Bilateral epileptogenesis in temporal lobe epilepsy due to unilateral hippocampal sclerosis: A case series.

INTRODUCTION: Bitemporal epilepsy (biTLE), a potential cause of failure in TLE surgery, is rarely associated with unilateral HS and could be suggested by not lateralizing ictal scalp EEG/interictal PET-FDG findings. We evaluated the proportion of biTLE in a population of drug-resistant TLE-HS subjects who underwent intracranial investigation for lateralizing purpose. METHODS: We retrospectively included all consecutive refractory TLE-HS patients and not lateralizing ictal scalp EEG/interictal PET-FDG findings, investigated by intracranial bilateral longitudinal hippocampal electrodes. Demographic characteristics, electroclinical findings and seizure outcome were evaluated. RESULTS: We identified 14 subjects (7 males; mean age 39.5 years; mean age at disease onset 14.4 years), 7 of them had biTLE diagnosed after intracranial investigations. In the remaining 7 with unilateral epileptogenesis (uniTLE) anterior temporal lobectomy was performed (6/7 were in Engel class I). Preoperative neuropsychological assessment differentiated biTLE from uniTLE, as it was normal in six uniTLE patients but only in one with biTLE (p < 0.05). CONCLUSIONS: Not lateralizing ictal scalp EEG and functional imaging findings in TLEHS should alert about the possibility of a true biTLE also in presence of unilateral findings at MRI. Intracranial investigations with bilateral longitudinal hippocampal electrodes can localize the EZ with a good risk-benefit profile. Consistently with the warning on memory functions in TLE patients explored by using longitudinal hippocampal electrodes, further studies are needed to better define the optimal investigation strategy.

Case Report: Idiopathic Sclerosing Orbital Inflammation.

SIGNIFICANCE: Idiopathic sclerosing orbital inflammation (ISOI) is characterized by insidious, chronic, progressive inflammation and fibrosis that damage ocular structures and produce a mass effect. This case highlights the challenges in diagnosis and management of ISOI, as well as the associated ocular morbidities, including potential vision loss. PURPOSE: The purpose of this study was to provide education regarding a rare condition that exhibits variable presentation and has an unpredictable success rate with regard to treatment paradigm. Improved therapeutic options are promising. Ultimately, early detection and management are key and may allow for better visual outcome. CASE REPORT: A 46-year-old woman presented with complaints of chronic right-sided facial headaches and eye pain and gradual right globe prominence over the previous 6 months. Worsening vision and decreased right peripheral visual field were also noted. Upon examination, an afferent pupillary defect and florid disc edema were evident. Imaging studies revealed an orbital and extraorbital infiltrative mass involving the right orbital apex, inferior orbital fissure, pterygopalatine fossa, and cavernous sinus. Right anterior orbitotomy with biopsy revealed fragments of fibroconnective and adipose tissue with sclerosis and chronic focal inflammation, consistent with ISOI. Treatment included intravenous methylprednisone, followed by oral prednisone, beginning at 60 mg/d with a slow taper thereafter. Signs and symptoms improved dramatically and eventually resolved. Vision significantly improved, and the afferent pupillary defect resolved. The patient remained asymptomatic at 3-month follow-up. CONCLUSIONS: Idiopathic sclerosing orbital inflammation is difficult to diagnose and manage. No large studies exist because of the rare nature of the disease. Slowly progressive, nonspecific signs and symptoms may delay recognition and treatment. Orbital imaging and histopathologic analysis are critical for definitive diagnosis. Conventional treatment with corticosteroids is not uniformly successful, but newer combined therapy options can improve outcomes. Early identification and treatment are key to management and ultimate preservation of function and vision.

A novel variant in the COL6A1 gene causing Ullrich congenital muscular dystrophy in a consanguineous family: a case report.

