Estrogenic influences in pain processing.

Gonadal hormones not only play a pivotal role in reproductive behavior and sexual differentiation, they also contribute to thermoregulation, feeding, memory, neuronal survival, and the perception of somatosensory stimuli. Numerous studies on both animals and human subjects have also demonstrated the potential effects of gonadal hormones, such as estrogens, on pain transmission. These effects most likely involve multiple neuroanatomical circuits as well as diverse neurochemical systems and they therefore need to be evaluated specifically to determine the localization and intrinsic characteristics of the neurons engaged. The aim of this review is to summarize the morphological as well as biochemical evidence in support for gonadal hormone modulation of nociceptive processing, with particular focus on estrogens and spinal cord mechanisms.

Immune response in blood before and after epileptic and psychogenic non-epileptic seizures.

Inflammatory processes may provoke epileptic seizures and seizures may promote an immune reaction. Hence, the systemic immune reaction is a tempting diagnostic and prognostic marker in epilepsy. We explored the immune response before and after epileptic and psychogenic non-epileptic seizures (PNES). Serum samples collected from patients with videoEEG-verified temporal or frontal lobe epilepsy (TLE or FLE) or TLE + PNES showed increased interleukin-6 (IL-6) levels in between seizures (interictally), compared to controls. Patients with PNES had no increase in IL-6. The IL-6 levels increased transiently even further within hours after a seizure (postictally) in TLE but not in FLE patients. The postictal to interictal ratio of additionally five immune factors were also increased in TLE patients only. We conclude that immune factors have the potential to be future biomarkers for epileptic seizures and that the heterogeneity among different epileptic and non-epileptic seizures may be disclosed in peripheral blood sampling independent of co-morbidities.

Hormonal replacement therapy does not affect self-estimated pain or experimental pain responses in post-menopausal women suffering from fibromyalgia: a double-blind, randomized, placebo-controlled trial.

OBJECTIVES: FM is a condition that preferentially affects women. Sex hormones, and in particular oestrogens, have been shown to affect pain processing and pain sensitivity, and oestrogen deficit has been considered a potentially promoting factor for FM. However, the effects of oestrogen treatment in patients suffering from FM have not been studied. Here, we examined the effect of transdermal oestrogen substitution treatment on experimental as well as self-estimated pain in women suffering from FM. METHODS: Twenty-nine post-menopausal women were randomized to either 8 weeks of treatment with transdermal 17ß-oestradiol (50 µg/day) or placebo according to a double-blind protocol. A self-estimation of pain, a set of quantitative sensory tests measuring thresholds to temperature, thermal pain, cold pain and pressure pain, and a cold pressor test were performed on three occasions: before treatment, after 8 weeks of treatment and 20 weeks after cessation of treatment. RESULTS: Hormonal replacement treatment significantly increased serum oestradiol levels as expected (P < 0.01). However, no differences in self-estimated pain were seen between treatment and placebo groups, nor were there any differences between the two groups regarding the results of the quantitative sensory tests or the cold pressor test at any of the examined time points. CONCLUSION: Eight weeks of transdermal oestradiol treatment does not influence perceived pain, pain thresholds or pain tolerance as compared with placebo treatment in post-menopausal women suffering from FM. TRIAL REGISTRATION: ClinicalTrials.gov Registration; http://www.clinicaltrials.gov; NCT01087593.

Facing the challenges of electrodiagnostic studies in the very elderly (>80 years) population.

OBJECTIVE: Studies on electrodiagnostic (EDX) methods usually exclude the very elderly. This also holds true for studies of normal EDX values. We analyzed the outcome and diagnostic value of EDX and collected reference data in a large cohort of patients ≥80 years of age. METHODS: Referral information, ICD-10 diagnoses and EDX data were retrieved from all patients ≥80 years of age referred for EDX studies at our department in 1995-2015. Normative data, including reference ranges, were obtained using the extrapolated norms (e-norms) method. RESULTS: 1966 unique patients (2335 examinations) were included. Only 11% were considered to have normal findings. 66% had pathological EDX findings in accordance with the indication for referral. Carpal tunnel syndrome was by far the most common diagnosis. Normative data retrieved using e-norms were similar to those of reference values from healthy subjects regarding EMG multiMUP data, but typically provided a wider normality window when applied to nerve conduction parameters. CONCLUSIONS: EDX studies are valuable in the diagnostic work-up of very elderly patients. Using the e-norms method may be a useful alternative when obtaining reference values in this age group. SIGNIFICANCE: Our findings provide additional insights to the challenges of evaluating very elderly patients with neuromuscular disease and underline the importance of including this growing part of the patient population in EDX research.

