Neuronal loss is an early component of subacute sclerosing panencephalitis
Deniz Yüksel, MD Barıs¸ Diren, MD Hakan Ulubay, MD S¸akir Altunbas¸ak, MD Banu Anlar, MD
Correspondence to Dr Yüksel: [email protected]
ABSTRACT
Objective: We performed diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) studies in a group of patients with subacute sclerosing panencephalitis (SSPE) in order to estimate the pathologic process underlying the phenotypic variability.
Methods: Patients with SSPE who had MRI including DTI and MRS examinations were evaluated according to their clinical status as determined by the SSPE Scoring System and their mental age as determined by tests appropriate for age and developmental level. Comparisons of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values and metabolite ratios of frontal periventricular white matter, parieto-occipital periventricular white matter, and globus pallidus in both hemispheres were made between control and SSPE groups, and between SSPE subgroups.
Results: Control (n 5 18) and SSPE (n 5 39) groups differed in all DTI and MRS parameters except FA, choline (Cho), and Cho/creatine (Cr). SSPE cases had higher ADC and lower N-acetylaspartate (NAA), NAA/Cho, and NAA/Cr in all regions of interest, suggesting cell loss. Disease progression rate and neurologic deficit appeared to be associated with the degree of ADC elevation and NAA reduction: the group with severe global deterioration had the lowest NAA (230.75 6 197.97 in forceps minor), and rapid progression was associated with acute reduction in NAA. Conclusions: The combination of MRS and diffusion MRI findings suggests neuronal loss can be a primary target in rapidly or subacutely progressing SSPE, and preservation or regeneration of axonal structure may be beneficial in chronic cases. Neurology® 2014;83:938–944 GLOSSARY ADC 5 apparent diffusion coefficient; Cho 5 choline; Cr 5 creatine; DTI 5 diffusion tensor imaging; FA 5 fractional anisotropy; Ig 5 immunoglobulin; MRS 5 magnetic resonance spectroscopy; NAA 5 N-acetylaspartate; NEX 5 number of excitations; ROI 5 region of interest; SSPE 5 subacute sclerosing panencephalitis; SSS 5 SSPE Scoring System; TE 5 echo time; TR 5 repetition time; VOI 5 volume of interest.
Subacute sclerosing panencephalitis (SSPE) is described as a progressive disease ending fatally in a few years caused by persistence of measles virus after primary infection encountered in young childhood or infancy. However, certain patients remain ambulatory for decades after diagnosis, experience long-lasting remissions after bedbound state, or, in contrast, undergo fulminant course and death in a few weeks.1 Reasons for this variability are unclear. The evolution pattern of the infection may play a role: pathologic and radiologic studies indicate initial involvement of occipital lobes progressing anteriorly and mesially in most patients. Basal ganglia and brainstem lesions usually appear at late stages: their early involvement is associated with rapid progression.2,3 The extent and degree of various pathologic processes may also play a part: microglial activation, astrocytosis, lymphocytic infiltration, neuronal death, axonal loss, demyelination, and tangle formation have all been demonstrated at various grades in SSPE.4–6 Advanced imaging techniques such as diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) can reveal information about myelin, axons, and cellular Supplemental data at Neurology.org All authors contributed equally to the manuscript. From the Department of Pediatric Neurology (D.Y.), Dr. Sami Ulus Children’s Hospital, Ankara; Department of Radiology (B.D., H.U.), Ankara Medicana Hospital, Ankara; Department of Pediatric Neurology (S.A.), Çukurova University Faculty of Medicine, Adana; and Department of Pediatric Neurology (B.A.), Hacettepe University Faculty of Medicine, Ankara, Turkey. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 938
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components of brain tissue. DTI is sensitive to diffusion patterns of water molecules, and fractional anisotropy (FA) measures directionality of water diffusion which is limited in fibrillary tissue, resulting in anisotropic diffusion. Although DTI produces variable results in disorders in which demyelination, axonal loss, gliosis, and inflammation co-occur, demyelination and inflammation generally reduce FA.7 Vasogenic edema, demyelination, and neuronal and synaptic loss expand the extracellular space and increase diffusion in apparent diffusion coefficient (ADC) maps. MRS allows estimation of neuronal loss and cellular turnover. We examined a series of SSPE patients with DTI and MRS in order to estimate pathologic processes underlying phenotypic variability. METHODS Patients. Thirty-nine patients diagnosed with SSPE were included (table e-1 on the Neurology® Web site at Neurology.org). The diagnosis was made according to the following criteria1: (1) clinical features: mental regression, behavioral changes, and myoclonia in a previously healthy child; (2) EEG findings of periodical high-amplitude sharp and slow waves not suppressed by IV diazepam; and (3) elevated measles immunoglobulin (Ig) G in CSF or measles-specific IgG index in the CSF (elevated index .1.5). Patients with SSPE who had MRI including DTI and MRS examinations were evaluated by the authors (B.A., D.Y.) according to their clinical status as determined by the SSPE Scoring System (SSS) and their mental age as determined by tests appropriate for age and developmental level.1,8 The SSS covers myoclonia, convulsions, behavior, hearing, speech, strength, movement, coordination, sensory and autonomic functions, and feeding (table e-2). There were 18 males and 21 females in the SSPE group, with a median age of 13 6 4.7 years (range: 7–37 years). The age-matched control group consisted of 10 males and 8 females, with a median age of 15.5 6 3.4 years (range: 5–20 years) who underwent imaging because of headache and received the final diagnosis of migraine or tension headache. Parental consent and ethical approval were obtained. Patients with SSPE who had been clinically stable in the last 2 years were grouped according to their motor and mental functions during this period: • Group 1 (preserved motor and mental function): mental age $50% of chronological age and no gross motor deficit on neurologic examination (walks and uses hands independently) • Group 2 (motor preserved and mental deteriorated): mental age #50% of chronological age and no major motor deficit on neurologic examination (walks and uses hands independently) • Group 3 (chronic motor and mental deteriorated): mental age #50% of chronological age and maximum motor capacity is standing with assistance In patients with evolving disease, clinical course was classified according to the rate of progression: • Rapidly progressive: SSS increases more than 30% per month • Subacute: SSS increases 5%–10% per month
• Slowly progressive: SSS increases 0.5%–5% per month • Remission: SSS decreases at least 10% per month, sustained for 3 months or longer
Standard protocol approvals, registrations, and patient consents. We received approval of the ethical standards committee (2010/8). Written parental consent and, when appropriate, child assent, was obtained in all cases.
