Concealment of Allergic Reactions to Alteplase by Face Masks in Non-Communicating Acute Stroke Patients: A Warning Call to Improve Our Physical Examination Practices during the COVID-19 Pandemic.

Neurological emergencies, such as acute stroke, are especially challenging during the current Coronavirus disease-2019 (COVID-19) pandemic. Symptoms as aphasia or dysarthria are severely impacting cooperation and communication with patients. During physical examination, both the patient and the medical team are fitted routinely with surgical masks to minimize potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, such a practice can lead to concealment of particularly relevant physical signs. We report a case series of four acute stroke patients who were transferred for endovascular mechanical thrombectomy to our institute after intravenous thrombolysis was initiated at primary stroke centers. Upon arrival, after removing their masks, we observed oral angioedema, as a reaction to thrombolytic agent alteplase. Symptoms remained obscured by face masks through patient care at the referring stroke unit and during transportation, nevertheless they resolved after treatment. Most probably, there are a number of similar cases encountered at emergency departments and acute stroke units. To improve patient safety, a compromise between ensuring protection against the novel coronavirus and facilitating detection of potentially life-threatening physical signs must be found.

The laminar profile of sleep spindles in humans.

Sleep spindles are functionally important NREM sleep EEG oscillations which are generated in thalamocortical, corticothalamic and possibly cortico-cortical circuits. Previous hypotheses suggested that slow and fast spindles or spindles with various spatial extent may be generated in different circuits with various cortical laminar innervation patterns. We used NREM sleep EEG data recorded from four human epileptic patients undergoing presurgical electrophysiological monitoring with subdural electrocorticographic grids (ECoG) and implanted laminar microelectrodes penetrating the cortex (IME). The position of IMEs within cortical layers was confirmed using postsurgical histological reconstructions. Many spindles detected on the IME occurred only in one layer and were absent from the ECoG, but with increasing amplitude simultaneous detection in other layers and on the ECoG became more likely. ECoG spindles were in contrast usually accompanied by IME spindles. Neither IME nor ECoG spindle cortical profiles were strongly associated with sleep spindle frequency or globality. Multiple-unit and single-unit activity during spindles, however, was heterogeneous across spindle types, but also across layers and patients. Our results indicate that extremely local spindles may occur in any cortical layer, but co-occurrence at other locations becomes likelier with increasing amplitude and the relatively large spindles detected on ECoG channels have a stereotypical laminar profile. We found no compelling evidence that different spindle types are associated with different laminar profiles, suggesting that they are generated in cortical and thalamic circuits with similar cortical innervation patterns. Local neuronal activity is a stronger candidate mechanism for driving functional differences between spindles subtypes.

Perisomatic Inhibition and Its Relation to Epilepsy and to Synchrony Generation in the Human Neocortex.

Inhibitory neurons innervating the perisomatic region of cortical excitatory principal cells are known to control the emergence of several physiological and pathological synchronous events, including epileptic interictal spikes. In humans, little is known about their role in synchrony generation, although their changes in epilepsy have been thoroughly investigated. This paper demonstraits how parvalbumin (PV)- and type 1 cannabinoid receptor (CB1R)-positive perisomatic interneurons innervate pyramidal cell bodies, and their role in synchronous population events spontaneously emerging in the human epileptic and non-epileptic neocortex, in vitro. Quantitative electron microscopy showed that the overall, PV+ and CB1R+ somatic inhibitory inputs remained unchanged in focal cortical epilepsy. On the contrary, the size of PV-stained synapses increased, and their number decreased in epileptic samples, in synchrony generating regions. Pharmacology demonstrated-in conjunction with the electron microscopy-that although both perisomatic cell types participate, PV+ cells have stronger influence on the generation of population activity in epileptic samples. The somatic inhibitory input of neocortical pyramidal cells remained almost intact in epilepsy, but the larger and consequently more efficient somatic synapses might account for a higher synchrony in this neuron population. This, together with epileptic hyperexcitability, might make a cortical region predisposed to generate or participate in hypersynchronous events.

Intracortical Dynamics Underlying Repetitive Stimulation Predicts Changes in Network Connectivity.

