Arylsulfatase A, a genetic modifier of Parkinson's disease, is an α-synuclein chaperone.

Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson's disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson's disease. Plasma ARSA protein levels were changed in Parkinson's disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein.

Ictal Direct Current Shifts Preceded Much Earlier Than High Frequency Oscillations After Status: Is It the Effect of Status or Antiseizure Medication?

PURPOSE: While spikes and sharp waves are considered as markers of epilepsy in conventional electroencephalography, ictal direct current (DC) shifts and high-frequency oscillations (HFOs) appear to be useful biomarkers for epileptogenicity. We analyzed how ictal DC shifts and HFOs were affected by focal status epilepticus and antiseizure medications (ASMs). METHODS: A 20-year-old female patient who underwent long-term intracranial electrode implantation for epilepsy surgery presented with 72 habitual seizures and a focal status epilepticus episode lasting for 4 h. Ten, 3, and 10 consecutive habitual seizures were analyzed before the status, after the status, and after ASM (valproate) loading, respectively. RESULTS: Before and immediately after the status, ictal DC shifts remained the same in terms of the amplitude, duration, and slope of DC shifts. High-frequency oscillations also remained the same in terms of the duration, frequency, and power except for the power of the lower frequency band. After ASM loading, the duration, amplitude, and slope of the ictal DC shift were significantly attenuated. The duration, frequency, and power of the HFOs were significantly attenuated. Furthermore, the interval between the DC onset and HFO onset was significantly longer and the interval between the HFO onset and ictal DC shift peak was significantly shorter. CONCLUSIONS: The attenuation of ictal DC shifts and HFOs after ASM loading implies that astrocyte and neuronal activity may be both attenuated by ASMs. This finding may help with our understanding of the pathophysiology of epilepsy and can aid with the discovery of new approaches for epilepsy management.

Case report: Young-onset large vessel ischemic stroke due to hyperhomocysteinemia associated with the C677T polymorphism on 5,10-methylenetetrahydrofolate reductase and multi-vitamin deficiency.

Hyperhomocysteinemia is an important risk factor for cerebral infarction. Herein, we report on a 30-year-old man previously diagnosed with epilepsy who presented with right hemiplegia and total aphasia. Magnetic resonance imaging showed a fronto-temporal ischemic lesion due to occlusion of the left middle cerebral artery. Clinical testing and imaging demonstrated that he had hyperhomocysteinemia induced by multiple factors including the C677T polymorphism on 5.10-methylenetetrahydrofolate reductase (MTHFR), and multiple vitamin deficiencies. The C677T polymorphism on MTHFR is closely related to hyperhomocysteinemia and folate deficiency in epileptic patients who are taking multiple anti-convulsants. Given hyperhomocysteinemia can independently cause stroke at a young age, physicians should periodically examine plasma homocysteine and serum folic acid levels in epileptic patients who are on long-term regimens of multiple anti-epileptic drugs.

Ictal direct current shifts contribute to defining the core ictal focus in epilepsy surgery.

Identifying the minimal and optimal epileptogenic area to resect and cure is the goal of epilepsy surgery. To achieve this, EEG analysis is recognized as the most direct way to detect epileptogenic lesions from spatiotemporal perspectives. Although ictal direct-current shifts (below 1 Hz) and ictal high-frequency oscillations (above 80 Hz) have received increasing attention as good indicators that can add more specific information to the conventionally defined seizure-onset zone, large cohort studies on postoperative outcomes are still lacking. This work aimed to clarify whether this additional information, particularly ictal direct-current shifts which is assumed to reflect extracellular potassium concentration, really improve postoperative outcomes. To assess the usefulness in epilepsy surgery, we collected unique EEG data sets recorded with a longer time constant of 10 s using an alternate current amplifier. Sixty-one patients (15 with mesial temporal lobe epilepsy and 46 with neocortical epilepsy) who had undergone invasive presurgical evaluation for medically refractory seizures at five institutes in Japan were retrospectively enrolled in this study. Among intracranially implanted electrodes, the two core electrodes of both ictal direct-current shifts and ictal high-frequency oscillations were independently identified by board-certified clinicians based on unified methods. The occurrence patterns, such as their onset time, duration, and amplitude (power) were evaluated to extract the features of both ictal direct-current shifts and ictal high-frequency oscillations. Additionally, we examined whether the resection ratio of the core electrodes of ictal direct-current shifts and ictal high-frequency oscillations independently correlated with favourable outcomes. A total of 53 patients with 327 seizures were analyzed for wide-band EEG analysis, and 49 patients were analyzed for outcome analysis. Ictal direct-current shifts were detected in the seizure-onset zone more frequently than ictal high-frequency oscillations among both patients (92% versus 71%) and seizures (86% versus 62%). Additionally, ictal direct-current shifts significantly preceded ictal high-frequency oscillations in patients exhibiting both biomarkers, and ictal direct-current shifts occurred more frequently in neocortical epilepsy patients than in mesial temporal lobe epilepsy patients. Finally, although a low corresponding rate was observed for ictal direct-current shifts and ictal high-frequency oscillations (39%) at the electrode level, complete resection of the core area of ictal direct-current shifts significantly correlated with favourable outcomes, similar to ictal high-frequency oscillation outcomes. Our results provide a proof of concept that the independent significance of ictal direct-current shifts from ictal high-frequency oscillations should be considered as reliable biomarkers to achieve favourable outcomes in epilepsy surgery. Moreover, the different distribution of the core areas of ictal direct-current shifts and ictal high-frequency oscillations may provide new insights into the underlying mechanisms of epilepsy, in which not only neurons but also glial cells may be actively involved via extracellular potassium levels.

