Real-life experiences with galcanezumab and predictors for treatment response in Turkey.

BACKGROUND: The complexity of clinical practice extends far beyond the controlled settings of trials, and there is a need for real-world studies aimed at identifying which patients will respond to anti-CGRP monoclonal antibodies in different countries. This study aimed to investigate the efficacy and safety of galcanezumab in treating migraine in a real-life setting in Turkey, as well as identify predictors of treatment response. METHODS: A total of 476 patients who diagnosed with migraine according to ICHD-3 criteria and treated with galcanezumab by headache specialists were voluntarily participated in this cross-sectional study. Galcanezumab is indicated for the prevention of migraine in adults who have at least 4 monthly migraine days in Turkey. All patients filled out a survey on Google Form that comprised 54 questions, addressing various aspects such as demographics, migraine characteristics, previous use of acute symptomatic medication, failures with preventive drug classes, comorbidities, most bothersome symptoms, as well as the interictal burden of migraine. RESULTS: Among the participants, 89.3% reported that galcanezumab treatment was beneficial for them. A decrease in the frequency (80.0%), severity (85.7%), and acute medication usage for migraine attacks (71.4%) was reported with galcanezumab treatment. An adverse effect related to galcanezumab was reported in 16.3% of cases, but no serious adverse reactions were observed. Remarkably, 14.3% of participants reported no longer experiencing any headaches, and 18.9% did not require any acute treatment while receiving galcanezumab treatment. A logistic regression model showed that male gender, lack of ictal nausea, and previous failure of more than 2 prophylactic agents may predict the non-responders. CONCLUSIONS: The first large series from Turkey showed that galcanezumab treatment is safe and effective in most of the patients diagnosed with migraine by headache experts in the real-life setting. Patients reported a significant decrease in both ictal and interictal burden of migraine and expressed satisfaction with this treatment.

Interrupted processing of paired somatosensory stimuli in short interstimulus intervals: role of thalamo-cortical oscillations.

BACKGROUND: Discrimination of consecutive sensory stimuli is imperative for proper sensory perception and behavioral response. We aimed to investigate the emergence of paired somatosensory responses in relation to the interstimulus interval (ISI) change. METHODS: Paired stimulus with 35 ms, 50 ms, 80 ms, 140 ms, and 500 ms ISI was applied to the median nerve and evoked responses were recorded from the primary somatosensory cortex in rats. Early and late components of both responses were analyzed in different frequency bands. RESULTS: The amplitudes were comparable for the 1st responses (S1), while the amplitude of the 2nd responses (S2), and S2/S1 sensory gating ratio were significantly lower at 35 and 50 ms ISI values. S2/S1 ratio was close to 1 at 500 ms ISI. The duration and latency of the 2nd response was also different at 35 ms ISI. In the 2nd responses, area of early high-frequency oscillations (150-400 Hz) was significantly lower at 35 ms ISI values. DISCUSSION: The shaping of 2nd somatosensory response is dependent on ISIs. Early high-frequency oscillations changes without accompanying late high-frequency oscillations alterations, may indicate that reduced thalamo-cortical drive to the cortex take a part in determining the 2nd response at short ISI. Further research is required by using neuropsychiatric disorder models where somatosensory perception is impaired.

Comparison of greater occipital nerve and greater occipital nerve + supraorbital nerve block effect in chronic medication overuse headache

Background /aim: In this study, we aimed to compare the efficacy of greater occipital nerve (GON) block alone and GON combined with supraorbital nerve (SON) block in the treatment of medication overuse headache (MOH). Material and methods: 82 patients were divided into two groups: 41 patients were administered bilateral GON block while the other 41 patients GON + SON block. Nerve blocks were administered every 10 days for a total of 5 sessions. After each administration and 20 days after the last injection, information on pre and post treatment numerical rating scale (NRS) score, number of painful days, analgesic intake, duration of pain were collected. Results: The decrease in headache evaluation parameters was similar in both groups after the block. The NRS scores in the GON and GON + SON groups before the treatment was (8.2 ± 0.7, 8.5 ± 0.7), the number of painful days in a month was (21.4 ± 6.9, 21.2 ± 4.6 days), the number of analgesics taken monthly was (45 ± 25.6, 47.5 ± 29.9), the duration of pain was (44.9 ± 24.6, 41.7 ± 22.8 h), respectively. On the 60th day of treatment, the NRS scores in the GON and GON + SON groups were found to be (6.8 ± 2.5, 4.8 ± 2.3), the number of painful days in a month was (4.2 ± 3.3, 2.2 ± 1.5), respectively. The number of monthly analgesic consumption was (4.4 ± 3.8, 0.9 ± 1.2), and the duration of pain was (28.4 ± 19.3, 19.4 ± 16.1 h). Conclusion: This study showed significant reductions in headache parameters in both groups. However, NRS score, analgesic intake, number of painful days, and pain duration significantly better improved in the GON block added SON block group.