Targeted stimulation can be used to modulate the activity of brain networks. Previously we demonstrated that direct electrical stimulation produces predictable poststimulation changes in brain excitability. However, understanding the neural dynamics during stimulation and its relationship to poststimulation effects is limited but critical for treatment optimization. Here, we applied 10 Hz direct electrical stimulation across several cortical regions in 14 human subjects (6 males) implanted with intracranial electrodes for seizure monitoring. The stimulation train was characterized by a consistent increase in high gamma (70-170 Hz) power. Immediately post-train, low-frequency (1-8 Hz) power increased, resulting in an evoked response that was highly correlated with the neural response during stimulation. Using two measures of network connectivity, corticocortical evoked potentials (indexing effective connectivity), and theta coherence (indexing functional connectivity), we found a stronger response to stimulation in regions that were highly connected to the stimulation site. In these regions, repeated cycles of stimulation trains and rest progressively altered the stimulation response. Finally, after just 2 min (∼10%) of repetitive stimulation, we were able to predict poststimulation connectivity changes with high discriminability. Together, this work reveals a relationship between stimulation dynamics and poststimulation connectivity changes in humans. Thus, measuring neural activity during stimulation can inform future plasticity-inducing protocols.SIGNIFICANCE STATEMENT Brain stimulation tools have the potential to revolutionize the treatment of neuropsychiatric disorders. Despite the widespread use of brain stimulation techniques such as transcranial magnetic stimulation, the therapeutic efficacy of these technologies remains suboptimal. This is in part because of a lack of understanding of the dynamic neural changes that occur during stimulation. In this study, we provide the first detailed characterization of neural activity during plasticity induction through intracranial electrode stimulation and recording in 14 medication-resistant epilepsy patients. These results fill a missing gap in our understanding of stimulation-induced plasticity in humans. In the longer-term, these data will also guide our translational efforts toward non-invasive, personalized, closed-loop neuromodulation therapy for neurological and psychiatric disorders in humans.

[Medication-overuse headache]. / Fájdalomcsillapító-túlhasználathoz társuló fejfájás.

Medication-overuse headache affects 1 to 2 percent of the population. Any kind of painkiller, if taken regularly at least 10 days per month can cause medication-overuse headache, and therefore the possibility of this headache has to be raised whenever a patient with a preexistent headache notices a significant increase in headache frequency during a period of frequent painkiller consumption. Medication-overuse headache is most prevalent in females between 40 and 50 years of age. Its main risk factors are smokig, obesity, depression, and anxiety. The pathomechanism of medication-overuse headache is complex, with a probable genetic propensity and other biological (neurochemical and neurophysiological), as well as psychological and behavioural factors (such as anticipatory anxiety, catastrophisation of pain and consequentially a compulsive painkiller use) contributing to its genesis. The prerequisite of successful treatment is the withdrawal of the overused substance, other necessary elements of the therapy include the treatment of withdrawal symptoms including rebound headache, the introduction of an effective preventative therapy, taking into consideration the highly prevalent comorbid disorders as well, and the education and psychological support of patients. As the relapse rate can be as high as 30 to 40% regardless of effective treatment, the prevention of medication-overuse headache is of paramount importance, and the role of general practitioners can hardly be overstated.

The comprehensive headache-related quality of life questionnaire shows significant improvement after withdrawal treatment in medication overuse headache: a pilot study.

BACKGROUND AND PURPOSE: Medication overuse headache (MOH) is a common form of disabling headache presenting in as much as 30% of the patients seen in headache subspecialty practice. Quality of life (QOL) is frequently used as a secondary endpoint in headache trials. In MOH, previous trials of QOL focused mostly on generic QOL. We report the results of a pilot study that examined the feasibility of using a new QOL questionnaire, the 23-item Comprehensive Headache-related Quality of life Questionnaire (CHQQ), as an indicator of treatment response in MOH. PATIENTS AND METHODS: Fifteen patients (13 women and two men; mean age: 39.7 +/- 12.5 years) suffering from MOH were enrolled in a complex treatment programme consisting of acute medication withdrawal, preventive pharmacological treatment, structured advice and lifestyle intervention. The clinical data were collected using a detailed headache diary. CHQQ was completed before and after the treatment programme. RESULTS: MOH patients had low QOL values at baseline which was comparable to the QOL of episodic migraine patients. The treatment programme resulted in significant reductions of the number of headache days and attacks, headache severity and analgesic consumption. The dimensions and total score of CHQQ showed a significant increase after the treatment period. Seventeen of CHQQ's 23 individual items also improved significantly. CONCLUSION: In this study the new headache-specific quality of life instrument CHQQ was able to demonstrate significant improvements after adequate treatment of MOH. This result indicates that the CHQQ may be an adequate tool for assessing quality of life in headache treatment trials.

