European Journal of Radiology 83 (2014) 212–218
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Measurement of the apparent diffusion coefficient in paediatric mitochondrial encephalopathy cases and a comparison of parenchymal changes associated with the disease using follow-up diffusion coefficient measurements夽 Fatma Uysal a,∗ , Handan C¸akmakc¸ı a,1 , Uluc¸ Yis¸ b,1 , Hülya Ellidokuz c,1 , Ays¸e Semra Hız b,1 a
Dokuz Eylül University, Department of Pediatric Radiology, Izmir, Turkey Dokuz Eylül University, Department of Pediatric Neurology, Izmir, Turkey c Dokuz Eylül University, Department of Medical Statistics, Izmir, Turkey b
a r t i c l e
i n f o
Article history: Received 10 January 2013 Received in revised form 17 June 2013 Accepted 18 June 2013 Keywords: Magnetic resonance imaging Diffusion-weighted magnetic resonance imaging Mitochondrial encephalopathy Brain ADC
a b s t r a c t Objectives: To reveal the contribution of MRI and diffusion-weighted imaging (DWI) to the diagnosis of mitochondrial encephalopathy (ME) and to evaluate the parenchymal changes associated with this disease in the involved parenchymal areas using the apparent diffusion coefficient (ADC) parameter. Methods: Ten patients who had undergone MRI and DWI analysis with a pre-diagnosis of neurometabolic disease, and who were subsequently diagnosed with ME in laboratory and/or genetic studies, were included in our study. ADC values were compared with a control group composed of 20 patients of similar age with normal brains. Evaluations involved measurements made in 20 different areas determined on the ADC map. The dominance or contribution of ADC coefficient measurements to the conventional sequences was compared with the controls. Results: In the first examination, an increase in both diffusion and ADC values was detected in six cases and diffusion restriction and a decrease in ADC values in three patients. While an increase in both diffusion and ADC values was demonstrated in four cases, there was diffusion restriction and a decrease in ADC values in three cases in the control examinations. Conclusions: DWI provides information that complements conventional MRI sequences in the diagnosis of ME. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction MRI has limited specificity in detecting brain lesions associated with childhood metabolic diseases [1,2]. Diffusion weighted imaging (DWI) provides unique information regarding tissue activity which cannot be obtained from conventional MRI sequences [2]. In our study, we aimed to evaluate the contribution of MRI and DWI carried out in our department to the diagnosis of 10 paediatric patients with mitochondrial encephalopathy (ME), and to investigate the parenchymal changes associated with this disease in the involved parenchymal areas using the apparent diffusion
夽 This study was presented as a Scientific Poster in Congress: ESMRMB. ∗ Corresponding author at: Dokuz Eylül University, Department of Radiology, Izmir, Turkey. Tel.: +90 5052874231. E-mail addresses: [email protected] (F. Uysal), [email protected] (H. C¸akmakc¸ı), [email protected] (U. Yis¸), [email protected] (H. Ellidokuz), [email protected] (A.S. Hız). 1 Tel.: +90 232 4125911. 0720-048X/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejrad.2013.06.031
coefficient (ADC) parameter. With this purpose in mind, ADC values were compared with control groups; evaluations involved measurements made in 20 different areas determined on the ADC map in the patient group, and the dominance or contribution of ADC coefficient measurement in relation to the conventional sequences were compared with the control group.
2. Methods Approval for this study was obtained from our ethical review board. Ten patients who had undergone MRI and DWI analysis with a pre-diagnosis of neurometabolic disease in our MRI unit, and who were subsequently diagnosed with ME in laboratory and/or genetic studies in the clinic were included in our study. Findings that established this diagnosis in patients were high lactate levels in blood or cerebrospinal fluid, radiological studies or postmortem examination of basal ganglia, or the involvement of the brainstem; diagnosis can additionally be established by means of muscle biopsy in some patients.
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Table 1 Age distribution, periods for obtaining control examinations, significant neurological findings, genders of the patients and the diagnosis methods. Case no.
Age
Period of examination
Gender
Onset finding
Lactic acidosis (serum-CSF)
Muscle biopsy
Additional neurological findings
Result
1
2 years
4 years
F
Progressive dystonia
Available
Normal
Dystonia, mental retardation
2
2 months
4 years
F
Available
Normal
3
2 years
N/A
F
Available
Normal
4
3 years
1 year
M
Progressive dystonia-seizures Acute metabolic encephalopathy Psychomotor retardation
Available
Normal
5
4 years
1 year
M
Psychomotor retardation
Available
Normal
6
1 month
N/A
M
Available
Abnormal
7
3.5 years
N/A
M
Available
Abnormal
8
3 years
1 year
F
Available
Not done
Ophthalmoplegia
9
8 years
1 year
M
Acute metabolic encephalopathy Acute metabolic encephalopathy Psychomotor retardation, convulsion Sensorimotor polyneuropathy
Ophthalmoplegia, mental retardation, ataxia Moderate mental retardation Moderate mental retardation Ptosis, sensorineural hearing loss, microcephaly Ptosis, sensorineural hearing loss, microcephaly Moderate mental retardation Ophthalmoplegia
Available
Normal
12 years
1 year
M
Available
Normal
Ophthalmoplegia, mental retardation, ataxia Epilepsy, cataract, microphthalmia
10
Psychomotor retardation, convulsion
Dystonia, mental retardation Ex due to Metabolic decompensated attack Progressive psychomotor retardation Progressive psychomotor retardation Ex due to metabolic decompensated attack Ex due to metabolic decompensated attack Mental retardation
Progressive psychomotor retardation Progressive psychomotor retardation
CSF, cerebrospinal fluid.