Medication overuse headache: The effectivity of iv lidocaine - magnesium.

BACKGROUND AND PURPOSE: The detoxification process in medication overuse headache is the most difficult process for the patient. We aimed to investigate the effectiveness of the combination of low dose IV lidocaine and magnesium (100 mg lidocaine and 1.25 mg magnesium) in patients with medication overuse headache during the detoxification process. METHODS: A total of 30 patients were included in the study; 15 received 24 hours of IV hydration, 15 received 1-hour lidocaine-magnesium infusion at the onset of pain in addition to the 24 hours of IV hydration. Headache severity (numeric rating scale, NRS), attack durations, onset of headache, monthly analgesic/triptan intakes, numbers of monthly headache days data were documented. We evaluated the severity of headache before and after daily treatment of two groups for one week. RESULTS: When both groups were compared, there was no significant difference in the pre-treatment NRS values, whe-reas, in the group receiving IV lidocaine-magnesium combination, there was a statistically significant decrease in the post-treatment NRS values in the first five days (p <0.05). CONCLUSION: An 1-hour combined infusion of lidocaine-magnesium may be considered as an alternative option for the patient to have a more quality detoxification process during the hospital stay, so that in parallel to the reduction in the use of multiple treatments (such as neuroleptics, benzodiazepines, antiemetics and opioids) and duration length of stay, the economic costs can also be reduced. The administration of combination will bring fewer side effects compared to their administration separately.

CGRP receptor antagonist MK-8825 attenuates cortical spreading depression induced pain behavior.

BACKGROUND AND OBJECTIVE: The present study aimed to investigate the effects of selective calcitonin gene related peptide (CGRP) receptor antagonist (MK-8825) on cortical spreading depression (CSD) induced pain behavior and anxiety in freely-moving rats, and neuronal activation in the correlated anatomical regions. METHODS: CSD was induced while keeping all meningeal layers and BBB intact and MK-8825 was administered in two different doses. Regional cerebral blood flow (rCBF), arterial pressure and DC shift were recorded. Behavioral studies were conducted in freely-moving rats. Spontaneous behavior, mechanical allodynia, ultrasonic vocalization, and anxiety were evaluated. Immunohistochemistry of c-fos, CGRP, calcitonin receptor like-receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were studied. RESULTS: MK-8825 did not block DC shifts in the cerebral cortex and accompanied hemodynamic response. CSD significantly induced freezing and grooming behavior in freely-moving rats. MK-8825 reversed increased episodes of freezing, grooming, wet dog shake and head shake behavior. MK-8825 increased CSD-induced reductions in von Frey thresholds, but did not change elevated plus maze results. MK-8825 blocked c-fos induction by CSD in the brainstem trigeminal nucleus caudalis (TNC) and reticular nucleus of thalamus (TRN) but not in the amygdala. Immunofluorescence analysis showed no co-localization of CGRP, CLR or RAMP1 with c-fos positive cells. CONCLUSION: CGRP receptor antagonist MK-8825 dose dependently attenuated CSD-induced trigeminal nerve mediated pain response without altering CSD waves and accompanied rCBF response. While blocking TNC activation, MK-8825 did not exert any effect on amygdala and anxiety behavior. CGRP receptor antagonists may also modulate thalamo-cortical gating.

The thalamic reticular nucleus is activated by cortical spreading depression in freely moving rats: prevention by acute valproate administration.