[Examining the diagnostic accuracy of a new migraine screener]. / Új önkitöltos migrénszuro eszköz diagnosztikus hatékonyságának vizsgálata.

BACKGROUND: Migraine affects more than 10% of the Hungarian population, causes significant disability and severely affects patients' generic and condition-specific quality of life. Despite these facts, a significant proportion of patients is not diagnosed and not treated adequately. Headache centres can provide care for only a fraction of all patients. The task of primary care providers would be greatly simplified by a reliable self-administered migraine screening questionnaire. OBJECTIVE: To develop a short and reliable questionnaire as a migraine screening tool. METHODS: Outpatients at the Headache Service, Department of Neurology, Semmelweis University completed a self-administered questionnaire which contained 9 yes/no questions about their headaches' characteristics. The number of 'yes' answers (the patients' total score) was evaluated in connection with the diagnosis based on the International Headache Society criteria. We calculated the sensitivity, specificity, positive and negative predictive value as well as the misclassification rate for each total score value and used these to establish the final cutoff value of the questionnaire. 306 patients (242 females, mean age 39.1 ± 13.3 years) were enrolled. The diagnosis was migraine in 244. RESULTS: Completing the questionnaire did not pose any difficulty for the patients. At a cutoff value of 5 points the questionnaire's sensitivity was 0.96 and specificity was 0.61. The positive predictive value was 0.91 and the negative pre- dictive value was 0.81. The misclassification rate was 0.11. DISCUSSION: Our results show that the questionnaire may help the diagnosis of migraine. In order to use it in medical practice, its further evaluation is necessary on a large representative sample of the Hungarian population.

Intracortical mechanisms of single pulse electrical stimulation (SPES) evoked excitations and inhibitions in humans.

Cortico-cortical evoked potentials (CCEPs) elicited by single-pulse electric stimulation (SPES) are widely used to assess effective connectivity between cortical areas and are also implemented in the presurgical evaluation of epileptic patients. Nevertheless, the cortical generators underlying the various components of CCEPs in humans have not yet been elucidated. Our aim was to describe the laminar pattern arising under SPES evoked CCEP components (P1, N1, P2, N2, P3) and to evaluate the similarities between N2 and the downstate of sleep slow waves. We used intra-cortical laminar microelectrodes (LMEs) to record CCEPs evoked by 10 mA bipolar 0.5 Hz electric pulses in seven patients with medically intractable epilepsy implanted with subdural grids. Based on the laminar profile of CCEPs, the latency of components is not layer-dependent, however their rate of appearance varies across cortical depth and stimulation distance, while the seizure onset zone does not seem to affect the emergence of components. Early neural excitation primarily engages middle and deep layers, propagating to the superficial layers, followed by mainly superficial inhibition, concluding in a sleep slow wave-like inhibition and excitation sequence.

The role of superficial and deep layers in the generation of high frequency oscillations and interictal epileptiform discharges in the human cortex.

Describing intracortical laminar organization of interictal epileptiform discharges (IED) and high frequency oscillations (HFOs), also known as ripples. Defining the frequency limits of slow and fast ripples. We recorded potential gradients with laminar multielectrode arrays (LME) for current source density (CSD) and multi-unit activity (MUA) analysis of interictal epileptiform discharges IEDs and HFOs in the neocortex and mesial temporal lobe of focal epilepsy patients. IEDs were observed in 20/29, while ripples only in 9/29 patients. Ripples were all detected within the seizure onset zone (SOZ). Compared to hippocampal HFOs, neocortical ripples proved to be longer, lower in frequency and amplitude, and presented non-uniform cycles. A subset of ripples (≈ 50%) co-occurred with IEDs, while IEDs were shown to contain variable high-frequency activity, even below HFO detection threshold. The limit between slow and fast ripples was defined at 150 Hz, while IEDs' high frequency components form clusters separated at 185 Hz. CSD analysis of IEDs and ripples revealed an alternating sink-source pair in the supragranular cortical layers, although fast ripple CSD appeared lower and engaged a wider cortical domain than slow ripples MUA analysis suggested a possible role of infragranularly located neural populations in ripple and IED generation. Laminar distribution of peak frequencies derived from HFOs and IEDs, respectively, showed that supragranular layers were dominated by slower (< 150 Hz) components. Our findings suggest that cortical slow ripples are generated primarily in upper layers while fast ripples and associated MUA in deeper layers. The dissociation of macro- and microdomains suggests that microelectrode recordings may be more selective for SOZ-linked ripples. We found a complex interplay between neural activity in the neocortical laminae during ripple and IED formation. We observed a potential leading role of cortical neurons in deeper layers, suggesting a refined utilization of LMEs in SOZ localization.

