Päivi Koskenkorva

Brain atrophy and neuropsychological outcome after treatment of ruptured anterior cerebral artery aneurysms: a voxel-based morphometric study

IntroductionCognitive impairment after aneurysmal subarachnoid hemorrhage (aSAH) is frequently detected. Here, we describe the pattern of cerebral (gray matter) atrophy and its clinical relevance after treatment of aSAH caused by a ruptured anterior cerebral artery (ACA) aneurysm.MethodsThirty-seven aSAH patients with ACA aneurysm (17 surgical, 20 endovascular treatment) and a good or moderate clinical outcome (Glasgow Outcome Scale V or IV) and 30 controls underwent brain MRI. Voxel-based morphometric analysis was applied to compare the patients and controls. Patients also underwent a detailed neuropsychological assessment.ResultsThe comparisons between controls and either all patients (n = 37) or the subgroup of surgically treated patients (n = 17) revealed bilateral cortical atrophy in the frontal lobes, mainly in the basal areas. The brainstem, bilateral thalamic and hypothalamic areas, and ipsilateral caudate nucleus were also involved. Small areas of atrophy were detected in temporal lobes. The hippocampus and parahippocampal gyrus showed atrophy ipsilateral to the surgical approach. In the subgroup of endovascularly treated patients (n = 15), small areas of atrophy were detected in the bilateral orbitofrontal cortex and in the thalamic region. Twenty patients (54%) showed cognitive deficits in neuropsychological assessment.ConclusionGroup analysis after aSAH and treatment of the ruptured ACA aneurysm revealed gray matter atrophy, principally involving the frontobasal cortical areas and hippocampus ipsilateral to the surgical approach. Areas of reduced gray matter were more pronounced after surgical than endovascular treatment. Together with possible focal cortical infarctions and brain retraction deficits in individual patients, this finding may explain the neuropsychological disturbances commonly detected after treatment of ruptured ACA aneurysms.

Motor cortex and thalamic atrophy in Unverricht–Lundborg disease: Voxel-based morphometric study

Objective: To evaluate possible changes in the gray matter volume of patients with Unverricht–Lundborg disease (EPM1) compared with healthy controls. Methods: Thirty-four genetically verified patients with EPM1 and 30 healthy controls matched for age and sex underwent MRI (T1-, T2-, fluid-attenuated inversion recovery-, and T1-weighted 3-dimensional images). T1-weighted 3-dimensional images were analyzed with voxel-based morphometry (VBM) to compare the regional differences in gray matter volumes between patients and controls. The patients with EPM1 were also clinically evaluated for myoclonus severity using the Unified Myoclonus Rating Scale. Results: VBM analysis revealed atrophy in the bilateral primary, premotor, and supplementary motor cortex. The thalamus and precuneus were also bilaterally affected. No infratentorial changes were detected in the group analysis. Conclusion: The cortical motor areas of the brain are particularly affected in EPM1, correlating with the motor symptoms of this disease. The combination of detailed imaging with neurophysiologic evaluation may help to reveal the pathogenesis of Unverricht–Lundborg disease.

Altered cortical inhibition in Unverricht—Lundborg type progressive myoclonus epilepsy (EPM1)

PURPOSE Progressive myoclonus epilepsies (PMEs) comprise a heterogeneous group of conditions characterized by an imbalance between excitatory and inhibitory neuronal mechanisms. The aim of this study was to assess the function of the motor cortex in Unverricht-Lundborg disease (ULD), progressive myoclonus epilepsy type 1 (EPM1). METHODS Genetically verified EPM1 patients (n=24) were studied and compared with healthy subjects (n=24). MRI-navigated transcranial magnetic stimulation (TMS) was used to study the function of the motor cortex. Motor threshold (MT) and cortical silent period (SP) were used as parameters to evaluate cortical excitability. Peripheral muscle responses were recorded at the thenar and hypothenar using on-line electromyography (EMG). RESULTS The normal shortening of SP duration with age was not evident in EPM1. Thus, older patients exhibited significantly prolonged SPs in comparison to healthy control subjects (p<0.05). The MTs, measured as both stimulator output percentage and induced electric field strength (EF), were significantly higher in EPM1 patients than in control subjects (p<0.001). The stimulation of the thenar caused a co-activation in the hypothenar with significantly higher amplitudes as compared to controls (p<0.05). CONCLUSIONS The prolongation of the SPs with age in EPM1 patients suggests a prevailing inhibitory tonus of the primary motor cortex (M1) as possible reactive mechanism to the disease. Antiepileptic drugs may contribute to the increased MT but do not affect the SP. The results and methodology of this study can lead to a better understanding of the pathophysiology and progression of EPM1.

