/PPT/Progressive_External_Ophthalmoplegia.ppt Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical School Mitochondrial Myopathy: http://library.med.utah.edu/NOVEL/Wray/PPT/Mitochondrial_Myopathy_guest_lecture.ppt Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical SchoolDroopy eyelidsIn 1995 I published this case alongside eleven personal cases, three with the Kearns-Sayer Syndrome (KSS) and five with Progressive External Opthalmoplegia (PEO). Am J of Neuroradiol:16 (5);1167-1173. This patient with KSS is still alive in 2009. In 1968, at the age of 15 he presented with a history of childhood strabismus treated surgically and the insidious onset of slowly progressive asymmetrical ptosis right eye greater than left eye. In 1971 at age 18, he was referred to rule out myasthenia gravis prior to ptosis surgery. Neuro-ophthalmological examination: Visual acuity was 20/20 OU Pupils, visual fields and fundus examination normal. Ocular Motility : Bilateral ptosis, palpebral fissure 2 to 3 mm, eyebrows immobilized. Conjugate limitation of eye movements in all directions Absent Bell's (deviation upwards of the eyes under forced eye closure). Diagnosis: Progressive external ophthalmoplegia (PEO) In 1973 at age 20, he developed atypical retinitis pigmentosa. Fundus examination showed normal optic discs and a mottled salt and pepper pigmentary retinal disturbance was evident fairly uniform in all areas but without any typical bone corpuscles characteristic of retinitis pigmentosa. (Fundus photographs Figures 1-4) Lumbar Puncture: CSF normal apart from elevated CSF protein > 100 mg/dl. Skeletal Muscle Biopsy: The muscle biopsy showed ragged red fibers and a 3.8 kilobase mtDNA deletion. Diagnosis: Mitochondrial Myopathy. (Figures 5-8). Electrocardiogram: Showed incomplete right bundle branch block Chest X-ray: Cardiomegaly Audiometry: In 1974 at age 21, audiologic testing documented a sensory neural hearing loss Brain MRI at age 22 showed significant cortical and cerebellar atrophy. (Figures 9-11. Table 2 (14)) At age 24 he developed complete heart block and required a pacemaker. (Table 1). These findings completed the triad for the Kearns-Sayer Syndrome. Progress: Over the next 10 years, follow-up examinations revealed multisystem involvement known to occur in the KSS - - bilateral deafness - night blindness - dysphagia - cerebellar ataxia - all alongside marked neurasthenia and depression. In 2000 at age 47, a cricopharyngeal myotomy was performed to correct dysphagia due to pharyngeal dystrophy. In 2002 at age 49, he developed bilateral maculopathy and a granular and tigroid appearance of the fundus with impaired vision. By 2003 at age 50, he had the insidious onset of proximal muscle weakness in the legs and nasal speech. By this time, the fundi showed pallor of the optic discs and extensive retinal atrophy (Figure 4). The term Mitochondrial Cytopathy is used to emphasize multisystem involvement in KSS as in this case with: Progressive External Ophthalmoplegia Atypical Pigmentary Retinal Degeneration Heart Block and Cardiomegaly Deafness Pharyngeal Dystrophy Ataxia with Cerebellar Atrophy Proximal Myopathy High CSF protein Cognitive impairmentThis 43 year old man with KSS has advanced multisystem disease due to a large 8.6 mtDNA deletion. The muscle involvement is diagnostic. The myopathic signs are: • Bilateral ptosis with overaction of the frontalis muscle. • Weakness of the orbicularis oculi muscle with impaired eye closure. • A complete external ophthalmoplegia with gaze fixed in primary position and total absence of horizontal and vertical eye movements on command. • Absent eye movements on horizontal Doll's Head movement. • Weakness of the lower face impairing the ability to grip the lips tightly together • Marked weakness of flexion of the head against moderate resistance.Brain MRI in this case (patient 2) and in other cases with PEO show: Figure 9. A 61-year old woman (patient 1) with KSS, moderately severe truncal and appendicular ataxia, and a documented mtDNA deletion. A T1-weighted Sagittal Image demonstrates severe cerebellar vermian atrophy (arrow) Figure 10. A 23-year old man (patient 2) with KSS, cognitive impairment, ataxia and an mtDNA deletion. A. T2 weighted Image demonstrates regions of hyperintense signal (arrows) in the subcortical white matter. The periventricular regions were spared. B. T2-weighted Image shows foci of hyperintense signal (arrows) in the dorsal midbrain. Figure 11. A 37-year old woman (patient 8) with CPEO manifested by external ophthalmoplegia, ataxia, and sensorineural hearing loss. A. Long-repetition-time/short-echo-time (proton density) axial Image. In the frontal lobes, abnormal hyperintense signal predominates in the subcortical white matter (arrows), whereas in the posterior temporal and parietal lobes the abnormal signal extended from the subcortical regions to the ventricular surface (curved arrows). B. T2-weighted axial MR Image demonstrates bilateral hyperintense signal abnormalities in the globus pallidus (arrows). Hyperintense white matter abnormalities and ventricular dilatation are also present. C. T1-weighted Sagittal Image demonstrates cerebral cortical and cerebellar vermian atrophy (arrow) and thinning of the corpus callosum. Other PEO patients are reported to show predominantly white matter damage that correlated with spongiform degeneration of the brain verified by autopsy examinations.A skeletal muscle biopsy is diagnostic in mitochondrial myopathy due to a mtDNA deletion. In mitochondrial myopathy defective oxidative phosphorylation results in mitochondrial proliferation in Type 1 and 2A muscle fibers. Fibers with the most severe biochemical defects may degenerate and adjacent fibers with less severe or no defects may appear normal. (Figure 5-8) The combination of a patchy moth-eaten appearance in individual muscle fibers along with mitochondrial proliferation gives rise to the ragged-red fiber seen on modified Gomori trichrome staining (Figure 6). NADH staining shows abnormal subsarcolemmal mitochondria in the muscle fibers (Figure 7). The electron microscopic sections of skeletal muscle show abnormal mitochondria. (Figure 8).Mutations in mtDNA are maternally inherited in a graded fashion. A single mtDNA mutation can lead to dramatically different clinical phenotypes, creating a very large spectrum of expressivity. For example, the A3243G mutation associated with mitrochondrial