The examinations were performed under oral sedation with chloral hydrate (50–75 mg/kg). All patients were examined using a 1.5-T magnetic resonance unit (Intera Achieva and Gyroscan Intera, Philips Medical Systems, Best, The Netherlands) equipped with a standard head coil. The duration of the entire MRI examination was 20–25 min per patient. After routine magnetic resonance imaging with spin echo T1-weighted sagittal, dual-echo turbo spin echo T2-axial, sagittal and fluid-attenuated inversion-recovery axial sequences, transverse single-shot echo planar diffusion-weighted imaging (TR/TE: 5200/105 ms; field of view: 240 mm; matrix: 128 × 128; section thickness: 5 mm; intersection gap: 1.5 mm) were performed. Control MRI and DWI analysis was carried out for 1–4 years on 7 of the 10 patients included in our study. Control analysis of the other three patients could not be performed because they died. ADC measurements were undertaken on both of the two hemispheres at 20 individual white-grey matter points; these were identified prior to measurement in all patients in both the control and patient groups. The anatomical locations at which the ADC measurements were made were as follows: frontal-parietal-occipital white matter; frontal-parietal-occipital grey matter; caudate nucleus; globus pallidus; putamen; thalamus; internal capsule anterior-posterior limb; mesencephalon anterior-posterior section; dentate nucleus; pons anterior-posterior section; bulbus; cerebellar white matter; and periventricular cerebral white matter. ADC measurements were undertaken using two separate standard measurement circles (region of interest: ROI) with areas of 25.2 and 56.5 mm2 . This ROI for the b = 0 data was placed on the point to be measured on the images and it was automatically transferred to the same point on the ADC map by the system. All conventional and diffusion MR images were evaluated by two radiologists, one of whom was experienced in paediatric radiology. In the evaluations, parenchymal signal intensity changes, lesion localisations, diffusion characteristics on DWI and diffusiveness of the lesions were considered; whether or not additional lesions were identified was also considered. The signal characteristics of DWIs were visually evaluated and ADC values were measured using
the standard ROI from 20 separate measurement points, identified prior to measurement in all patients in both the control and patient groups. All patients were compared with the control group which was composed of 20 patients of similar age and gender who had normal brain MRI-DWI analyses. In both of the examinations, the comparison of patient ages was performed using the Mann–Whitney U test, and the comparison of genders was performed using the Fisher exact test (chi-square); the selection of the control group was found to be appropriate. ADC values obtained in statistical comparison of axial single-shot echo planar imaging (EPI) DW-MRI were compared with the control group using the Mann–Whitney U test. 3. Results Of the cases in our study, four were girls and six were boys. Their ages varied between 1 month and 13 years, and the average age was calculated at 47.7 months. Control MRI and DWI examinations were undertaken on seven of the patients at 1–4 years after the first examination. Control examinations of the three remaining patients could not be carried out because they had died. Age distribution, periods over which control examinations were conducted, significant neurological findings, patient gender and the diagnostic methods are shown in Table 1. Increased diffusion and ADC values were evident at the first examination in six (cases 3, 6, 7–10) out of the 10 patients included in the current study. Diffusion restriction and a decrease in ADC values were identified in three patients (cases 1, 4 and 5). In control examinations, while there was an increase in diffusion and ADC values in four patients (cases 1, 8–10), diffusion restriction and a decrease in ADC values was found in three patients (cases 2, 4 and 5). Diffusion restriction detected using DWI and a decrease in ADC values was apparent at the first examination in three patients (cases 1, 4 and 5). An increase in ADC values was noted in one patient (case 1) in the control examination performed 4 years later (Fig. 1). In the other two patients (cases 4 and 5), while there was a slight increase
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Fig. 1. Female patient initial MRI at 2 years old (a) and DW images (b) show decreased signal on the ADC map and increased signal on T2 weighted images at the basal ganglia. Controls MRI at 6 years of age (c–d) demonstrate increased diffusion on the same basal ganglia areas.
in ADC values relative to case 1 seen in the control examination performed 1 year later, values were still low relative to the control group. There was an increase in diffusion evident using DWI and increased ADC values in three patients (cases 3, 6 and 7) who did not undergo control examination and died. While the first examination of one patient (case 2) was normal, ADC values were found to have decreased in the examination performed 4 years later (Fig. 2). Increased diffusion and ADC values were evident in the first examination and control examination in three patients (cases 8–10). There was an increase in the number of lesions in two patients (cases 1 and 2) and in the size of the lesions in one patient (case 8) in the follow-up examination. Cases 4 and 5 were siblings and globus pallidus involvement and an increase in ADC values in that area were apparent in both cases. Cases 9 and 10 were also siblings. Involvement in the putamen and an increase in ADC values were found in these two cases. Lesion locations and the diffusion characteristics of the patients in the first examinations are detailed in Table 2. The diffusion characteristics and location of the lesions in the patients in the control examinations are given in Table 3; lesion locations and ADC values obtained in the first examinations and control examinations of the patients are collectively detailed in Table 4. However, in comparison with the control group no statistically significant difference was identified. This was because there was an increase or a decrease in the ADC values in line with the acute or chronic phase of the disease. Homogeneous groups, including a sufficient number of patients in similar phases, could not be included in our study as this disease is rarely encountered. Accordingly, statistical analysis could not be carried out in a convenient way. Thus,
the patients were individually compared with the patients of similar age and gender in the control group. 4. Discussion ME comprises the group of heterogeneous neuromuscular diseases possibly caused by structural and functional mitochondrial defects in the energy production of the oxidative metabolic pathway. The prevalence of mtDNA mutations is reported to be approximately 4–5/100,000 live births [5]. ME includes well defined diseases such as MELAS syndrome, Kearns-Sayre syndrome, Leigh’s disease and MERRF syndrome [3,4]. Mitochondrial diseases comprise the most frequent group of the neurometabolic diseases in childhood [5]. Mostly the organs which need high energy such as the central nervous system and/or skeletal muscle are affected [6]. ME is a hereditary, progressive and neurodegenerative disease that can be seen in infancy and early childhood, and the course and prognosis of the disease is quite variable [7]. The onset of symptoms is nonspecific and can include encephalopathy, growth retardation, seizures, ophthalmoplegia and hearing loss [8]. Progressive cognitive disorders can be seen in some cases [9]. As specific treatment is not available for ME, conservative treatment has been performed. Some positive results have been reported using a treatment that involves the administration of a cocktail that consists of coenzyme Q10, riboflavin, L-carnitine and high dose multivitamins, in combination with the ketogenic diet [10]. It has been determined that useful modalities for diagnosis and follow-up of ME include: clinical findings; imaging techniques such as computed tomography and MRI; and evaluation of
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Table 2 Lesion locations and diffusion characteristics of the patients in the first examinations. Case no.
1 2 3 4 5 6 7 8 9 10
DWI characterisation
Diffusion ↓ Normal Diffusion ↑ Diffusion ↓ Diffusion ↓ Diffusion ↑ Diffusion ↑ Diffusion ↑ Diffusion ↑ Diffusion ↑
Lesion location
Caudate nucleus
Putamen
Globus pallidus
Thalamus
Periventricular white matter
Brainstem
Cerebellar white matter
Available N/A Available N/A N/A N/A N/A N/A N/A N/A
Available N/A Available N/A N/A N/A Available N/A Available Available
Available N/A Available Available Available N/A Available N/A N/A N/A
N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
N/A N/A N/A N/A N/A N/A N/A Available N/A N/A
N/A N/A N/A N/A N/A Available N/A N/A N/A N/A
N/A N/A N/A N/A N/A Available N/A N/A N/A N/A
DWI, diffusion weighted imaging. Table 3 Lesion locations and diffusion characteristics of the living patients in the control examinations. Case no.
1 2 4 5 8 9 10
DWI characterisation
Diffusion ↑ Moderate diffusion ↓ Diffusion ↓ Diffusion ↓ Diffusion ↑ Diffusion ↑ Diffusion ↑
Lesion location
Caudate nucleus
Putamen
Globus pallidus
Thalamus
Periventricular white matter
Brainstem
Cerebellar white matter
Available Available
Available Available
Available Available
N/A N/A
N/A N/A
Available Available
N/A Available
N/A N/A N/A N/A N/A
N/A N/A N/A Available Available
Available Available N/A N/A N/A
N/A N/A N/A N/A N/A
N/A N/A Available N/A N/A
N/A N/A N/A N/A N/A
N/A N/A N/A N/A N/A
DWI, diffusion weighted imaging. Table 4 Lesion locations and ADC values in the first examinations and control examinations of patient ADC values (×10−5 cm2 /s). Location of lesions in the first MRI examination
Lesion locations and ADC values in the first DWI
Location of lesions in control examination
Lesion location and ADC values in the control DWI
1
Caudate nucleus Globus pallidus Putamen
Caudate nucleus 0.65 Globus pallidus 0.39 Putamen 0.50 Mesencephalon ant. 0.78 Mesencephalon post. 0.75
Caudate nucleus Globus pallidus Putamen Mesencephalon ant. Mesencephalon post.
