The place of corticosteroids in migraine attack management: A 65-year systematic review with pooled analysis and critical appraisal.

BACKGROUND AND OBJECTIVES: Headaches recur in up to 87% of migraine patients visiting the emergency department (ED), making ED recidivism a management challenge. We aimed herein to determine the role of corticosteroids in the acute management of migraine in the ED and outpatient care. METHODS: Advanced search strategies employing PubMed/MEDLINE, Web of Science, and Cochrane Library databases inclusive of a relevant gray literature search was employed for Clinical Studies and Systematic Reviews by combining the terms "migraine" and "corticosteroids" spanning all previous years since the production of synthetic corticosteroids ca. 1950 until August 30, 2014. Methods were in accordance with MOOSE guidelines. RESULTS: Twenty-five studies (n = 3989, median age 37.5 years, interquartile range or IQR 35-41 years; median male:female ratio 1:4.23, IQR 1:2.1-6.14; 52% ED-based, 56% randomized-controlled) and four systematic reviews were included. International Classification of Headache Disorders criteria were applied in 64%. Nineteen studies (76%) indicated observed outcome differences favoring benefits of corticosteroids, while six (24%) studies indicated non-inferior outcomes for corticosteroids. Median absolute risk reduction was 30% (range 6%-48.2%), and 11% (6%-48.6%) for 24-, and 72-hour headache recurrence, respectively. Parenteral dexamethasone was the most commonly (56%) administered steroid, at a median single dose of 10 mg (range 4-24 mg). All meta-analyses revealed efficacy of adjuvant corticosteroids to various abortive medications-indicating generalizability. Adverse effects were tolerable. Higher disability, status migrainosus, incomplete pain relief, and previous history of headache recurrence predicted outcome favorability. CONCLUSIONS: Our literature review suggests that with corticosteroid treatment, recurrent headaches become milder than pretreated headaches and later respond to nonsteroidal therapy. Single-dose intravenous dexamethasone is a reasonable option for managing resistant, severe, or prolonged migraine attacks.

What is the evidence for the use of corticosteroids in migraine?

Corticosteroids are widely prescribed for the management of migraine attacks. The earliest clinical studies examining the efficacy of corticosteroid monotherapy for managing migraine attacks date back to 1952. Since then, 26 heterogeneous clinical studies and four meta-analyses have been conducted to assess the efficacy of corticosteroids in either aborting acute migraine attacks, prolonged migraine attacks or recurrent headaches. Most of these (86 %) studies employed different comparator arms with corticosteroids monotherapy administration while some studies (14 %) evaluated adjunctive corticosteroid therapy. The majority of these clinical studies revealed the superior efficacy of corticosteroids as mono- or adjunctive-therapy both for recurrent and acute migraine attacks, while the remaining showed non-inferior efficacy. Different forms of oral and parenteral corticosteroids in either single-dose or short-tapering schedules are prescribed; there are clinical studies supporting the efficacy of both methods. Corticosteroids can be administered safely up to six times annually. Corticosteroids are also useful in managing patients who frequent emergency departments with "medication-seeking behavior." Migraine patients with refractory headaches, history of recurrent headaches, severe baseline disability, and status migrainosus were found to have the most beneficial response from corticosteroid therapy.

Granulomatous amebic encephalitis: an under-recognized cause of infectious mortality after hematopoietic stem cell transplantation.

Granulomatous amebic encephalitis (GAE) is a rare, nearly always fatal form of encephalitis that occurs mostly in the setting of immune compromise or chronic disease. The prevalence and clinical characteristics of this Acanthamoeba infection in hematopoietic stem cell transplant (HSCT) recipients are not well described. We present an HSCT patient in whom the diagnosis of GAE was made at autopsy. A systematic review of previously reported cases is provided to highlight the clinical presentation and early diagnostic features of GAE in HSCT recipients. Amebic infection usually initially involves the skin or lungs over a period of months, and becomes rapidly fatal once it crosses the blood-brain barrier. GAE is usually discovered postmortem owing to lack of awareness of this deadly infection and delay in diagnosis. Subacute presentation of multiple recurrent panniculitis-like subcutaneous nodules associated with eosinophilia and a history of chronic rhinitis or sinusitis warrant investigation for a possible amebic infection. Prolonged corticosteroid use and a recent exposure to unhygienic water are potential risk factors for GAE. Successful outcomes may be achieved with early intensive treatment using a combination of effective drugs.