Manifold-adaptive dimension estimation revisited.

Data dimensionality informs us about data complexity and sets limit on the structure of successful signal processing pipelines. In this work we revisit and improve the manifold adaptive Farahmand-Szepesvári-Audibert (FSA) dimension estimator, making it one of the best nearest neighbor-based dimension estimators available. We compute the probability density function of local FSA estimates, if the local manifold density is uniform. Based on the probability density function, we propose to use the median of local estimates as a basic global measure of intrinsic dimensionality, and we demonstrate the advantages of this asymptotically unbiased estimator over the previously proposed statistics: the mode and the mean. Additionally, from the probability density function, we derive the maximum likelihood formula for global intrinsic dimensionality, if i.i.d. holds. We tackle edge and finite-sample effects with an exponential correction formula, calibrated on hypercube datasets. We compare the performance of the corrected median-FSA estimator with kNN estimators: maximum likelihood (Levina-Bickel), the 2NN and two implementations of DANCo (R and MATLAB). We show that corrected median-FSA estimator beats the maximum likelihood estimator and it is on equal footing with DANCo for standard synthetic benchmarks according to mean percentage error and error rate metrics. With the median-FSA algorithm, we reveal diverse changes in the neural dynamics while resting state and during epileptic seizures. We identify brain areas with lower-dimensional dynamics that are possible causal sources and candidates for being seizure onset zones.

Bursting of excitatory cells is linked to interictal epileptic discharge generation in humans.

Knowledge about the activity of single neurons is essential in understanding the mechanisms of synchrony generation, and particularly interesting if related to pathological conditions. The generation of interictal spikes-the hypersynchronous events between seizures-is linked to hyperexcitability and to bursting behaviour of neurons in animal models. To explore its cellular mechanisms in humans we investigated the activity of clustered single neurons in a human in vitro model generating both physiological and epileptiform synchronous events. We show that non-epileptic synchronous events resulted from the finely balanced firing of excitatory and inhibitory cells, which was shifted towards an enhanced excitability in epileptic tissue. In contrast, interictal-like spikes were characterised by an asymmetric overall neuronal discharge initiated by excitatory neurons with the presumptive leading role of bursting pyramidal cells, and possibly terminated by inhibitory interneurons. We found that the overall burstiness of human neocortical neurons is not necessarily related to epilepsy, but the bursting behaviour of excitatory cells comprising both intrinsic and synaptically driven bursting is clearly linked to the generation of epileptiform synchrony.

Changes of the outcomes of epilepsy surgery within 10 years in the National Institute of Clinical Neurosciences, Hungary / Az epilepsziasebészet eredményességének változása 2006 és 2016 között az Országos Klinikai Idegtudományi Intézetben.

