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Background Antiepileptic drugs (AEDs) are mainly used to control cortical hyperexcitability. Some of them ( e.g. phenytoin (PHT) and topiramate (TPM)) have also effects on the peripheral nervous system (PNS). Lacosamide (LCM) is a novel AED that stabilizes hyperexcitable neuronal membranes by selectively enhancing the slow inactivation of voltage-gated sodium channels (VGSCs). Although the mechanism of action of LCM is fairly well understood, there are no in vitro data available regarding any possible PNS effects of LCM. Objective To investigate, in vitro , the effects of LCM on peripheral nerve excitability in comparison with PHT and TPM, two AEDs that act, in part, by stabilizing the fast inactivation state of VGSCs. Methods Experiments were conducted on the isolated sciatic nerve of the adult rat using standard electrophysiological methods. The effects of LCM on the amplitude and latency of the evoked compound action potential (CAP) during a 48 h period of drug exposure were recorded and compared with the effects of PHT and TPM. Results LCM produced inhibitory effects on CAP at concentrations significantly higher than the therapeutic levels (>25 μg/ml). At these concentrations (62.57–125.15 μg/ml), an acute and immediate increment of the latency and decrement of the amplitude of the CAP were observed. In contrast to LCM, PHT caused an acute decrement in the amplitude as well as an increment in the latency of the CAP even at subtherapeutic levels (5 μg/ml). With regard to TPM, the amplitude of the CAP was not affected at the supratherapeutic concentrations but at the therapeutic concentration of 33.94 μg/ml a reduced decrement of the CAP amplitude compared to the controls was observed. Conclusions LCM, PHT and TPM exert differential effects on peripheral nerve excitability. PHT inhibited the sciatic nerve CAP even at subtherapeutic levels whereas LCM was safe within the therapeutic concentration range. TPM did not affect the CAP amplitude even at high supratherapeutic concentrations whereas in the therapeutic range a neuroprotective effect was observed. Possible underlying mechanisms and the clinical implications of these findings are discussed. [ABSTRACT FROM AUTHOR]

A pilot prospective follow-up study of the role of the branched chain amino acids as additional therapy to the ketogenic diet was carried out in 17 children, aged between 2 and 7 years, with refractory epilepsy. All of these patients were on the ketogenic diet; none of them was seizure free, while only 13 had more or less benefited from the diet. The addition of branched chain amino acids induced a 100% seizure reduction in 3 patients, while a 50% to 90% reduction was noticed in 5. Moreover, in all of the patients, no reduction in ketosis was recorded despite the change in the fat-to-protein ratio from 4:1 to 2.5:1. Although our data are preliminary, we suggest that branched chain amino acids may increase the effectiveness of the ketogenic diet and the diet could be more easily tolerated by the patients because of the change in the ratio of fat to protein. [ABSTRACT FROM AUTHOR]

This study reports on a patient with episodes of right hand paralysis and complete sensory loss, considered to be functional because of a glove-like distribution of the sensory deficit, normal motor and sensory nerve conduction studies of median and ulnar nerve as well as normal median nerve somatosensory evoked potentials. Transcranial magnetic stimulation indicated increased threshold of the left hemisphere. Neuroimaging studies revealed a large venous angioma in the left frontal lobe. [Copyright &y& Elsevier]

Bithalamic infarcts are usually attributed to thromboembolism of the top of the basilar artery. However, in some cases, deep cerebral venous thrombosis and thrombosis of cerebral venous sinuses was proved to be the cause. The case of a 47-year-old female with ischemic thalamic and mesencephalic lesions is reported, that was attributed to thrombosis of internal cerebral veins. In cases of bithalamic infarcts, apart from the top of the basilar artery syndrome, deep cerebral venous thrombosis should be taken into consideration. Neuroimaging findings such as generalized cerebral edema, multiple infarcts or hemorrhages, hyperdense appearance of cerebral sinuses or veins and filling defects in the cerebral venous sinuses in contrast-CCT, can lead to the proper diagnosis. [Copyright &y& Elsevier]