White Matter Degeneration with Unverricht-Lundborg Progressive Myoclonus Epilepsy: A Translational Diffusion-Tensor Imaging Study in Patients and Cystatin B–Deficient Mice

PURPOSE To study white matter (WM) changes in patients with Unverricht-Lundborg progressive myoclonus epilepsy (EPM1) caused by mutations in the cystatin B gene and in the cystatin B-deficient (Cstb-/-) mouse model and to validate imaging findings with histopathologic analysis of mice. MATERIALS AND METHODS Informed consent was obtained and the study was approved by an institutional ethics committee. Animal work was approved by the Animal Experiment Board of Finland. Diffusion-tensor imaging and tract-based spatial statistics (TBSS) were used to compare fractional anisotropic (FA) results and axial, radial, and mean diffusion among patients with EPM1 (n = 19) and control subjects (n = 18). Ex vivo diffusion-tensor imaging and TBSS were used to compare Cstb-/- mice (n = 9) with wild controls (n = 4). Areas of FA decrease in mice were characterized by means of immunohistochemical analysis and transmission electron microscopy. Student t test statistics were applied to report significant findings (threshold-free cluster enhancement, P < .05). RESULTS Patients with EPM1 showed significantly (P < .05) reduced FA and increased radial and mean diffusion in all major WM tracts compared with those of control subjects, shown as global FA decrease along the TBSS skeleton (0.41 ± 0.03 vs 0.45 ± 0.02, respectively; P < 5 × 10(-6)). Cstb-/- mice exhibited significantly reduced FA (P < .05) and antimyelin basic protein staining. Transmission electron microscopy revealed degenerating axons in Cstb-/- mice vs controls (979 axons counted, 51 degenerating axons; 2.09 ± 0.29 per field vs 1072 axons counted, nine degenerating axons; 0.48 ± 0.19 per field; P = .002). CONCLUSION EPM1 is characterized by widespread alterations in subcortical WM, the thalamocortical system, and the cerebellum, which result in axonal degeneration and WM loss. These data suggest that motor disturbances and other symptoms in patients with EPM1 involve not only the cortical system but also the thalamocortical system and cerebellum.

3D texture analysis reveals imperceptible MRI textural alterations in the thalamus and putamen in progressive myoclonic epilepsy type 1, EPM1.

Progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessively inherited neurodegenerative disorder characterized by young onset age, myoclonus and tonic-clonic epileptic seizures. At the time of diagnosis, the visual assessment of the brain MRI is usually normal, with no major changes found later. Therefore, we utilized texture analysis (TA) to characterize and classify the underlying properties of the affected brain tissue by means of 3D texture features. Sixteen genetically verified patients with EPM1 and 16 healthy controls were included in the study. TA was performed upon 3D volumes of interest that were placed bilaterally in the thalamus, amygdala, hippocampus, caudate nucleus and putamen. Compared to the healthy controls, EPM1 patients had significant textural differences especially in the thalamus and right putamen. The most significantly differing texture features included parameters that measure the complexity and heterogeneity of the tissue, such as the co-occurrence matrix-based entropy and angular second moment, and also the run-length matrix-based parameters of gray-level non-uniformity, short run emphasis and long run emphasis. This study demonstrates the usability of 3D TA for extracting additional information from MR images. Textural alterations which suggest complex, coarse and heterogeneous appearance were found bilaterally in the thalamus, supporting the previous literature on thalamic pathology in EPM1. The observed putamenal involvement is a novel finding. Our results encourage further studies on the clinical applications, feasibility, reproducibility and reliability of 3D TA.