Imaging. All MRIs were performed on a 1.5T MRI unit (Achieva, Philips Medical, Best, the Netherlands) with an actively shielded whole-body magnetic field gradient set (maximal strength of 33 mT/m) and a quadrature birdcage head coil. The conventional MRI protocol included a T2-weighted fast spinecho sequence with repetition time (TR)/echo time (TE)/echo train length/number of excitations (NEX) 5 4,000/100 ms/16/2; a T1-weighted spin-echo sequence with TR/TE/NEX 5 500/15 ms/1; and a fluid-attenuated inversion recovery sequence with TR/TE/inversion time 5 8,000/120/2,000 ms. DTI data were acquired using a single-shot echo-planar dual spin-echo sequence with ramp sampling. The diffusion-weighting b-factor was set to 800 seconds/mm2, TR 7.6 seconds, TE 75 ms. A total of 36 axial sections were acquired with an image matrix of 256 3256 (following zero-filling). All imaging was performed in the axial plane and had identical geometric parameters: field of view 5 224 3 224 mm2, section thickness 5 2 mm, section gap 5 0, number of sections 5 36. The DTI data were processed as described elsewhere.9 The tensor field data and eigenvalues were used to compute the FA values. ADC was calculated and displayed on an ADC map. To facilitate region of interest (ROI) placement for quantitative analysis, we displayed the DTI-derived maps and overlaid them on images with different contrasts in 3 orthogonal planes for visual inspection. Regional FA and ADC values were obtained by placing rectangular ROIs on the periventricular frontal white matter (forceps minor), periventricular parieto-occipital white matter (forceps major), and globus pallidus at transverse plane through the third ventricle (figure 1, A and B). ROIs were placed on the same location in both cerebral hemispheres. The size of the ROI varied from 4 3 4 to 6 3 6 pixels (figure 1D). These ROIs were chosen because the periventricular areas are most commonly involved in SSPE and basal ganglia involvement appears to be related to prognosis.2,3,10 Multivoxel MRS datasets were acquired using point-resolved spectroscopy with the acquisition parameters of 2,000/144/1 (TR/ TE/NEX) and a transverse field of view of 224 mm with a 16 3 16 rectangular sampling array (figure 1C). After 3 orthogonal baseline images were obtained with automatic shimming of the magnetic field, a 30-mm-thick volume of interest (VOI) was identified. The VOI was placed through the third ventricle using the same positioning as in DTI maps, covering the frontal periventricular white matter and parieto-occipital white matter bilaterally. MRS data were accumulated after the optimal water signal intensity was suppressed using the chemical shift-selective technique. The spectrum was referenced to creatine (Cr) peak (3.02 ppm). The signals from choline (Cho), Cr, and N-acetylaspartate (NAA) were integrated. Resonances were assigned as described.11 All MRI examinations and measurements were evaluated by 2 experienced neuroradiologists (B.D., H.U.) blinded to the SSPE groups. Statistical analysis. Clinical data were compared statistically using multiple comparisons in case of statistical significance. Groups smaller than n 5 5 (slowly progressive, remission) were not analyzed statistically. Neurology 83
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Figure 1
Regions of interest, multivoxel spectroscopy technique, and lesion probability map
(A, B) Regions of interest (ROIs) placed in the periventricular white matter and globus pallidus. (C) Multivoxel spectroscopy technique from the same areas (right forceps minor). (D) Lesion probability map superimposed with ROIs: 75%–95% of lesions were in the areas of forceps minor-major (red), 15%–22% in the frontal and parieto-occipital subcortical white matter (pink), 10% in the central gray matter areas (globus pallidus-putamen) (green), and 2.5% in the temporal subcortical white matter (blue). 1 5 right forceps minor; 2 5 left forceps minor; 3 5 right globus pallidus/putamen; 4 5 left globus pallidus/putamen; 5 5 right forceps major; 6 5 left forceps major.
Comparisons of FA and ADC values and metabolite ratios of frontal periventricular white matter, parieto-occipital periventricular white matter, and globus pallidus in both hemispheres were made between control and SSPE groups, and between SSPE subgroups. Data were analyzed using SPSS for Windows 11.5 (version 11.5, Chicago, IL). The distribution of continuous variables was tested by the Shapiro-Wilk test for closeness to normal distribution. Descriptive statistics were expressed as mean 6 SD or median (minimum-maximum) for continuous variables; categorical variables were expressed as number of cases and percentile. Group mean values were compared by Student t test when there were 2 independent groups and with 1-way analysis of variance when there were more than 2 groups. Median values were compared using Mann–Whitney U test for 2 groups and Kruskal-Wallis test for more than 2 groups. When Kruskal-Wallis test results were significant, Conover nonparametric multiple comparison was used to determine the groups causing the difference. Categorical variables were examined with Pearson x2 or Fisher exact x2 test. The relation between continuous variables was examined by Spearman correlation test. A p value , 0.05 was considered significant. RESULTS Clinical data are shown in table 1. Control (n 5 18) and SSPE (n 5 39) groups, and SSPE 940