encephalomyopathy, lactic academia, stroke-like episodes (MELAS) can also cause cardiomyopathy, diabetes and deafness, or external ophthalmoplegia. Deletions of mtDNA in skeletal muscle, ranging in size from 3.8 to 9.1 kilobases, were found in an identical location on muscle biopsy in five of eleven personal cases (3 KSS, 8 PEO). (Table 1). The deletion encompasses structural genes for the mitochondrial respiratory chain and is associated with impaired mitochondrial function. The variable involvement of multiple organs, (e.g. heart, brain and retina in PEO and KSS) may be attributable to a mixed population of mutant and normal genomes in varying amounts in different tissues. Both muscle and brain are also involved in patients with mitochondrial encephalomyopathy, namely, the MELAS syndrome which is characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; and MERRF, characterized by myoclonic epilepsy associated with ragged-red fibers. In MELAS, dysfunction of the central nervous system dominates the clinical picture. While there is considerable overlap of symptoms and signs between PEO, KSS, MELAS, and MERRF, there is general agreement that cases of mitochondrial myopathy, PEO and KSS, with or without clinical involvement of the brain, should be considered separately. The term mitochondrial encephalomyopathy or cytopathy has been applied to the multisystem diseases involving brain, skeletal muscle, and other organs. These disorders and the clinical phenotypes of mtDNA disease span the spectrum of all known oxidative phosphorylation disorders and include PEO., deafness, cardiomyopathy, MELAS and MERRF.Co-enzyme Q (ubiquinone) deficiency is present in KSS and treatment strategies for KSS are based on supplying electron transport chain cofactors and substraits, and antioxidants in an attempt to protect against mtDNA free-radical damage. Co-enzyme Q10 (ubiquinone) 4 mg-kg/day has the largest literature-supported efficacy in mitochondrial disease. This 43 year old patient has taken Co-enzyme Q10 for over 8 years.1. DiMauro S, Bonilla E. Zeviani M, Nakagawa M, DeVivo DC. Mitochondrial myopathies. Ann Neurol 1985; 17:521-538. http://www.ncbi.nlm.nih.gov/pubmed/3927817 2. Evans OB, Parker CC, Haas, RH, Naidu S, Moser HW, Bock, HGO. Clinical and Laboratory Features of Mitrochondrial Encephalomyopathy Syndromes. In Inborn Errors of Metabolism of the Nervous System. In Neurology in Clinical Practice, 3rd Ed. Vol II. Butterworth Henemann 2000;68:1595-1662. 3. Gallastegui J, Hariman RJ, Handler B, Lev M, Bharati S. Cardiac involvement in the Kearns-Sayre syndrome. Am J Cardiol 1987 Aug 1:60(4): 385-8. http://www.ncbi.nlm.nih.gov/pubmed/3618501 4. Holt IJ, Harding, AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988;331:717-719. http://www.ncbi.nlm.nih.gov/pubmed/2830540 5. Holt IJ, Harding AE, Cooper JM, Schapira AH, Toscano A, Clark JB, Morgan-Hughes JA. Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann Neurol. 1989 Dec;26(6):699-708. http://www.ncbi.nlm.nih.gov/pubmed/2604380 6. Kearns TP, Sayre GP, Retinitis pigmentosa, external ophthalmoplegia and complete heart block: unusual syndrome with histologic study in one of two cases. AMA Arch Ophthalmol. 1958 Aug:60(2):280-9. http://www.ncbi.nlm.nih.gov/pubmed/13558799 7. Kosmorsky G, Johns DR. Neuro-ophthalmologic manifestations of mitochondrial DNA disorders: chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and Leber's hereditary optic neuropathy. Neurol Clin. 1991 Feb;9(1):147-61. Review. http://www.ncbi.nlm.nih.gov/pubmed/2011107 8. Mitsumoto H, Aprille JR, Wray SH, Nemni R, Bradley WG. Progressive External Ophthalmoplegia (PEO): clinical, morphologic and biochemical studies. Neurology. 1983 Apr:33(4):452-61. http://www.ncbi.nlm.nih.gov/pubmed/6300733 9. Moraes CT, DiMauro S, Zevani M et al Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre Syndrome. N Eng J Med. 1989;320:1293-1299. http://www.ncbi.nlm.nih.gov/pubmed/2541333 10. Naviauz RK. Mitochondrial DNA Disorders. Eur J Pediatr. 2000;159 (Suppl 3):S219-226. Review. http://www.ncbi.nlm.nih.gov/pubmed/11216904 11. Van Goethem G, Martin JJ, Van Broeckhoven C. Progressive external ophthalmoplegia characterized by multiple deletions of mitochondrial DNA: unraveling the pathogenesis of human mitochondrial DNA instability and the initiation of a genetic classification. Neuromolecular Med. 2003;3(3):129-46. Review. http://www.ncbi.nlm.nih.gov/pubmed/12835509 12. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ II, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988; 242:1427-1430. http://www.ncbi.nlm.nih.gov/pubmed/3201231 13. Wallace DC Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science. 1992 May 1;256(5057):628-32. http://www.ncbi.nlm.nih.gov/pubmed/1533953 14. Wray SH, Provenzale JM, Johns DR, Thulborn KR. MR of the brain in mitochondrial myopathy. Am J Neuroradiol. 1995;16(5):1167-73. http://www.ncbi.nlm.nih.gov/pubmed/7639148 15. Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, Rowland LP. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 1988; 38:1339-1346. http://www.ncbi.nlm.nih.gov/pubmed/3412580VPchronicprogressiveexternalophthalmoplegi
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Progressive External Ophthalmoplegia
Spencer S. Eccles Health Sciences Library University of Utah, 1991Co-Authors: Shirley H. Wray, Professor Of Neurology Harvard Medical School, Unit For Neurovisual Disorders, Massachusetts General HospitalAbstract:Bilateral Ptosis; Facial Weakness; Complete External Ophthalmoplegia; Normal Pupils; Absent ConvergencePowerPoint Presentations: Progressive External Ophthalmoplegia: http://library.med.utah.edu/NOVEL/Wray/PPT/Progressive_External_Ophthalmoplegia.ppt Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical School Mitochondrial Myopathy: http://library.med.utah.edu/NOVEL/Wray/PPT/Mitochondrial_Myopathy_guest_lecture.ppt Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical SchoolDifficulty in moving her eyes. Droopy eyelidsThe patient is a retired physician, age 70, who recalls having eye muscle exercises as a child way back in 1924. Years later, she noted difficulty in focusing her eyes on horizontal gaze to the right and left which preceded the onset of bilateral ptosis. She presented in 1985, at age 65, with marked limitation of eye movements in all directions and she found that she needed to turn her head in order to look to either side. At this time she