Sperm are a simple cell type with few components, yet they exhibit tremendous between-species morphological variation in those components thought to reflect selection in different fertilization environments. However, within a species, sperm components are expected to be selected to be functionally integrated for optimal fertilization of eggs. Here, we take advantage of within-species variation in sperm form and function to test whether sperm components are functionally and genetically integrated both within and between sperm morphologies using a quantitative genetics approach. Drosophila pseudoobscura males produce two sperm types with different functions but which positively interact together in the same fertilization environment; the long eusperm fertilizes eggs and the short parasperm appear to protect eusperm from a hostile female reproductive tract. Our analysis found that all sperm traits were heritable, but short sperm components exhibited evolvabilities 10 times that of long sperm components. Genetic correlations indicated functional integration within, but not between, sperm morphs. These results suggest that sperm, despite sharing a common developmental process, can become developmentally and functionally non-integrated, evolving into separate modules with the potential for rapid and independent responses to selection.
Drosophila pseudoobscura; functional integration; quantitative genetics; modularity; evolvability
We evaluated the association of plasma uric acid alone and in combination with b-type natriuretic peptide (BNP) for emergency department (ED) diagnosis and 30-day prognosis in patients evaluated for acute heart failure (AHF).
We prospectively enrolled 322 adult ED patients with suspected AHF. Wilcoxon rank sum test, multivariable logistic regression and likelihood ratio (LR) tests were used for statistical analyses.
Uric acid’s diagnostic utility was poor and failed to show significant associations with 30-day clinical outcomes. Uric acid also did not add significantly to BNP results.
Among ED patients with suspected AHF, uric acid has poor diagnostic and prognostic utility.
Acute heart failure; uric acid; b-type natriuretic peptide; prognostic outcomes
We sought to compare and contrast the clinical criterion standards currently used in a cohort of ED patients to diagnose acute heart failure syndromes (AHFS).
In a prospective observational study of patients with signs and symptoms of AHFS we examined three criterion standards: 1) the treating ED physician’s diagnosis; 2) the hospital discharge diagnosis; and 3) a diagnosis based on a medical record review by a panel of cardiologists. Using Cohen’s kappa (κ), we assessed agreement and then compared the different standards by repeatedly setting one as the criterion standard and the other two as index tests.
483 patients were enrolled. Across all criterion standards those with AHFS were more likely to have a history of AHFS, congestion on physical exam and chest radiography, and elevated natriuretic peptide levels than those without AHFS. The standards agreed well (cardiology review vs. hospital discharge diagnosis, κ=0.74; cardiology review vs. ED diagnosis, κ=0.66; ED diagnosis vs. hospital discharge diagnosis κ =0.59). Each method had similar sensitivity, but differing specificities.
Different criterion standards identify different patients from among those being evaluated for AHFS. Researchers should consider this when choosing between the various criterion standard approaches when evaluating new index tests.
Correlates of prenatal physical activity can inform interventions, but are not well-understood.
Participants in the Pregnancy, Infection, and Nutrition 3 Study were recruited before 20 weeks gestation. Women self-reported frequency, duration, and mode of moderate and vigorous physical activities. We used logistic regression to identify correlates of any physical activity (≥10 minutes/week of any mode), any recreational activity (≥10 minutes/week), and high volume recreational activity (either ≥150 minutes/week of moderate or ≥75 minutes/week of vigorous). Our analysis included 1752 women at 19-weeks gestation and 1722 at 29 weeks.
Higher education, white race, and enjoyment of physical activity were positively correlated with all 3 outcomes. Any recreational activity was negatively associated with parity, body mass index, and history of miscarriage. The associations of history of miscarriage and body mass index differed at 19 weeks compared with 29 weeks. Single marital status, health professional physical activity advice, and time for activity were associated with high volume recreational activity only.