[Diagnosing epileptic seizures and epilepsy]. / Utredning av epileptiska anfall och misstänkt epilepsi - Anamnes och vittnesbeskrivning är avgörande för rätt diagnos.

There are many episodic conditions which may be confused with epileptic seizures. The diagnosis of epileptic seizures is still dependent on a good history and witness report, as well as good knowledge of seizure semiology, and of the symptoms of a variety of differential diagnostic conditions. The principal differential diagnoses in adults and children are outlined in this review. The diagnostic problems do not exist only initially, so it is important to reconsider the diagnosis when deemed relevant. The possibility of home video recordings of recurring attacks may be helpful. Neuroimaging and interictal EEG cannot confirm or exclude epilepsy but can demonstrate relevant pathology and are of prognostic importance.

Diagnostic Utility of Repetitive Nerve Stimulation in a Large Cohort of Patients With Myasthenia Gravis.

PURPOSE: Optimizing the diagnostic utility of repetitive nerve stimulation in myasthenia gravis (MG) may include tailoring the examination to clinical phenotype. Therefore, we analyzed all available repetitive nerve stimulation parameters in a large cohort of patients with confirmed MG diagnosis. METHODS: All repetitive nerve stimulation examinations at the Uppsala University Hospital rendering an MG diagnosis during 1996 to 2014 were analyzed. The deltoid, trapezius, anconeus, nasalis, abductor digiti quinti, and frontalis muscles were examined. RESULTS: Two hundred one patients with MG were diagnosed. Abnormal amplitude decrement was found in 54% of patients with ocular MG, 77% of patients with predominantly bulbar fatigue, and in 83% of patients with predominantly limb fatigue. The deltoid muscle had the highest sensitivity in all MG subtypes, with a mean of 77% sensitivity in all clinical subtypes, and the most pronounced decrement for amplitude (P = 0.0002) and area (P < 0.0001). Technical issues were rare. CONCLUSIONS: These data contribute to further optimization of repetitive nerve stimulation strategies regarding muscle selection and technical performance in the electrodiagnostic workup of MG.

Trigeminal nerve stimulation does not acutely affect cortical excitability in healthy subjects.

BACKGROUND: Trigeminal nerve stimulation (TNS) has recently emerged as a new therapeutic option for patients with drug-resistant epilepsy but its potential mechanisms of action are not known. Since other antiepileptic treatments have been shown to alter cortical excitability, thereby reducing the liability to seizures, it has been suggested that cranial nerve stimulation such as TNS may act in the same way. OBJECTIVE: To study whether TNS has the potential to alter cortical excitability in healthy subjects. METHODS: An adaptive paired-pulse transcranial magnetic stimulation protocol stimulating the dominant hand motor area was used to measure resting motor threshold (rMT), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and long-interval intracortical inhibition (LICI) before, during, and after 40 min of 120 Hz bilateral external continuous trigeminal nerve stimulation. Neuronavigation was used for guidance. RESULTS: TNS was well tolerated by all subjects. No significant changes were seen in the parameters studied. CONCLUSION: Unlike for example anti-epileptic drugs and the ketogenic diet, trigeminal nerve stimulation does not seem to alter cortical excitability in healthy subjects. This is the first study on cortical excitability in relation to continuous trigeminal nerve stimulation. It still remains to be proven that TNS has the prerequisites to effectively counteract epileptic events in humans.

A rapid lateral fluid percussion injury rodent model of traumatic brain injury and post-traumatic epilepsy.

