Harnessing the conditioned pain modulation response in migraine diagnosis, outcome prediction, and treatment-A narrative review.

OBJECTIVE: To present the potential use and relevance of the conditioned pain modulation (CPM) response to migraine diagnosis, outcome prediction, and treatment. BACKGROUND: The CPM response is a widely used laboratory test to examine inhibitory pain modulation capabilities. METHODS: This narrative review summarizes and synthesizes the findings on the CPM response in patients with migraine. RESULTS: For diagnosis, we summarized the studies comparing CPM responses between patients with migraine and individuals without migraine or with other headache syndromes, as well as between patients with subtypes of migraine. For prediction, we summarized the studies utilizing the CPM response to predict migraine outcome, such as response to interventions. For treatment, we described a device that utilizes the CPM response for acute and preventative migraine treatment. In addition, we suggest the requirements needed for the CPM response to be used for migraine diagnosis, outcome prediction, and treatment. CONCLUSIONS: Although more research is needed, the CPM response could be a useful tool for improving migraine management.

Effects of Procedural Discomfort and Expectation of Benefit on Therapy Continuation in Chronic Migraine Patients Treated With OnabotulinumtoxinA.

BACKGROUND: OnabotulinumtoxinA (BTX) has become a mainstream treatment for chronic migraine (CM). Patients often have varied expectations for treatment success but little is known about how these initial impressions influence continuation of therapy. OBJECTIVE: To record expectations of benefit and procedural discomfort (PD) from initial BTX treatment and to investigate their association with treatment success, defined as continuation of treatment for >3 sessions within a 2-year period. METHODS: A retrospective chart review of CM patients receiving initial treatment with BTX was performed. Patients were questioned about their expectations of benefit and PD as rated on a 0-10 scale. Responses were then compared with continuation of therapy beyond 3 sessions to identify the presence of significant association. RESULTS: Responses from patients (N = 297) were analyzed. About 173 subjects continued with BTX therapy for more than 3 sessions (173/297, 58.3%). Unadjusted odds ratios (OR) for expectation of benefit (EOB) (OR 1.11, 95% CI 0.99-1.24, P = .087) and PD (OR 1.02, 95% CI 0.90-1.16, P = .780) were not significantly predictive of continuing treatment. After considering sex, age, year of treatment, and previous headache preventative trials, only female sex (OR 2.02, 95% CI 1.09-3.74, P = .025) was found to be significantly associated with treatment continuation. CONCLUSIONS: In the usual care setting, PD and EOB are not significantly associated with therapy continuation in patients receiving initial treatment with BTX for the prevention of CM. However, after considering sex, age, year of treatment, and number of previous headache preventives attempted, we found that female patients had twice the likelihood of continuing with BTX therapy compared to male patients with CM.

γ-Hydroxybutyric acid-induced electrographic seizures.

We describe a case of absence-like electrographic seizures during NREM sleep in a patient who was taking sodium oxybate, a sodium salt of γ-hydroxybutyric acid (GHB). An overnight full montage electroencephalography (EEG) study revealed numerous frontally predominant rhythmic 1.5-2 Hz sharp waves and spike-wave activity during stage N2 and N3 sleep at the peak dose time for sodium oxybate, resembling atypical absence-like electrographic seizures. The patient was later weaned off sodium oxybate, and a repeat study did not show any such electrographic seizures. Absence-like seizures induced by GHB had previously been described in experimental animal models. We present the first reported human case of absence-like electrographic seizure associated with sodium oxybate.

Brainstem glioma presenting as pruritus in children with neurofibromatosis-1.

Children with neurofibromatosis type 1 (NF1) are at increased risk of developing tumors of the nervous system. The most common intracranial tumors are low-grade astrocytomas, which most frequently involve the optic pathway, and less often, the brainstem. In cases of brainstem glioma in NF1, treatment decisions are frequently complicated by the paucity of symptoms referable to the tumor. Here, we describe 2 children with NF1 whose initial presentation of a growing brainstem glioma was localized pruritus. This unusual presentation emphasizes the importance of appreciating subtle, often hard to localize, symptoms in this high-risk population.