[The Oscillatory Phenomena in Human Epileptic Seizure: From A Glial-Neuronal Function Perspective in the Brain].

The brain is a kind of very large-scale integration circuit or its beyond that produces extremely various ranges of electroencephalogram. Epilepsy is a state caused by explosively hyperexcitable brain activities. Recently, it has been suggested that not only the hyperexcitability of neurons but also glial cells, which were previously thought to be silent or plain, play a crucial role in the acquisition of epileptogenicity. In this review article, we will comprehensively describe the utility of the analysis of brain activities from extremely low to high frequency oscillations. Our multi-institute study confirmed that ictal direct current shifts (ictal DC) precedes ictal high-frequency oscillations (ictal HFOs), being more prominent in neocortical epilepsy than in temporal lobe epilepsy. Moreover, we revealed that the complete resection of the core regions of ictal DC shifts significantly correlated with favorable outcomes after epileptic surgery. Taking our findings and previous knowledge into account, we will address the importance of not only neuronal but also glial functions towards the better understanding of pathogenesis of the so-called "chronic" state of epilepsy.

Electrical cortical stimulations modulate spike and post-spike slow-related high-frequency activities in human epileptic foci.

OBJECTIVE: Using interictal epileptiform discharges (IEDs), consisting of spikes and post-spike slow waves (PSSs), and IED-related high-frequency activities (HFAs), we elucidated inhibitory effects of electrical cortical stimulation (ECS) on human epileptic foci. METHODS: We recruited 8 patients with intractable focal epilepsy, and 50-Hz ECS was applied to the seizure-onset zone (SOZ) and non-SOZ. Before (5-min) and after (20-min) ECS, we evaluated the number of IED, the amplitudes of spikes and PSSs, spike-related HFA power, and PSS-related low gamma (30-50 Hz) activities. RESULTS: SOZ stimulation significantly decreased the number of IEDs and amplitude of spikes. Spike-related HFA power values in fast ripple (200-300 Hz) and ripple (80-150 Hz) bands were significantly suppressed only by SOZ stimulation in 4 and 3 patients, respectively. Among 4 patients with discrete PSSs, the amplitude ratio of spike/PSS decreased and the PSS-related low gamma activity power increased significantly in 2 patients and marginally in 1 patient. CONCLUSIONS: ECS potentially modulates cortical excitability by reducing excitation and increasing inhibition, and monitoring IED-related HFAs may help achieve the optimal effects of ECS. SIGNIFICANCE: IED and IED-related HFAs are dynamic, potential surrogate markers for epileptic excitability during the interictal period.

Active direct current (DC) shifts and "Red slow": two new concepts for seizure mechanisms and identification of the epileptogenic zone.

An accurate identification of the epileptogenic zone is essential for patients with intractable epilepsy who are candidates to neurosurgery. EEG recordings can provide predictive biomarkers of the epileptogenic zone. Wide-band EEG makes it possible to record from infraslow (including DC shifts) to high frequency (HFO, over 300 Hz) oscillations for diagnostic purposes in patients with epilepsy. Although the presence of HFOs have been proposed to sign the epileptogenic zone, DC-like recordings demonstrate that DC shifts precede HFOs at seizure onset. This led to the proposal that "ictal active DC shifts" are causally related to seizure onset as opposed to "ictal passive DC shifts". Thus, active DC shifts may constitute predictive biomarkers of the epileptogenic zone in epilepsy. Since DC shift is commonly associated to a rise in extracellular potassium, potassium homeostasis regulated by Kir4.1 channels in astrocytes may play an key role at seizure onset. In addition, we hypothesize that, during the interictal period, the co-occurrence of slow events and interictal HFOs, so-called "Red slow", may also delineate an epileptogenic zone, even if a seizure would not be actually recorded.

A taxonomy of seizure dynamotypes.

Seizures are a disruption of normal brain activity present across a vast range of species and conditions. We introduce an organizing principle that leads to the first objective Taxonomy of Seizure Dynamics (TSD) based on bifurcation theory. The 'dynamotype' of a seizure is the dynamic composition that defines its observable characteristics, including how it starts, evolves and ends. Analyzing over 2000 focal-onset seizures from multiple centers, we find evidence of all 16 dynamotypes predicted in TSD. We demonstrate that patients' dynamotypes evolve during their lifetime and display complex but systematic variations including hierarchy (certain types are more common), non-bijectivity (a patient may display multiple types) and pairing preference (multiple types may occur during one seizure). TSD provides a way to stratify patients in complement to present clinical classifications, a language to describe the most critical features of seizure dynamics, and a framework to guide future research focused on dynamical properties.