2
No lesion
Normal
Caudate nucleus Putamen Globus pallidus
3
Caudate nucleus Putamen Globus pallidus Globus pallidus Globus pallidus Mesencephalon post. Dentate nucleus Pons Bulbus Globus pallidus Putamen Mesencephalon post. Dentate nucleus Pons Bulbus Periventricular white matter
Caudate nucleus 1.0 Putamen 1.0 Globus pallidus 1.2 Globus pallidus 0.67 Globus pallidus 0.80 Mesencephalon post. 1.41 Dentate nucleus 1.31 Pons 1.21 Bulbus 1.37 Globus pallidus 1.40 Putamen 1.73 Mesencephalon post.1.22 Dentate nucleus 1.51 Pons 1.21 Bulbus 1.37 Periventricular white matter 1.41
X
Caudate nucleus 1.7 Globus pallidus 1.3 Putamen 2.1 Mesencephalon ant. 1.2 Mesencephalon post. 1.2 Bulbus 1.2 Thalamus 1.2 Caudate nucleus 0.80 Putamen 0.75 Globus pallidus 0.70 Mesencephalon ant. 0.78 Mesencephalon post. 0.80 Dentate nucleus 0.70 Cerebellar white matter 0.70 X
Globus pallidus Globus pallidus X
Globus pallidus 0.88 Globus pallidus 0.97 X
X
X
Periventricular white matter 2.04
Putamen Putamen
Putamen 1.96 Putamen 1.92
Periventricular white matter Putamen Putamen
Patient no.
4 5 6
7
8 9 10
ADC, apparent diffusion coefficient; DWI, diffusion weighted imaging.
Putamen 2.02 Putamen 2.17
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Fig. 2. Female patient initial MRI at 2 months old (a) and DW images (b) show normal signal on the ADC map and T2 weighted images at the basal ganglia. Control MRI at 4 years of age (c–d) demonstrates decreased diffusion on the same basal ganglia areas.
brain metabolites using DWI and magnetic resonance spectroscopy (MRS) [11]. The diagnosis is generally established by means of radiological imaging of the symmetrical lesions affecting the basal ganglia, brainstem and subthalamic nuclei [12]. Radiological findings generally involve an abnormal increase in signal intensity in the basal ganglia, calcification in the basal ganglia, cerebral and cerebellar atrophy, bilateral striatal necrosis, cerebellar hypoplasia, infarcts and leukoencephalopathy [3,4]. In MRI examinations of ME patients, there is generally an increase in T2 signal intensity, especially in the putamen and caudate nucleus, the basal ganglia, pons, mesencephalon, cerebral and cerebellar white matter [11–13]. Myelin oedema caused by the spongy degeneration of white matter, diffusion restriction due to the distension of astrocytes and low ADC values are defined in the early stages. An increase in diffusion and high ADC values are defined using DWI in the advanced stages of the disease [11–14]. We can distinguish the diseases which do not indicate myelin oedema from those that indicate mild, moderate and severe myelin oedema by means of DWI. Information can be gained concerning the course and the histopathological characteristics of these diseases. However, it has been found that some diseases which have the same histopathological characteristics can have different DWI findings [2]. In neurometabolic diseases, DWI is used to determine the progress of the disease and structural changes in the white matter. ADC values provide useful and complementary information about the diagnosis and the degree of involvement of various hereditary paediatric neurometabolic encephalopathies [15].
Clinical findings such as progressive dystonia, seizures, encephalopathy, psychomotor retardation, polyneuropathy, ophthalmoplegia, mental retardation, ataxia, hearing loss, laboratory findings (blood, cerebrospinal fluid lactate levels), and pathological findings have been identified, and diagnosis of ME in accordance with radiological data has been established in the 10 patients included in our study. In MRI examinations of ME patients, an increase in T2 signal intensity has generally been observed, especially in the putamen and caudate nucleus, basal ganglia, pons, brainstem, and cerebral and cerebellar white matter [11–13]. Lesions were observed in the periventricular white matter of one patient (case 8), in the globus pallidus of two patients (cases 4 and 5), in the putamen of two patients (cases 9 and 10), in the brainstem of one patient (case 6), and in both the basal ganglia and brainstem of two patients (cases 1 and 7) included in our study; these findings are in keeping with the literature. While no lesions were identified during the first examination of case 2, lesions in the basal ganglia and brainstem were identified in the follow-up examination 4 years later. This was due to the fact that the first examination had been performed in the earliest stage of the disease. While both the acute and chronic histopathological changes were observed as hyperintense areas on T2 weighted images, they presented significant differences on DWI scans. Information about the activity of the disease can be obtained using DWI. As the hereditary white matter diseases are progressive, different diffusion signal characteristics and ADC values can be observed according to
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the time of examination. There are differences between the findings obtained in the early stages and those obtained in the advanced stages of the diseases. The end stages of white matter diseases are generally similar to each other [16]. Myelin oedema caused by the spongy degeneration of white matter and diffusion restriction due to the distension of astrocytes and low ADC values are defined in the early stages, and increased diffusion and high ADC values are defined in the advanced stages of the disease using DWI [11–14]. By means of DWI, Atalar et al. detected significantly low ADC levels in the basal ganglia and also in the thalamus in their case report which included a 4 year old patient [17]. These authors correlated the restricted diffusion pattern in Leigh’s disease with a decrease in the motion of water molecules in the myelin sheath [17]. In their case report involving three patients with a diagnosis of ME (two with Kearns Sayre syndrome and one with Leigh’s syndrome) Sakai et al. detected hyperintense lesions in the pons, mesencephalon and tegmentum of children using DWI, and showed that the signal increase lasted longer than 1 year [18]. However, they measured lower ADC values in lesions than in neighbouring tissues, and reported that this finding was correlated with the reversible cytotoxic oedema in a lesion in the brainstem [18]. Increased diffusion has been reported in the affected areas on DWI examination of a case with Leigh’s disease [19]. This increased diffusion was related to vasogenic oedema and demyelination [19]. Increased diffusion and ADC values were found in the first examination in six (cases 3 and 6–10) out of the 10 patients included in the present study. Diffusion restriction and a decrease in ADC values were identified in three patients (cases 1, 4 and 5). In the control examination, while there was an increase in diffusion and in ADC values in four patients (cases 1 and 8–10), diffusion restriction and a decrease in ADC values was evident in three patients (cases 2, 4 and 5). Increased diffusion and ADC values identified using DWI were correlated with spongiform degeneration, vasogenic oedema and demyelination in the chronic stage of the disease in keeping with the literature [19]. Diffusion restriction and a decrease in ADC values observed using DWI have been shown to be correlated with the cytotoxic oedema seen in the early stage of Leigh’s disease [17]. Diffusion restriction and a decrease in ADC values detected using DWI were apparent in the first examinations of three patients (cases 1, 4 and 5) in the current study. The diffusion restriction identified in these patients was correlated with cytotoxic oedema. An increase in ADC values was detected in one of these patients in the control examination performed 4 years after the first examination. With