Traumatic brain injury is a leading cause of acquired epilepsy. Initially described in 1989, lateral fluid percussion injury (LFPI) has since become the most extensively used and well-characterized rodent traumatic brain injury and post-traumatic epilepsy model. Universal findings, particularly seizures that reliably develop after an initial latent period, are evident across studies from multiple laboratories. However, the LFPI procedure is a two-stage process, requiring initial surgical attachment of a skull fluid cannula and then reanesthesia for delivery of the epidural fluid pressure wave. We now describe a modification of the original technique, termed 'rapid lateral fluid percussion injury' (rLFPI), which allows for a one-stage procedure and thus shorter operating time and reduced anesthesia exposure. Anesthetized male Long-Evans rats were subjected to rLFPI through a length of plastic tubing fitted with a pipette tip cannula with a 4-mm aperture. The cannula opening was positioned over a craniectomy of slightly smaller diameter and exposed dura such that the edges of the cannula fit tightly when pressed to the skull with a micromanipulator. Fluid percussion was then delivered immediately thereafter, in the same surgery session. rLFPI resulted in nonlethal focal cortical injury in all animals. We previously demonstrated that the rLFPI procedure resulted in post-traumatic seizures and regional gliosis, but had not examined other histopathologic elements. Now, we show apoptotic cell death confined to the perilesional cortex and chronic pathologic changes such as ipsilesional ventriculomegaly that are seen in the classic model. We conclude that the rLFPI method is a viable alternative to classic LFPI, and--being a one-stage procedure--has the advantage of shorter experiment turnaround and reduced exposure to anesthetics.

Influence of estrogen levels on thermal perception, pain thresholds, and pain tolerance: studies on women undergoing in vitro fertilization.

UNLABELLED: We examined the relationship between estrogen and pain in women undergoing in vitro fertilization (IVF). Quantitative sensory tests (QST) were performed twice during the IVF-regimen: once during hormonal down-regulation and once during hormonal up-regulation. A group of healthy men and a group of women using monophasic contraceptives were also examined, to control for session-to-session effects. Among the women undergoing IVF, serum 17ß-estradiol levels differed strongly between treatments as expected, and increased from 65.7 (SD = 26) pmol/L during the down-regulation phase, to 5,188 (SD = 2,524) pmol/L during the up-regulation phase. Significant outcomes in the QST were only seen for temperature perception thresholds (1.7 °C versus 2.2 °C; P = .003) and cold pain threshold (11.5 °C versus 14.5 °C; P = .04). A similar change in cold pain threshold was also seen in the 2 control groups, however, and statistical analysis suggested that this change was due to a session-to-session effect rather than being the result of hormonal modulation. Heat pain thresholds, heat tolerance, pressure pain thresholds, and the cold pressor test showed no significant differences between sessions. These data demonstrate that pain perception and pain thresholds in healthy women show little, if any, changes even with major variations in serum estradiol levels. PERSPECTIVE: This study shows that pain perception and tolerance in women undergoing in vitro fertilization do not vary, despite the dramatic changes in 17ß-estradiol levels induced by the treatment regimen. The result thus suggests that in humans, contrary to experimental animals, changes in estrogen levels have little influence on pain sensitivity.

Estrogen receptor-alpha expression in nociceptive-responsive neurons in the medullary dorsal horn of the female rat.

Estrogens exert a substantial influence on the transmission of nociceptive stimuli and the susceptibility to pain disorders as made evident by studies in both animals and human subjects. The estrogen receptor (ER) seems to be of crucial importance to the cellular mechanisms underlying such an influence. However, it has not been clarified whether nociceptive neurons activated by pain express ERs. In this study, a noxious injection of formalin was given into the lower lip of female rats, thereby activating nociceptive neurons in the trigeminal subnucleus caudalis as demonstrated by immunohistochemical labeling of Fos. Using a dual-label immunohistochemistry protocol ERalpha-containing cells were visualized in the same sections. In the superficial layers of the medullary dorsal horn, 12% of ERalpha-labeled cells, mainly located in lamina II, also expressed noxious-induced Fos. These findings show that nociceptive-responsive neurons in the medullary dorsal horn express ERalpha, thus providing a possible morphological basis for the hypothesis that estrogens directly regulate pain transmission at this level.