BACKGROUND: Collagen VI-related dystrophies are a subtype of congenital muscular dystrophy caused by pathogenic variants in COL6A1, COL6A2 or COL6A3 genes affecting skeletal muscles and connective tissue. The clinical phenotype ranges from the milder Bethlem myopathy to the severe Ullrich congenital muscular dystrophy (UCMD). Herein, we report the first consanguineous Sri Lankan family with two children affected with UCMD due to a novel variant in the COL6A1 gene. CASE PRESENTATION: Two sisters, aged 10-years and 7-years, presented with progressive, bilateral proximal muscle weakness. Both probands had delayed motor milestones and demonstrated difficulty in standing from a squatting position, climbing stairs and raising arms above the shoulders. Cognitive, language and social development were age appropriate. Examination showed proximal muscle weakness of the upper and lower extremities and hyperlaxity of the wrist and fingers in both with some variability in clinical severity noted between the two siblings. Serum creatine kinase levels were elevated, and electromyography showed low polyphasic motor unit potentials in the 10-year-old and myopathic features with short duration motor unit potentials with no polyphasia in the 7-year-old. Whole exome sequencing (WES) was performed and a novel, homozygous missense, likely pathogenic variant in exon 25 of COL6A1 gene [NM_001848: c.1667G > T;NP_001839.2:p.Gly556Val] was identified in both probands. This variant was validated by Sanger sequencing in proband 1 as well as proband 2, and the parents and an unaffected sibling were found to be heterozygote carriers for the same variant. CONCLUSIONS: The findings in this family add to the expanding number of COL6A1 variants identified and provides a better understanding of the genotype-phenotype correlations associated with UCMD.

Evaluation of nucleus pulposus fluid velocity and pressure alteration induced by cartilage endplate sclerosis using a poro-elastic finite element analysis.

The nucleus pulposus (NP) in the intervertebral disk (IVD) depends on diffusive fluid transport for nutrients through the cartilage endplate (CEP). Disruption in fluid exchange of the NP is considered a cause of IVD degeneration. Furthermore, CEP calcification and sclerosis are hypothesized to restrict fluid flow between the NP and CEP by decreasing permeability and porosity of the CEP matrix. We performed a finite element analysis of an L3-L4 lumbar functional spine unit with poro-elastic constitutive equations. The aim of the study was to predict changes in the solid and fluid parameters of the IVD and CEP under structural changes in CEP. A compressive load of 500 N was applied followed by a 10 Nm moment in extension, flexion, lateral bending, and axial rotation to the L3-L4 model with fully saturated IVD, CEP, and cancellous bone. A healthy case of L3-L4 physiology was then compared to two cases of CEP sclerosis: a calcified cartilage endplate and a fluid constricted sclerotic cartilage endplate. Predicted NP fluid velocity increased for the calcified CEP and decreased for the calcified + less permeable CEP. Decreased NP fluid velocity was prominent in the axial direction through the CEP due to a less permeable path available for fluid flux. Fluid pressure and maximum principal stress in the NP were predicted to increase in both cases of CEP sclerosis compared to the healthy case. The porous medium predictions of this analysis agree with the hypothesis that CEP sclerosis decreases fluid flow out of the NP, builds up fluid pressure in the NP, and increases the stress concentrations in the NP solid matrix.

Collagen VI-related limb-girdle syndrome caused by frequent mutation in COL6A3 gene with conflicting reports of pathogenicity.

Recently the scientific community has started to view Bethlem myopathy 1 and Ullrich congenital muscular dystrophy as two extremes of a collagen VI-related myopathy spectrum rather than two separate entities, as both are caused by mutations in one of the collagen VI genes. Here we report three individuals in two families who are homozygous for a COL6A3 mutation (c.7447A> G; p.Lys2483Glu), and compare their clinical features with seven previously published cases. Individuals carrying homozygous or compound heterozygous c.7447A> G, (p.Lys2483Glu) mutation exhibit mild phenotype without loss of ambulation, similar to the cases described previously as Collagen VI-related limb-girdle syndrome. The phenotype could arise due to an aberrant assembly of Von Willebrand factor A domains. Based on these data, we propose that c.7447A> G, (p.Lys2483Glu) is a common pathogenic mutation.