Összefoglaló. Bevezetés és célkituzés: A terápiarezisztens fokális epilepsziák sebészeti kezelése elterjedten használt kezelési lehetoség. Célunk az epilepsziasebészet-hatékonyság változásának vizsgálata egy évtizednyi távlatból a budapesti centrumban. Módszerek: Az Országos Klinikai Idegtudományi Intézetben reszektív epilepsziasebészeti beavatkozásokon átesett fokális epilepsziás betegek adatai kerültek feldolgozásra. A vizsgált 10 év beteganyagát két periódusra osztottuk a mutét idopontja szerint (2006-2010 és 2011-2016). Vizsgálati szempontjaink: demográfiai adatok, az epilepszia kezdete és típusa, mágnesesrezonancia-lelet, preoperatív rohamfrekvencia, mutéttípus és szövettani lelet. Az epileptológiai kimenetelt az Engel-klasszifikáció alapján értékeltük. Eredmények: Epilepsziasebészeti beavatkozás 187 betegen történt, akik közül 137-nél került sor reszekciós mutétre. A betegek 65%-ában temporalis, 18%-ában frontalis, míg 7%-ában olyan multilobaris epilepszia igazolódott, mely a temporalis vagy a frontalis lebenyt érintette. Teljes rohammentességet (Engel I/A) az 1. évben 68%-ban, a 2. évben 64%-ban, míg az 5. évben 63%-ban mértünk. A két intervallum összehasonlításakor az 1 éves rohammentesség aránya 60%-ról (temporalis: 67%, extratemporalis: 50%) 73%-ra (temporalis: 79%, extratemporalis: 62%) javult a második periódusban. Az etiológia szempontjából a hippocampalis sclerosis aránya 28%-ról 14%-ra csökkent, a fokális corticalis dysplasiák aránya 22%-ról 31%-ra növekedett. Következtetés: A sebészeti kezelés fokális epilepsziák esetén - alapos elozetes kivizsgálást követoen - általában biztonságos és a legnagyobb arányban sikeres beavatkozás. A legkedvezobb kimenetel temporalis lokalizációban érheto el. A hatékonyság az évek során egyre javuló tendenciát mutatott az egyre nehezebb sebészeti esetek ellenére. Ez magyarázható a sebészeti technikák fejlodésével, illetve a jobb, mutét elotti elektrofiziológiai és képalkotó technikákkal, amelyek bevezetésével pontosabb lokalizáció adható. Orv Hetil. 2021; 162(6): 219-226. INTRODUCTION AND OBJECTIVE: The surgical treatment of medically intractable focal epilepsies is a well established practice. Our aim was to examine the efficacy of epilepsy surgery within a decade long period in our centre in Budapest. METHODS: Data of drug-resistant patients with resective epilepsy surgery in the National Institute of Clinical Neurosciences were evaluated. The examined 10-year period was divided based on the year of the operation in two parts (2006-2010 and 2011-2016). The following data were collected: demography, beginning and type of epilepsy, magnetic resonance, preoperative seizure frequency, type of surgery and histology. Epileptological outcome was based on modified Engel's classification. RESULTS: Out of 187 surgeries, we identified 137 patients with resective intervention: 65% temporal lobe, 18% frontal, and 7% multilobar epilepsy. Seizure-freedom (Engel I/A) was 68% in the first postoperative year, 64% in the second, and 63% in the fifth year. In the first period, 1-year seizure freedom was 60% (temporal: 67% extratemporal: 50%), while in the second period it was 73% (temporal 79%, extratemporal 62%). Hippocampal sclerosis ratio dropped from 28% to 14%, while focal cortical dysplasia ratio increased from 22% to 31%. CONCLUSION: Surgical treatment in focal epilepsy - after thorough presurgical evaluation - is generally safe and successful. The most favorable outcome is in temporal localization. The efficacy tended to improve over time despite of the more challenging cases. This can be explained with the development of surgical techniques and improvement of presurgical localization. Orv Hetil. 2021; 162(6): 219-226.

Reorganization of Large-Scale Functional Networks During Low-Frequency Electrical Stimulation of the Cortical Surface.

We investigated the functional network reorganization caused by low-frequency electrical stimulation (LFES) of human brain cortical surface. Intracranial EEG data from subdural grid positions were analyzed in 16 pre-surgery epileptic patients. LFES was performed by injecting current pulses (10mA, 0.2ms pulse width, 0.5Hz, 25 trials) into all adjacent electrode contacts. Dynamic functional connectivity analysis was carried out on two frequency bands (low: 1-4Hz; high: 10-40Hz) to investigate the early, high frequency and late, low frequency responses elicited by the stimulation. The centralization increased in early compared to late responses, suggesting a more prominent role of direct neural links between primarily activated areas and distant brain regions. Injecting the current into the seizure onset zone (SOZ) evoked a more integrated functional topology during the early (N1) period of the response, whereas during the late (N2) period - regardless of the stimulation site - the connectedness of the SOZ was elevated compared to the non-SOZ tissue. The abnormal behavior of the epileptic sub-network during both part of the responses supports the idea of the pathogenic role of impaired inhibition and excitation mechanisms in epilepsy.