Sensorimotor, Visual, and Auditory Cortical Atrophy in Unverricht-Lundborg Disease Mapped with Cortical Thickness Analysis

BACKGROUND AND PURPOSE: EPM1, caused by mutations in the CSTB gene, is the most common form of PME. The most incapacitating symptom of EPM1 is action-activated and stimulus-sensitive myoclonus. The clinical severity of the disease varies considerably among patients, but so far, no correlations have been observed between quantitative structural changes in the brain and clinical parameters such as duration of the disease, age at onset, or myoclonus severity. The aim of this study was to evaluate possible changes in CTH of patients with EPM1 compared with healthy controls and to correlate those changes with clinical parameters. MATERIALS AND METHODS: Fifty-three genetically verified patients with EPM1 and 70 healthy volunteers matched for age and sex underwent 1.5T MR imaging. T1-weighted 3D images were analyzed with CTH analysis to detect alterations. The patients were clinically evaluated for myoclonus severity by using the UMRS. Higher UMRS scores indicate more severe myoclonus. RESULTS: CTH analysis revealed significant thinning of the sensorimotor and visual and auditory cortices of patients with EPM1 compared with healthy controls. CTH was reduced with increasing age in both groups, but in patients, the changes were confined specifically to the aforementioned areas, while in controls, the changes were more diffuse. Duration of the disease and the severity of myoclonus correlated negatively with CTH. CONCLUSIONS: Cortical thinning in the sensorimotor areas in EPM1 correlated significantly with the degree of the severity of the myoclonus and is most likely related to the widespread stimulus sensitivity in EPM1.

Severer Phenotype in Unverricht-Lundborg Disease (EPM1) Patients Compound Heterozygous for the Dodecamer Repeat Expansion and the c.202C>T Mutation in the CSTB Gene

Background/Aims: Unverricht-Lundborg disease (EPM1) is caused by mutations in the cystatin B (CSTB) gene. Most patients are homozygous for the expanded dodecamer repeat mutation alleles, but 9 other EPM1-associated mutations have also been identified. We describe the clinical, cognitive and imaging characteristics of 5 Finnish EPM1 patients who are compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations. Methods: Five compound heterozygous patients and 21 patients homozygous for the expansion mutation, participating in an ongoing nationwide clinical and molecular genetics study, were evaluated using the Unified Myoclonus Rating Scale test and comprehensive neuropsychological testing. All patients underwent MR imaging. The MR data were also compared with those of 24 healthy control subjects. Results: Age at onset of symptoms was significantly lower in the compound heterozygotes than in the homozygous EPM1 patients. They also had severer myoclonus and drug-resistant tonic-clonic seizures. Moreover, they had lower cognitive performance. In MRI a voxel-based morphometry analysis of primary and premotor cortex, supplementary motor cortex and thalami revealed gray matter volume loss when compared with the healthy controls, similar to patients homozygous for the expansion mutation. Conclusion: Patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations seem to have a severer form of EPM1 than patients homozygous for the expansion mutation. These findings have implications for counseling of EPM1 patients with different genetic defects.

Refining the phenotype of Unverricht-Lundborg disease (EPM1): A population-wide Finnish study