had ptosis of the left lid. By 1987, at age 66, external ophthalmoplegia had progressed and she had only a few degrees of eye movement in all directions. Progressive bilateral ptosis was treated by ptosis surgery at this time. Also at age 66 a cardiac evaluation revealed an incomplete right bundle branch block. At this time, a deltoid muscle biopsy showed ragged red fibers with trichrome stains. Diagnosis: Mitochondrial Myopathy. A sural nerve biopsy revealed a chronic axonal and demyelinating peripheral neuropathy. In 1991, at age 70, a repeat muscle biopsy confirmed the diagnosis of a mitochondrial myopathy with mtDNA deletions. Therapy: Co-enzyme Q10. In Nov. 1991, at age 70, she noted instability of her gait "walking as if drunk" with relentless progression over the next 10 months. The patient was lost to follow-up in 1991. The term mitochondrial cytopathy has been used to emphasize multisystem involvement in progressive external ophthalmoplegia (PEO). This patient had the constellation of: Progressive External Ophthalmoplegia Facial Weakness Right Bundle Branch Block Chronic Axonal and Demyelinating Peripheral Neuropathy AtaxiaThis 70 year old physician with Progressive External Ophthalmoplegia (PEO) has advanced multisystem disease due to a large mtDNA deletion. Muscle involvement is diagnostic. The myopathic signs illustrated are: 1. Partial bilateral ptosis post ptosis surgery 2. Weakness of the orbicularis oculi muscle with impaired eye closure and inability to bury her eyelashes fully 3. A complete external ophthalmoplegia with absent convergence. 4. Weakness of the lower face impairing the ability to grip the lips tightly together. 5. Marked weakness of flexion of the head against moderate resistance. 6. A history of instability of gait and ataxiaNeuroimaging studies were not done in this case. MR of the Brain in Mitochondrial Myopathy published in 1995 illustrates MR Images in KSS and PEO (14). The figures included: A 61-year old woman (patient 1) with KSS, moderately severe truncal and appendicular ataxia, and a documented mtDNA deletion. A. T1-weighted Sagittal Image demonstrates severe cerebellar vermian atrophy (arrow) A 23-year old man (patient 2) with KSS, cognitive impairment, ataxia and an mtDNA deletion. A. T2 weighted Image demonstrates regions of hyperintense signal (arrows) in the subcortical white matter. The periventricular regions were spared. B. T2-weighted Image shows foci of hyperintense signal (arrows) in the dorsal midbrain. A 37-year old woman (patient 8) with CPEO manifested by external ophthalmoplegia, ataxia, and sensorineural hearing loss. A. Long-repetition-time/short-echo-time (proton density) axial Image. In the frontal lobes, abnormal hyperintense signal predominates in the subcortical white matter (arrows), whereas in the posterior temporal and parietal lobes the abnormal signal extended from the subcortical regions to the ventricular surface (curved arrows). B. T2-weighted axial MR Image demonstrates bilateral hyperintense signal abnormalities in the globus pallidus (arrows). Hyperintense white matter abnormalities and ventricular dilatation are also present. C. T1-weighted Sagittal Image demonstrates cerebral cortical and cerebellar vermian atrophy (arrow) and thinning of the corpus callosum. Other PEO patients are reported show predominantly white matter damage that correlated with spongiform degeneration of the brain verified by autopsy examinations.A skeletal muscle biopsy is diagnostic in mitochondrial myopathy due to a mtDNA deletion. In mitochondrial myopathy defective oxidative phosphorylation results in mitochondrial proliferation in Type 1 and 2A muscle fibers. Fibers with the most severe biochemical defects may degenerate and adjacent fibers with less severe or no defects may appear normal. The combination of a patchy moth-eaten appearance in individual muscle fibers along with mitochondrial proliferation gives rise to the ragged-red fiber seen on modified Gomori trichrome staining. NADH staining shows abnormal subsarcolemmal mitochondria in the muscle fibers. The electron microscopic sections of skeletal muscle show abnormal mitochondria.Mutations in mtDNA are maternally inherited in a graded fashion. A single mtDNA mutation can lead to dramatically different clinical phenotypes, creating a very large spectrum of expressivity. For example, the A3243G mutation associated with mitrochondrial encephalomyopathy, lactic academia, stroke-like episodes (MELAS) can also cause cardiomyopathy, diabetes and deafness, or external ophthalmoplegia. Deletions of mtDNA in skeletal muscle, ranging in size from 3.8 to 9.1 kilobases, were found in an identical location on muscle biopsy in five of eleven personal cases (3 KSS, 8 PEO). The deletion encompasses structural genes for the mitochondrial respiratory chain and is associated with impaired mitochondrial function. The variable involvement of multiple organs, (e.g. heart, brain and retina in PEO and KSS) may be attributable to a mixed population of mutant and normal genomes in varying amounts in different tissues. Both muscle and brain are also involved in patients with mitochondrial encephalomyopathy, namely, the MELAS syndrome which is characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; and MERRF, characterized by myoclonic epilepsy associated with ragged-red fibers. In MELAS, dysfunction of the central nervous system dominates the clinical picture. While there is considerable overlap of symptoms and signs between PEO, KSS, MELAS, and MERRF, there is general agreement that cases of mitochondrial myopathy, PEO and KSS, with or without clinical involvement of the brain, should be considered separately. The term mitochondrial encephalomyopathy or cytopathy has been applied to the multisystem diseases involving brain, skeletal muscle, and other organs. These disorders and the clinical phenotypes of mtDNA disease span the spectrum of all known oxidative phosphorylation disorders and include PEO., deafness, cardiomyopathy, MELAS and MERRF.Co-enzyme Q (ubiquinone) deficiency is present in KSS and PEO and treatment strategies are based on supplying electron transport chain cofactors and substraits, and antioxidants in an attempt to protect against mtDNA free-radical damage. Co-enzyme Q10 (ubiquinone) 4 mg-kg/day has the largest literature-supported efficacy in mitochondrial disease.1) DiMauro S, Bonilla E. Zeviani M, Nakagawa M, DeVivo DC. Mitochondrial myopathies. Ann Neurol 1985; 17:521-538. 