Generalized spike wave discharges (GSWDs) are the typical electroencephalographic findings of Idiopathic Generalized Epilepsies (IGEs). These discharges are either interictal or ictal and recent evidence suggests differences in their pathogenesis. The aim of this study is to investigate, through functional connectivity analysis, the pre-interictal network state in IGEs, which precedes the formation of the interictal GSWDs. A high-density electroencephalogram (HD-EEG) was recorded in twenty-one patients with IGEs, and cortical connectivity was analyzed based on lagged coherence and individual anatomy. Graph theory analysis was used to estimate network features, assessed using the characteristic path length and clustering coefficient. The functional connectivity analysis identified two distinct networks during the pre-interictal state. These networks exhibited reversed connectivity attributes, reflecting synchronized activity at 3–4 Hz (delta2), and desynchronized activity at 8–10.5 Hz (alpha1). The delta2 network exhibited a statistically significant (p < 0.001) decrease in characteristic path length and an increase in the mean clustering coefficient. In contrast, the alpha1 network showed opposite trends in these features. The nodes influencing this state were primarily localized in the default mode network (DMN), dorsal attention network (DAN), visual network (VIS), and thalami. In conclusion, the coupling of two networks defined the pre-interictal state in IGEs. This state might be considered as a favorable condition for the generation of interictal GSWDs. [ABSTRACT FROM AUTHOR]

Background: Epileptic patients frequently encounter cognitive impairment. Functions that are mostly affected involve memory, attention, and executive function; however, this is mainly dependent on the location of the epileptic activity. The aim of the present study is to assess cognitive functions in MRI-negative epilepsy patients by means of neurophysiological and neuropsychological measures, as well as study the concept of transient cognitive impairment in patients with epileptiform discharges during EEG acquisition. Methods: The patients were enrolled from an outpatient Epilepsy/Clinical Neurophysiology clinic over a time period of 6 months. The study sample comprised 20 MRI-negative epilepsy patients (mean age ± standard deviation (SD), 30.3 ± 12.56 years; age range, 16–60 years; average disease duration, 13.95 years) and 10 age-matched controls (mean age ± SD, 24.22 ± 15.39 years), who were also education-matched (p > 0.05). Patients with epileptogenic lesions were excluded from the study. Informed consent was obtained from all subjects involved in the study. Auditory ERPs and the cognitive screening tool EpiTrack were administered to all subjects. Results: Latencies of P300 and slow waves were prolonged in patients compared to controls (p < 0.05). The ASM load and patients' performance in the EpiTrack maze subtest were the most significant predictors of P300 latency. A decline in the memory, attention, and speed of information processing was observed in patients with cryptogenic epilepsy compared to age-matched controls, as reflected by P300 latency and EpiTrack scores. [ABSTRACT FROM AUTHOR]

Background: Neuroleptic malignant syndrome (NMS) is a rare life-threatening disorder resulting from treatment with neuroleptic agents and other drugs that act as dopamine antagonists. NMS most often occurs shortly after the initiation, dose increase or withdrawal of the offending agent, but can rarely occur after long-term treatment at stable doses. Immediate discontinuation of the causative agent (or re-administration if the cause is the withdrawal of neuroleptic therapy) along with supportive therapy to maintain cardiorespiratory stability and to reduce fever are the cornerstone of the management of NMS. Additional 'specific' treatments include dantrolene, bromocriptine and amantadine, but their role in the management of NMS is controversial. Case study: This study reports the case of NMS associated with long-term treatment with olanzapine at a stable dose. Administration of dantrolene was well-tolerated and resulted in prompt resolution of NMS symptoms. [ABSTRACT FROM AUTHOR]