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subgroups, had similar age and sex distribution. By definition, mental age and SSS were different among stable SSPE subgroups, and disease duration differed between stable and other groups. Most lesions visible on MRI were located in the periventricular white matter (figure 1D). ROIs with and without lesions on conventional MRI did not show any difference in FA, ADC, and MRS measurements and were analyzed together. In general, lesioned and nonlesioned ROIs of SSPE cases and control ROIs differed in all DTI and MRS parameters except FA, Cho, and Cho/Cr. SSPE cases had higher ADC and lower NAA, NAA/Cho, and NAA/Cr values in bilateral forceps major, forceps minor, and globus pallidus measurements. ADC increased when FA decreased in most regions, and NAA was reduced in correlation with increased Cho in all regions measured. Comparisons between SSPE and controls, and between SSPE subgroups, are summarized in table 2 and figure 2, A–C. Group 1, preserved motor and mental function (n 5 9), had lower FA and higher ADC in bilateral forceps major compared to the control group, while FA in forceps minor and globus pallidus was similar to controls. ADC was higher than control subjects in forceps major, forceps minor, and globus pallidus, and similar to group 2. NAA was reduced to 30%– 84% of control values in all regions. NAA/Cr and NAA/Cho were lower than control subjects in all regions, and similar to group 2. Group 2, motor preserved and mental deteriorated (n 5 6), had FA values similar to controls in forceps major, forceps minor, and globus pallidus, while ADC was higher than control subjects in forceps major, forceps minor, and globus pallidus, and similar to group 1. NAA, NAA/Cr, and NAA/Cho were lower than (20%–72% of) control measurements in all regions and not different from group 1. Cho and Cho/Cr were similar to the control group in all regions. In group 3, chronic motor and mental deteriorated (n 5 10), FA was lowest among all groups in forceps major and minor while globus pallidus was similar to controls. ADC was highest in all locations and NAA lowest compared to control and other SSPE groups. Cho and Cho/Cr were not different from controls; NAA/Cr and NAA/Cho were lowest in all areas compared to control and SSPE groups 1 and 2. These values were similar to rapidly progressive and subacute groups. There were smaller groups (n 5 5 each) of rapidly progressive and subacute patients in whom low NAA was the main finding (table e-3). DISCUSSION Several reports have been published on MRI, MRS, and DTI findings in SSPE. Conventional MRI can be initially normal or demonstrate high signal intensity areas on T2-weighted images, which
Table 1
Clinical data of patients with SSPE
Group 1 (n 5 9)
Sex, M:F
Age, y
Disease duration, y
SSS
Mental status, %a
2:7
13 6 8.4 (9–37)
4 6 5.6 (1–20)
3 6 2.3 (0–8)
54 6 18 (40–100)
Group 2 (n 5 6)
2:4
13.5 6 2.5 (10–16)
5.5 6 0.9 (5–7)
5.5 6 2.8 (2–10)
25 6 14 (15–50)
Group 3 (n 5 10)
6:4
14 6 3 (10–20)
6 6 3 (3–12)
45 6 11.3 (23–60)
2.5 6 4.2 (1–12)
Rapidly progressive (n 5 5)
3:2
11 6 2 (10–15)
0.25 6 0.17 (1–6 months)
30 6 21 (6–55)
13 6 18 (0–38)
Subacute (n 5 5)
3:2
11 6 3.2 (7–16)
3 6 3.3 (1–8 months)
25 6 20 (6–58)
46 6 20 (18–63)
Slowly progressive (n 5 2)
1:1
11 6 1.4 (10–12)
0.95 6 0.7 (5–18 months)
2.5 6 0.7 (2–3)
68 6 2.8 (66–70)
Remission (n 5 2)
1:1
11.5 6 0.7 (11–12)
3.75 6 1.7 (2.5–5)
7.5 6 3.5 (5–10)
47.5 6 9 (41–54)
Total (n 5 39)
18:21
13 6 4.7 (7–37)
4 6 3.9 (1 month-20 years)
9 6 20 (0–60)
36 6 26 (0–100)
Abbreviations: SSPE 5 subacute sclerosing panencephalitis; SSS 5 SSPE Scoring System1 (maximum score is 80). Data are presented as mean 6 SD (range), unless otherwise indicated. a Mental status is the ratio of mental age/chronological age.
“normal areas” on routine MRI can be similar to lesioned areas, as observed in our study.13,14 In our series, the majority of the lesioned areas included the forceps major, where imaging parameters also tended to be abnormal. All studies using advanced imaging techniques in SSPE have examined the results in relation to the
are frequently asymmetrical and involve the parietooccipital more than frontal white matter. Cerebral cortex is involved early, and deep white matter and midline structures are involved later in the disease.2,12 Abnormalities on DTI and MRS have been described even in regions of normal appearance on routine MRI. Therefore DTI and MRS measurements of the
Table 2
Comparisons between SSPE subgroups and controls Subgroups according to neurologic status Control
Group 1
Group 2
Group 3
0.35 6 0.03
0.29 6 0.07a
0.34 6 0.10d
0.18 6 0.07b,c,d
a
0.17 6 0.07c,d,e
FA F.maj F.min
0.32 6 0.07
0.31 6 0.06
0.37 6 0.05
G.pal
0.60 6 0.17
0.42 6 0.10
0.42 6 0.11
0.85 6 0.27
1.20 6 0.19a
1.30 6 0.39a
1.55 6 0.30b,c,d
F.min
0.86 6 0.15
1.00 6 0.18
a
a
1.51 6 0.29b,c,d
G.pal
0.75 6 0.14
0.81 6 0.11a
0.85 6 0.10a
1.01 6 0.52c,e,f
F.maj
1,692.31 6 813.66
528.75 6 421.58c
473.13 6 552.12c
339.10 6 234.24b,c,d
F.min
850.45 6 449.50
709.12 6 361.27
511.35 6 413.36a
230.75 6 197.97b,c,d
G.pal
1,908.25 6 540.16
1,448.25 6 442.25a
1,404.38 6 398.91a
724.30 6 311.52c,e,f
F.maj
2.93 6 0.70
1.04 6 0.50c
1.31 6 0.05a
0.59 6 0.33b,c,d
F.min
2.04 6 0.92
1.13 6 0.30a
1.01 6 0.07a
0.99 6 0.79c
2.25 6 0.51
a
a
0.38 6 0.10a
ADC F.maj
1.08 6 0.19
NAA
NAA/Cr
G.pal
1.52 6 0.73
1.59 6 0.82
1.14 6 0.42b,c,d
Abbreviations: ADC 5 apparent diffusion coefficient; Cr 5 creatine; FA 5 fractional anisotropy; F.maj 5 forceps major; F.min 5 forceps minor; G.pal 5 globus pallidus; NAA 5 N-acetylaspartate; SSPE 5 subacute sclerosing panencephalitis. Data are mean 6 SD. a Comparison between control and other subgroups (p , 0.05). b Comparison between group 2 and other subgroups (p , 0.05). c Comparison between control and other subgroups (p , 0.001). d Comparison between group 1 and other subgroups (p , 0.05). e Comparison between group 2 and other subgroups (p , 0.001). f Comparison between group 1 and other subgroups (p , 0.001). Neurology 83
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Figure 2
Comparisons between SSPE and control: FA, ADC, and NAA
Comparisons between SSPE and control, and between SSPE subgroups: FA (A), ADC (B), NAA (C). *Significantly different from the control group. **Significantly different from other SSPE subgroups. ADC 5 apparent diffusion coefficient; FA 5 fractional anisotropy; NAA 5 N-acetylaspartate; SSPE 5 subacute sclerosing panencephalitis.