This study investigated the effect of repetitive cortical spreading depression (CSD) on behaviour and the anatomical and physiological patterns of cellular activation of cortical and subcortical areas in awake, moving rats. Rat behaviours in response to repetitive CSD events evoked by the application of KCl were quantified with electrophysiological recording. Immunohistochemistry was used to quantify anatomical regions of cellular activation. The effects of acute valproic acid administration on the behavioural parameters and cellular activation were evaluated. CSD significantly decreased locomotor activity and induced freezing in awake, moving rats, and stimulated c-Fos expression in the cortex, trigeminal nucleus caudalis (TNC), and amygdala. CSD also resulted in a prominent increase in c-Fos expression in the ipsilateral thalamic reticular nucleus (TRN) visual sector. Electrophysiological recordings revealed propagation of CSD into the TRN. Valproic acid pretreatment decreased the duration of CSD-induced freezing episodes and reversed the CSD-induced reduction in locomotor activity. Acute valproic acid administration also significantly blocked CSD-induced c-Fos expression in the TNC and TRN. These findings show that CSD events cause consistent behavioural responses and activate specific brain regions in awake, freely moving rats. Selective activation of TRN by CSD and the suppression of this activation by valproic acid suggest that this brain region may play an important role in migraine pathogenesis and may represent a novel target for migraine therapy.

Evaluation of volumetric asymmetry of the dorsolateral prefrontal cortex and medial temporal lobe in Alzheimer's disease using the atlas-based method.

Brain areas affected during neurodegenerative disease progression are considered anatomically connected to the first affected areas. The dorsolateral prefrontal cortex (DLPFC) has connections with the medial temporal lobe (MTL), which includes regions that become atrophic in Alzheimer's disease. In this study, we aimed to investigate the degree of volumetric asymmetry of DLPFC and MTL structures. This is a cross-sectional volumetric study involving 25 Alzheimer's disease patients and 25 healthy adults who underwent MRI with a 3D turbo spin echo sequence at 1.5 Tesla. The atlas-based method incorporated MRIStudio software to automatically measure the volume of brain structures. We compared the asymmetry index and volumetric changes across study groups and correlated them with Mini-Mental State Examination scores. We observed significant volumetric rightward lateralization in the DLPFC and superior frontal gyrus in Alzheimer's disease patients compared to the healthy controls. There was a significant volume loss in the MTL structures of Alzheimer's disease patients. Atrophy of MTL structures was positively correlated with right DLPFC volume changes in Alzheimer's disease patients. Volumetric asymmetry of the DLPFC may be a characteristic for determining disease progression in Alzheimer's disease patients. Future studies are recommended to evaluate whether these volumetric asymmetrical changes are specific to Alzheimer's disease and whether asymmetry measurements can serve as diagnostic markers.

NOTCH3 Variants in Patients with Suspected CADASIL.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) is the most common hereditary form of cerebral small vessel disease. It is clinically, radiologically, and genetically heterogeneous and is caused by NOTCH3 mutations. Methods: In this study, we analyzed NOTCH3 in 368 patients with suspected CADASIL using next-generation sequencing. The significant variants detected were reported along with the clinical and radiological features of the patients. Results: Heterozygous NOTCH3 changes, mostly missense mutations, were detected in 44 of the 368 patients (~12%). Conclusions: In this single-center study conducted on a large patient group, 30 different variants were detected, 17 of which were novel. CADASIL, which can result in mortality, has a heterogeneous phenotype among individuals in terms of clinical, demographic, and radiological findings regardless of the NOTCH3 variant.

Is Two-Point Discrimination Test a New Diagnostic Method for the Diagnosis of Fibromyalgia?