Correlates of physical activity differed by mode and volume of activity and by gestational age. This suggests that researchers planning physical activity interventions should consider the mode and amount of activity and the gestational age of the participants.
leisure activity; gestational age; intervention; barriers; psychosocial
Porphyrins are attractive chromophores for incorporation into light harvesting devices. Some of the most efficient porphyrin derivatives in this regard are synthetically complex platforms with specially tailored electronic properties. This work details the unique geometric and electronic structure of the phlorin framework. X-ray crystallography and NMR spectroscopy demonstrate that unlike typical tetrapyrrole macrocycles, the phlorin is not aromatic. These unusual electronics are manifest in distinct photophysical and redox properties, as the phlorin displays a rich multielectron redox chemistry. The phlorin also displays an intriguing supramolecular chemistry and can reversibly bind up to two equivalents of fluoride in cooperative fashion. Accordingly, this synthetically accessible sensitizer displays a rich multielectron redox chemistry, excellent spectral coverage and an intriguing anion binding chemistry that distinguishes this system from more commonly studied porphyrinoids.
Phlorin; Porphyrin; Corrole; DSC; Solar Energy
Theory predicts that male response to reduced paternity will depend on male state and interactions between the sexes. If there is little chance of reproducing again, then males should invest heavily in current offspring, regardless of their share in paternity. We tested this by manipulating male age and paternity assurance in the burying beetle Nicrophorus vespilloides. We found older males invested more in both mating effort and parental effort than younger males. Furthermore, male age, a component of male state, mediated male response to perceived paternity. Older males provided more prenatal care, whereas younger males provided less prenatal care, when perceived paternity was low. Adjustments in male care, however, did not influence selection acting indirectly on parents, through offspring performance. This is because females adjusted their care in response to the age of their partner, providing less care when paired with older males than younger males. As a result offspring, performance did not differ between treatments. Our study shows, for the first time, that a male state variable is an important modifier of paternity–parental care trade-offs and highlights the importance of social interactions between males and females during care in determining male response to perceived paternity.
burying beetle; mating effort; parental care; parental selection; terminal investment; paternity
While preterm delivery is a well-established risk factor for cerebral palsy (CP), preterm deliveries contribute only a minority of affected infants. There is little information on the relation of CP risk to gestational age in the term range, where most CP occurs.
To determine whether timing of birth in the term and post-term period is associated with risk of CP.
Design, Setting, and Participants
Population-based follow-up study using the Medical Birth Registry of Norway to identify 1,682,441 singleton children born 1967-2001 with a gestational age of 37-44 weeks and no congenital anomalies. The cohort was followed through 2005 by linkage to other national registries.
Main Outcome Measures
Absolute and relative risk of CP for children surviving at least to 4 years of age.
Of the cohort of term and post-term children, 1,938 were registered with CP in the National Insurance Scheme. Infants born at 40 weeks had the lowest risk of CP, with a prevalence of 0.99 per thousand (95% confidence interval [CI], 0.90-1.08). Risk for CP was higher with earlier or later delivery, with relative risk reaching 1.9 at 37 weeks (95% CI, 1.6-2.3) and 1.4 at 42 weeks (95% CI, 1.2-1.6). These associations were even stronger in a subset with gestational age based on ultrasound measurements – at 37 weeks the risk was 3.7 (95% CI, 1.5-9.1), and at 42 weeks 2.4 (95% CI, 1.1-5.3). Adjustment for infant sex, maternal age and various socioeconomic measures had little effect.
Compared with delivery at 40 weeks gestation, delivery at 37 weeks or at 42 weeks was associated with an increased risk of CP
Current U.S. pregnancy-related physical activity recommendations do not provide specific guidance for vigorous intensity activity. Our objective was to examine the associations between vigorous physical activity during pregnancy and length of gestation and birthweight. Women were recruited before 10 weeks gestation. At 13-16 weeks gestation, participants reported the type, frequency, and duration of their typical weekly vigorous physical activities. Activity domains included recreational, occupational, household, and child/adult care. Infant birth date was obtained from medical or vital records; if unavailable, self-report was used. Birthweight (from vital records) was studied among term births. We analyzed gestational age among 1,647 births using discrete-time survival analysis. We used logistic and linear regression to analyze preterm birth (birth at <37 weeks) and birthweight, respectively. Vigorous recreational activity was associated with longer gestation (any vs. none, hazard ratio (HR) [95% CI]: 0.85 [0.70, 1.05]) and we did not detect any dose-response association. Higher frequency of vigorous recreational activity sessions (adjusted for total volume of activity) was associated with a decreased odds of preterm birth (≥ 4 sessions/week vs. 0 or 1, OR [95% CI]: 0.08 (0.006, 1.0). Birthweight was not associated with physical activity measures. In summary, vigorous physical activity does not appear to be detrimental to the timing of birth or birthweight. Our data support a reduced risk of preterm birth with vigorous recreational activity, particularly with increased frequency of recreational activity sessions. Future studies should investigate the components of physical activity (i.e. intensity, duration, and frequency) in relation to birth outcomes.