stage of the disease.13,15 Although clinical staging is a good indicator of motor disability, it does not take into account mental status and duration of disease: a stage 2 patient may have been affected for many years while another patient can progress to stage 3 in a few months. The current study correlates imaging findings with 2 clinical variables, rate of progression and type of deficit, in order to estimate the corresponding pathologic processes and their regional distribution. Reduced FA on DTI may represent abnormalities of white matter tracts.7 ADC maps provide information about the structure of brain tissue. Subtle pathologic damage resulting in diffusion of water in the 942
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extracellular compartment, such as vasogenic edema, can be undetected on conventional MRI but observed on ADC maps.16 One consistent finding was increased ADC in the presence of unchanged FA in groups 1 and 2 who have preserved function, at least in the motor domain. This suggests widening of extracellular space but intact axonal tracts, which could be due to vasogenic edema or cell loss. We consider the latter more likely because NAA was also reduced in the same areas. FA is sensitive to microstructural changes in the white matter: pathologic conditions often reduce FA, but demyelination may increase FA. No ADC change but low FA was observed in certain areas, such as the internal capsule, in early SSPE, interpreted as inflammation and myelin debris reducing diffusivity in some recent studies.13,17 Our results showed the opposite: unchanged FA disproves structural disturbance, and increased diffusion in most areas suggests loss of myelin or cells. Only in chronic SSPE with mental and motor deficit were ADC changes accompanied by FA changes, which also argues against a short-term process such as edema and supports cell loss as the underlying mechanism. Two studies of 18 and 26 patients with SSPE found elevated ADC, higher in stage 3 than stage 2.18,19 Two rapidly progressive cases of SSPE with elevated or, on the contrary, reduced diffusion coefficients on ADC maps, markedly decreased NAA, and normal Cho in the lesions were reported.20,21 Rapidly progressive SSPE can indeed show a mixed diffusion pattern.22 The progression rate, in addition to the clinical status, is a factor likely to affect imaging results. We did not explore radial or axial diffusivity separately: further studies can assess axonal damage in relation to course. FA was lower in the white matter compared to the globus pallidus in our patient and control groups. This finding may be due to the effect of fiber crossing and the forceps major and minor not being compact white matter tracts such as the corpus callosum or corticospinal tract. Indeed, FA values of frontal white matter and globus pallidus often overlap because the globus pallidus has higher FA than the other deep gray nuclei while the frontal white matter has lower FA than the corpus callosum.23,24 On MRS, reduced NAA and unchanged Cr in T1-hypointense lesions agree with several previous studies reporting markedly decreased NAA peaks in most SSPE cases, attributed to severe neuronal loss.10,14,20 Reduced NAA could be attributed to metabolic dysfunction resulting from viral infection; however, the chronicity of these lesions, and the very remarkable NAA reduction in the most chronic patients, favors the possibility of neuronal loss. We found low NAA but unchanged Cho in normalappearing parenchyma, suggesting axonal or neuronal loss even in regions with no apparent lesion or black
hole. Cell death can be due to apoptosis or oxidative stress in SSPE.25–27 Among our clinical subgroups, the only difference between group 1 and group 29s diffusivity parameters was lower FA in the forceps major in group 1, a finding unlikely to explain group 1’s higher mental function. NAA was higher in the forceps minor of group 1 compared to group 2 (84% vs 60% of control value). This difference might underlie the relative superiority of mental function in group 1. Group 3 with motor and mental deterioration had generally very low FA except in the globus pallidus and very high ADC and very low NAA in all regions, supporting axonal and neuronal loss associated with severe, global deficit. Rapidly progressive and subacute cases had low NAA but normal DTI parameters. Our previous report of 2 rapidly progressive cases also demonstrated uniformly reduced NAA.22 This finding supports early neuronal loss as the main pathogenetic mechanism determining rate of progression. On the other hand, subacute and remission patients have lower FA and higher ADC like group 3 (unpublished data), supporting the role of disease duration in diffusion changes. More patients in remission need to be studied to support these findings. In SSPE, biopsy and autopsy material show mononuclear cell infiltration into the meninges and brain tissues. Gliosis, astrocytic proliferation, neuronal degeneration, and demyelination are observed at various degrees.1 We did not have any biopsy or autopsy material from these cases. Combination of advanced imaging studies and pathologic findings would considerably improve knowledge regarding pathogenesis. This study examines clinical, DTI, and MRS data simultaneously in patients with SSPE. Patients with SSPE had higher ADC and reduced NAA, NAA/ Cho, and NAA/Cr compared to controls. The combination of MRS and diffusion MRI findings suggests that neuronal loss can be a primary target in rapidly progressing SSPE, and preservation or regeneration of axonal structure may be beneficial in chronic cases. AUTHOR CONTRIBUTIONS Deniz Yüksel: analysis and interpretation of data and manuscript preparation. Barıs¸ Diren: acquisition of data. Hakan Ulubay: acquisition of data. S¸akir Altunbas¸ak: patient selection and acquisition of data. Banu Anlar: study concept and design and manuscript preparation.
ACKNOWLEDGMENT The authors thank As¸kın Yes¸ilyurt for technical assistance; the SSPE Association, Istanbul/Turkey for their support of the study; colleagues Ilknur Erol, MD and Alev Guven, MD for their contribution of patient data; and all patients and parents who participated.
STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
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Neuronal loss is an early component of subacute sclerosing panencephalitis Deniz Yüksel, Baris Diren, Hakan Ulubay, et al. Neurology 2014;83;938-944 Published Online before print August 1, 2014 DOI 10.1212/WNL.0000000000000749 This information is current as of August 1, 2014 Updated Information & Services
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Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/08/01/WNL.0000000000 000749.DC1.html
References
This article cites 26 articles, 9 of which you can access for free at: http://www.neurology.org/content/83/10/938.full.html##ref-list-1
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This article, along with others on similar topics, appears in the following collection(s): All Demyelinating disease (CNS) http://www.neurology.org//cgi/collection/all_demyelinating_disease_cn s MRS http://www.neurology.org//cgi/collection/mrs Post-infectious http://www.neurology.org//cgi/collection/postinfectious_ Viral infections http://www.neurology.org//cgi/collection/viral_infections
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Deniz Yüksel, MD Barıs¸ Diren, MD Hakan Ulubay, MD S¸akir Altunbas¸ak, MD Banu Anlar, MD
Correspondence to Dr Yüksel: [email protected]
ABSTRACT
Objective: We performed diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) studies in a group of patients with subacute sclerosing panencephalitis (SSPE) in order to estimate the pathologic process underlying the phenotypic variability.
