Seizure Frequency Can Alter Brain Connectivity: Evidence from Resting-State fMRI

BACKGROUND AND PURPOSE:The frequency of seizures is an important factor that can alter functional brain connectivity. Analysis of this factor in patients with epilepsy is complex because of disease- and medication-induced confounders. Because patients with hot-water epilepsy generally are not on long-term drug therapy, we used seed-based connectivity analysis in these patients to assess connectivity changes associated with seizure frequency without confounding from antiepileptic drugs.MATERIALS AND METHODS:Resting-state fMRI data from 36 patients with hot-water epilepsy (18 with frequent seizures [>2 per month] and 18 with infrequent seizures [≤2 per month]) and 18 healthy age- and sex-matched controls were analyzed for seed-to-voxel connectivity by using 106 seeds. Voxel wise paired t-test analysis (P < .005, corrected for false-discovery rate) was used to identify significant intergroup differences between these groups.RESULTS:Connectivity analysis revealed significant differences between the 2 groups (P < .001). Patients in the frequent-seizure group had increased connectivity within the medial temporal structures and widespread areas of poor connectivity, even involving the default mode network, in comparison with those in the infrequent-seizure group. Patients in the infrequent-seizure group had focal abnormalities with increased default mode network connectivity and decreased left entorhinal cortex connectivity.CONCLUSIONS:The results of this study suggest that seizure frequency can alter functional brain connectivity, which can be visualized by using resting-state fMRI. Imaging features such as diffuse network abnormalities, involvement of the default mode network, and recruitment of medial temporal lobe structures were seen only in patients with frequent seizures. Future studies in more common epilepsy groups, however, will be required to further establish this finding.

Behind the unquestionable clinical and electroencephalographic manifestations of an epileptic seizure, there lie several molecular, metabolic, cellular, and hemodynamic events that alter the function of the brain in a complex manner. These alterations may be transient, but many such events can have a cumulative effect, resulting in psychological and memory deficits, personality changes, and reduced functioning in patients with epilepsy. Advances in neurophysiology, functional imaging, and computational neurosciences have made it possible to derive models mathematically to describe such complex diseases.Disease-state network analysis with resting-state fMRI is becoming increasingly popular because of its superior spatial resolution, nondependence on task, ease of acquisition, and ability to visualize whole-brain functional networks, which are amenable to long-term changes related to disease states.¹ Application of connectivity principles to these data has promoted research in various aspects of epileptic seizures, and there has been overwhelming report of decreased connectivity around the seizure-onset zone^2–6 and the default mode network (DMN) by several groups.^7,8 In 2012, Jehi⁷ and Morgan et al⁹ reported that connectivity patterns were different in patients with right and left mesial temporal sclerosis and that there was decreased connectivity between the regions of the DMN and the hippocampus and amygdala in patients with mesial temporal sclerosis. Similarly, hemispheric connectivity analysis in patients with unilateral mesial temporal sclerosis revealed decreased local and intrahemispheric connectivity and increased interhemispheric connectivity.¹⁰ In contradistinction to the aforementioned results, there have been reports on increased hippocampal connectivity that was presumed to be a compensatory mechanism because it linearly correlated with a disease duration of >10 years.^1–4,6 Graph-theory analysis of resting-state fMRI data from patients with epilepsy also revealed decreased functional nodal topologic properties of the DMN that were positively correlated with disease duration.^8,11–14 Regional homogeneity analysis of resting-state fMRI data was even used as a presurgical tool for seizure identification in patients with MR-negative focal epilepsy.¹⁵ Thus, various models of data analysis have helped in understanding epilepsy further, and now there is increasing interest in using these models to reclassify epilepsy as a focal epileptogenic area^10,15 or as a network of seizure-generating areas.^16–18Gower''s clinical observation that “seizures beget seizures” in 1881 triggered several studies, especially animal models that addressed the genesis of epilepsy. Kindling is a phenomenon in which the repetition of subconvulsive electrical stimuli results in a progressive epileptic state and an increased frequency of seizures.^19,20 Kindling is a continuous temporal process that remodels the mechanisms and circuits in the brain. Early changes, beginning with modulation of presynaptic and postsynaptic functioning in glutamate, N-methyl-d-aspartate, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and late changes, including mossy fiber sprouting, synaptogenesis/neurogenesis, and neurotrophic factor regulation, are known to occur as a result of kindling.^20–22 The increased risk for seizure recurrence with increasing numbers of seizures was first demonstrated clinically by Hauser and Lee.²³ The effects of seizure frequency and chronic epilepsy have been studied sparsely by using imaging techniques.¹ For example, Widjaja et al²⁴ found no significant correlation with seizure frequency, age of seizure onset, or duration of epilepsy in a group of children with medically refractory epilepsy.Apart from other disease-related confounders such as type of seizure, duration of epilepsy, age of onset, family history of epilepsy, etc, each of which can induce connectivity differences independently, a major limitation of interpreting the results of functional connectivity in patients with epilepsy is the use of antiepileptic drugs. Patients with hot-water epilepsy (HWE) present with a history of complex partial seizures clinically suggestive of temporal lobe onset with or without secondary generalization. Most patients are drug naive at their first evaluation, which provided us an opportunity to study networks that were affected by seizure frequency and matched for other disease-related confounders but not antiepileptic drugs. On the basis of the phenomenon of kindling, we hypothesized that seizures can alter brain connectivity and that the frequency of seizures can influence the magnitude of this alteration. We predicted that patients with a higher seizure frequency would have widespread changes in comparison with patients with a lower seizure frequency. We used seed-to-voxel–based resting-state fMRI connectivity in 36 drug-naive patients with HWE who were comparable in terms of various factors such as age, sex, education, and epilepsy-related confounders. We hope that such quantifiable noninvasive in vivo evidence further enhances knowledge of the etiopathogenesis of HWE and, if applicable to refractory epilepsy, can identify such patients early to avoid time-consuming trial-and-error methods of pharmacotherapy and facilitate early intervention to minimize cognitive deficits.     