Clinical features of collagen VI-related dystrophies: A large Brazilian cohort.

OBJECTIVES: Collagen VI-related dystrophies (COL6-RDs) have a broad clinical spectrum and are caused by mutations in the COL6A1, COL6A2 and COL6A3 genes. Despite the clinical variability, two phenotypes are classically recognized: Bethlem myopathy (BM, milder form) and Ullrich congenital muscular dystrophy (UCMD, more severe form), with many patients presenting an intermediate phenotype. In this work, we present clinical and genetic data from 28 patients (27 families), aged 6-38 years (mean of 16.96 years), with COL6-RDs. PATIENTS AND METHODS: Clinical, muscle histology and genetic data are presented. COL6A1, COL6A2 and COL6A3 genes were analyzed by next-generation sequencing (NGS). RESULTS: Homozygous or heterozygous variants were found in COL6A1 (12 families), COL6A2 (12 families) and COL6A3 (3 families). Patients with the severe UCMD phenotype (three cases) had a homogeneous clinical picture characterized by neonatal onset of manifestations, no gait acquisition and a stable course, but with severe respiratory involvement. Most of the patients with the mild UCMD phenotype had neonatal onset of manifestations (88.8 %), delayed motor development (66.6 %), slowly progressive course, pulmonary involvement (55.5 %) and loss of the walking capacity before the age of 10 (66.6 %). In the intermediate group (nine patients), some children had neonatal onset of manifestations (44.5 %) and delayed motor development (88.9 %); but all of them achieved the ability to walk and were still ambulatory. Some patients that had the BM phenotype presented neonatal manifestations (57.1 %); however, all of them had normal motor development and normal pulmonary function. Only one patient from the group of BM lost the walking capacity during the evolution of the disease. Other frequent findings observed in all groups were joint retractions, spinal deformities, distal hyperextensibility, congenital hip dislocation and keloid formation. CONCLUSION: COL6-RDs present variable clinical manifestations, but common findings are helpful for the clinical suspicion. NGS is a valuable approach for diagnosis, providing useful information for the genetic counseling of families.

SOST Deficiency Aggravates Osteoarthritis in Mice by Promoting Sclerosis of Subchondral Bone.

As the initial part in the development of osteoarthritis (OA), subchondral bone sclerosis has been considered to be initiated by excess mechanical loading and proven to be correlated to other pathological changes. Sclerostin, which is an essential mechanical stress response protein, is encoded by the SOST gene. It is expressed in osteocytes and mature chondrocytes and has been proven to be closely correlated to OA. However, the relationship and mechanism between the SOST gene and the development of OA remain unclear. The aim of the present study was to investigate the role of the SOST gene in OA pathogenesis in the subchondral bone. A knee anterior cruciate ligament transection (ACLT) mouse osteoarthritis (OA) model on SOST-knockout (SOST KO) and wild-type (WT) mice was established. The pathogenic and phenotypic changes in the subchondral bone were investigated by histology, micro-CT, immunohistochemistry, TRAP staining, Masson staining, and Toluidine blue staining. It was found that sclerostin expression decreased in both the calcified cartilage and mineralized subchondral structures during the development of OA. Joint instability induced a severe cartilage degradation phenotype, with higher OARSI scores in SOST KO mice, when compared to WT mice. SOST KO mice with OA exhibited a higher BMD and BV/TV ratio, as well as a higher rate of bone remodeling and TRAP-positive cell number, when compared to the WT counterparts, but the difference was not significant between the sham-operation groups. It was concluded that loss of sclerostin aggravates knee OA in mice by promoting subchondral bone sclerosis and increasing catabolic activity of cartilage.