Methods: Patients with SSPE who had MRI including DTI and MRS examinations were evaluated according to their clinical status as determined by the SSPE Scoring System and their mental age as determined by tests appropriate for age and developmental level. Comparisons of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values and metabolite ratios of frontal periventricular white matter, parieto-occipital periventricular white matter, and globus pallidus in both hemispheres were made between control and SSPE groups, and between SSPE subgroups.
Results: Control (n 5 18) and SSPE (n 5 39) groups differed in all DTI and MRS parameters except FA, choline (Cho), and Cho/creatine (Cr). SSPE cases had higher ADC and lower N-acetylaspartate (NAA), NAA/Cho, and NAA/Cr in all regions of interest, suggesting cell loss. Disease progression rate and neurologic deficit appeared to be associated with the degree of ADC elevation and NAA reduction: the group with severe global deterioration had the lowest NAA (230.75 6 197.97 in forceps minor), and rapid progression was associated with acute reduction in NAA. Conclusions: The combination of MRS and diffusion MRI findings suggests neuronal loss can be a primary target in rapidly or subacutely progressing SSPE, and preservation or regeneration of axonal structure may be beneficial in chronic cases. Neurology® 2014;83:938–944 GLOSSARY ADC 5 apparent diffusion coefficient; Cho 5 choline; Cr 5 creatine; DTI 5 diffusion tensor imaging; FA 5 fractional anisotropy; Ig 5 immunoglobulin; MRS 5 magnetic resonance spectroscopy; NAA 5 N-acetylaspartate; NEX 5 number of excitations; ROI 5 region of interest; SSPE 5 subacute sclerosing panencephalitis; SSS 5 SSPE Scoring System; TE 5 echo time; TR 5 repetition time; VOI 5 volume of interest.
Subacute sclerosing panencephalitis (SSPE) is described as a progressive disease ending fatally in a few years caused by persistence of measles virus after primary infection encountered in young childhood or infancy. However, certain patients remain ambulatory for decades after diagnosis, experience long-lasting remissions after bedbound state, or, in contrast, undergo fulminant course and death in a few weeks.1 Reasons for this variability are unclear. The evolution pattern of the infection may play a role: pathologic and radiologic studies indicate initial involvement of occipital lobes progressing anteriorly and mesially in most patients. Basal ganglia and brainstem lesions usually appear at late stages: their early involvement is associated with rapid progression.2,3 The extent and degree of various pathologic processes may also play a part: microglial activation, astrocytosis, lymphocytic infiltration, neuronal death, axonal loss, demyelination, and tangle formation have all been demonstrated at various grades in SSPE.4–6 Advanced imaging techniques such as diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) can reveal information about myelin, axons, and cellular Supplemental data at Neurology.org All authors contributed equally to the manuscript. From the Department of Pediatric Neurology (D.Y.), Dr. Sami Ulus Children’s Hospital, Ankara; Department of Radiology (B.D., H.U.), Ankara Medicana Hospital, Ankara; Department of Pediatric Neurology (S.A.), Çukurova University Faculty of Medicine, Adana; and Department of Pediatric Neurology (B.A.), Hacettepe University Faculty of Medicine, Ankara, Turkey. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 938
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components of brain tissue. DTI is sensitive to diffusion patterns of water molecules, and fractional anisotropy (FA) measures directionality of water diffusion which is limited in fibrillary tissue, resulting in anisotropic diffusion. Although DTI produces variable results in disorders in which demyelination, axonal loss, gliosis, and inflammation co-occur, demyelination and inflammation generally reduce FA.7 Vasogenic edema, demyelination, and neuronal and synaptic loss expand the extracellular space and increase diffusion in apparent diffusion coefficient (ADC) maps. MRS allows estimation of neuronal loss and cellular turnover. We examined a series of SSPE patients with DTI and MRS in order to estimate pathologic processes underlying phenotypic variability. METHODS Patients. Thirty-nine patients diagnosed with SSPE were included (table e-1 on the Neurology® Web site at Neurology.org). The diagnosis was made according to the following criteria1: (1) clinical features: mental regression, behavioral changes, and myoclonia in a previously healthy child; (2) EEG findings of periodical high-amplitude sharp and slow waves not suppressed by IV diazepam; and (3) elevated measles immunoglobulin (Ig) G in CSF or measles-specific IgG index in the CSF (elevated index .1.5). Patients with SSPE who had MRI including DTI and MRS examinations were evaluated by the authors (B.A., D.Y.) according to their clinical status as determined by the SSPE Scoring System (SSS) and their mental age as determined by tests appropriate for age and developmental level.1,8 The SSS covers myoclonia, convulsions, behavior, hearing, speech, strength, movement, coordination, sensory and autonomic functions, and feeding (table e-2). There were 18 males and 21 females in the SSPE group, with a median age of 13 6 4.7 years (range: 7–37 years). The age-matched control group consisted of 10 males and 8 females, with a median age of 15.5 6 3.4 years (range: 5–20 years) who underwent imaging because of headache and received the final diagnosis of migraine or tension headache. Parental consent and ethical approval were obtained. Patients with SSPE who had been clinically stable in the last 2 years were grouped according to their motor and mental functions during this period: • Group 1 (preserved motor and mental function): mental age $50% of chronological age and no gross motor deficit on neurologic examination (walks and uses hands independently) • Group 2 (motor preserved and mental deteriorated): mental age #50% of chronological age and no major motor deficit on neurologic examination (walks and uses hands independently) • Group 3 (chronic motor and mental deteriorated): mental age #50% of chronological age and maximum motor capacity is standing with assistance In patients with evolving disease, clinical course was classified according to the rate of progression: • Rapidly progressive: SSS increases more than 30% per month • Subacute: SSS increases 5%–10% per month
• Slowly progressive: SSS increases 0.5%–5% per month • Remission: SSS decreases at least 10% per month, sustained for 3 months or longer
Standard protocol approvals, registrations, and patient consents. We received approval of the ethical standards committee (2010/8). Written parental consent and, when appropriate, child assent, was obtained in all cases.