Brachial plexus block with midazolam and bupivacaine improves analgesia

PURPOSE: Adjuncts to local anesthetics for brachial plexus block may enhance the quality and duration of analgesia. Midazolam, a water-soluble benzodiazepine, is known to produce antinociception and enhance the effect of local anesthetics when given epidurally or intrathecally. The purpose of this study was to assess the effect of midazolam added to brachial plexus anesthesia. METHODS: A prospective, randomized, double blind study was conducted on 40 ASA I or II adult patients undergoing upper limb surgeries under supraclavicular brachial plexus block. Patients were randomly divided into two groups. Patients in Group B (n = 20) were administered 30 mL of 0.5% bupivacaine and Group BM (n = 20) were given 30 mL of 0.5% bupivacaine with midazolam 50 microg x kg(-1). Hemodynamic variables (i.e., heart rate, noninvasive blood pressure), pain scores and rescue analgesic requirements were recorded for 24 hr postoperatively. RESULTS: The onset of sensory and motor block was significantly faster in Group BM compared to Group B (P < 0.05). Pain scores were significantly higher in Group B compared to Group BM from two hours to 24 hr postoperatively (P < 0.05). Rescue analgesic requirements were significantly less in Group BM compared to Group B (P < 0.05). Hemodynamics and sedation scores did not differ between groups in the post-operative period. CONCLUSION: Midazolam (50 microg x kg(-1)) in combination with 30 mL of bupivacaine (0.5%) hastened onset of sensory and motor block, and improved postoperative analgesia when used in brachial plexus block, without producing any adverse events.     

Acromioclavicular joint dislocation: a comparative biomechanical study of the palmaris-longus tendon graft reconstruction with other augmentative methods in cadaveric models

Background  

Acromioclavicular injuries are common in sports medicine. Surgical intervention is generally advocated for chronic instability of Rockwood grade III and more severe injuries. Various methods of coracoclavicular ligament reconstruction and augmentation have been described. The objective of this study is to compare the biomechanical properties of a novel palmaris-longus tendon reconstruction with those of the native AC+CC ligaments, the modified Weaver-Dunn reconstruction, the ACJ capsuloligamentous complex repair, screw and clavicle hook plate augmentation.     

Titanium elastic nailing in femoral diaphyseal fractures of children in 6-16 years of age

Background:

Management of femoral diaphyseal fractures in the age group of 6-16 years is controversial. There has been a resurgence worldwide for operative fixation.

Materials and Methods:

Twenty-two children (18 boys, 4 girls) aged 6-16 years with recent (> 3 days) femoral diaphyseal fractures (20 closed, 2 open) were stabilized with Titanium Elastic Nail (TEN). These fractures were in proximal third (n=3), middle third (n=15) and in the distal third (n=4) 17 patients underwent surgery within seven days of their injury. The results were evaluated using Flynn''s scoring criteria. Statistical analysis was done using Fischer''s exact test.

Results:

All 22 patients were available for evaluation after a mean of 26 months (14-36 months) of followup. Radiological union in all cases were achieved in a mean time of 8.7 weeks. Full weight bearing was possible in a mean time of 8.8 weeks. Mean duration of hospital stay was 9.8 days. The results were excellent in 13 patients (59.0%), successful in six (27.2%) and poor in three patients (13.6%). All patients had early return to school.

Conclusion:

Intramedullary fixation titanium elastic nailing is an effective treatment of diaphyseal fractures of the femur in properly selected patients of the 6-16 years age group.     

Outcome of low level lasers versus ultrasonic therapy in de Quervain's tenosynovitis

Background:

de Quervain''s tenosynovitis is an inflammation of abductor pollicis longus (APL) and extensor pollicis brevis (EPB) muscle tendon sheaths at the level of radial styloid process. Its conservative management includes nonsteroidal anti-inflammatory drugs, wrist and thumb immobilization, ultrasonic therapy (US Th.) and low level laser therapy (LLLT). Literature is scanty on comparative efficacy of US Th. and LLLT for its management. This prospective study evaluates outcome of US Th. versus LLLT in de Quervain''s disease.

Materials and Methods:

Thirty patients clinically diagnosed de Quervains tenosynovitis were included in the study and randomly assigned to two groups. The average age was 36 years (range: 21-45 years). One group was given LLLT and the other US Th. for a total of 7 exposures on alternate days. The clinical criteria used were Finkelstein''s test, tenderness over radial styloid (Ritchie''s tenderness scale), grip strength, pain (visual analog scale [VAS]) and radiological criteria was ultrasonographic assessment of change in thickness of APL and EPB tendon sheath. They were measured before commencement and at the end of seven sessions of therapy, as per standard procedure.

Results:

Significant improvement was seen within both groups in the following outcome measures assessed: Ritchie''s tenderness scale, grip strength and VAS. Finkelstein''s test was not significantly improved in either groups. Ultrasonographic measurement of tendon sheath diameters, the mediolateral (ML), and anteroposterior (AP) diameters was not found to be significantly different in the US Th. group and the laser therapy group after treatment. On comparing both the groups, no statistically significant difference was found. However, looking at the mean values, the grip strength and VAS showed better improvement in the US Th. group as compared to the laser therapy group.