[Suspected hippocampal sclerosis in an european shorthair cat diagnosed with polycythemia vera]. / Verdacht auf Hippocampussklerose bei einer Europäisch-Kurzhaar-Katze mit der Diagnose Polycythaemia vera.

A 7-year-old male castrated cat was presented because of an acute onset of lethargy and vestibular ataxia. The cat was diagnosed with polycythemia vera. Later the patient developed additional clinical signs including orofacial twitching, aggressivity, hypersalivation, circling and a head tilt. A magnetic resonance imaging was performed and revealed hippocampal alterations compatible with hippocampal sclerosis. The presented case report describes the clinical signs and hematologic findings in a cat with polycythemia vera and the response of treatment. Another part is the discussion about the hypothesis that the hippocampal alterations were due to a cerebral hypoperfusion caused by the polycythemic condition.

Automated detection of hippocampal sclerosis using clinically empirical and radiomics features.

OBJECTIVE: Temporal lobe epilepsy is a common form of epilepsy that might be amenable to surgery. However, magnetic resonance imaging (MRI)-negative hippocampal sclerosis (HS) can hamper early diagnosis and surgical intervention for patients in clinical practice, resulting in disease progression. Our aim was to automatically detect and evaluate the structural alterations of HS. METHODS: Eighty patients with pharmacoresistant epilepsy and histologically proven HS and 80 healthy controls were included in the study. Two automated classifiers relying on clinically empirical and radiomics features were developed to detect HS. Cross-validation was implemented on all participants, and specificity was assessed in the 80 controls. The performance, robustness, and clinical utility of the model were also evaluated. Structural analysis was performed to investigate the morphological abnormalities of HS. RESULTS: The computational model based on clinical empirical features showed excellent performance, with an area under the curve (AUC) of 0.981 in the primary cohort and 0.993 in the validation cohort. One of the features, gray-white matter boundary blurring in the temporal pole, exhibited the highest weight in model performance. Another model based on radiomics features also showed satisfactory performance, with AUC of 0.997 in the primary cohort and 0.978 in the validation cohort. In particular, the model improved the detection rate of MRI-negative HS to 96.0%. The novel feature of cortical folding complexity of the temporal pole not only played a crucial role in the classifier but also had significant correlation with disease duration. SIGNIFICANCE: Machine learning with quantitative clinical and radiomics features is shown to improve HS detection. HS-related structural alterations were similar in the MRI-positive and MRI-negative HS patient groups, indicating that misdiagnosis originates mainly from empirical interpretation. The cortical folding complexity of the temporal pole is a potentially valuable feature for exploring the nature of HS.

Longitudinal changes in clinical outcome measures in COL6-related dystrophies and LAMA2-related dystrophies.

OBJECTIVE: To identify the rate of change of clinical outcome measures in children with 2 types of congenital muscular dystrophy (CMD), COL6-related dystrophies (COL6-RDs) and LAMA2-related dystrophies (LAMA2-RDs). METHODS: Over the course of 4 years, 47 individuals (23 with COL6-RD and 24 with LAMA2-RD) 4 to 22 years of age were evaluated. Assessments included the Motor Function Measure 32 (MFM32), myometry (knee flexors and extensors, elbow flexors and extensors), goniometry (knee and elbow extension), pulmonary function tests, and quality-of-life measures. Separate linear mixed-effects models were fitted for each outcome measurement, with subject-specific random intercepts. RESULTS: Total MFM32 scores for COL6-RDs and LAMA2-RDs decreased at a rate of 4.01 and 2.60 points, respectively, each year (p < 0.01). All muscle groups except elbow flexors for individuals with COL6-RDs decreased in strength between 1.70% (p < 0.05) and 2.55% (p < 0.01). Range-of-motion measurements decreased by 3.21° (p < 0.05) at the left elbow each year in individuals with LAMA2-RDs and 2.35° (p < 0.01) in right knee extension each year in individuals with COL6-RDs. Pulmonary function demonstrated a yearly decline in sitting forced vital capacity percent predicted of 3.03% (p < 0.01) in individuals with COL6-RDs. There was no significant change in quality-of-life measures analyzed. CONCLUSION: Results of this study describe the rate of change of motor function as measured by the MFM32, muscle strength, range of motion, and pulmonary function in individuals with COL6-RDs and LAMA2-RDs.