2) Evans OB, Parker CC, Haas, RH, Naidu S, Moser HW, Bock, HGO. Clinical and Laboratory Features of Mitrochondrial Encephalomyopathy Syndromes. In Inborn Errors of Metabolism of the Nervous System. In Neurology in Clinical Practice, 3rd Ed. Vol II. Butterworth Henemann 2000;68:1595-1662. 3) Gallastegui J, Hariman RJ, Handler B, Lev M, Bharati S. Cardiac involvement in the Kearns-Sayre syndrome. Am J Cardiol 1987 Aug 1:60(4): 385-8. http://www.ncbi.nlm.nih.gov/pubmed/3618501 4) Holt IJ, Harding, AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988;331:717-719. http://www.ncbi.nlm.nih.gov/pubmed/2830540 5) Holt IJ, Harding AE, Cooper JM, Schapira AH, Toscano A, Clark JB, Morgan-Hughes JA. Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann Neurol. 1989 Dec;26(6):699-708. http://www.ncbi.nlm.nih.gov/pubmed/2604380 6) Kearns TP, Sayre GP, Retinitis pigmentosa, external ophthalmoplegia and complete heart block: unusual syndrome with histologic study in one of two cases. AMA Arch Ophthalmol. 1958 Aug:60(2):280-9. http://www.ncbi.nlm.nih.gov/pubmed/13558799 7) Kosmorsky G, Johns DR. Neuro-ophthalmologic manifestations of mitochondrial DNA disorders: chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and Leber's hereditary optic neuropathy. Neurol Clin. 1991 Feb;9(1):147-61. Review. http://www.ncbi.nlm.nih.gov/pubmed/2011107 8) Mitsumoto H, Aprille JR, Wray SH, Nemni R, Bradley WG. Progressive External Ophthalmoplegia (PEO): clinical, morphologic and biochemical studies. Neurology. 1983 Apr:33(4):452-61. http://www.ncbi.nlm.nih.gov/pubmed/6300733 9) Moraes CT, DiMauro S, Zevani M et al Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre Syndrome. N Eng J Med. 1989;320:1293-1299. http://www.ncbi.nlm.nih.gov/pubmed/2541333 10) Naviauz RK. Mitochondrial DNA Disorders. Eur J Pediatr. 2000;159 (Suppl 3):S219-226. Review. http://www.ncbi.nlm.nih.gov/pubmed/11216904 11) Van Goethem G, Martin JJ, Van Broeckhoven C. Progressive external ophthalmoplegia characterized by multiple deletions of mitochondrial DNA: unraveling the pathogenesis of human mitochondrial DNA instability and the initiation of a genetic classification. Neuromolecular Med. 2003;3(3):129-46. Review. http://www.ncbi.nlm.nih.gov/pubmed/12835509 12) Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ II, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988; 242:1427-1430. http://www.ncbi.nlm.nih.gov/pubmed/3201231 13) Wallace DC Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science. 1992 May 1;256(5057):628-32. http://www.ncbi.nlm.nih.gov/pubmed/1533953 14) Wray SH, Provenzale JM, Johns DR, Thulborn KR. MR of the brain in mitochondrial myopathy. AJNR Am J Neuroradiol. 1995 May;16(5):1167-73. http://www.ncbi.nlm.nih.gov/pubmed/7639148 15) Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, Rowland LP. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 1988; 38:1339-1346. http://www.ncbi.nlm.nih.gov/pubmed/3412580VPchronicprogressiveexternalophthalmoplegi
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Progressive External Ophthalmoplegia
Spencer S. Eccles Health Sciences Library University of Utah, 1991Co-Authors: Shirley H. Wray, Professor Of Neurology Harvard Medical School, Unit For Neurovisual Disorders, Massachusetts General HospitalAbstract:Unilateral Ptosis; Impairment of Lid Closure - Unable to Bury Eyelashes Fully; External Ophthalmoplegia Affecting Upgaze; Normal PupilsPowerPoint Presentations: Progressive External Ophthalmoplegia: http://library.med.utah.edu/NOVEL/Wray/PPT/Progressive_External_Ophthalmoplegia.ppt Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical School Mitochondrial Myopathy: http://library.med.utah.edu/NOVEL/Wray/PPT/Mitochondrial_Myopathy_guest_lecture.ppt Shirley H. Wray, M.D., Ph.D., FRCP Harvard Medical SchoolDroopy eyelids. Lack of energyThis 48 year old woman, who was first seen by a neurologist in March 1989, with a 7 year history of progressive unilateral ptosis, mild facial weakness and generalized fatigue. On examination she had ptosis of the right eye and bilateral limitation of upward gaze. Myasthenia Gravis was ruled out by a negative Tensilon test, negative anti-acetylcholine receptor antibodies, and normal single fiber electromyography of the frontalis muscle. A trial on Mestinon 60 mg t.i.d. provided no improvement. At age 45, progression of external ophthalmoplegia led to impaired eye movements in all directions of gaze. At age 46, a muscle biopsy showed ragged red fibers and a mitochondrial DNA deletion. Family History: A muscle biopsy in her mother and in her daughter were normal. In 1991, at age 47, further progression in her weakness, external ophthalmoplegia and ptosis was noted and at this time she developed late onset diabetes and depression. Her cardiac status remained normal, her visual acuity was 20/20 and a fundus exam showed no abnormality. In 1992, at age 48, a brain MRI showed no abnormality. In 1993, at age 49, she had ptosis surgery of the right eye and she was started on Co-enzyme Q10 200 mg b.i.d. increasing to t.i.d. By 1997, at age 53, she was confined to a wheelchair because of extreme fatigue on exertion. In 1999, at age 55, she moved into a retirement home in Maine and was lost to follow-up. The term Mitochondrial Cytopathy has been used to emphasize multisystem involvement in progressive external ophthalmoplegia (PEO). This patient had the constellation of: Progressive External Ophthalmoplegia Facial Weakness Late Onset Diabetes Depression Extreme Fatigue on ExertionThis 48 year old woman, with progressive external ophthalmoplegia (PEO), due to a mitochondrial DNA deletion, is unusual in her presentation. Instead of the typical bilateral ptosis, she presented with unilateral ptosis of the right eye. The myopathic signs illustrated are: 1. Unilateral ptosis of the right eye with overaction of the right frontalis muscle. 2. Weakness of the orbicularis oculi muscle with bilateral impaired eye closure and inability to bury the eyelashes fully. 3. A partial external ophthalmoplegia affecting primarily conjugate upgaze. Horizontal and vertical downgaze eye movements are of normal velocity and are full. 4. Weakness of the lower face impairing the ability to grip the lips tightly together and 5. Impairing her ability to whistle. 