Epileptic seizures have been recognized for centuries. But it was only in the 1930s that it was realized that seizures are the result of out-of-control electrical activity in the brain. By placing electrodes on the scalp, doctors can identify when and where in the brain a seizure begins. But they cannot tell much about how the seizure behaves, that is, how it starts, stops or spreads to other areas. This makes it difficult to control and prevent seizures. It also helps explain why almost a third of patients with epilepsy continue to have seizures despite being on medication. Saggio, Crisp et al. have now approached this problem from a new angle using methods adapted from physics and engineering. In these fields, "dynamics research" has been used with great success to predict and control the behavior of complex systems like electrical power grids. Saggio, Crisp et al. reasoned that applying the same approach to the brain would reveal the dynamics of seizures and that such information could then be used to categorize seizures into groups with similar properties. This would in effect create for seizures what the periodic table is for the elements. Applying the dynamics research method to seizure data from more than a hundred patients from across the world revealed 16 types of seizure dynamics. These "dynamotypes" had distinct characteristics. Some were more common than others, and some tended to occur together. Individual patients showed different dynamotypes over time. By constructing a way to classify seizures based on the relationships between the dynamotypes, Saggio, Crisp et al. provide a new tool for clinicians and researchers studying epilepsy. Previous clinical tools have focused on the physical symptoms of a seizure (referred to as the phenotype) or its potential genetic causes (genotype). The current approach complements these tools by adding the dynamotype: how seizures start, spread and stop in the brain. This approach has the potential to lead to new branches of research and better understanding and treatment of seizures.

Interictal Slow and High-Frequency Oscillations: Is it an Epileptic Slow or Red Slow?

PURPOSE: We reported the presence of interictal slow and high-frequency oscillations (HFOs) (IIS + HFO) and its temporal change so as to elucidate its clinical usefulness as a surrogate marker of epileptogenic zone in a patient with intractable focal epilepsy. METHODS: We focused on one of the core electrodes of epileptogenicity, and investigated IIS + HFO in the pre- and post-segment of 30 minutes to all the 6 seizures. We adopted interictal slow in duration of 0.33 to 10 seconds, amplitude ≥50 µV and co-occurring with HFOs, and then divided into 5 groups depending on the amplitude of slow wave. RESULTS: Before and after all the 6 seizures, the number of IIS + HFO was 2,890 at one electrode in the core epileptogenic zone. The number of IIS + HFO significantly decreased for 30 minutes after seizures. Furthermore, the number of IIS + HFO with the amplitude of 200 to 399 µV significantly decreased after seizures. CONCLUSIONS: IIS + HFO with the amplitude of 200 to 399 µV was influenced by and decreased after seizures. It may reflect the core part of epileptogenic area as similarly as ictal direct current shifts and ictal HFOs do. IIS + HFO could be called as the term "red slow," which may be useful to delineate at least a part of the epileptogenic zone.

A case of neurosyphilis presenting with limbic encephalitis.

A 46-year-old man presented with a history of personality change and memory disturbance for 5 months. He gradually became difficult in doing a daily job. Brain MRI showed abnormal hyperintensity within bilateral mesial temporal lobes on T2 weighted image. Therefore, viral and autoimmune limbic encephalitis was initially suspected. However, because treponemal and non-treponemal specific antibodies were positive in serum and cerebrospinal fluid (CSF), the diagnosis of neurosyphilis was made. Patients of neurosyphilis with mesiotemporal T2 weighted hyperintensity reportedly showed common features such as relatively young age, HIV-negative, subacute cognitive impairment and seizure, as seen in our patient. Neurosyphilis should be included in the differential diagnosis for mesiotemporal abnormality in patients with these features. In addition, in our patient, anti-glutamate receptor ε2 antibody (ELISA) was strongly positive in CSF that suggested additional autoimmune pathophysiological mechanism.

Periodic synchronous discharge occurred in an elderly with acute valacyclovir-associated encephalopathy.

An 81-year-old woman suffering from sarcoidosis, chronic renal failure caused by hypertention was treated by valacyclovir 500 mg/day, for the diagnosis of herpes zoster of her right back. Her consciousness gradually became worse, and 3 days after taking the drug, she was sent to the emergency department of the hospital. Her conscious level was E2V2M5 (Glasgow Coma Scale) and myoclonus especially in her lower extremities occurred. Head CT and MRI show no obvious, acute abnormal findings other than chronic ischemic lesions, while an electroencephalogram (EEG) shows periodic synchronous discharges (PSDs) and disorganized background activity. Based on these findings, she was diagnosed as valacyclovir-associated acute encephalopathy. After conservative therapy of maintenance hemodialysis, her consciousness gradually improved, and PSDs disappeared accordingly and background activity of EEG became improved. In this case report, we presented valacyclovir-associated neurotoxicity with PSDs in EEG as potentially a surrogate marker. We should be cautious to use valaciclovir which may cause drug-induced encephalopathy especially in elderly or patients with renal failure even though the dose was adjusted in advance.