Interference of High Dose Biotin Supplementation with Thyroid Parameters in Immunoassays Utilizing the Interaction between Streptavidin and Biotin: a Case Report and Review of Current Literature.

BACKGROUND: Automated immunoassays utilizing the interaction between streptavidin and biotin are widely used. Nonetheless, biotin remains an often overlooked confounder. METHODS: We report the case of a 54-year-old female patient with progressive multiple sclerosis and Hashimoto's thyroiditis who presented herself for a follow-up. Measurements on Roche's cobas® 8000 modular analyzer series suggested severe hyperthyroidism. Initially, no relevant confounders could be identified. RESULTS: All requested thyroid parameters were measured with alternative methods, yielding plausible results. CONCLUSIONS: Biotin is a significant confounder in many immunoassays. Alternative measurement methods or methods of biotin neutralization need to be implemented for certain situations.

Sclerosing Angiomatoid Nodular Transformation of the Spleen: Lessons from a Rare Case and Review of the Literature.

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is an extremely rare benign lesion. We herein report a case of asymptomatic SANT of the spleen in a middle-aged woman with early breast carcinoma and an undiagnosed splenic mass, which was successfully treated by laparoscopic splenectomy and diagnosed postoperatively. We also review the literature on SANT to help make knowledge more accessible when clinicians encounter a splenic tumor. The present case taught us the following lesson: the presence of a splenic lesion during follow-up for malignancy is not always indicative of metastasis. Therefore, SANT should be considered in the differential diagnosis.

Hippocampal sclerosis induced in mice by a Taenia crassiceps metacestode factor.

An experimental Taenia crassiceps mouse model was used to assess the role of Taenia solium metacestode factor (Fac) in human neurocysticercosis. Intraperitoneal infection with T. crassiceps metacestodes or subcutaneous inoculation with a T. crassiceps metacestode factor (Fac) produced significant impairment of performance (learning) in the Barnes maze and induced bilateral hippocampal sclerosis in mice. Several staining techniques revealed important cell dispersion, extensive apoptosis and cell loss in the dentate gyrus, hilus and CA1-CA3 regions of both hippocampi, as well as intense deterioration of the adjacent cortex. An outstanding disruption of its histoarchitecture in the surrounding tissue of all these regions and apoptosis of the endothelial cells were also observed.

Idiothetic signal processing and spatial orientation in patients with unilateral hippocampal sclerosis.

The role of the hippocampus in spatial navigation and the presence of vestibular-responsive neurons in limbic areas are well-established from animal experiments. However, hippocampal spatial processing in humans is not fully understood. Here, we employed real whole body and head-on-trunk rotations to investigate how vestibular signals, either alone or in combination with neck-proprioceptive stimulation, shape the spatial frame of reference in patients with unilateral hippocampal sclerosis (HS). Patients were asked to point in darkness with a light spot, moved on a cylindrical screen by means of a joystick, into their visual straight-ahead direction (VSA), to remember this direction in space, and to revert back to this point after the rotations. Estimates in patients with HS were compared with those of healthy controls and of patients with epilepsy without hippocampal involvement. All groups produced similar errors after low-frequency vestibular stimuli. These errors were eliminated when rotations involved concurrent neck stimulation. Significantly increased variability was observed, however, in both the VSA and reposition estimates after the rotations in patients with HS compared with controls. These results suggest that cognitive processing of idiothetic signals for self-motion perception is inaccurate in patients with HS. Importantly, however, the responses of patients with HS showed no spatial lateralization with regard to right or left HS, suggesting that the underlying neuronal loss attenuates the precision of head-direction signal decoding in a nondirectional manner. Hence, patients are unable to use these signals as efficiently as normal subjects in the construction of a stable head-centric spatial frame of reference. NEW & NOTEWORTHY Spatial perception relies on combined processing of various idiothetic (vestibular and proprioceptive) and allothetic (visual and auditory) sensory signals. Despite the established knowledge of rodent vestibular-hippocampal interactions, human data are lacking. We investigated idiothetic orientational processing in subjects with unilateral hippocampal sclerosis using various combinations of vestibular and proprioceptive stimuli. Hippocampal impairment leads to less accurate, noisy decoding of the signal related to idiothetic orientation. However, patients did not show any lateralized deficits of visual straight-ahead perception or of target/self-displacement perception after idiothetic stimulation.