Imaging sentinel lymph nodes (SLN) could provide us with critical information about the progression of a cancerous disease. Real-time high-resolution intraoperative photoacoustic imaging (PAI) in conjunction with a near infrared (NIR) probe may offer the opportunities for the immediate imaging for direct identification and resection of SLN or collecting tissue samples. In this work a commercially amenable synthetic methodology is revealed for developing luminescent carbon nanoparticles with rapid clearance properties. A one-pot “green” technique is pursued, which involved rapid surface passivation of carbon nanoparticles with organic macromolecules (e.g. polysorbate, polyethyleneglycol) in a solvent free condition. Interestingly, the naked carbon nanoparticles are derived for the first time, from commercial food grade honey. Surface coated particles are markedly smaller (~7 nm) than the previously explored particles (gold, SWNT, copper) for SLN imaging. Results indicate an exceptionally rapid signal enhancement (~2 min) of the SLN. Owing to their strong optical absorption in the near infrared region, tiny size and rapid lymphatic transport, this platform offers great potential for faster resection of SLN and may lower complications caused by axillary investigation for mismarking with dyes or low-resolution imaging techniques.
Carbon nanoparticle; honey; contrast agents; photoacoustic tomography; real-time imaging
We describe the design, synthesis and biological characterization of manganese oxocluster-based “single molecule magnets (SMMs)”. We demonstrate that polymeric micellar nanoparticles can serve as a carrier and help to stabilize delicate SMM molecules from breaking down easily and thus prevent their property loss. Concentrating thousands of Mn-clusters per micelle provided a high ionic and per-particle relaxivity allowing sensitive MR imaging in vivo. This reports one of the earliest examples of in vivo imaging of a rationally designed polymeric micelles that features SMM.
The triple-tracer (TT) dilution technique has been proposed to be the gold standard method to measure postprandial glucose appearance. However, validation against an independent standard has been missing. We addressed this issue and also validated the simpler dual-tracer (DT) technique. Sixteen young subjects with type 1 diabetes (age 19.5 ± 3.8 yr, BMI 23.4 ± 1.5 kg/m2, HbA1c 8.7 ± 1.7%, diabetes duration 9.0 ± 6.9 yr, total daily insulin 0.9 ± 0.2 U·kg−1·day−1, mean ± SD) received a variable intravenous 20% dextrose infusion enriched with [U-13C]glucose over 8 h to achieve postprandial-resembling glucose excursions while intravenous insulin was administered to achieve postprandial-resembling levels of plasma insulin. Primed [6,6-2H2]glucose was infused in a manner that mimicked the expected endogenous glucose production and [U-13C; 1,2,3,4,5,6,6-2H7]glucose was infused in a manner that mimicked the expected glucose appearance from a standard meal. Plasma glucose enrichment was measured by gas chromatography-mass spectrometry. The intravenous dextrose infusion served as an independent standard and was reconstructed using the TT and DT techniques with the two-compartment Radziuk/Mari model and an advanced stochastic computational method. The difference between the infused and reconstructed dextrose profile was similar for the two methods (root mean square error 6.6 ± 1.9 vs. 8.0 ± 3.5 μmol·kg−1·min−1, TT vs. DT, P = NS, paired t-test). The TT technique was more accurate in recovering the overall dextrose infusion (100 ± 9 and 92 ± 12%; P = 0.02). The root mean square error associated with the mean dextrose infusion profile was 2.5 and 3.3 μmol·kg−1·min−1 for the TT and DT techniques, respectively. We conclude that the TT and DT techniques combined with the advanced computational method can measure accurately exogenous glucose appearance. The TT technique tends to outperform slightly the DT technique, but the latter benefits from reduced experimental and computational complexity.