Background: To the best of our knowledgedd, there is currently no case in the literature reporting the comorbidity of Wilson's and Creutzfeldt-Jakob disease (CJD), linked through copper. Case presentation: A 44-year-old male with a history of inherited Wilson's disease (hepatolenticular degeneration), which manifested as mild liver injury and psychiatric symptoms, was admitted to our department due to speech and cognitive disturbances. Upon his admission, he had motor aphasia as well as psychomotor retardation with an otherwise normal neurological examination. Laboratory tests, including liver enzymes, copper and serum ammonia were all within normal range. The brain MRI showed increased T2 signal in the caudate nuclei, attributed to copper deposition in the context of Wilson's disease. In the electroencephalogram, periodic sharp discharges were eminent, initially unilateral and then generalized. The positive 14–3-3 protein in the cerebrospinal fluid (CSF) and the new brain MRI, that demonstrated elevated DWI signal not only in the basal ganglia but also in parts of the cerebral cortex (cortical ribbon sign), all supportive of a possible CJD diagnosis. The detection of PrPSc in the patient's CSF, using the RT-QuIC method, which has a 99.4–100% specificity for CJD, made the diagnosis of CJD highly probable. Conclusion: This is the first report of Wilson's and Creutzfeldt-Jakob diseases co-morbidity in the literature, which could evoke a possible role of copper in the pathogenesis of CJD. [ABSTRACT FROM AUTHOR]

• Network disorganization in people with Subjective Cognitive Decline (SCD) was found in the majority of the reported studies. • Brain connectome in SCD is disrupted in a similar way as in mild cognitive impairment compared to Healthy Controls. • Small-world and rich-club were preserved in SCDs while aberrant local connections were observed. We performed a systematic literature review on Subjective Cognitive Decline (SCD) in order to examine whether the resemblance of brain connectome and functional connectivity (FC) alterations in SCD with respect to MCI, AD and HC can help us draw conclusions on the progression of SCD to more advanced stages of dementia. We searched for studies that used any neuroimaging tool to investigate potential differences/similarities of brain connectome in SCD with respect to HC, MCI, and AD. Sixteen studies were finally included in the review. Apparent FC connections and disruptions were observed in the white matter, default mode and gray matter networks in SCD with regards to HC, MCI, and AD. Interestingly, more apparent connections in SCD were located over the posterior regions, while an increase of FC over anterior regions was observed as the disease progressed. Elders with SCD display a significant disruption of the brain network, which in most of the cases is worse than HC across multiple network parameters. The present review provides comprehensive and balanced coverage of a timely target research activity around SCD with the intention to identify similarities/differences across patient groups on the basis of brain connectome properties. [ABSTRACT FROM AUTHOR]

Abstract Theory of Mind (ToM) is a critical component of social cognition, and thus, its impairment may adversely affect social functioning and quality of life. Recent evidence has suggested that it is impaired in epilepsy. What is not clear, however, is whether it is related to particular types of epilepsy or other factors. We undertook the present study to explore ToM in patients with focal versus those with generalized epilepsy, the particular pattern of ToM deficits, and the potential influence of antiepileptic medication load. Our sample included 149 adults: 79 patients with epilepsy (34 with generalized epilepsy and 45 with focal epilepsy) and 70 healthy controls. Theory of Mind tasks included a) comprehension of hinting, b) comprehension of sarcasm and metaphor, c) comprehension of false beliefs and deception, d) recognition of faux pas, and e) a visual ToM task in cartoon form. We found significant ToM impairment in the group with focal epilepsy relative to the performance of both the healthy group and the group with generalized epilepsy on all tasks, with the exception of faux pas, on which the group with generalized epilepsy also performed more poorly than the healthy group. Additionally, early age at seizure onset, but not antiepileptic drug (AED) load, was associated with ToM performance. Our findings suggest that focal temporal and frontal lobe, but not generalized, epilepsies were associated with impaired ToM. This may reflect the neuroanatomical abnormalities in the relevant neuronal networks and may have implications for differential cognitive-behavioral interventions based on epilepsy type. Highlights • Broad ToM impairment in focal epilepsy • ToM abilities in patients with generalized epilepsy impaired only in faux pas • ToM was associated with early age of seizure onset, but not AED load. • Focal epilepsy ToM impairment has implications for outcome & cognitive interventions. [ABSTRACT FROM AUTHOR]

Background: Autosomal recessive hereditary spastic paraplegia (HSP) due to AP4M1 mutations is a very rare neurodevelopmental disorder reported for only a few patients.Methods: We investigated a Greek HSP family using whole exome sequencing (WES).Results: A novel AP4M1A frameshift insertion, and a very rare missense variant were identified in all three affected siblings in the compound heterozygous state (p.V174fs and p.C319R); the unaffected parents were carriers of only one variant. Patients were affected with a combination of: (a) febrile seizures with onset in the first year of life (followed by epileptic non-febrile seizures); (b) distinctive facial appearance (e.g., coarse features, bulbous nose and hypomimia); (c) developmental delay and intellectual disability; (d) early-onset spastic weakness of the lower limbs; and (e) cerebellar hypoplasia/atrophy on brain MRI.Conclusions: We review genotype-phenotype correlations and discuss clinical overlaps between different AP4-related diseases. The AP4M1 belongs to a complex that mediates vesicle trafficking of glutamate receptors, being likely involved in brain development and neurotransmission. [ABSTRACT FROM AUTHOR]

Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A recently identified group of premature aging syndromes is linked to mutation of the LMNA gene encoding lamins A and C, and is associated with nuclear deformation and dysfunction. Hutchinson-Gilford progeria syndrome (HGPS) was the first premature aging syndrome linked to LMNA mutation and its molecular bases have been deeply investigated. It is due to a recurrent de novo mutation leading to aberrant splicing and the production of a truncated and toxic nuclear lamin A precursor (prelamin AΔ50), also called progerin. In this work and based on the literature data, we propose to distinguish two main groups of premature aging laminopathies: (1) HGPS and HGP-like syndromes, which share clinical features due to hampered processing and intranuclear toxic accumulation of prelamin A isoforms; and (2) APS (atypical progeria syndromes), due to dominant or recessive missense mutations affecting lamins A and C. Among HGPS-like patients, several deleted prelamin A transcripts (prelamin AΔ50, AΔ35 and AΔ90) have been described. The purpose of this work was to characterize those transcripts in eight patients affected with HGP-like rare syndromes. When fibroblasts were available, the relationships between the presence and ratios of these transcripts and other parameters were studied, aiming to increase our understanding of genotype-phenotype relationships in HGPS-like patients. Altogether our results evidence that progerin accumulation is the major pathogenetic mechanism responsible for HGP-like syndromes due to mutations near the donor splice site of exon 11. [ABSTRACT FROM AUTHOR]

Glucose metabolism of children with drug-resistant epilepsy, controlled by antiepileptic drugs epilepsy, and first-time nonfebrile seizures was studied through the performance of an oral glucose tolerance test and through insulin, C-peptide, and glycosylated hemoglobin measurements. In the refractory epilepsy group, there were more abnormal oral glucose tolerance test results (62.07%) in comparison to the controlled epilepsy group (25%) and the group of first-time seizures (21.21%). There was a significant difference between the group of refractory epilepsy and every other group concerning the abnormality of the oral glucose tolerance test (P < .05). The mean values of insulin, HbA1c, and C-peptide levels were normal for all groups. The results of the present study suggest that there is a distinction of refractory epilepsies from the drug-controlled ones and the first-induced seizures relating to their metabolic profile, regardless of the type of seizures. [ABSTRACT FROM AUTHOR]

Alpha-dystroglycanopathies such as Walker Warburg syndrome represent an important subgroup of the muscular dystrophies that have been related to defective O-mannosylation of alpha-dystroglycan. In many patients, the underlying genetic etiology remains unsolved. Isolated muscular dystrophy has not been described in the congenital disorders of glycosylation (CDG) caused by N-linked protein glyco-sylation defects. Here, we present a genetic N-glycosylation disorder with musculardystrophy in the group of CDG type I. Extensive biochemical investigations revealed a strongly reduced dolichol-phosphate-mannose (Dol-P-Man) synthase activity. Sequencing of the three DPM subunits and complementation of DPM3-deficient CHO2.38 cells showed a pathogenic p.L85S missense mutation in the strongly conserved coiled-coil domain of DPM3 that tethers catalytic DPM1 to the ER membrane. Cotransfection experiments in CHO cells showed a reduced binding capacity of DPM3(L855) for DPM1. Investigation of the four Dol-P-Man-dependent glycosylation pathways in the ER revealed strongly reduced 0-mannosylation of alpha-dystroglycan in a muscle biopsy, thereby explaining the clinical phenotype of muscular dystrophy. This mild Dol-P-Man biosynthesis defect due to DPM3 mutations is a cause for alpha-dystroglycanopathy, thereby bridging the congenital disorders of glycosylation with the dystroglycanopathies. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to perform quantitative measurements of the magnetization transfer rate (Kfor) and native T1 relaxation time (T1free) in the brain tissue of normal individuals and patients with multiple sclerosis (MS) by means of multiple gradient echo acquisitions, and to correlate these measurements with the magnetization transfer ratio (MTR). Quantitative magnetization transfer imaging was performed in five normal volunteers and 12 patients with relapsing-remitting MS on a 1.5 T magnetic resonance (MR) scanner. The T1 relaxation time under magnetization transfer irradiation (T1sat) was calculated by means of fitting the signal intensity over the flip angle in several 3D spoiled gradient echo acquisitions (3°, 15°, 30°, and 60°), while a single acquisition without MT irradiation (flip angle of 3°) was utilized to calculate the MTR. The Kfor and T1free constants were quantified on a pixel-by-pixel basis and parametric maps were reconstructed. We performed 226 measurements of Kfor, T1free, and the MTR on normal white matter (NWM) of healthy volunteers (n=50), and normal-appearing white matter (NAWM) and pathological brain areas of MS patients (n=120 and 56, respectively). Correlation coefficients between Kfor-MTR, T1free-MTR, and T1free-Kfor were calculated. Lesions were classified, according to their characteristics on T1-weighted images, into isointense (compared to white matter), mildly hypointense (showing signal intensity lower than white matter and higher than gray matter), and severely hypointense (revealing signal intensity lower than gray matter). “Dirty” white matter (DWM) corresponded to areas with diffused high signal, as identified on T2-weighted images. Strong correlation coefficients were obtained between MTR and Kfor for all lesions studied (r2=0.9,p<0.0001), for mildly hypointense plaques (r2=0.82,p<0.0001), and for DWM (r2=0.78,p=0.0007). In contrast, comparison between MTR and T1free values yielded rather low correlation coefficients for all groups assessed. In severely hypointense lesions, an excellent correlation was found between Kfor and T1free measurements (r2=0.98,p<0.0001). Strong correlations between Kfor and T1free were found for the rest of the subgroups, except for the NAWM, in which a moderate correlation was obtained (r2=0.5,p<0.0001). We conclude that Kfor and T1free measurements are feasible and may improve our understanding of the pathological brain changes that occur in MS patients. [ABSTRACT FROM AUTHOR]