Imaging. All MRIs were performed on a 1.5T MRI unit (Achieva, Philips Medical, Best, the Netherlands) with an actively shielded whole-body magnetic field gradient set (maximal strength of 33 mT/m) and a quadrature birdcage head coil. The conventional MRI protocol included a T2-weighted fast spinecho sequence with repetition time (TR)/echo time (TE)/echo train length/number of excitations (NEX) 5 4,000/100 ms/16/2; a T1-weighted spin-echo sequence with TR/TE/NEX 5 500/15 ms/1; and a fluid-attenuated inversion recovery sequence with TR/TE/inversion time 5 8,000/120/2,000 ms. DTI data were acquired using a single-shot echo-planar dual spin-echo sequence with ramp sampling. The diffusion-weighting b-factor was set to 800 seconds/mm2, TR 7.6 seconds, TE 75 ms. A total of 36 axial sections were acquired with an image matrix of 256 3256 (following zero-filling). All imaging was performed in the axial plane and had identical geometric parameters: field of view 5 224 3 224 mm2, section thickness 5 2 mm, section gap 5 0, number of sections 5 36. The DTI data were processed as described elsewhere.9 The tensor field data and eigenvalues were used to compute the FA values. ADC was calculated and displayed on an ADC map. To facilitate region of interest (ROI) placement for quantitative analysis, we displayed the DTI-derived maps and overlaid them on images with different contrasts in 3 orthogonal planes for visual inspection. Regional FA and ADC values were obtained by placing rectangular ROIs on the periventricular frontal white matter (forceps minor), periventricular parieto-occipital white matter (forceps major), and globus pallidus at transverse plane through the third ventricle (figure 1, A and B). ROIs were placed on the same location in both cerebral hemispheres. The size of the ROI varied from 4 3 4 to 6 3 6 pixels (figure 1D). These ROIs were chosen because the periventricular areas are most commonly involved in SSPE and basal ganglia involvement appears to be related to prognosis.2,3,10 Multivoxel MRS datasets were acquired using point-resolved spectroscopy with the acquisition parameters of 2,000/144/1 (TR/ TE/NEX) and a transverse field of view of 224 mm with a 16 3 16 rectangular sampling array (figure 1C). After 3 orthogonal baseline images were obtained with automatic shimming of the magnetic field, a 30-mm-thick volume of interest (VOI) was identified. The VOI was placed through the third ventricle using the same positioning as in DTI maps, covering the frontal periventricular white matter and parieto-occipital white matter bilaterally. MRS data were accumulated after the optimal water signal intensity was suppressed using the chemical shift-selective technique. The spectrum was referenced to creatine (Cr) peak (3.02 ppm). The signals from choline (Cho), Cr, and N-acetylaspartate (NAA) were integrated. Resonances were assigned as described.11 All MRI examinations and measurements were evaluated by 2 experienced neuroradiologists (B.D., H.U.) blinded to the SSPE groups. Statistical analysis. Clinical data were compared statistically using multiple comparisons in case of statistical significance. Groups smaller than n 5 5 (slowly progressive, remission) were not analyzed statistically. Neurology 83
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Figure 1
Regions of interest, multivoxel spectroscopy technique, and lesion probability map
(A, B) Regions of interest (ROIs) placed in the periventricular white matter and globus pallidus. (C) Multivoxel spectroscopy technique from the same areas (right forceps minor). (D) Lesion probability map superimposed with ROIs: 75%–95% of lesions were in the areas of forceps minor-major (red), 15%–22% in the frontal and parieto-occipital subcortical white matter (pink), 10% in the central gray matter areas (globus pallidus-putamen) (green), and 2.5% in the temporal subcortical white matter (blue). 1 5 right forceps minor; 2 5 left forceps minor; 3 5 right globus pallidus/putamen; 4 5 left globus pallidus/putamen; 5 5 right forceps major; 6 5 left forceps major.
Comparisons of FA and ADC values and metabolite ratios of frontal periventricular white matter, parieto-occipital periventricular white matter, and globus pallidus in both hemispheres were made between control and SSPE groups, and between SSPE subgroups. Data were analyzed using SPSS for Windows 11.5 (version 11.5, Chicago, IL). The distribution of continuous variables was tested by the Shapiro-Wilk test for closeness to normal distribution. Descriptive statistics were expressed as mean 6 SD or median (minimum-maximum) for continuous variables; categorical variables were expressed as number of cases and percentile. Group mean values were compared by Student t test when there were 2 independent groups and with 1-way analysis of variance when there were more than 2 groups. Median values were compared using Mann–Whitney U test for 2 groups and Kruskal-Wallis test for more than 2 groups. When Kruskal-Wallis test results were significant, Conover nonparametric multiple comparison was used to determine the groups causing the difference. Categorical variables were examined with Pearson x2 or Fisher exact x2 test. The relation between continuous variables was examined by Spearman correlation test. A p value , 0.05 was considered significant. RESULTS Clinical data are shown in table 1. Control (n 5 18) and SSPE (n 5 39) groups, and SSPE 940