Objective: This Finnish nationwide study aimed to refine the clinical phenotype variability and to identify factors that could explain the extensive variability in the clinical severity of the symptoms observed among patients with Unverricht-Lundborg disease (progressive myoclonus epilepsy type 1 [EPM1]) homozygous for the dodecamer expansion mutation in the cystatin B (CSTB) gene. Methods: The study population consisted of 66 (33 men and 33 women) patients with genetically confirmed EPM1 homozygous for the CSTB expansion mutation for whom the sizes of the expanded alleles were determined. The clinical evaluation included videorecorded Unified Myoclonus Rating Scale and retrospectively collected medical history. The navigated transcranial magnetic stimulation test was used to determine motor threshold (MT) and silent period (SP) of the motor cortex. Results: An earlier age at onset for EPM1 and longer disease duration were associated with more severe action myoclonus, lower performance IQ, increased MT, and prolonged SP. The number of dodecamer repeats in CSTB alleles varied between 38 and 77. On average, the size of the longer expanded alleles of patients was independently associated with MT, but exerted only a modulating effect on age at onset, myoclonus severity, and SP. Conclusions: As a group, earlier disease onset and longer duration are associated with more severe phenotype. Even though the vast majority of patients with EPM1 have a uniform genetic mutation, the actual size of the longer CSTB expansion mutation allele is likely to have a modulating effect on the age at disease onset, myoclonus severity, and cortical neurophysiology.

Alterations of motor cortical excitability and anatomy in Unverricht‐Lundborg disease

Unverricht‐Lundborg disease is the most common form of progressive myoclonus epilepsies. In addition to generalized seizures, it is characterized by myoclonus, which usually is the most disabling feature of the disease. Classically, the myoclonus has been attributed to increased excitability of the primary motor cortex. However, inhibitory cortical phenomena have also been described along with anatomical alterations. We aimed to characterize the relationship between the excitability and anatomy of the motor cortex and their association with the severity of the clinical symptoms. Seventy genetically verified patients were compared with forty healthy controls. The symptoms were evaluated with the Unified Myoclonus Rating Scale. Navigated transcranial magnetic stimulation was applied to characterize the excitability of the primary motor cortex by determining the motor thresholds and cortical silent periods. In addition, the induced cortical electric fields were estimated using individual scalp‐to‐cortex distances measured from MRIs. A cortical thickness analysis was performed to elucidate possible disease‐related anatomical alterations. The motor thresholds, cortical electric fields, and silent periods were significantly increased in the patients (P < 0.01). The silent periods correlated with the myoclonus scores (r = 0.48 to r = 0.49, P < 0.001). The scalp‐to‐cortex distance increased significantly with disease duration (r = 0.56, P < 0.001) and correlated inversely with cortical thickness. The results may reflect the refractory nature of the myoclonus and indicate a possible reactive cortical inhibitory mechanism to the underlying disease process. This is the largest clinical series on Unverricht‐Lundborg disease and the first study describing parallel pathophysiological and structural alterations associated with the severity of the symptoms.

Primary motor cortex alterations in a compound heterozygous form of Unverricht–Lundborg disease (EPM1)

PURPOSE Unverricht-Lundborg disease (EPM1) is the most common form of progressive myoclonus epilepsies. The genetic background is a homozygous dodecamer repeat extension mutation in the cystatin B (CSTB) gene. However, mutations occurring in a compound heterozygous form with the expansion mutation have also been reported. In Finland, we have found five EPM1 patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutation in the CSTB gene (chEPM1). There are no previous clinical or neurophysiological studies on these patients. Thus, we aimed to characterize possible functional alterations in primary motor cortical areas. METHODS Five chEPM1 patients were compared with homozygous patients and healthy controls. All patients underwent a clinical evaluation to characterize the severity of the symptoms. Navigated transcranial magnetic stimulation (TMS) was used to study cortical excitability by determining the motor thresholds (MT), silent periods (SP) and motor evoked potential (MEP) characteristics. Continuous electroencephalography (EEG) was recorded during the measurements. Voxel-based MRI morphometry (VBM) was used to study differences in gray matter volume. RESULTS The chEPM1 patients exhibited an inhibitory cortical tonus reflected as elevated MTs and prolonged SPs. EEG showed spontaneous focal epileptiform activity in centro-temporal and parietal areas in addition to more widespread and generalized discharges. VBM revealed loss of gray matter volume in primary motor cortical areas and thalami. DISCUSSION The chEPM1 patients exhibited functional and structural changes in primary motor cortical areas. The functional changes are more profound as compared to homozygous patients, suggesting a neurophysiological background for the more severe clinical symptoms.