6. Weakness of flexion of the head against moderate resistance. Patient also has: 1. Profound exertional fatigue. It was this disabling symptom that resulted in her being confined to a wheelchair.Neuroimaging studies were not done in this case. MR of the Brain in Mitochondrial Myopathy published in 1995 illustrates MR Images in KSS and PEO (14). The figures included: A 61-year old woman (patient 1) with KSS, moderately severe truncal and appendicular ataxia, and a documented mtDNA deletion. A. T1-weighted Sagittal Image demonstrates severe cerebellar vermian atrophy (arrow) A 23-year old man (patient 2) with KSS, cognitive impairment, ataxia and an mtDNA deletion. A. T2 weighted Image demonstrates regions of hyperintense signal (arrows) in the subcortical white matter. The periventricular regions were spared. B. T2-weighted Image shows foci of hyperintense signal (arrows) in the dorsal midbrain. A 37-year old woman (patient 8) with CPEO manifested by external ophthalmoplegia, ataxia, and sensorineural hearing loss. A. Long-repetition-time/short-echo-time (proton density) axial Image. In the frontal lobes, abnormal hyperintense signal predominates in the subcortical white matter (arrows), whereas in the posterior temporal and parietal lobes the abnormal signal extended from the subcortical regions to the ventricular surface (curved arrows). B. T2-weighted axial MR Image demonstrates bilateral hyperintense signal abnormalities in the globus pallidus (arrows). Hyperintense white matter abnormalities and ventricular dilatation are also present. C. T1-weighted Sagittal Image demonstrates cerebral cortical and cerebellar vermian atrophy (arrow) and thinning of the corpus callosum. Other PEO patients are reported show predominantly white matter damage that correlated with spongiform degeneration of the brain verified by autopsy examinations.A skeletal muscle biopsy is diagnostic in mitochondrial myopathy due to a mtDNA deletion. In mitochondrial myopathy defective oxidative phosphorylation results in mitochondrial proliferation in Type 1 and 2A muscle fibers. Fibers with the most severe biochemical defects may degenerate and adjacent fibers with less severe or no defects may appear normal. The combination of a patchy moth-eaten appearance in individual muscle fibers along with mitochondrial proliferation gives rise to the ragged-red fiber seen on modified Gomori trichrome staining. NADH staining shows abnormal subsarcolemmal mitochondria in the muscle fibers. The electron microscopic sections of skeletal muscle show abnormal mitochondria.Mutations in mtDNA are maternally inherited in a graded fashion. A single mtDNA mutation can lead to dramatically different clinical phenotypes, creating a very large spectrum of expressivity. For example, the A3243G mutation associated with mitrochondrial encephalomyopathy, lactic academia, stroke-like episodes (MELAS) can also cause cardiomyopathy, diabetes and deafness, or external ophthalmoplegia. Deletions of mtDNA in skeletal muscle, ranging in size from 3.8 to 9.1 kilobases, were found in an identical location on muscle biopsy in five of eleven personal cases (3 KSS, 8 PEO). The deletion encompasses structural genes for the mitochondrial respiratory chain and is associated with impaired mitochondrial function. The variable involvement of multiple organs, (e.g. heart, brain and retina in PEO and KSS) may be attributable to a mixed population of mutant and normal genomes in varying amounts in different tissues. Both muscle and brain are also involved in patients with mitochondrial encephalomyopathy, namely, the MELAS syndrome which is characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; and MERRF, characterized by myoclonic epilepsy associated with ragged-red fibers. In MELAS, dysfunction of the central nervous system dominates the clinical picture. While there is considerable overlap of symptoms and signs between PEO, KSS, MELAS, and MERRF, there is general agreement that cases of mitochondrial myopathy, PEO and KSS, with or without clinical involvement of the brain, should be considered separately. The term mitochondrial encephalomyopathy or cytopathy has been applied to the multisystem diseases involving brain, skeletal muscle, and other organs. These disorders and the clinical phenotypes of mtDNA disease span the spectrum of all known oxidative phosphorylation disorders and include PEO., deafness, cardiomyopathy, MELAS and MERRF.Co-enzyme Q (ubiquinone) deficiency is present in KSS and PEO and treatment strategies are based on supplying electron transport chain cofactors and substraits, and antioxidants in an attempt to protect against mtDNA free-radical damage. Co-enzyme Q10 (ubiquinone) 4 mg-kg/day has the largest literature-supported efficacy in mitochondrial disease.1. DiMauro S, Bonilla E. Zeviani M, Nakagawa M, DeVivo DC. Mitochondrial myopathies. Ann Neurol 1985; 17:521-538. http://www.ncbi.nlm.nih.gov/pubmed/3927817 2. Evans OB, Parker CC, Haas, RH, Naidu S, Moser HW, Bock, HGO. Clinical and Laboratory Features of Mitrochondrial Encephalomyopathy Syndromes. In Inborn Errors of Metabolism of the Nervous System. In Neurology in Clinical Practice, 3rd Ed. Vol II. Butterworth Henemann 2000;68:1595-1662. 3. Gallastegui J, Hariman RJ, Handler B, Lev M, Bharati S. Cardiac involvement in the Kearns-Sayre syndrome. Am J Cardiol 1987 Aug 1:60(4): 385-8. http://www.ncbi.nlm.nih.gov/pubmed/3618501 4. Holt IJ, Harding, AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988;331:717-719. http://www.ncbi.nlm.nih.gov/pubmed/2830540 5. Holt IJ, Harding AE, Cooper JM, Schapira AH, Toscano A, Clark JB, Morgan-Hughes JA. Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann Neurol. 1989 Dec;26(6):699-708. http://www.ncbi.nlm.nih.gov/pubmed/2604380 6. Kearns TP, Sayre GP, Retinitis pigmentosa, external ophthalmoplegia and complete heart block: unusual syndrome with histologic study in one of two cases. AMA Arch Ophthalmol. 1958 Aug:60(2):280-9. http://www.ncbi.nlm.nih.gov/pubmed/13558799 7. Kosmorsky G, Johns DR. Neuro-ophthalmologic manifestations of mitochondrial DNA disorders: chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and Leber's hereditary optic neuropathy. Neurol Clin. 1991 Feb;9(1):147-61. Review. http://www.ncbi.nlm.nih.gov/pubmed/2011107 8. Mitsumoto H, Aprille JR, Wray SH, Nemni R, Bradley WG. Progressive External Ophthalmoplegia (PEO): clinical, morphologic and biochemical studies. Neurology. 