regard to this finding, the chronic stage that is also defined in the literature was evaluated as being secondary to vasogenic oedema and demyelination in the disease. In the other 2 patients (cases 4 and 5), while there was a slight increase in ADC values relative to the first patient (case 1) observed in the control examination performed 1 year later, values were still low as compared with the control group. This situation was interpreted as indicating that the findings of the acute period which were also defined in the study of Sakai et al. [18] can last longer than 1 year. While the first examination of a patient (case 2) in our study was normal, the ADV values were found to have decreased in the basal ganglia and brainstem in the examination that was undertaken 4 years later. This situation suggested that the MRI and DWI findings were initially normal because evaluations were undertaken at the earliest stage of the disease in the first examination, and that the breakdown associated with the disease progressively increased and diffusion restriction developed in association with cytotoxic oedema over the 4 year period. An increase in diffusion and in ADC values was found in the first examination and control examination in three patients (cases 8–10). While the ADC values were found to be similar in one of these patients in the control examination, a significant increase was
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detected in the ADC values in the other two patients. While this finding suggested that the disease did not have a significant progression within that period in the patient with a similar ADC value to that in the control examination performed 1 year later, it suggested progression of the disease in association with the increased degeneration in two patients who had increased ADC values. There was an increase in the number of lesions in two patients (cases 1 and 2) and in the size of the lesions in one patient (case 8) in the follow-up examination. An increase in the ADC values for lesions was evident, although no new lesions were detected in the conventional sequence in other cases. This is also a finding that indicates that the disease is progressive. Although the disease is considered not to have progressed when no new lesion is detected using conventional MRI, the increase in the ADC levels of the lesions indicates that degeneration actually continues and that the disease is progressive [16]. Involvement of ME in similar locations in four patients (cases 4, 5, 9 and 10) in the present study who were siblings was correlated with the hereditary characteristic of the disease [3,4]. MELAS is the first single entity from the mitochondrial encephalopathies, which was recently investigated by various authors by means of DWI [20–22]. MELAS includes mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. It shows sudden neurological deficits known as the ‘stroke-like episodes’ [20]. As far as the pathophysiology of stroke-like episodes is concerned, mitochondrial angiopathy and cytopathy theories have been proposed but the subject remains the topic of much debate. ADCs in non-affected areas in MELAS patients are elevated when compared to normal subjects. Pathological changes take place in the non-affected areas [21]. In patients with MELAS the cytotoxic oedema evolves gradually, following an acute stroke-like episode, and that may overlap with hyper-perfusion and vasogenic oedema. The edematous swelling is either reversible or will evolve to encephalomalacia, what suggests irreversible damage [22]. Gelal et al., in their study regarding the role of DWI in children younger than 2 years, evaluated 60 patients retrospectively [23]. They added single-shot EPI spin echo DWI examination to routine brain MRI protocols and reported that DWI provided additional information for the routine examination in patients with acute neurological symptoms (lasting < 7 days) [23]. However, these authors did not undertake ADC measurements in lesions, although they used an ADC map in their study. Sener classified various cerebral pathologies according to the white matter ADC values in his study, in which paediatric and adult patients were included. However, the separate ADC values for each patient group were not reported [24]. The difference found in ADC values relative to the control group in the areas in which no signal change were detected in the conventional sequences in two patients in our study, indicated that DWI makes an additional diagnostic contribution to the routine examination by defining additional lesions, demarking the lesions with certain limits and determining the different diffusion characteristics in the lesions which are homogeneous hyperintense in spin echo T2 images, in agreement with a study carried out by Gelal et al. [23]. There have been only a limited number of previous studies performed using DWI in children with ME. In this disease, the cytotoxic oedema in the pathologic regions may not cause a sufficiently large shift in water molecule flow for it to be identified on conventional MRI sequences. While the conventional images remain as false negative in these regions, DWI can detect them more accurately because it is sensitive to the motions of water molecules. Additionally, difference can be demonstrated by comparing the measurements made in locations with diffusion abnormalities on the ADC map with the normal control group.
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Few studies on the DWI and ADC measurements regarding ME have been published, and these have involved a limited number of patients. The findings of our study were similar to these studies. However, there is very little information regarding follow-up examinations in the literature. In this respect our study provides valuable new information. It the current study, we found that DWI, which we used in addition to conventional MRI examination, increased diagnostic effectiveness by defining additional lesions and revealing their prevalence and intensity more accurately. DWI can also distinguish whether or not the lesions are in an early or late stage of development by supporting the evaluation of the underlying pathology; this is achieved by identifying the different diffusion characteristics in the homogeneous hyperintense lesions on T2 weighted images. One of the important advantages of this method is that numerical values can be obtained by undertaking ADC measurements. Therefore, the pathological areas can be objectively evaluated. The evaluation of isotropic diffusion weighted MR images using the ADC map prevents the T2 prolongation (T2 shine-through effect) mimicking the restricted diffusion. In conclusion, DWI provides information that complements conventional MR sequences in the diagnosis of ME in paediatric patients and makes an important contribution to the determination of a lesion’s age, degeneration rate and involvement in the areas in which no signal change is seen; it is also useful in the follow-up of disease progression. While there can be a numerical and spatial increase in lesions, the increase in ADC values indicates continuing in-lesion degeneration and disease progression. ADC measurement should be included as part of the sequence in routine brain MRI examination. There have been a limited number of studies on this subject in the literature, and our study provides important new findings. Studies involving more patients and including control follow-ups are needed in the future. Conflict of interest None declared. Acknowledgement We thank to “Edanz Editing-Springer” for language advice. References [1] Lyon G, Fattal-Valevski A, Kolodny EH. Leukodystrophies: clinical and genetic aspects. Top Magn Reson Imaging 2006;17:219–42.