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subgroups, had similar age and sex distribution. By definition, mental age and SSS were different among stable SSPE subgroups, and disease duration differed between stable and other groups. Most lesions visible on MRI were located in the periventricular white matter (figure 1D). ROIs with and without lesions on conventional MRI did not show any difference in FA, ADC, and MRS measurements and were analyzed together. In general, lesioned and nonlesioned ROIs of SSPE cases and control ROIs differed in all DTI and MRS parameters except FA, Cho, and Cho/Cr. SSPE cases had higher ADC and lower NAA, NAA/Cho, and NAA/Cr values in bilateral forceps major, forceps minor, and globus pallidus measurements. ADC increased when FA decreased in most regions, and NAA was reduced in correlation with increased Cho in all regions measured. Comparisons between SSPE and controls, and between SSPE subgroups, are summarized in table 2 and figure 2, A–C. Group 1, preserved motor and mental function (n 5 9), had lower FA and higher ADC in bilateral forceps major compared to the control group, while FA in forceps minor and globus pallidus was similar to controls. ADC was higher than control subjects in forceps major, forceps minor, and globus pallidus, and similar to group 2. NAA was reduced to 30%– 84% of control values in all regions. NAA/Cr and NAA/Cho were lower than control subjects in all regions, and similar to group 2. Group 2, motor preserved and mental deteriorated (n 5 6), had FA values similar to controls in forceps major, forceps minor, and globus pallidus, while ADC was higher than control subjects in forceps major, forceps minor, and globus pallidus, and similar to group 1. NAA, NAA/Cr, and NAA/Cho were lower than (20%–72% of) control measurements in all regions and not different from group 1. Cho and Cho/Cr were similar to the control group in all regions. In group 3, chronic motor and mental deteriorated (n 5 10), FA was lowest among all groups in forceps major and minor while globus pallidus was similar to controls. ADC was highest in all locations and NAA lowest compared to control and other SSPE groups. Cho and Cho/Cr were not different from controls; NAA/Cr and NAA/Cho were lowest in all areas compared to control and SSPE groups 1 and 2. These values were similar to rapidly progressive and subacute groups. There were smaller groups (n 5 5 each) of rapidly progressive and subacute patients in whom low NAA was the main finding (table e-3). DISCUSSION Several reports have been published on MRI, MRS, and DTI findings in SSPE. Conventional MRI can be initially normal or demonstrate high signal intensity areas on T2-weighted images, which
Table 1
Clinical data of patients with SSPE
Group 1 (n 5 9)
Sex, M:F
Age, y
Disease duration, y
SSS
Mental status, %a
2:7
13 6 8.4 (9–37)
4 6 5.6 (1–20)
3 6 2.3 (0–8)
54 6 18 (40–100)
Group 2 (n 5 6)
2:4
13.5 6 2.5 (10–16)
5.5 6 0.9 (5–7)
5.5 6 2.8 (2–10)
25 6 14 (15–50)
Group 3 (n 5 10)
6:4
14 6 3 (10–20)
6 6 3 (3–12)
45 6 11.3 (23–60)
2.5 6 4.2 (1–12)
Rapidly progressive (n 5 5)
3:2
11 6 2 (10–15)
0.25 6 0.17 (1–6 months)
30 6 21 (6–55)
13 6 18 (0–38)
Subacute (n 5 5)
3:2
11 6 3.2 (7–16)
3 6 3.3 (1–8 months)
25 6 20 (6–58)
46 6 20 (18–63)
Slowly progressive (n 5 2)
1:1
11 6 1.4 (10–12)
0.95 6 0.7 (5–18 months)
2.5 6 0.7 (2–3)
68 6 2.8 (66–70)
Remission (n 5 2)
1:1
11.5 6 0.7 (11–12)
3.75 6 1.7 (2.5–5)
7.5 6 3.5 (5–10)
47.5 6 9 (41–54)
Total (n 5 39)
18:21
13 6 4.7 (7–37)
4 6 3.9 (1 month-20 years)
9 6 20 (0–60)
36 6 26 (0–100)
Abbreviations: SSPE 5 subacute sclerosing panencephalitis; SSS 5 SSPE Scoring System1 (maximum score is 80). Data are presented as mean 6 SD (range), unless otherwise indicated. a Mental status is the ratio of mental age/chronological age.
“normal areas” on routine MRI can be similar to lesioned areas, as observed in our study.13,14 In our series, the majority of the lesioned areas included the forceps major, where imaging parameters also tended to be abnormal. All studies using advanced imaging techniques in SSPE have examined the results in relation to the
are frequently asymmetrical and involve the parietooccipital more than frontal white matter. Cerebral cortex is involved early, and deep white matter and midline structures are involved later in the disease.2,12 Abnormalities on DTI and MRS have been described even in regions of normal appearance on routine MRI. Therefore DTI and MRS measurements of the
Table 2
Comparisons between SSPE subgroups and controls Subgroups according to neurologic status Control
Group 1
Group 2
Group 3
0.35 6 0.03
0.29 6 0.07a
0.34 6 0.10d
0.18 6 0.07b,c,d
a
0.17 6 0.07c,d,e
FA F.maj F.min
0.32 6 0.07
0.31 6 0.06
0.37 6 0.05
G.pal
0.60 6 0.17
0.42 6 0.10
0.42 6 0.11
0.85 6 0.27
1.20 6 0.19a
1.30 6 0.39a
1.55 6 0.30b,c,d
F.min
0.86 6 0.15
1.00 6 0.18
a
a
1.51 6 0.29b,c,d
G.pal
0.75 6 0.14
0.81 6 0.11a
0.85 6 0.10a
1.01 6 0.52c,e,f
F.maj
1,692.31 6 813.66
528.75 6 421.58c
473.13 6 552.12c
339.10 6 234.24b,c,d
F.min
850.45 6 449.50
709.12 6 361.27
511.35 6 413.36a
230.75 6 197.97b,c,d
G.pal
1,908.25 6 540.16
1,448.25 6 442.25a
1,404.38 6 398.91a
724.30 6 311.52c,e,f
F.maj
2.93 6 0.70
1.04 6 0.50c
1.31 6 0.05a
0.59 6 0.33b,c,d
F.min
2.04 6 0.92
1.13 6 0.30a
1.01 6 0.07a
0.99 6 0.79c
2.25 6 0.51
a
a
0.38 6 0.10a
ADC F.maj
1.08 6 0.19
NAA
NAA/Cr
G.pal
1.52 6 0.73
1.59 6 0.82
1.14 6 0.42b,c,d
Abbreviations: ADC 5 apparent diffusion coefficient; Cr 5 creatine; FA 5 fractional anisotropy; F.maj 5 forceps major; F.min 5 forceps minor; G.pal 5 globus pallidus; NAA 5 N-acetylaspartate; SSPE 5 subacute sclerosing panencephalitis. Data are mean 6 SD. a Comparison between control and other subgroups (p , 0.05). b Comparison between group 2 and other subgroups (p , 0.05). c Comparison between control and other subgroups (p , 0.001). d Comparison between group 1 and other subgroups (p , 0.05). e Comparison between group 2 and other subgroups (p , 0.001). f Comparison between group 1 and other subgroups (p , 0.001). Neurology 83
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Figure 2
Comparisons between SSPE and control: FA, ADC, and NAA
Comparisons between SSPE and control, and between SSPE subgroups: FA (A), ADC (B), NAA (C). *Significantly different from the control group. **Significantly different from other SSPE subgroups. ADC 5 apparent diffusion coefficient; FA 5 fractional anisotropy; NAA 5 N-acetylaspartate; SSPE 5 subacute sclerosing panencephalitis.