1983 Apr:33(4):452-61. http://www.ncbi.nlm.nih.gov/pubmed/6300733 9. Moraes CT, DiMauro S, Zevani M et al Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre Syndrome. N Eng J Med. 1989;320:1293-1299. http://www.ncbi.nlm.nih.gov/pubmed/2541333 10. Naviauz RK. Mitochondrial DNA Disorders. Eur J Pediatr. 2000;159 (Suppl 3):S219-226. Review. http://www.ncbi.nlm.nih.gov/pubmed/11216904 11. Van Goethem G, Martin JJ, Van Broeckhoven C. Progressive external ophthalmoplegia characterized by multiple deletions of mitochondrial DNA: unraveling the pathogenesis of human mitochondrial DNA instability and the initiation of a genetic classification. Neuromolecular Med. 2003;3(3):129-46. Review. http://www.ncbi.nlm.nih.gov/pubmed/12835509 12. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ II, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988; 242:1427-1430. http://www.ncbi.nlm.nih.gov/pubmed/3201231 13. Wallace DC. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science. 1992 May 1;256(5057):628-32. http://www.ncbi.nlm.nih.gov/pubmed/1533953 14. Wray SH, Provenzale JM, Johns DR, Thulborn KR. MR of the brain in mitochondrial myopathy. AJNR Am J Neuroradiol. 1995 May;16(5):1167-73. http://www.ncbi.nlm.nih.gov/pubmed/7639148 15. Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, Rowland LP. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 1988; 38:1339-1346. http://www.ncbi.nlm.nih.gov/pubmed/3412580curriculum_fellow; GVSkearnssayr
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Progressive External Ophthalmoplegia
Spencer S. Eccles Health Sciences Library University of Utah, 1991Co-Authors: Shirley H. Wray, Professor Of Neurology Harvard Medical School, Unit For Neurovisual Disorders, Massachusetts General HospitalAbstract:Bilateral Ptosis; Facial Weakness; Complete External Ophthalmoplegia; Adie's Pupil; Absent ConvergencePowerPoint Presentations: Progressive External Ophthalmoplegia: http://library.med.utah.edu/NOVEL/Wray/PPT/Progressive_External_Ophthalmoplegia.ppt Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical School Mitochondrial Myopathy: http://library.med.utah.edu/NOVEL/Wray/PPT/Mitochondrial_Myopathy_guest_lecture.ppt Shirley H. Wray, M.D., Ph.D., FRCP, Harvard Medical SchoolDroopy eyelidsIn 1995 I published this case alongside eleven personal cases, three with the Kearns-Sayer Syndrome (KSS) and five with Progressive External Opthalmoplegia (PEO). Am J of Neuroradiol:16 (5);1167-1173. The patient was under the care of Dr. Raymond Adams from age 13 years. In 1991, at age 40 years, I was asked to see her and follow her with him. She presented at age 9 with bilateral ptosis and 5 months later external ophthalmoplegia which progressed to almost complete fixation of all eye movements. Diagnosis: Progressive external ophthalmoplegia (PEO) In 7th grade, she developed hearing loss and ultimately became totally deaf. In 1972, at age 21, a fundus examination showed a mottled pigment disturbance in the macula area of both eyes. Diagnosis: Atypical retinitis pigmentosa. (Figure 1) At age 29, she started to use ptosis crutches on her glasses to keep her eyes open. (Figures 2 and 3) At age 33, she developed a peripheral sensory neuropathy, elevated CSF protein > 100 mg/dl, and an Adie's myotonic pupil in the right eye which has congenital heterochromia. (Figure 4) Electromyographic studies confirmed at this time a proximal myopathy with mild weakness in the proximal muscles of her legs. At age 38, she noted increasing difficulty with her balance and coordination and the onset of dysphagia due to pharyngeal dystrophy. At age 39, a muscle biopsy showed on modified Gomori trichrome staining, ragged-red fibers and a large 9.1kb mtDNA deletion was identified. Diagnosis: Mitochondrial Myopathy The patient was started on a trial of Folate and Co-Enzyme Q10. Brain MRI at age 61,showed moderate cerebellar atrophy and slight dilatation of the third ventricle. In 1995 she entered a home for assisted living and was lost to follow-up. Her cardiac status, which was frequently evaluated, remained normal. The term Mitochondrial Cytopathy has been used to emphasize multisystem involvement in KSS. This patient illustrates this, with: Progressive External Ophthalmoplegia Atypical Retinitis Pigmentosa Deafness Peripheral Sensory Neuropathy Adie's Myotonic Pupil Proximal Myopathy Pharyngeal Dystrophy Ataxia/Cerebellar AtrophyThis 60 year old deaf woman has advanced multisystem disorder due to a mitochondrial DNA deletion. The myopathic signs are: 1. Bilateral ptosis with overaction of the frontalis muscle. 2. Weakness of the orbicularis oculi muscle with impaired eye closure. 3. A complete external ophthalmoplegia with gaze fixed in primary position and total absence of horizontal and vertical eye movements on command. 4. Weakness of the lower face impairing the ability to grip the lips tightly together and 5. Marked weakness of flexion of the head against moderate resistance. The cerebellum is also affected causing 1. Unsteadiness of gait and 2. Impaired accuracy and incoordination (ataxia) on finger to nose testing.Neuroimaging studies were not done in this case. MR of the Brain in Mitochondrial Myopathy published in 1995 illustrates MR Images in KSS and PEO (14). The figures included: A 61-year old woman (patient 1) with KSS, moderately severe truncal and appendicular ataxia, and a documented mtDNA deletion. A. T1-weighted Sagittal Image demonstrates severe cerebellar vermian atrophy (arrow) A 23-year old man (patient 2) with KSS, cognitive impairment, ataxia and an mtDNA deletion. A. T2 weighted Image demonstrates regions of hyperintense signal (arrows) in the subcortical white matter. The periventricular regions were spared. B. T2-weighted Image shows foci of hyperintense signal (arrows) in the dorsal midbrain. A 37-year old woman (patient 8) with CPEO manifested by external ophthalmoplegia, ataxia, and sensorineural hearing loss. A. Long-repetition-time/short-echo-time (proton density) axial Image. In the frontal lobes, abnormal hyperintense signal predominates in the subcortical white matter (arrows), whereas in the posterior temporal and parietal lobes the abnormal signal extended from the subcortical regions to the ventricular surface (curved arrows). B. T2-weighted axial MR Image demonstrates bilateral hyperintense signal abnormalities in the globus pallidus (arrows). Hyperintense white matter abnormalities and ventricular dilatation are also present. C. T1-weighted Sagittal Image demonstrates cerebral cortical and cerebellar