[2] Patay Z. Diffusion-weighted MR imaging in leukodystrophies. Eur Radiol 2005;15:2284–303. [3] Di Mauro S, Hirano M. Mitochondrial encephalomyopathies: an update. Neuromuscul Disord 2005;15:276–86. [4] Morava E, Van Den Heuvel L, Hol F, et al. Mitochondrial disease criteria diagnostic applications in children. Neurology 2006;67:1823–6. [5] Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol 2001;49:377–83. [6] DiMauro S, Bonilla E, De Vivo DC. Does the patient have a mitochondrial encephalomyopathy? J Child Neurol 1999;14(Suppl. 1):S23–35. [7] Yis U, Hiz Kurul S, Dirik E, Cakmakc¸i H, Ozer E. Clinical, pathological and radiological survey of patients with Leigh syndrome. Minerva Pediatr 2009;61:371–8. [8] Longo N. Mitochondrial encephalopathy. Neurol Clin 2003;21:817–31. [9] Finsterer J. Cognitive dysfunction in mitochondrial disorders. Acta Neurol Scand 2012, http://dx.doi.org/10.1111/j.1600-0404.2012.01649. [10] Kang HC, Lee YM, Kim HD, Lee JS, Slama A. Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects. Epilepsia 2007;48:82–8. [11] van der Knaap MS, Valk J. Magnetic resonance of myelination and myelin disorders. 3rd ed. Heidelberg: Springer; 2005. [12] Schmiedel J, Jackson S, Schafer J, Reichmann H. Mitochondrial cytopathies. J Neurol 2003;250:267–77. [13] Arii J, Tanabe T. Leigh syndrome: serial MR imaging and clinical follow-up. AJNR Am J Neuroradiol 2000;21:1502–9. [14] Srikanth SG, Chandrashekar HS, Nagarajan K, Jayakumar PN. Restricted diffusion in Canavan disease. Childs Nerv Syst 2007;23:465–8. [15] Cakmakci H, Pekcevik Y, Yis U, Unalp A, Kurul S. Diagnostic value of proton MR spectroscopy and diffusion-weighted MR imaging in childhood inherited neurometabolic brain diseases and review of the literature. Eur J Radiol 2010;74:e161–71. [16] Danielsen ER, Ross B. Magnetic resonance spectroscopy diagnosis of neurological diseases. New York: Mackel Dekker; 1999. [17] Atalar MH, Egilmez H, Bulut S, Icagasioglu D. Magnetic resonance spectroscopy and diffusion-weighted imaging findings in a child with Leigh’s disease. Pediatr Int 2005;47:601–3. [18] Sakai Y, Kira R, Torisu H, Ihara K, Yoshiura T, Hara T. Persistent diffusion abnormalities in the brain stem of three children with mitochondrial diseases. AJNR Am J Neuroradiol 2006;27:1924–6. [19] Engelbrecht V, Scherer A, Rassek M, Witsack JH, Mödder U. Diffusion-weighted MR imaging in the brain in children: findings in the normal brain and in the brain with white matter disease. Radiology 2002;222:410–8. [20] Ito H, Mori K, Kagami S. Neuroimaging of stroke-like episodes in MELAS. Brain Dev 2011;33:283–8, http://dx.doi.org/10.1016/j.braindev.2010.06.010. [21] Liu Z, Liu X, Hui L, et al. The appearance of ADCs in the nonaffected areas of the patients with MELAS. Neuroradiology 2011;53:227–32, http://dx.doi.org/10.1007/s00234-010-0729-y. [22] Kim JH, Lim MK, Jeon TY, et al. Diffusion and perfusion characteristics of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, andstroke-like episode) in thirteen patients. Korean J Radiol 2011;12:15–24, http://dx.doi.org/10.3348/kjr.2011.12.1.15. [23] Gelal FM, Grant PE, Fiscbein NJ, Henry RG, Vigneron DB, Barkovich AJ. The role of isotropic diffusion MRI in children under 2 years of age. Eur Radiol 2001;11:1006–14. [24] Sener RN. Diffusion MRI: apparent diffusion coefficient (ADC) values in the normal brain and a classification of brain disorders based on ADC values. Comput Med Imaging Graph 2001;25:299–326.
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Measurement of the apparent diffusion coefficient in paediatric mitochondrial encephalopathy cases and a comparison of parenchymal changes associated with the disease using follow-up diffusion coefficient measurements夽 Fatma Uysal a,∗ , Handan C¸akmakc¸ı a,1 , Uluc¸ Yis¸ b,1 , Hülya Ellidokuz c,1 , Ays¸e Semra Hız b,1 a
Dokuz Eylül University, Department of Pediatric Radiology, Izmir, Turkey Dokuz Eylül University, Department of Pediatric Neurology, Izmir, Turkey c Dokuz Eylül University, Department of Medical Statistics, Izmir, Turkey b
a r t i c l e
i n f o
Article history: Received 10 January 2013 Received in revised form 17 June 2013 Accepted 18 June 2013 Keywords: Magnetic resonance imaging Diffusion-weighted magnetic resonance imaging Mitochondrial encephalopathy Brain ADC
a b s t r a c t Objectives: To reveal the contribution of MRI and diffusion-weighted imaging (DWI) to the diagnosis of mitochondrial encephalopathy (ME) and to evaluate the parenchymal changes associated with this disease in the involved parenchymal areas using the apparent diffusion coefficient (ADC) parameter. Methods: Ten patients who had undergone MRI and DWI analysis with a pre-diagnosis of neurometabolic disease, and who were subsequently diagnosed with ME in laboratory and/or genetic studies, were included in our study. ADC values were compared with a control group composed of 20 patients of similar age with normal brains. Evaluations involved measurements made in 20 different areas determined on the ADC map. The dominance or contribution of ADC coefficient measurements to the conventional sequences was compared with the controls. Results: In the first examination, an increase in both diffusion and ADC values was detected in six cases and diffusion restriction and a decrease in ADC values in three patients. While an increase in both diffusion and ADC values was demonstrated in four cases, there was diffusion restriction and a decrease in ADC values in three cases in the control examinations. Conclusions: DWI provides information that complements conventional MRI sequences in the diagnosis of ME. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction MRI has limited specificity in detecting brain lesions associated with childhood metabolic diseases [1,2]. Diffusion weighted imaging (DWI) provides unique information regarding tissue activity which cannot be obtained from conventional MRI sequences [2]. In our study, we aimed to evaluate the contribution of MRI and DWI carried out in our department to the diagnosis of 10 paediatric patients with mitochondrial encephalopathy (ME), and to investigate the parenchymal changes associated with this disease in the involved parenchymal areas using the apparent diffusion
夽 This study was presented as a Scientific Poster in Congress: ESMRMB. ∗ Corresponding author at: Dokuz Eylül University, Department of Radiology, Izmir, Turkey. Tel.: +90 5052874231. E-mail addresses: [email protected] (F. Uysal), [email protected] (H. C¸akmakc¸ı), [email protected] (U. Yis¸), [email protected] (H. Ellidokuz), [email protected] (A.S. Hız). 1 Tel.: +90 232 4125911. 0720-048X/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejrad.2013.06.031
coefficient (ADC) parameter. With this purpose in mind, ADC values were compared with control groups; evaluations involved measurements made in 20 different areas determined on the ADC map in the patient group, and the dominance or contribution of ADC coefficient measurement in relation to the conventional sequences were compared with the control group.
2. Methods Approval for this study was obtained from our ethical review board. Ten patients who had undergone MRI and DWI analysis with a pre-diagnosis of neurometabolic disease in our MRI unit, and who were subsequently diagnosed with ME in laboratory and/or genetic studies in the clinic were included in our study. Findings that established this diagnosis in patients were high lactate levels in blood or cerebrospinal fluid, radiological studies or postmortem examination of basal ganglia, or the involvement of the brainstem; diagnosis can additionally be established by means of muscle biopsy in some patients.
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Table 1 Age distribution, periods for obtaining control examinations, significant neurological findings, genders of the patients and the diagnosis methods. Case no.
Age
Period of examination
Gender
Onset finding
Lactic acidosis (serum-CSF)
Muscle biopsy
Additional neurological findings
Result
1
2 years
4 years
F
Progressive dystonia
Available
Normal
Dystonia, mental retardation
2
2 months
4 years
F
Available
Normal
3
2 years
N/A
F
Available
Normal
4
3 years
1 year
M
Progressive dystonia-seizures Acute metabolic encephalopathy Psychomotor retardation
Available
Normal
5
4 years
1 year
M
Psychomotor retardation
Available
Normal
6
1 month
N/A
M
Available
Abnormal
7
3.5 years
N/A
M
Available
Abnormal
8
3 years
1 year
F
Available
Not done
Ophthalmoplegia
9
8 years
1 year
M
Acute metabolic encephalopathy Acute metabolic encephalopathy Psychomotor retardation, convulsion Sensorimotor polyneuropathy
Ophthalmoplegia, mental retardation, ataxia Moderate mental retardation Moderate mental retardation Ptosis, sensorineural hearing loss, microcephaly Ptosis, sensorineural hearing loss, microcephaly Moderate mental retardation Ophthalmoplegia
Available
Normal
12 years
1 year
M
Available
Normal
Ophthalmoplegia, mental retardation, ataxia Epilepsy, cataract, microphthalmia
10
Psychomotor retardation, convulsion
Dystonia, mental retardation Ex due to Metabolic decompensated attack Progressive psychomotor retardation Progressive psychomotor retardation Ex due to metabolic decompensated attack Ex due to metabolic decompensated attack Mental retardation
Progressive psychomotor retardation Progressive psychomotor retardation
CSF, cerebrospinal fluid.