New frontiers in headache therapy.

There are numerous headache therapies available for our patients, more for migraine than for any of the other primary headache disorders. Only four medications have been approved for migraine prevention in the last few decades in the US and onabotulinumtoxinA was recently approved in the UK and the US for chronic migraine. We have been more fortunate in the acute care arena where in the US we have had seven triptans and one nonsteroidal anti-inflammatory medication approved by the FDA and currently available. There are several other acute care medications in various stages of development and there are two new methods of administering a triptan and others under investigation. We are always looking for faster, easier and more efficient administration of medications with fewer adverse events, as optimal migraine therapy requires these characteristics. What follows is a brief review of the progress in development for four of the many new acute care medications being investigated: the CGRP antagonist tablet telcagepant, the sumatriptan iontophoretic patch, sumatriptan powder for use in the OptiNose apparatus and the dihydroergotamine oral inhaler. I will not include transcranial magnetic stimulation, a 5-HT(1F) agonist, large conductance calcium-activated potassium channel openers, glial modulators or other medications and devices in early stages of development [1].

Chronic migraine and medication overuse headache: clarifying the current International Headache Society classification criteria.

Despite the recent advances in the understanding and classification of the chronic daily headaches, considerable controversy still exists regarding the classification of individual headaches, including chronic migraine (CM) and medication overuse headache (MOH). The original criteria, published in 2004, were difficult to apply to most patients with these disorders and were subsequently revised, resulting in broader clinical applicability. Nonetheless, they remain a topic of debate, and the revisions to the criteria have further added to the confusion. Even some prominent headache specialists are unsure which criteria to use. We aimed to explain the nature of the controversies surrounding the entities of CM and MOH. A clinical case will be used to illustrate some of the problems faced by clinicians in diagnosing patients with chronic daily headache.

New daily persistent headache in the paediatric population.

We conducted a clinic-based study focusing on the clinical features of new-onset chronic daily headaches (CDH) in children and adolescents. The clinical records and headache diaries of 306 children and adolescents were reviewed, to identify 187 with CDH. Relevant information was transferred to a standardized form that included operational criteria for the diagnoses of the headaches. Since we were interested in describing the clinical features of these headaches, we followed the criteria A and B of the 2nd edn of the International Classification of Headache Disorders (ICHD-2) and refer to them as new daily persistent headaches (NDPH) regardless of the presence of migraine features (therefore, this is a modified version of the ICHD-2 criteria). From the 56 adolescents with NDPH, most (91.8%) did not overuse medications. Nearly half (48.1%) reported they could recall the month when their headaches started. NDPH was more common than chronic tension-type headache in both adolescents overusing and not overusing medication. Individuals with NDPH had headaches fulfilling criteria for migraine on an average of 18.5 days per month. On most days, they had migraine-associated symptoms (one of nausea, photophobia or phonophobia)). NDPH is common in children and adolescents with CDH. Most subjects do not overuse medication. Migraine features are common.

Antimigraine drugs: new frontiers.

There are many acute care and preventive medications for the treatment of migraine. However, patients may often find that their headaches are not under optimal control. There are several targets that have been looked at and studied for the production of new, more effective medications. There are also effective devices for therapy of migraine. A list of targets will be put forth and a small number of them will be described in greater detail in this paper.

Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin.

OBJECTIVE: To evaluate the efficacy and tolerability of the treatment with valproic acid (VPA) in patients with status epilepticus (SE) or acute repetitive seizures (ARS) comparing it with phenytoin (PHT) treatment. MATERIALS AND METHODS: Patients with SE or ARS were treated in a consecutive manner with either VPA or PHT intravenously. The primary endpoint was defined as clinical seizure cessation; the secondary endpoint was evaluation of drug tolerability. RESULTS: Seventy-four adult patients with SE or ARS participated in the study, 49 with VPA i.v. and 25 PHT i.v. In 43 (87.8%) of the VPA patients, the seizures discontinued, and no rescue medication was needed. Similar results were found in the PHT group in which seizures of 22 (88%) patients were well controlled. Side effects were found in 12% of the PHT group, and in none of the VPA group. CONCLUSIONS: VPA i.v. seems to be effective and well tolerated in adult patients with SE or ARS.

Chaotic scattering by steep repelling potentials.

Consider a classical two-dimensional scattering problem: a ray is scattered by a potential composed of several tall, repelling, steep mountains of arbitrary shape. We study when the traditional approximation of this nonlinear far-from-integrable problem by the corresponding simpler billiard problem, of scattering by hard-wall obstacles of similar shape, is justified. For one class of chaotic scatterers, named here regular Sinai scatterers, the scattering properties of the smooth system indeed limit to those of the billiards. For another class, the singular Sinai scatterers, these two scattering problems have essential differences: though the invariant set of such singular scatterers is hyperbolic (possibly with singularities), that of the smooth flow may have stable periodic orbits, even when the potential is arbitrarily steep. It follows that the fractal dimension of the scattering function of the smooth flow may be significantly altered by changing the ratio between the steepness parameter and a parameter which measures the billiards' deviation from a singular scatterer. Thus, even in this singular case, the billiard scattering problem is utilized as a skeleton for studying the properties of the smooth flow. Finally, we see that corners have nontrivial and significant impact on the scattering functions.

[Prognostication of the results of treatment of retinal detachment with silicone oil tamponade using pattern recognition methods].

The aim of this work was to solve the problem of prognostification of anatomic and functional results of treatment of retinal detachment (RD) with silicone oil tamponade. Analysis of the treatment of 257 eyes was performed using pattern recognition methods. All the patients were characterized according to 32 signs related the preoperative status only. As a result, an informative sign system was developed; the present data proved to be not representative enough, which manifested mostly in the class of RD recurrence, where the rate of correct end result recognition was 75% (in the class of "normal condition" it was 95%). One of the most significant RD signs, PVR degree, in this study was placed in the second ten according to its informative value, probably due to the fact that PVR classification is not detailed enough.

Immunity for tumors and microbes after autotransplantation: if you build it, they will (not) come.

Relapses after autologous stem cell transplants for hematopoietic malignancies are frequent and post-transplant infections continue to cause significant post-transplant morbidity and even mortality. The post-transplant period is typically characterized by low lymphocyte counts and impaired immune cell function. Early restoration of immune function may contribute to better disease control and enhance protection from infections. Indeed the attainment of a 'minimal residual disease' status following high-dose therapy makes the early post-transplant period ideal for the introduction of antitumor immunotherapy. Attempts to generate immunity against tumor and microbial antigens after autotransplantation have included vaccinations, T cell infusions (both resting and activated) and combinations of vaccinations and adoptive T cell infusions. One successful strategy for generating robust immune responses against microbial antigens was the combination of pre and post-transplant immunizations along with an early (post-transplant) infusion of in vivo vaccine-primed and ex vivo co-stimulated autologous T cells. Whether this or similar strategies will lead to the generation of effective antitumor immunity is unknown. The lessons gained from efforts to rebuild immune system function in the setting of autotransplantation may also be applicable to the problem of restoring immunity in other immunodeficient groups such as patients with cancer or HIV disease and the elderly.

Autologous stem cell transplantation followed by consolidation chemotherapy for patients with multiple myeloma.

Although high-dose therapy and autologous stem cell transplant (ASCT) is superior to conventional chemotherapy for treatment of myeloma, most patients relapse and the time to relapse depends upon the initial prognostic factors. The administration of non-cross-resistant chemotherapies during the post-transplant period may delay or prevent relapse. We prospectively studied the role of consolidation chemotherapy (CC) after single autologous peripheral blood stem cell transplant (auto-PBSCT) in 103 mostly newly diagnosed myeloma patients (67 patients were < or =6 months from the initial treatment). Patients received conditioning with BCNU, melphalan+/-gemcitabine and auto-PBSCT followed by two cycles of the DCEP+/-G regimen (dexamethasone, cyclophosphamide, etoposide, cisplatin+/-gemcitabine) at 3 and 9 months post-transplant and alternating with two cycles of DPP regimen (dexamethasone, cisplatin, paclitaxel) at 6 and 12 months post-transplant. With a median follow-up of 61.2 months, the median event-free survival (EFS) and overall survival (OS) are 26 and 54.1 months, respectively. The 5-year EFS and OS are 23.1 and 42.5%, respectively. Overall, 51 (49.5%) patients finished all CC, suggesting that a major limitation of this approach is an inability to deliver all planned treatments. In order to improve results following autotransplantation, novel agents or immunologic approaches should be studied in the post-transplant setting.

One hundred autotransplants for relapsed or refractory Hodgkin's disease and lymphoma: value of pretransplant disease status for predicting outcome.

PURPOSE: One hundred autotransplants for Hodgkin's disease (HD) or non-Hodgkin's lymphoma (NHL) were examined prospectively to identify variables with prognostic significance. PATIENTS AND METHODS: Ninety-six patients with relapsed or refractory HD or NHL underwent 100 autotransplants. Patients received high-dose carmustine (BCNU), etoposide, cytarabine, and cyclophosphamide (BEAC) followed by unpurged autologous stem-cell rescue. RESULTS: The 3-year actuarial event-free survival (EFS) rate for the 47 HD patients is 49%, with a median followup duration of 2 years. For the 53 NHL patients, the 3-year actuarial EFS rate is 40%, with a median follow-up duration of 19 months. By multivariate analysis, minimal disease on admission (all areas < or = 2 cm) is associated with improved EFS (HD, P = .003, NHL, P = .03). The projected EFS rate for HD patients entering with minimal disease is 70% versus 15% for patients with bulky disease (P = .0001). The projected EFS rate for NHL patients with minimal disease is 48% versus 25% for patients with bulky disease (P = .04). Posttransplant involved-field radiotherapy, administered to 26 of the last 61 patients, was associated with an improved EFS rate for NHL patients (P = .015). The BEAC regimen was well tolerated by patients who entered the study with minimal disease (mortality rate, < 5%), but caused significant toxicity in patients with bulky disease (mortality rate, 25%). CONCLUSION: Disease burden before autotransplantation is an important predictor of regimen-related toxicity and EFS. Posttransplant involved-field radiotherapy may improve outcomes in select patients with NHL. The BEAC regimen is safe and effective, particularly for patients with minimal disease.

Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic stem-cell transplants.

PURPOSE: To identify predictors of oral mucositis and gastrointestinal toxicity after high-dose therapy. PATIENTS AND METHODS: Mucositis and gastrointestinal toxicity were prospectively evaluated in 202 recipients of high-dose therapy and autologous or allogeneic stem-cell rescue. Of 10 outcome variables, three were selected as end points: the peak value for the University of Nebraska Oral Assessment Score (MUCPEAK), the duration of parenteral nutritional support, and the peak daily output of diarrhea. Potential covariates included patient age, sex, diagnosis, treatment protocol, transplantation type, stem-cell source, and rate of neutrophil recovery. The three selected end points were also examined for correlation with blood infections and transplant-related mortality. RESULTS: A diagnosis of leukemia, use of total body irradiation, allogeneic transplantation, and delayed neutrophil recovery were associated with increased oral mucositis and longer parenteral nutritional support. No factors were associated with diarrhea. Also, moderate to severe oral mucositis (MUCPEAK > or = 18 on a scale of 8 to 24) was correlated with blood infections and transplant-related mortality: 60% of patients with MUCPEAK > or = 18 had positive blood cultures versus 30% of patients with MUCPEAK less than 18 (P =.001); 24% of patients with MUCPEAK > or = 8 died during the transplantation procedure versus 4% of patients with MUCPEAK less than 18 (P =.001). CONCLUSION: Gastrointestinal toxicity is a major cause of transplant-related morbidity and mortality, emphasizing the need for corrective strategies. The peak oral mucositis score and the duration of parenteral nutritional support are useful indices of gastrointestinal toxicity because these end points are correlated with clinically significant events, including blood infections and treatment-related mortality.

Consequences of amino-terminal deletions of preproparathyroid hormone signal sequence.

PTH is initially synthesized as a larger precursor, containing a 25 amino acid signal sequence. Modification of cDNA encoding the hormone precursor resulted in the synthesis of proteins whose signal sequences were shortened at their amino termini. The effects of these mutations were analyzed using a cell-free translation system and rat pituitary GH4 cells in culture. Removal of the first six amino acids of the signal sequence had no effect on the efficiency or kinetics of protein processing as measured in the two assay systems. Mutants lacking 10 or 13 amino acids were not processed efficiently in the cells, nor were they translocated across microsomes in the cell-free translation system. These studies suggest that a modest change in the hydrophobic domain of the signal sequence, which might not have been predicted to alter function, led to a dramatic decline in signal activity.

Human preproparathyroid hormone synthesized in Escherichia coli is transported to the surface of the bacterial inner membrane but not processed to the mature hormone.

cDNA encoding human preproPTH (hpreproPTH) was expressed in Escherichia coli to study the processing of the precursor to hPTH and its secretion by the bacterial secretory apparatus. We first constructed hybrid genes that differed randomly in the distance between the E. coli lac promoter's ribosomal binding site and DNA encoding a fusion protein with beta-galactosidase activity and the prepro sequence of hpreproPTH on the aminoterminus. Starting with clones identified as efficient producers of beta-galactosidase on indicator agar plates, the coding sequence for hpreproPTH was reconstituted intact. In a different construction we placed the hpreproPTH coding sequence downstream from the lac promoter at a distance of 12 base pairs from the ribosomal binding site. PTH immunoreactive proteins from multiple clones were identified by protein gel electrophoresis and by protein microsequencing. PTH-related proteins encoded by different plasmids were shown to be hpreproPTH with amino-terminal extensions of either two or four amino acids and as authentic hpreproPTH. Two hPTH fragments, hPTH(3-84) and hPTH(8-84), were also observed. The trypsin accessibility of hpreproPTH and of the two hPTH fragments in pulse-chase, cell-fractionation experiments using intact and lysed spheroplasts lets us conclude that the mammalian signal sequence directs hpreproPTH to the surface of the spheroplast membrane but is not appropriately cleaved by the signal peptidase.

Interpreting outcome data in hematopoietic cell transplantation for leukemia: tackling common biases.

Although patient outcomes after allogeneic hematopoietic cell transplantation (allo-HCT) have significantly improved in recent years, complications and associated mortality remain substantial. Although many transplants are performed worldwide, the number of patients enrolled prospectively into clinical trials is small. Patient and physician preferences often override treatment assignments in randomized transplant trials, biasing the common intention-to-treat analyses. Large retrospective and observational database studies are likely to detect the real effect of allo-HCT. However, they may be subject to immortal time and other biases derived from heterogeneity of allo-HCT indications and approaches and differences in referral or institutional policies affecting patient selection. Timing of the transplant procedure may be fundamental but studies commencing at start of transplant may neglect the influence of pretransplant therapies. Conversely, a prolonged lag period between the decision and execution of transplant may artificially 'improve' the outcome by 'natural' selection weeding out patients relapsing or dying before transplant. Finally, comparative nonrandomized transplantation trials often suffer from unbalanced assignment for therapy arms. We herein present common clinical dilemmas discussing proper application of available evidence in daily clinical practice. Pitfalls and caveats frequent in clinical studies of allo-SCT are highlighted to promote a balanced interpretation of available data.

Signal sequence of human preproparathyroid hormone is inactive in yeast.

The biosynthesis of human preproparathyroid hormone (hpreproPTH) and the processing to mature parathyroid hormone (hPTH) was investigated in yeast. Cells were transformed with a plasmid that carried a fusion gene made of the yeast pyruvate kinase promoter, complementary DNA (cDNA) encoding a slightly modified form of hpreproPTH and the transcription termination signal from yeast triosephosphate-isomerase. In transformed yeast cells we identified a protein that was recognized by a PTH antiserum and, on gel electrophoresis, comigrated with hpreproPTH marker. The amino-terminal sequence of the protein was consistent with that of hpreproPTH, indicating that the hormone precursor is not processed. It was localized inside the cell, when analyzed in pulse-chase experiments by trypsin accessibility in intact and lysed spheroplasts. In contrast, when mRNA from these yeast cells and from human parathyroid tissue was translated into preproPTH in a reticulocyte lysate supplemented with canine pancreatic microsomes, the preproPTHs from both mRNAs were transported and cleaved with identical efficiencies. We conclude that hpreproPTH is synthesized in yeast but not recognized and processed like a precursor of a secreted protein by the yeast secretory apparatus.