vermian atrophy (arrow) and thinning of the corpus callosum. Other PEO patients are reported show predominantly white matter damage that correlated with spongiform degeneration of the brain verified by autopsy examinations.A skeletal muscle biopsy confirms the diagnosis of Mitochondrial Myopathy due to a mtDNA deletion. In mitochondrial myopathy defective oxidative phosphorylation results in mitochondrial proliferation in Type 1 and 2A muscle fibers. Fibers with the most severe biochemical defects may degenerate and adjacent fibers with less severe or no defects may appear normal. The combination of a patchy moth-eaten appearance in individual muscle fibers along with mitochondrial proliferation gives rise to the ragged-red fiber seen on modified Gomori trichrome staining. NADH staining shows abnormal subsarcolemmal mitochondria in the muscle fibers. The electron microscopic sections of skeletal muscle show abnormal mitochondria.Mutations in mtDNA are maternally inherited in a graded fashion. A single mtDNA mutation can lead to dramatically different clinical phenotypes, creating a very large spectrum of expressivity. For example, the A3243G mutation associated with mitrochondrial encephalomyopathy, lactic academia, stroke-like episodes (MELAS) can also cause cardiomyopathy, diabetes and deafness, or external ophthalmoplegia. Deletions of mtDNA in skeletal muscle, ranging in size from 3.8 to 9.1 kilobases, were found in an identical location on muscle biopsy in five of eleven personal cases (3 KSS, 8 PEO). The deletion encompasses structural genes for the mitochondrial respiratory chain and is associated with impaired mitochondrial function. The variable involvement of multiple organs, (e.g. heart, brain and retina in PEO and KSS) may be attributable to a mixed population of mutant and normal genomes in varying amounts in different tissues. Both muscle and brain are also involved in patients with mitochondrial encephalomyopathy, namely, the MELAS syndrome which is characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; and MERRF, characterized by myoclonus epilepsy associated with ragged-red fibers. In MELAS, dysfunction of the central nervous system dominates the clinical picture. While there is considerable overlap of symptoms and signs between PEO, KSS, MELAS, and MERRF, there is general agreement that cases of mitochondrial myopathy, PEO and KSS, with or without clinical involvement of the brain, should be considered separately. The term mitochondrial encephalomyopathy or cytopathy has been applied to the multisystem diseases involving brain, skeletal muscle, and other organs. These disorders and the clinical phenotypes of mtDNA disease span the spectrum of all known oxidative phosphorylation disorders and include PEO, deafness, cardiomyopathy, MELAS and MERRF.Co-enzyme Q (ubiquinone) deficiency is present in KSS and treatment strategies for KSS are based on supplying electron transport chain cofactors and substraits, and antioxidants in an attempt to protect against mtDNA free-radical damage. Co-enzyme Q10 (ubiquinone) 4 mg-kg/day has the largest literature-supported efficacy in mitochondrial disease.1) DiMauro S, Bonilla E. Zeviani M, Nakagawa M, DeVivo DC. Mitochondrial myopathies. Ann Neurol 1985; 17:521-538. http://www.ncbi.nlm.nih.gov/pubmed/3927817 2) Evans OB, Parker CC, Haas, RH, Naidu S, Moser HW, Bock, HGO. Clinical and Laboratory Features of Mitrochondrial Encephalomyopathy Syndromes. In Inborn Errors of Metabolism of the Nervous System. In Neurology in Clinical Practice, 3rd Ed. Vol II. Butterworth Henemann 2000;68:1595-1662. 3) Gallastegui J, Hariman RJ, Handler B, Lev M, Bharati S. Cardiac involvement in the Kearns-Sayre syndrome. Am J Cardiol 1987 Aug 1:60(4): 385-8. http://www.ncbi.nlm.nih.gov/pubmed/3618501 4) Holt IJ, Harding, AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988;331:717-719. http://www.ncbi.nlm.nih.gov/pubmed/2830540 5) Holt IJ, Harding AE, Cooper JM, Schapira AH, Toscano A, Clark JB, Morgan-Hughes JA. Mitochondrial myopathies: clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA. Ann Neurol. 1989 Dec;26(6):699-708. http://www.ncbi.nlm.nih.gov/pubmed/2604380 6) Kearns TP, Sayre GP, Retinitis pigmentosa, external ophthalmoplegia and complete heart block: unusual syndrome with histologic study in one of two cases. AMA Arch Ophthalmol. 1958 Aug:60(2):280-9. http://www.ncbi.nlm.nih.gov/pubmed/13558799 7) Kosmorsky G, Johns DR. Neuro-ophthalmologic manifestations of mitochondrial DNA disorders: chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and Leber's hereditary optic neuropathy. Neurol Clin. 1991 Feb;9(1):147-61. Review. http://www.ncbi.nlm.nih.gov/pubmed/2011107 8) Mitsumoto H, Aprille JR, Wray SH, Nemni R, Bradley WG. Progressive External Ophthalmoplegia (PEO): clinical, morphologic and biochemical studies. Neurology. 1983 Apr:33(4):452-61. http://www.ncbi.nlm.nih.gov/pubmed/6300733 9) Moraes CT, DiMauro S, Zevani M et al Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre Syndrome. N Eng J Med. 1989;320:1293-1299. http://www.ncbi.nlm.nih.gov/pubmed/2541333 10) Naviauz RK. Mitochondrial DNA Disorders. Eur J Pediatr. 2000;159 (Suppl 3):S219-226. Review. http://www.ncbi.nlm.nih.gov/pubmed/11216904 11) Van Goethem G, Martin JJ, Van Broeckhoven C. Progressive external ophthalmoplegia characterized by multiple deletions of mitochondrial DNA: unraveling the pathogenesis of human mitochondrial DNA instability and the initiation of a genetic classification. Neuromolecular Med. 2003;3(3):129-46. Review. http://www.ncbi.nlm.nih.gov/pubmed/12835509 12) Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ II, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988; 242:1427-1430. http://www.ncbi.nlm.nih.gov/pubmed/3201231 13) Wallace DC Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science. 1992 May 1;256(5057):628-32. http://www.ncbi.nlm.nih.gov/pubmed/1533953 14) Wray SH, Provenzale JM, Johns DR, Thulborn KR. MR of the brain in mitochondrial myopathy. Am J Neuroradiol. 1995 May;16(5):1167-73. http://www.ncbi.nlm.nih.gov/pubmed/7639148 15) Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, Rowland LP. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology 1988; 38:1339-1346. http://www.ncbi.nlm.nih.gov/pubmed/3412580curriculum_fellow; VPchronicprogressiveexternalophthalmoplegia; KBDfacialweaknes
Y Qin - One of the best experts on this subject based on the ideXlab platform.