The examinations were performed under oral sedation with chloral hydrate (50–75 mg/kg). All patients were examined using a 1.5-T magnetic resonance unit (Intera Achieva and Gyroscan Intera, Philips Medical Systems, Best, The Netherlands) equipped with a standard head coil. The duration of the entire MRI examination was 20–25 min per patient. After routine magnetic resonance imaging with spin echo T1-weighted sagittal, dual-echo turbo spin echo T2-axial, sagittal and fluid-attenuated inversion-recovery axial sequences, transverse single-shot echo planar diffusion-weighted imaging (TR/TE: 5200/105 ms; field of view: 240 mm; matrix: 128 × 128; section thickness: 5 mm; intersection gap: 1.5 mm) were performed. Control MRI and DWI analysis was carried out for 1–4 years on 7 of the 10 patients included in our study. Control analysis of the other three patients could not be performed because they died. ADC measurements were undertaken on both of the two hemispheres at 20 individual white-grey matter points; these were identified prior to measurement in all patients in both the control and patient groups. The anatomical locations at which the ADC measurements were made were as follows: frontal-parietal-occipital white matter; frontal-parietal-occipital grey matter; caudate nucleus; globus pallidus; putamen; thalamus; internal capsule anterior-posterior limb; mesencephalon anterior-posterior section; dentate nucleus; pons anterior-posterior section; bulbus; cerebellar white matter; and periventricular cerebral white matter. ADC measurements were undertaken using two separate standard measurement circles (region of interest: ROI) with areas of 25.2 and 56.5 mm2 . This ROI for the b = 0 data was placed on the point to be measured on the images and it was automatically transferred to the same point on the ADC map by the system. All conventional and diffusion MR images were evaluated by two radiologists, one of whom was experienced in paediatric radiology. In the evaluations, parenchymal signal intensity changes, lesion localisations, diffusion characteristics on DWI and diffusiveness of the lesions were considered; whether or not additional lesions were identified was also considered. The signal characteristics of DWIs were visually evaluated and ADC values were measured using
the standard ROI from 20 separate measurement points, identified prior to measurement in all patients in both the control and patient groups. All patients were compared with the control group which was composed of 20 patients of similar age and gender who had normal brain MRI-DWI analyses. In both of the examinations, the comparison of patient ages was performed using the Mann–Whitney U test, and the comparison of genders was performed using the Fisher exact test (chi-square); the selection of the control group was found to be appropriate. ADC values obtained in statistical comparison of axial single-shot echo planar imaging (EPI) DW-MRI were compared with the control group using the Mann–Whitney U test. 3. Results Of the cases in our study, four were girls and six were boys. Their ages varied between 1 month and 13 years, and the average age was calculated at 47.7 months. Control MRI and DWI examinations were undertaken on seven of the patients at 1–4 years after the first examination. Control examinations of the three remaining patients could not be carried out because they had died. Age distribution, periods over which control examinations were conducted, significant neurological findings, patient gender and the diagnostic methods are shown in Table 1. Increased diffusion and ADC values were evident at the first examination in six (cases 3, 6, 7–10) out of the 10 patients included in the current study. Diffusion restriction and a decrease in ADC values were identified in three patients (cases 1, 4 and 5). In control examinations, while there was an increase in diffusion and ADC values in four patients (cases 1, 8–10), diffusion restriction and a decrease in ADC values was found in three patients (cases 2, 4 and 5). Diffusion restriction detected using DWI and a decrease in ADC values was apparent at the first examination in three patients (cases 1, 4 and 5). An increase in ADC values was noted in one patient (case 1) in the control examination performed 4 years later (Fig. 1). In the other two patients (cases 4 and 5), while there was a slight increase
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Fig. 1. Female patient initial MRI at 2 years old (a) and DW images (b) show decreased signal on the ADC map and increased signal on T2 weighted images at the basal ganglia. Controls MRI at 6 years of age (c–d) demonstrate increased diffusion on the same basal ganglia areas.
in ADC values relative to case 1 seen in the control examination performed 1 year later, values were still low relative to the control group. There was an increase in diffusion evident using DWI and increased ADC values in three patients (cases 3, 6 and 7) who did not undergo control examination and died. While the first examination of one patient (case 2) was normal, ADC values were found to have decreased in the examination performed 4 years later (Fig. 2). Increased diffusion and ADC values were evident in the first examination and control examination in three patients (cases 8–10). There was an increase in the number of lesions in two patients (cases 1 and 2) and in the size of the lesions in one patient (case 8) in the follow-up examination. Cases 4 and 5 were siblings and globus pallidus involvement and an increase in ADC values in that area were apparent in both cases. Cases 9 and 10 were also siblings. Involvement in the putamen and an increase in ADC values were found in these two cases. Lesion locations and the diffusion characteristics of the patients in the first examinations are detailed in Table 2. The diffusion characteristics and location of the lesions in the patients in the control examinations are given in Table 3; lesion locations and ADC values obtained in the first examinations and control examinations of the patients are collectively detailed in Table 4. However, in comparison with the control group no statistically significant difference was identified. This was because there was an increase or a decrease in the ADC values in line with the acute or chronic phase of the disease. Homogeneous groups, including a sufficient number of patients in similar phases, could not be included in our study as this disease is rarely encountered. Accordingly, statistical analysis could not be carried out in a convenient way. Thus,
the patients were individually compared with the patients of similar age and gender in the control group. 4. Discussion ME comprises the group of heterogeneous neuromuscular diseases possibly caused by structural and functional mitochondrial defects in the energy production of the oxidative metabolic pathway. The prevalence of mtDNA mutations is reported to be approximately 4–5/100,000 live births [5]. ME includes well defined diseases such as MELAS syndrome, Kearns-Sayre syndrome, Leigh’s disease and MERRF syndrome [3,4]. Mitochondrial diseases comprise the most frequent group of the neurometabolic diseases in childhood [5]. Mostly the organs which need high energy such as the central nervous system and/or skeletal muscle are affected [6]. ME is a hereditary, progressive and neurodegenerative disease that can be seen in infancy and early childhood, and the course and prognosis of the disease is quite variable [7]. The onset of symptoms is nonspecific and can include encephalopathy, growth retardation, seizures, ophthalmoplegia and hearing loss [8]. Progressive cognitive disorders can be seen in some cases [9]. As specific treatment is not available for ME, conservative treatment has been performed. Some positive results have been reported using a treatment that involves the administration of a cocktail that consists of coenzyme Q10, riboflavin, L-carnitine and high dose multivitamins, in combination with the ketogenic diet [10]. It has been determined that useful modalities for diagnosis and follow-up of ME include: clinical findings; imaging techniques such as computed tomography and MRI; and evaluation of
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Table 2 Lesion locations and diffusion characteristics of the patients in the first examinations. Case no.