stage of the disease.13,15 Although clinical staging is a good indicator of motor disability, it does not take into account mental status and duration of disease: a stage 2 patient may have been affected for many years while another patient can progress to stage 3 in a few months. The current study correlates imaging findings with 2 clinical variables, rate of progression and type of deficit, in order to estimate the corresponding pathologic processes and their regional distribution. Reduced FA on DTI may represent abnormalities of white matter tracts.7 ADC maps provide information about the structure of brain tissue. Subtle pathologic damage resulting in diffusion of water in the 942
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extracellular compartment, such as vasogenic edema, can be undetected on conventional MRI but observed on ADC maps.16 One consistent finding was increased ADC in the presence of unchanged FA in groups 1 and 2 who have preserved function, at least in the motor domain. This suggests widening of extracellular space but intact axonal tracts, which could be due to vasogenic edema or cell loss. We consider the latter more likely because NAA was also reduced in the same areas. FA is sensitive to microstructural changes in the white matter: pathologic conditions often reduce FA, but demyelination may increase FA. No ADC change but low FA was observed in certain areas, such as the internal capsule, in early SSPE, interpreted as inflammation and myelin debris reducing diffusivity in some recent studies.13,17 Our results showed the opposite: unchanged FA disproves structural disturbance, and increased diffusion in most areas suggests loss of myelin or cells. Only in chronic SSPE with mental and motor deficit were ADC changes accompanied by FA changes, which also argues against a short-term process such as edema and supports cell loss as the underlying mechanism. Two studies of 18 and 26 patients with SSPE found elevated ADC, higher in stage 3 than stage 2.18,19 Two rapidly progressive cases of SSPE with elevated or, on the contrary, reduced diffusion coefficients on ADC maps, markedly decreased NAA, and normal Cho in the lesions were reported.20,21 Rapidly progressive SSPE can indeed show a mixed diffusion pattern.22 The progression rate, in addition to the clinical status, is a factor likely to affect imaging results. We did not explore radial or axial diffusivity separately: further studies can assess axonal damage in relation to course. FA was lower in the white matter compared to the globus pallidus in our patient and control groups. This finding may be due to the effect of fiber crossing and the forceps major and minor not being compact white matter tracts such as the corpus callosum or corticospinal tract. Indeed, FA values of frontal white matter and globus pallidus often overlap because the globus pallidus has higher FA than the other deep gray nuclei while the frontal white matter has lower FA than the corpus callosum.23,24 On MRS, reduced NAA and unchanged Cr in T1-hypointense lesions agree with several previous studies reporting markedly decreased NAA peaks in most SSPE cases, attributed to severe neuronal loss.10,14,20 Reduced NAA could be attributed to metabolic dysfunction resulting from viral infection; however, the chronicity of these lesions, and the very remarkable NAA reduction in the most chronic patients, favors the possibility of neuronal loss. We found low NAA but unchanged Cho in normalappearing parenchyma, suggesting axonal or neuronal loss even in regions with no apparent lesion or black
hole. Cell death can be due to apoptosis or oxidative stress in SSPE.25–27 Among our clinical subgroups, the only difference between group 1 and group 29s diffusivity parameters was lower FA in the forceps major in group 1, a finding unlikely to explain group 1’s higher mental function. NAA was higher in the forceps minor of group 1 compared to group 2 (84% vs 60% of control value). This difference might underlie the relative superiority of mental function in group 1. Group 3 with motor and mental deterioration had generally very low FA except in the globus pallidus and very high ADC and very low NAA in all regions, supporting axonal and neuronal loss associated with severe, global deficit. Rapidly progressive and subacute cases had low NAA but normal DTI parameters. Our previous report of 2 rapidly progressive cases also demonstrated uniformly reduced NAA.22 This finding supports early neuronal loss as the main pathogenetic mechanism determining rate of progression. On the other hand, subacute and remission patients have lower FA and higher ADC like group 3 (unpublished data), supporting the role of disease duration in diffusion changes. More patients in remission need to be studied to support these findings. In SSPE, biopsy and autopsy material show mononuclear cell infiltration into the meninges and brain tissues. Gliosis, astrocytic proliferation, neuronal degeneration, and demyelination are observed at various degrees.1 We did not have any biopsy or autopsy material from these cases. Combination of advanced imaging studies and pathologic findings would considerably improve knowledge regarding pathogenesis. This study examines clinical, DTI, and MRS data simultaneously in patients with SSPE. Patients with SSPE had higher ADC and reduced NAA, NAA/ Cho, and NAA/Cr compared to controls. The combination of MRS and diffusion MRI findings suggests that neuronal loss can be a primary target in rapidly progressing SSPE, and preservation or regeneration of axonal structure may be beneficial in chronic cases. AUTHOR CONTRIBUTIONS Deniz Yüksel: analysis and interpretation of data and manuscript preparation. Barıs¸ Diren: acquisition of data. Hakan Ulubay: acquisition of data. S¸akir Altunbas¸ak: patient selection and acquisition of data. Banu Anlar: study concept and design and manuscript preparation.
ACKNOWLEDGMENT The authors thank As¸kın Yes¸ilyurt for technical assistance; the SSPE Association, Istanbul/Turkey for their support of the study; colleagues Ilknur Erol, MD and Alev Guven, MD for their contribution of patient data; and all patients and parents who participated.
STUDY FUNDING No targeted funding reported.
DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
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944
Neurology 83
September 2, 2014
Neuronal loss is an early component of subacute sclerosing panencephalitis Deniz Yüksel, Baris Diren, Hakan Ulubay, et al. Neurology 2014;83;938-944 Published Online before print August 1, 2014 DOI 10.1212/WNL.0000000000000749 This information is current as of August 1, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/83/10/938.full.html
Supplementary Material
Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/08/01/WNL.0000000000 000749.DC1.html
References
This article cites 26 articles, 9 of which you can access for free at: http://www.neurology.org/content/83/10/938.full.html##ref-list-1
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