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investigation of Sagittal Image acquisition for 4d mri with body area as respiratory surrogate
Medical Physics, 2014Co-Authors: Yilin Liu, F Yin, Z Chang, Brian G Czito, Manisha Palta, Mustafa R Bashir, Y Qin, Jing CaiAbstract:Purpose: The authors have recently developed a novel 4D-MRI technique for imaging organ respiratory motion employing cine acquisition in the axial plane and using body area (BA) as a respiratory surrogate. A potential disadvantage associated with axial Image acquisition is the space-dependent phase shift in the superior–inferior (SI) direction, i.e., different axial slice positions reach the respiratory peak at different respiratory phases. Since respiratory motion occurs mostly in the SI and anterior–posterior (AP) directions, Sagittal Image acquisition, which embeds motion information in these two directions, is expected to be more robust and less affected by phase-shift than axial Image acquisition. This study aims to develop and evaluate a 4D-MRI technique using Sagittal Image acquisition. Methods: The authors evaluated axial BA and Sagittal BA using both 4D-CT Images (11 cancer patients) and cine MR Images (6 healthy volunteers and 1 cancer patient) by comparing their corresponding space-dependent phase-shift in the SI direction ( δ SPS SI ) and in the lateral direction ( δ SPS LAT ) , respectively. To evaluate Sagittal BA 4D-MRI method, a motion phantom study and a digital phantom study were performed. Additionally, six patients who had cancer(s) in the liver were prospectively enrolled in this study. For each patient, multislice Sagittal MR Images were acquired for 4D-MRI reconstruction. 4D retrospective sorting was performed based on respiratory phases. Single-slice cine MRI was also acquired in the axial, coronal, and Sagittal planes across the tumor center from which tumor motion trajectories in the SI, AP, and medial–lateral (ML) directions were extracted and used as references from comparison. All MR Images were acquired in a 1.5 T scanner using a steady-state precession sequence (frame rate ∼ 3 frames/s). Results: 4D-CT scans showed that δ SPS SI was significantly greater than δ SPS LAT (p-value: 0.012); the median phase-shift was 16.9% and 7.7%, respectively. Body surface motion measurement from axial and Sagittal MR cines also showed δ SPS SI was significantly greater than δ SPS LAT . The median δ SPS SI and δ SPS LAT was 11.0% and 9.2% (p-value = 0.008), respectively. Tumor motion trajectories from 4D-MRI matched with those from single-slice cine MRI: the mean (±SD) absolute differences in tumor motion amplitude between the two were 1.5 ± 1.6 mm, 2.1 ± 1.9 mm, and 1.1 ± 1.0 mm in the SI, ML, and AP directions from this patient study. Conclusions: Space-dependent phase shift is less problematic for Sagittal acquisition than for axial acquisition. 4D-MRI using Sagittal acquisition was successfully carried out in patients with hepatic tumors.
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su d 218 02 4d mri based on body area ba surrogate and Sagittal Image acquisition
Medical Physics, 2012Co-Authors: Y Qin, F Yin, Z Chang, W P Segars, Jing CaiAbstract:Purpose: 4D‐MRI based on body area (BA) surrogate using axial Image acquisition has been demonstrated. Since respiratory motion mostly occurs in the superior‐inferior (SI) direction, it is expected that Sagittal acquisition may provide more robust and accurate breathing signal than axial acquisition. The aim of this study was to investigate the feasibility of extracting breathing signals from Sagittal Images using BA surrogate and its application in 4D‐MRI. Methods: 7 human subjects were Imaged continuously in a single (n=5) or multiple (n=2) Sagittal planes using a steady‐state precession sequence. Imaging parameters were: TR/TE, 3.7ms/1.21ms; Matrix, 256×166; FOV, 350×300mm; flip angle, 52°; slice thickness, 5mm; frame rate: ∼3 frames/s. Imaging time per slice is 2 minutes for single slice acquisition and ∼10 seconds for multi‐slice acquisition. Breathing signals were generated for all subjects by tracking the change of BA. The multi‐slice Sagittal acquisition was performed on a MRI‐ compatible motion phantom with a cylindrical gel target and was simulated on a 4D digital human phantom. Breathing signals were extracted from the Sagittal Images using the BA surrogate. Respiratory phases were calculated. 4D‐MRI of both phantoms were retrospectively reconstructed based on the respiratory phases. Results: Breathing signals extracted from both single slice and multi‐slice Sagittal acquisitions showed stable and well‐ characterized patterns. 4D‐MRI of the physical phantom showed clear sinusoidal motion of the gel target in all three planes with minimal artifacts. Simulated ‘4D‐MRI’ of the 4D digital phantom matched well with original Images: the mean absolute difference in motion amplitude of the ‘tumor’ was 0.4±0.3mm. Small artifacts of discontinuity were observed in the SI direction in certain phases. Conclusions: It is feasible to extract breathing signals from Sagittal Images for 4D‐MRI application. Further investigation is needed to test whether Sagittal acquisition is more robust and accurate than axial acquisition for breathing signal extraction.
Chunwu Zhou - One of the best experts on this subject based on the ideXlab platform.
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F47, poorly differentiated squamous cell carcinoma of the cervix (stage II A2) invades the vaginal fornix and cervical canal mucosa.
2015Co-Authors: Meng Lin, Han Ouyang, Yan Chen, Chunwu ZhouAbstract:Directly acquired contrast-enhanced Sagittal Image (A) shows a tumor in the anterior cervical lip with relative lower signal compared with the surrounding cervical stroma. Oblique Sagittal Image (B) and coronal CPR Image (C), which were both reconstructed by the Isotropy, show more clearly that the lesion has spread to the cervical canal and vaginal fornix (arrow).
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F55, poorly differentiated squamous cell carcinoma (stage IIA1).
2015Co-Authors: Meng Lin, Han Ouyang, Yan Chen, Chunwu ZhouAbstract:Directly acquired contrast-enhanced Sagittal Image (A) shows a tumor in the posterior cervical lip invading the vaginal fornix (arrow), with relative lower signal compared with the surrounding cervical stroma. Directly acquired contrast-enhanced coronal Image (B) fails to show the entire uterus and the relationship between the lesion and vagina due to uterine anteversion. CPR from isotropic sequence (C) reconstructs the uterine and vaginal lesions in the same slice so that the relationship between the lesion and the vagina is more clearly displayed (arrow).