1 2 3 4 5 6 7 8 9 10
DWI characterisation
Diffusion ↓ Normal Diffusion ↑ Diffusion ↓ Diffusion ↓ Diffusion ↑ Diffusion ↑ Diffusion ↑ Diffusion ↑ Diffusion ↑
Lesion location
Caudate nucleus
Putamen
Globus pallidus
Thalamus
Periventricular white matter
Brainstem
Cerebellar white matter
Available N/A Available N/A N/A N/A N/A N/A N/A N/A
Available N/A Available N/A N/A N/A Available N/A Available Available
Available N/A Available Available Available N/A Available N/A N/A N/A
N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
N/A N/A N/A N/A N/A N/A N/A Available N/A N/A
N/A N/A N/A N/A N/A Available N/A N/A N/A N/A
N/A N/A N/A N/A N/A Available N/A N/A N/A N/A
DWI, diffusion weighted imaging. Table 3 Lesion locations and diffusion characteristics of the living patients in the control examinations. Case no.
1 2 4 5 8 9 10
DWI characterisation
Diffusion ↑ Moderate diffusion ↓ Diffusion ↓ Diffusion ↓ Diffusion ↑ Diffusion ↑ Diffusion ↑
Lesion location
Caudate nucleus
Putamen
Globus pallidus
Thalamus
Periventricular white matter
Brainstem
Cerebellar white matter
Available Available
Available Available
Available Available
N/A N/A
N/A N/A
Available Available
N/A Available
N/A N/A N/A N/A N/A
N/A N/A N/A Available Available
Available Available N/A N/A N/A
N/A N/A N/A N/A N/A
N/A N/A Available N/A N/A
N/A N/A N/A N/A N/A
N/A N/A N/A N/A N/A
DWI, diffusion weighted imaging. Table 4 Lesion locations and ADC values in the first examinations and control examinations of patient ADC values (×10−5 cm2 /s). Location of lesions in the first MRI examination
Lesion locations and ADC values in the first DWI
Location of lesions in control examination
Lesion location and ADC values in the control DWI
1
Caudate nucleus Globus pallidus Putamen
Caudate nucleus 0.65 Globus pallidus 0.39 Putamen 0.50 Mesencephalon ant. 0.78 Mesencephalon post. 0.75
Caudate nucleus Globus pallidus Putamen Mesencephalon ant. Mesencephalon post.
2
No lesion
Normal
Caudate nucleus Putamen Globus pallidus
3
Caudate nucleus Putamen Globus pallidus Globus pallidus Globus pallidus Mesencephalon post. Dentate nucleus Pons Bulbus Globus pallidus Putamen Mesencephalon post. Dentate nucleus Pons Bulbus Periventricular white matter
Caudate nucleus 1.0 Putamen 1.0 Globus pallidus 1.2 Globus pallidus 0.67 Globus pallidus 0.80 Mesencephalon post. 1.41 Dentate nucleus 1.31 Pons 1.21 Bulbus 1.37 Globus pallidus 1.40 Putamen 1.73 Mesencephalon post.1.22 Dentate nucleus 1.51 Pons 1.21 Bulbus 1.37 Periventricular white matter 1.41
X
Caudate nucleus 1.7 Globus pallidus 1.3 Putamen 2.1 Mesencephalon ant. 1.2 Mesencephalon post. 1.2 Bulbus 1.2 Thalamus 1.2 Caudate nucleus 0.80 Putamen 0.75 Globus pallidus 0.70 Mesencephalon ant. 0.78 Mesencephalon post. 0.80 Dentate nucleus 0.70 Cerebellar white matter 0.70 X
Globus pallidus Globus pallidus X
Globus pallidus 0.88 Globus pallidus 0.97 X
X
X
Periventricular white matter 2.04
Putamen Putamen
Putamen 1.96 Putamen 1.92
Periventricular white matter Putamen Putamen
Patient no.
4 5 6
7
8 9 10
ADC, apparent diffusion coefficient; DWI, diffusion weighted imaging.
Putamen 2.02 Putamen 2.17
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Fig. 2. Female patient initial MRI at 2 months old (a) and DW images (b) show normal signal on the ADC map and T2 weighted images at the basal ganglia. Control MRI at 4 years of age (c–d) demonstrates decreased diffusion on the same basal ganglia areas.
brain metabolites using DWI and magnetic resonance spectroscopy (MRS) [11]. The diagnosis is generally established by means of radiological imaging of the symmetrical lesions affecting the basal ganglia, brainstem and subthalamic nuclei [12]. Radiological findings generally involve an abnormal increase in signal intensity in the basal ganglia, calcification in the basal ganglia, cerebral and cerebellar atrophy, bilateral striatal necrosis, cerebellar hypoplasia, infarcts and leukoencephalopathy [3,4]. In MRI examinations of ME patients, there is generally an increase in T2 signal intensity, especially in the putamen and caudate nucleus, the basal ganglia, pons, mesencephalon, cerebral and cerebellar white matter [11–13]. Myelin oedema caused by the spongy degeneration of white matter, diffusion restriction due to the distension of astrocytes and low ADC values are defined in the early stages. An increase in diffusion and high ADC values are defined using DWI in the advanced stages of the disease [11–14]. We can distinguish the diseases which do not indicate myelin oedema from those that indicate mild, moderate and severe myelin oedema by means of DWI. Information can be gained concerning the course and the histopathological characteristics of these diseases. However, it has been found that some diseases which have the same histopathological characteristics can have different DWI findings [2]. In neurometabolic diseases, DWI is used to determine the progress of the disease and structural changes in the white matter. ADC values provide useful and complementary information about the diagnosis and the degree of involvement of various hereditary paediatric neurometabolic encephalopathies [15].