Introduction: Fibromyalgia is a syndrome of obscure pathogenesis without objective diagnostic criteria and is frequently associated with diagnostic delays due to symptomatic heterogeneity. This study aimed at assessing the response to two-point discrimination test in extremities, neutrophil/lymphocyte ratio (NLR), Numeric Rating Scale (NRS) score, and Widespread Pain Index (WPI) score in patients with fibromyalgia. Methods: The patient group consisted of 26 subjects diagnosed with fibromyalgia based on the 2016 revision to the American College of Rheumatology 2010 diagnostic criteria, while 25 healthy individuals comprised the control group. In both groups, basal amplitude and somatosensorial temporal discrimination (STD) measurements at the dorsum of the hands and feet were performed in addition to NLR measurements. Also, NRS and WPI were determined in fibromyalgia patients. Results: STD was significantly prolonged in all extremities among fibromyalgia patients as compared to controls. WPI and NRS were also increased, paralleling the STD measurements in all extremities (p<0.05). NLR was higher in the patient group than in controls, although the difference was insignificant. Conclusion: STD values were high in fibromyalgia patients. So, STD appears to have a potential role as an auxiliary diagnostic tool in fibromyalgia. Still, further studies are needed to support this conclusion.

Volume estimation of brain ventricles using Cavalieri's principle and Atlas-based methods in Alzheimer disease: Consistency between methods.

Automatic estimations of brain ventricles are needed to assess disease progression in neurodegenerative disorders such as Alzheimer Disease (AD). The objectives of this study are to evaluate the diagnostic performances of an automated volumetric assessment tool in estimating lateral ventricle volumes in AD and to compare this with Cavalieri's principle, which is accepted as the gold standard method. This is across-sectional volumetric study including 25 Alzheimer patients and 25 healthy subjects undergoing magnetic resonance images (MRI) with a 3D turbo spin echo sequence at 1.5 Tesla. The Atlas-based method incorporated MRIStudio software to automatically measure he volumes of brain ventricles. To compare the corresponding measurements, we used manual point-counting and semi-automatic planimetry methods based on Cavalieri's principle. Bland-Altman test results indicated an excellent agreement between Cavalieri's principle and the Atlas-based method in all volumetric measurements (p < 0.05). We obtained a 64% sensitivity and 92% specificity for lateral ventricular volumes according to the Atlas-based method. AD subjects had significantly larger left and right lateral ventricle volume (LVV) when compared to control subjects in respect to three volumetric methods (p < 0.01). Lateral ventricle-to-brain ratio (VBR) statistically increased 49.23% in measurements done with the point-counting method, 45.12% with the planimetry method, and 45.49% with the Atlas-based method in AD patients (p < 0.01). As a result, the Atlas-based method may be used instead of manual volumetry to estimate brain volumes. Additionally, this method provides rapid and accurate estimations of brain ventricular volumes in-vivo examination of MRI.

Diagnostic Accuracy Comparison of Artificial Immune Algorithms for Primary Headaches.

The present study evaluated the diagnostic accuracy of immune system algorithms with the aim of classifying the primary types of headache that are not related to any organic etiology. They are divided into four types: migraine, tension, cluster, and other primary headaches. After we took this main objective into consideration, three different neurologists were required to fill in the medical records of 850 patients into our web-based expert system hosted on our project web site. In the evaluation process, Artificial Immune Systems (AIS) were used as the classification algorithms. The AIS are classification algorithms that are inspired by the biological immune system mechanism that involves significant and distinct capabilities. These algorithms simulate the specialties of the immune system such as discrimination, learning, and the memorizing process in order to be used for classification, optimization, or pattern recognition. According to the results, the accuracy level of the classifier used in this study reached a success continuum ranging from 95% to 99%, except for the inconvenient one that yielded 71% accuracy.

Reduced retinal nerve fiber layer thickness and macular volume in pediatric multiple sclerosis.

Retinal atrophy is well known in adult-onset multiple sclerosis but remains unexplored in children. We aimed to determine retinal nerve fiber layer thickness and macular volume in pediatric patients, with and without optic neuritis and their relations with visual evoked potentials. We also examined macular volume changes at month 12. Retinal nerve fiber layer thickness of all quadrants and macular volume were measured in 28 relapsing remitting multiple sclerosis eyes and 30 control eyes using optical coherence tomography and were found reduced in patients compared with controls. This reduction was more prominent in eyes with longer time interval from optic neuritis. Retinal nerve fiber thickness was lower in eyes with delayed visual evoked potentials. Visual evoked potential amplitudes were reduced in affected eyes compared to patients without optic neuritis. Macular volume reduced nonsignificantly in patients at month 12. Retinal atrophy occurs in pediatric multiple sclerosis, and previous optic neuritis accelerates this atrophy.