The aim of the current study was to perform T2 relaxation time measurements in multiple sclerosis (MS) patients and correlate them with magnetization transfer ratio (MTR) measurements, in order to investigate in more detail the various histopathological changes that occur in lesions and normal-appearing white matter (NAWM). A total number of 291 measurements of MTR and T2 relaxation times were performed in 13 MS patients and 10 age-matched healthy volunteers. Measurements concerned MS plaques (105), NAWM (80), and “dirty” white matter (DWM; 30), evenly divided between the MS patients, and normal white matter (NWM; 76) in the healthy volunteers. Biexponential T2 relaxation-time analysis was performed, and also possible linearity between MTR and mean T2 relaxation times was evaluated using linear regression analysis in all subgroups. Biexponential relaxation was more pronounced in “black-hole” lesions (16.6%) and homogeneous enhancing plaques (10%), whereas DWM, NAWM, and mildly hypointense lesions presented biexponential behavior with a lower frequency(6.6, 5, and 3.1%, respectively). Non-enhancing isointense lesions and normal white matter did not reveal any biexponentional behavior. Linear regression analysis between monoexponential T2 relaxation time and MTR measurements demonstrated excellent correlation for DWM(r=-0.78, p<0.0001), very good correlation for black-hole lesions(r=-0.71, p=0.002), good correlation for isointense lesions(r=-0.60, p=0.005), moderate correlation for mildly hypointense lesions(r=-0.34, p=0.007), and non-significant correlation for homogeneous enhancing plaques, NAWM, and NWM. Biexponential T2 relaxation-time behavior is seen in only very few lesions (mainly on plaques with high degree of demyelination and axonal loss). A strong correlation between MTR and monoexponential T2 values was found in regions where either inflammation or demyelination predominates; however, when both pathological conditions coexist, this linear relationship is lost. [ABSTRACT FROM AUTHOR]

A pilot prospective follow-up study of the role of the ketogenic diet was carried out on 30 children, aged between 4 and 10 years, with autistic behavior. The diet was applied for 6 months, with continuous administration for 4 weeks, interrupted by 2-week diet-free intervals. Seven patients could not tolerate the diet, whereas five other patients adhered to the diet for 1 to 2 months and then discontinued it. Of the remaining group who adhered to the diet, 18 of 30 children (60%), improvement was recorded in several parameters and in accordance with the Childhood Autism Rating Scale. Significant improvement (> 12 units of the Childhood Autism Rating Scale) was recorded in two patients (pre-Scale: 35.00 ± 1.41[mean ± SD]), average improvement (> 8-12 units) in eight patients (pre-Scale: 41.88 ± 3.14[mean ± SD]), and minor improvement (2-8 units) in eight patients (pre-Scale: 45.25 ± 2.76 [mean ± SD]). Although these data are very preliminary, there is some evidence that the ketogenic diet may be used in autistic behavior as an additional or alternative therapy. [ABSTRACT FROM AUTHOR]

This study aimed to ascertain the frequency and type of hematological findings in a defined group of patients with inborn errors on Crete. The key role of these hematological findings in the diagnosis of the inborn errors in daily practice was explored. A variety of hematological findings were obtained from 31 of the 132 subjects who had been referred to the University Hospital of Heraklion. A diagnosis of inborn errors of metabolism (IEM) was confirmed in 21 subjects, but in 12 of them the diagnosis was combined with hematological findings. The hematological findings consist of a neglected area in the diagnosis of the IEM, and cooperation of primary care physicians and neurologists could help hematologists in the management of people with unexplained hematological symptoms and signs. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented that describes a genetic mutation associated with stroke-like episodes in the brain stem.

Presents a letter to the editor about the development of subdural effusions in association with pyruvate dehydrogenase deficiency.

Abstract: We report the case of a 57-year-old man complaining of headaches and adult onset seizures. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a process which proved to be a huge frontal sinus mucocele, eroding the posterior wall of the frontal sinus and compressing the left frontal lobe. An osteoplastic flap procedure with cranialization and obliteration of the frontal sinus was performed. The seizures and headache disappeared postoperatively. Clinical manifestations, diagnosis and surgical approaches for grand frontal sinus mucoceles are briefly discussed. [Copyright &y& Elsevier]