meal tolerance test; triple-tracer technique; dual-tracer technique; glucose flux; glucose tracer; Radziuk/Mari model
Genome-wide association studies are now used routinely to identify genes implicated in complex traits. The panels used for such analyses can detect single nucleotide polymorphisms and copy number variants, both of which may help to identify small deleted regions of the genome that may contribute to a particular disease
We performed a candidate gene analysis involving 1221 SNPs in 333 candidate genes for orofacial clefting using 2823 samples from 725 two- and three-generation families with a proband with clefts of the lip and/or palate. We used SNP genotyping, DNA sequencing, high-resolution DNA microarray analysis and long-range PCR to confirm and characterize the deletion events
This dataset had a high duplicate reproducibility rate (99.98%), high Mendelian consistency rate (99.93%), and low missing data rate (0.55%), which provided a powerful opportunity for deletion detection. Apparent Mendelian inconsistencies between parents and child suggested deletion events in 15 individuals in 11 genomic regions. We confirmed deletions involving CYP1B1, FGF10, SP8, SUMO1, TBX1, TFAP2A, and UGT7A1, including both de novo and familial cases. Deletions of SUMO1, TBX1, and TFAP2A are likely to be etiologic
These deletions suggest the potential roles of genes or regulatory elements contained within deleted regions in the etiology of clefting. Our analysis took advantage of genotypes from a candidate-gene-based SNP survey and proved to be an efficient analytical approach to interrogate genes potentially involved in clefting. This can serve as a model to find genes playing a role in complex traits in general.
cleft lip; cleft palate; microdeletion; SNPs; CNV; candidate genes
Galectin 3 (G3) is a mediator of fibrosis and remodeling in heart failure.
Patients diagnosed with and treated for Acute Heart Failure Syndromes were prospectively enrolled in the Decision Making in Acute Decompensated Heart Failure multicenter trial.
Patients with a higher G3 had a history of renal disease, a lower heart rate and acute kidney injury. They also tended to have a history of HF and 30-day adverse events compared with B-type natriuretic peptide.
In Acute Heart Failure Syndromes, G3 levels do not provide prognostic value, but when used complementary to B-type natriuretic peptide, G3 is associated with renal dysfunction and may predict 30-day events.
acute heart failure; renal disease; risk stratification
Few predictors of treatment outcome or early discontinuation have been identified in persons with borderline personality disorder (BPD).
The aim of the study was to examine the relationship between baseline clinical variables and treatment response and early discontinuation in a randomized controlled trial of System Training for Emotional Predictability and Problem Solving, a new cognitive group treatment.
Improvement was rated using the Zanarini Rating Scale for BPD, the Clinical Global Impression Scale, the Global Assessment Scale and the Beck Depression Inventory. Subjects were assessed during the 20 week trial and a 1-year follow-up.
Higher baseline severity was associated with greater improvement in global functioning and BPD-related symptoms. Higher impulsivity was predictive of early discontinuation. Optimal improvement was associated with attending ≥15 sessions.
Subjects likely to improve have the more severe BPD symptoms at baseline, while high levels of impulsivity are associated with early discontinuation
group therapy; cognitive-behavioral treatment; Systems Training For Emotional Predictability and Problem Solving; borderline personality disorder; response predictors
Adverse conditions in Africa produce some of the highest rates of infant mortality in the world. Fetal growth restriction and preterm delivery are commonly regarded as major pathways through which conditions in the developing world affect infant survival. The aim of this article was to compare patterns of birthweight, preterm delivery, and perinatal mortality between black people in Tanzania and the USA.
Referral hospital data from North Eastern Tanzania and US Vital Statistics.
Consisted of 14 444 singleton babies from a hospital-based registry (1999–2006) and 3 530 335 black singletons from US vital statistics (1995–2000).
Main outcome measures
birthweight, gestational age and perinatal mortality.
Restricting to babies born with at least 500g, we compared birthweight, gestational age, and perinatal mortality (stillbirths and deaths in the first week) in the two study populations.
Perinatal mortality in the Tanzanian sample was 41/1000, compared with 10/100 among USA blacks. Tanzanian babies were slightly smaller on average (43g), but fewer were preterm (before 37 weeks) (10.0% vs 16.2%). Applying the USA weight-specific mortality rates to Tanzanian babies born at term suggested that birthweight does not play a role in their increased mortality relative to USA blacks.