High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene.

TGFbeta acts as a tumor suppressor in normal epithelial cells and early-stage tumors and becomes an oncogenic factor in advanced tumors. The molecular mechanisms involved in the malignant function of TGFbeta are not fully elucidated. We demonstrate that high TGFbeta-Smad activity is present in aggressive, highly proliferative gliomas and confers poor prognosis in patients with glioma. We discern the mechanisms and molecular determinants of the TGFbeta oncogenic response with a transcriptomic approach and by analyzing primary cultured patient-derived gliomas and human glioma biopsies. The TGFbeta-Smad pathway promotes proliferation through the induction of PDGF-B in gliomas with an unmethylated PDGF-B gene. The epigenetic regulation of the PDGF-B gene dictates whether TGFbeta acts as an oncogenic factor inducing PDGF-B and proliferation in human glioma.

Prickle and Strabismus form a functional complex to generate a correct axis during planar cell polarity signaling.

Frizzled (Fz) signaling regulates the establishment of planar cell polarity (PCP). The PCP genes prickle (pk) and strabismus (stbm) are thought to antagonize Fz signaling. We show that they act in the same cell, R4, adjacent to that in which the Fz/PCP pathway is required in the Drosophila eye. We demonstrate that Stbm and Pk interact physically and that Stbm recruits Pk to the cell membrane. Through this interaction, Pk affects Stbm membrane localization and can cause clustering of Stbm. Pk is also known to interact with Dsh and is thought to antagonize Dsh by affecting its membrane localization. Thus our data suggest that the Stbm/Pk complex modulates Fz/Dsh activity, resulting in a symmetry-breaking step during polarity signaling.

Beta-catenin/Tcf-regulated transcription prior to the midblastula transition.

Following fertilization, the zygotic genome in many organisms is quiescent until the midblastula transition (MBT), when large-scale transcription begins. In Xenopus embryos, for example, transcription is believed to be repressed until the twelfth cell division. Thus, although dorsal-ventral patterning begins during the first cell cycle, little attention has been given to transcriptional regulation in pre-MBT development. We present evidence that regulated transcription begins during early cleavage stages and that the beta-catenin-Tcf complex is required for the transcription of the Xenopus nodal genes Xnr5 and Xnr6 as early as the 256-cell stage. Moreover, inhibition of beta-catenin/Tcf function can block dorsal development, but only if the inhibition begins early and is maintained throughout pre-MBT stages. Dorsal development can be rescued in ventralized embryos if Tcf-dependent transcription is activated prior to MBT, but activation of Tcf after MBT cannot rescue ventralized embryos, suggesting that beta-catenin/Tcf-dependent transcription is required prior to MBT for dorsal-ventral patterning in Xenopus.

The planar polarity gene strabismus regulates convergent extension movements in Xenopus.

The signaling mechanisms that specify, guide and coordinate cell behavior during embryonic morphogenesis are poorly understood. We report that a Xenopus homolog of the Drosophila planar cell polarity gene strabismus (stbm) participates in the regulation of convergent extension, a critical morphogenetic process required for the elongation of dorsal structures in vertebrate embryos. Overexpression of Xstbm, which is expressed broadly in early development and subsequently in the nervous system, causes severely shortened trunk structures; a similar phenotype results from inhibiting Xstbm translation using a morpholino antisense oligo. Experiments with Keller explants further demonstrate that Xstbm can regulate convergent extension in both dorsal mesoderm and neural tissue. The specification of dorsal tissues is not affected. The Xstbm phenotype resembles those obtained with several other molecules with roles in planar polarity signaling, including Dishevelled and Frizzled-7 and -8. Unlike these proteins, however, Stbm has little effect on conventional Wnt/beta-catenin signaling in either frog or fly assays. Thus our results strongly support the emerging hypothesis that a vertebrate analog of the planar polarity pathway governs convergent extension movements.