Clinical findings such as progressive dystonia, seizures, encephalopathy, psychomotor retardation, polyneuropathy, ophthalmoplegia, mental retardation, ataxia, hearing loss, laboratory findings (blood, cerebrospinal fluid lactate levels), and pathological findings have been identified, and diagnosis of ME in accordance with radiological data has been established in the 10 patients included in our study. In MRI examinations of ME patients, an increase in T2 signal intensity has generally been observed, especially in the putamen and caudate nucleus, basal ganglia, pons, brainstem, and cerebral and cerebellar white matter [11–13]. Lesions were observed in the periventricular white matter of one patient (case 8), in the globus pallidus of two patients (cases 4 and 5), in the putamen of two patients (cases 9 and 10), in the brainstem of one patient (case 6), and in both the basal ganglia and brainstem of two patients (cases 1 and 7) included in our study; these findings are in keeping with the literature. While no lesions were identified during the first examination of case 2, lesions in the basal ganglia and brainstem were identified in the follow-up examination 4 years later. This was due to the fact that the first examination had been performed in the earliest stage of the disease. While both the acute and chronic histopathological changes were observed as hyperintense areas on T2 weighted images, they presented significant differences on DWI scans. Information about the activity of the disease can be obtained using DWI. As the hereditary white matter diseases are progressive, different diffusion signal characteristics and ADC values can be observed according to
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the time of examination. There are differences between the findings obtained in the early stages and those obtained in the advanced stages of the diseases. The end stages of white matter diseases are generally similar to each other [16]. Myelin oedema caused by the spongy degeneration of white matter and diffusion restriction due to the distension of astrocytes and low ADC values are defined in the early stages, and increased diffusion and high ADC values are defined in the advanced stages of the disease using DWI [11–14]. By means of DWI, Atalar et al. detected significantly low ADC levels in the basal ganglia and also in the thalamus in their case report which included a 4 year old patient [17]. These authors correlated the restricted diffusion pattern in Leigh’s disease with a decrease in the motion of water molecules in the myelin sheath [17]. In their case report involving three patients with a diagnosis of ME (two with Kearns Sayre syndrome and one with Leigh’s syndrome) Sakai et al. detected hyperintense lesions in the pons, mesencephalon and tegmentum of children using DWI, and showed that the signal increase lasted longer than 1 year [18]. However, they measured lower ADC values in lesions than in neighbouring tissues, and reported that this finding was correlated with the reversible cytotoxic oedema in a lesion in the brainstem [18]. Increased diffusion has been reported in the affected areas on DWI examination of a case with Leigh’s disease [19]. This increased diffusion was related to vasogenic oedema and demyelination [19]. Increased diffusion and ADC values were found in the first examination in six (cases 3 and 6–10) out of the 10 patients included in the present study. Diffusion restriction and a decrease in ADC values were identified in three patients (cases 1, 4 and 5). In the control examination, while there was an increase in diffusion and in ADC values in four patients (cases 1 and 8–10), diffusion restriction and a decrease in ADC values was evident in three patients (cases 2, 4 and 5). Increased diffusion and ADC values identified using DWI were correlated with spongiform degeneration, vasogenic oedema and demyelination in the chronic stage of the disease in keeping with the literature [19]. Diffusion restriction and a decrease in ADC values observed using DWI have been shown to be correlated with the cytotoxic oedema seen in the early stage of Leigh’s disease [17]. Diffusion restriction and a decrease in ADC values detected using DWI were apparent in the first examinations of three patients (cases 1, 4 and 5) in the current study. The diffusion restriction identified in these patients was correlated with cytotoxic oedema. An increase in ADC values was detected in one of these patients in the control examination performed 4 years after the first examination. With regard to this finding, the chronic stage that is also defined in the literature was evaluated as being secondary to vasogenic oedema and demyelination in the disease. In the other 2 patients (cases 4 and 5), while there was a slight increase in ADC values relative to the first patient (case 1) observed in the control examination performed 1 year later, values were still low as compared with the control group. This situation was interpreted as indicating that the findings of the acute period which were also defined in the study of Sakai et al. [18] can last longer than 1 year. While the first examination of a patient (case 2) in our study was normal, the ADV values were found to have decreased in the basal ganglia and brainstem in the examination that was undertaken 4 years later. This situation suggested that the MRI and DWI findings were initially normal because evaluations were undertaken at the earliest stage of the disease in the first examination, and that the breakdown associated with the disease progressively increased and diffusion restriction developed in association with cytotoxic oedema over the 4 year period. An increase in diffusion and in ADC values was found in the first examination and control examination in three patients (cases 8–10). While the ADC values were found to be similar in one of these patients in the control examination, a significant increase was
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detected in the ADC values in the other two patients. While this finding suggested that the disease did not have a significant progression within that period in the patient with a similar ADC value to that in the control examination performed 1 year later, it suggested progression of the disease in association with the increased degeneration in two patients who had increased ADC values. There was an increase in the number of lesions in two patients (cases 1 and 2) and in the size of the lesions in one patient (case 8) in the follow-up examination. An increase in the ADC values for lesions was evident, although no new lesions were detected in the conventional sequence in other cases. This is also a finding that indicates that the disease is progressive. Although the disease is considered not to have progressed when no new lesion is detected using conventional MRI, the increase in the ADC levels of the lesions indicates that degeneration actually continues and that the disease is progressive [16]. Involvement of ME in similar locations in four patients (cases 4, 5, 9 and 10) in the present study who were siblings was correlated with the hereditary characteristic of the disease [3,4]. MELAS is the first single entity from the mitochondrial encephalopathies, which was recently investigated by various authors by means of DWI [20–22]. MELAS includes mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes. It shows sudden neurological deficits known as the ‘stroke-like episodes’ [20]. As far as the pathophysiology of stroke-like episodes is concerned, mitochondrial angiopathy and cytopathy theories have been proposed but the subject remains the topic of much debate. ADCs in non-affected areas in MELAS patients are elevated when compared to normal subjects. Pathological changes take place in the non-affected areas [21]. In patients with MELAS the cytotoxic oedema evolves gradually, following an acute stroke-like episode, and that may overlap with hyper-perfusion and vasogenic oedema. The edematous swelling is either reversible or will evolve to encephalomalacia, what suggests irreversible damage [22]. Gelal et al., in their study regarding the role of DWI in children younger than 2 years, evaluated 60 patients retrospectively [23]. They added single-shot EPI spin echo DWI examination to routine brain MRI protocols and reported that DWI provided additional information for the routine examination in patients with acute neurological symptoms (lasting < 7 days) [23]. However, these authors did not undertake ADC measurements in lesions, although they used an ADC map in their study. Sener classified various cerebral pathologies according to the white matter ADC values in his study, in which paediatric and adult patients were included. However, the separate ADC values for each patient group were not reported [24]. The difference found in ADC values relative to the control group in the areas in which no signal change were detected in the conventional sequences in two patients in our study, indicated that DWI makes an additional diagnostic contribution to the routine examination by defining additional lesions, demarking the lesions with certain limits and determining the different diffusion characteristics in the lesions which are homogeneous hyperintense in spin echo T2 images, in agreement with a study carried out by Gelal et al. [23]. There have been only a limited number of previous studies performed using DWI in children with ME. In this disease, the cytotoxic oedema in the pathologic regions may not cause a sufficiently large shift in water molecule flow for it to be identified on conventional MRI sequences. While the conventional images remain as false negative in these regions, DWI can detect them more accurately because it is sensitive to the motions of water molecules. Additionally, difference can be demonstrated by comparing the measurements made in locations with diffusion abnormalities on the ADC map with the normal control group.
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Few studies on the DWI and ADC measurements regarding ME have been published, and these have involved a limited number of patients. The findings of our study were similar to these studies. However, there is very little information regarding follow-up examinations in the literature. In this respect our study provides valuable new information. It the current study, we found that DWI, which we used in addition to conventional MRI examination, increased diagnostic effectiveness by defining additional lesions and revealing their prevalence and intensity more accurately. DWI can also distinguish whether or not the lesions are in an early or late stage of development by supporting the evaluation of the underlying pathology; this is achieved by identifying the different diffusion characteristics in the homogeneous hyperintense lesions on T2 weighted images. One of the important advantages of this method is that numerical values can be obtained by undertaking ADC measurements. Therefore, the pathological areas can be objectively evaluated. The evaluation of isotropic diffusion weighted MR images using the ADC map prevents the T2 prolongation (T2 shine-through effect) mimicking the restricted diffusion. In conclusion, DWI provides information that complements conventional MR sequences in the diagnosis of ME in paediatric patients and makes an important contribution to the determination of a lesion’s age, degeneration rate and involvement in the areas in which no signal change is seen; it is also useful in the follow-up of disease progression. While there can be a numerical and spatial increase in lesions, the increase in ADC values indicates continuing in-lesion degeneration and disease progression. ADC measurement should be included as part of the sequence in routine brain MRI examination. There have been a limited number of studies on this subject in the literature, and our study provides important new findings. Studies involving more patients and including control follow-ups are needed in the future. Conflict of interest None declared. Acknowledgement We thank to “Edanz Editing-Springer” for language advice. References [1] Lyon G, Fattal-Valevski A, Kolodny EH. Leukodystrophies: clinical and genetic aspects. Top Magn Reson Imaging 2006;17:219–42.
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