Phenotypic spectrum in families with mesial temporal lobe epilepsy probands.

PURPOSE: The traditional perception of mesial temporal lobe epilepsy (MTLE) as a predominantly acquired disorder is challenged due to emerging evidence of familial aggregation. In this study, we ascertained the extent of familial occurrence of epilepsy in MTLE patients, as well as phenotypic heterogeneity in affected relatives. METHODS: We identified and reevaluated patients with MTLE, treated at Epilepsy Department for a period of two years. All eligible putatively affected relatives were asked to participate in the study. In addition to comprehensive epilepsy interview, they underwent EEG and MRI studies. RESULTS: 52 patients with MTLE were included; nine of them (17%) had at least one family member with epilepsy. Subsequently, we analyzed nine probands with MTLE and a total of 15 relatives with seizures. Among affected relatives, spectrums of clinical manifestations were observed. Typical MTL seizures were described in five individuals, while other types of focal or generalized tonic-clonic seizures were reported in other ten relatives. A total of seven individuals had febrile seizures. Hippocampal sclerosis was found in three probands and none of the relatives. Two of affected family members had a traumatic brain injury in addition to febrile seizures, prior to the occurrence of their epilepsy. CONCLUSION: We demonstrate that familiar occurrence of epilepsy and subsequently putative genetic background, accounts for a substantial proportion MTLE patients. In addition, we foreground the remarkable intra- and interfamilial phenotypic heterogeneity than usually described, displaying the complexity of the genotype-phenotype correlations.

A Qualitative Approach to Health Related Quality-of-Life in Congenital Muscular Dystrophy.

Congenital muscular dystrophies (CMD) cause progressive muscle weakness resulting in severe motor disabilities. Previous studies focused on the effects of motor disability. Here, we explore other factors affecting health related quality-of-life (HRQOL) in CMD. Qualitative interviews were conducted with participant-parent dyads to identify symptoms having the greatest impact on HRQOL. Symptoms were classified into themes and domains representing physical, mental, social health, and disease specific issues. Social role limitations and specific activity impairment were frequently mentioned. A greater understanding of symptoms impacting HRQOL will provide a framework for improved clinical care and patient centered outcomes as new therapies are developed.

Kienböck Disease in the Skeletally Immature Patient.

Kienböck disease is uncommon in skeletally immature patients. Although there is no gold standard treatment for Kienböck disease in the skeletally immature patient, surgical and nonsurgical treatment options have been shown to be effective. Initial immobilization with a cast, protection with an orthosis, and avoidance of repetitive forceful activities have been shown to be effective in some cases. Surgery may be offered to the skeletally immature patient when nonsurgical treatment is ineffective. Among several surgical techniques used for treatment in the skeletally immature patient with Kienböck disease, distal radial osteotomies have been the most frequently performed surgery; however, radial overgrowth is a concern. There is a great potential for revascularization and remodeling of the lunate in the skeletally immature patients with Kienböck disease. Good and excellent clinical and radiological outcomes can be achieved with both nonsurgical and surgical treatments.