Higher mortality independent of birthweight and preterm delivery for Tanzanian babies, suggests the need to address the contribution of other pathways that can further reduce the excess perinatal mortality.
birthweight; developing country; fetal development; perinatal mortality; preterm birth
The local structural changes in amorphous calcium phosphate (ACP) based dental composites were studied under isothermal conditions using both static, bulk measurement techniques and a recently developed methodology based on combined ultra-small angle X-ray scattering – X-ray photon correlation spectroscopy (USAXS-XPCS), which permits a dynamic approach. While results from conventional bulk measurements do not show clear signs of structural change, USAXS-XPCS results reveal unambiguous evidence for local structural variations on a similar time scale to that of water loss in the ACP fillers. A thermal-expansion based simulation indicates that thermal behavior alone does not account for the observed dynamics. Together, these results suggest that changes in the water content of ACP affect the composite morphology due to changes in ACP structure that occur without an amorphous-to-crystalline conversion. It is also noted that biomedical materials research could benefit greatly from USAXS-XPCS, a dynamic approach.
Amorphous calcium phosphate; Polymeric dental composites; Microstructure; Ultra-small-angle X-ray scattering; X-ray photon-correlation spectroscopy
We conducted literature searches and analyses to describe the current state of multilevel intervention (MLI) research and to identify opportunities to advance cancer control and prevention. We found single-level studies that considered other contextually important levels, and multilevel health-care systems research and community-wide studies. This literature is characterized by limited reporting of theoretical, contextual, temporal, and implementation factors. Most MLIs focus on prevention and screening, rather than diagnosis, treatment, or survivorship. Opportunities relate to 1) dynamic, adaptive emergent interventions and research designs that evolve over time by attending to contextual factors and interactions across levels; 2) analyses that include simulation modeling, or multimethod approaches that integrate quantitative and qualitative methods; and 3) translation and intervention approaches that locally reinvent MLIs in different contexts. MLIs have great potential to reduce cancer burden by using theory and integrating quantitative, qualitative, participatory, and transdisciplinary methods that continually seek alignment across intervention levels, pay attention to context, and adapt over time.
In a recent genome wide association study (GWAS) from an international consortium, evidence of linkage and association in chr8q24 was much stronger among non-syndromic cleft lip/palate (CL/P) case-parent trios of European ancestry than among trios of Asian ancestry. We examined marker information content and haplotype diversity across 13 recruitment sites (from Europe, USA and Asia) separately, and conducted principal components analysis (PCA) on parents. As expected, PCA revealed large genetic distances between Europeans and Asians, and a north-south cline from Korea to Singapore in Asia, with Filipino parents forming a somewhat distinct Southeast Asian cluster. Hierarchical clustering of SNP heterozygosity revealed two major clades consistent with PCA results. All genotyped SNPs giving p<10−6 in the allelic TDT showed higher heterozygosity in Europeans than Asians. On average, European ancestry parents had higher haplotype diversity than Asians. Imputing additional variants across chr8q24 increased the strength of statistical evidence among Europeans and also revealed a significant signal among Asians (although it did not reach genome-wide significance). Tests for SNP-population interaction were negative, indicating the lack of strong signal for 8q24 in families of Asian ancestry was not due to any distinct genetic effect, but could simply reflect low power due to lower allele frequencies in Asians.
cleft lip with/without cleft palate; 8q24; genome wide association; imputation
We report a novel molecular imaging agent based on Ytterbium (Yb) designed for use with Spectral “multi-color” Computed Tomogrphy (CT). Spectral CT or multi-ycolored CT provides all of the benefits of traditional CT, i.e., rapid tomographic X-ray imaging, but in addition, it simultaneously discriminates metal-rich contrast agents based on the elements unique x-ray K-edge energy signature. Our synthetic approach involved the use of organically soluble Yb(III)-complex to produce nanocolloids of Yb of noncrystalline nature incorporating high density of Yb (>500K/nanoparticle) into a stable metal particle. The resultant particles are constrained to vasculature (~200nm) and are highly selective for binding fibrin in the ruptured atherosclerotic plaque. Nanoparticles exhibited excellent signal sensitivity and the spectral CT technique uniquely discriminates the k-edge signal (60keV) of Yb from calcium (bones). Bio-elimination and preliminary bio-distribution studied reflected the overall safety and defined clearance of these particles in a rodent model.
Ytterbium; Nanoparticle; Spectral CT Imaging; Contrast Agent; Multicolor Imaging; Thrombus
We performed a genome wide association analysis of maternally-mediated genetic effects and parent-of-origin effects on risk of orofacial clefting using over 2,000 case-parent triads collected through an international cleft consortium. We used log-linear regression models to test individual SNPs. For SNPs with a p-value <10−5 for maternal genotypic effects, we also applied a haplotype-based method, TRIMM, to extract potential information from clusters of correlated SNPs. None of the SNPs were significant at the genome wide level. Our results suggest neither maternal genome nor parent of origin effects play major roles in the etiology of orofacial clefting in our sample. This finding is consistent with previous genetic studies and recent population-based cohort studies in Norway and Denmark, which showed no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefting. We, however, cannot completely rule out maternal genome or parent of origin effects as risk factors because very small effects might not be detectable with our sample size, they may influence risk through interactions with environmental exposures or may act through a more complex network of interacting genes. Thus the most promising SNPs identified by this study may still be worth further investigation.
GWAS; CL/P; CP; maternal genes; parent-of-origin; family-based study; association study
A comparative analysis across insects, birds, fish, and mammals reveals why it sometimes pays for males to care for the offspring of other males.
In most species, males do not abandon offspring or reduce paternal care when they are cuckolded by other males. This apparent lack of adjustment of paternal investment with the likelihood of paternity presents a potential challenge to our understanding of what drives selection for paternal care. In a comparative analysis across birds, fish, mammals, and insects we identify key factors that explain why cuckolded males in many species do not reduce paternal care. Specifically, we show that cuckolded males only reduce paternal investment if both the costs of caring are relatively high and there is a high risk of cuckoldry. Under these circumstances, selection is expected to favour males that reduce paternal effort in response to cuckoldry. In many species, however, these conditions are not satisfied and tolerant males have outcompeted males that abandon young.
In most species where it has been studied, males do not abandon or reduce paternal care when they are cuckolded by other males. These observations have presented a long-standing challenge to our understanding of what drives selection for paternal care. Our analysis of cuckolded fathers from 50 species of birds, fish, mammals, and insects, however, shows that sometimes it pays for males to stick around. In the case of humans and burying beetles, this is because females are relatively monogamous—by deserting, it is most likely the case that fathers will be deserting their own young. In species such as the chacma baboon, males face a significant risk of cuckoldry, and face potentially high penalties in terms of future breeding success by wasting precious resources on the young of other males. Unlike in humans, promiscuous females in these species will almost certainly lose the support of her mate in the effort to raise her young to adulthood.
Traffic-derived particulate matter (PM) is associated with cardiovascular morbidity and mortality, but the mechanism of this association is unclear. Prothrombotic processes have been linked to PM in epidemiological and animal models, but have not been consistently implicated in controlled human models. Diesel exhaust (DE) is a major contributor to PM. We conducted a controlled human exposure of DE in subjects with metabolic syndrome. The study objective was to evaluate DE exposure effects on prothrombotic markers in a population vulnerable to cardiovascular disease. A randomized, crossover, double-blinded design was used: 16 subjects with metabolic syndrome exposed on 3 different days (≥2 wk washout) to DE at 0 (filtered air, FA), 100 μg PM2.5/m3 (DE100) and 200 μg PM2.5/m3 (DE200). We assessed DE-associated changes in D-dimer, von Willebrand factor (VWF), and plasmin activator inhibitor-1 (PAI-1) at 3, 7, and 22 h after exposure initiation. A DE200-attributable decrease (1.17-fold; CI 1.04 to 1.34) in VWF was noted at 7 h. Significant changes did not occur in other primary endpoints. As previously noted with healthy subjects, strong diurnal patterns in PAI-1 were observed. Thus, in a novel study, we were unable to demonstrate a prothrombotic effect of moderate-dose diesel exhaust exposure in a population at risk for cardiovascular disease.
To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy.
Observational, retrospective case series.
Mayo Clinic Health System.
Thirty-two patients with an exclusive (n=11) or predominant (n = 21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more anti-epileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response-mediator protein 5 in 6%; and Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each.
Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclo-phosphamide.
Main Outcome Measure
After a median interval of 17 months (range, 3–72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05). All voltage-gated potassium channel complex antibody–positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody–positive patient was seizure free after thyroid cancer resection; another responded to antiepileptic drug change alone.
When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome.