Ictal autonomic activity recorded via wearable-sensors plus machine learning can discriminate epileptic and psychogenic nonepileptic seizures.

Differentiating epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) is commonly based on electroencephalogram and concurrent video recordings (vEEG). Here, we demonstrate that these two types of seizures can be discriminated based on signals related to autonomic nervous system activity recorded via wearable sensors. We used Empatica E4 Wristband sensors worn on both arms in vEEG confirmed seizures, and machine learning methods to train classifiers, specifically, extreme gradient boosting (XGBoost). Classification performance achieved a predictive accuracy of 78 ± 1.5% on previously unseen data for whether a seizure was epileptic or psychogenic, which is 6 standard deviations above the baseline of 68% accuracy. Our dataset contained altogether 35 seizures from 18 patients out of which 8 patients had 13 convulsive seizures. Prediction of seizure type was based on simple features derived from the segments of autonomic activity measurements (electrodermal activity, body temperature, blood volume pulse, and heart rate) and forearm acceleration. Features related to heart rate and electrodermal activity were ranked as the top predictors in XGBoost classifiers. We found that patients with PNES had a higher ictal heart rate and electrodermal activity than patients with ES. In contrast to existing published studies of mainly convulsive seizures, our classifier focuses on autonomic signals to differentiate convulsive or nonconvulsive semiology ES from PNES. Our results show that autonomic activity recorded via wearable sensors provides promising signals for detection and discrimination of psychogenic and epileptic seizures, but more work is necessary to improve the predictive power of the model.

Nonepileptic seizures - objective phenomena.

This chapter describes the evaluation process for the diagnosis of psychogenic nonepileptic seizures (PNES), which is determined based on concordance of the composite evidence available, including historic and physical exam findings, seizure semiology, and ictal/interictal electroencephalogram (EEG). No single clinical feature is pathognomonic of PNES. The diagnosis of PNES can be at times challenging, such as when seizure documentation on video-EEG cannot be readily achieved. A multicomponent approach to the diagnosis of PNES, with use of all available evidence, may facilitate diagnosis and then care of patients with PNES. Emerging evidence supports the use of symptom identification by the patient as part of the treatment of these patients. With advances in diagnostic methods and criteria, the diagnosis of PNES can be made reliably.

Decreased serum BDNF levels in patients with epileptic and psychogenic nonepileptic seizures.

OBJECTIVE: Neurotrophins promote neurogenesis and help regulate synaptic reorganization. Their dysregulation has been implicated in a number of neurologic and psychiatric disorders. Previous studies have shown decreased levels of brain-derived neurotrophic factor (BDNF) in the serum of patients with psychiatric disorders such as major depressive disorder (MDD) and conversion disorder (CD). In human patients with temporal lobe epilepsy, there is an increase in both BDNF mRNA and protein levels in surgically resected hippocampi compared to controls. One study of children with epilepsy has found normal to increased serum BDNF levels compared to controls. Plasma [corrected] BDNF levels have not been investigated in adult patients with epileptic seizures (ES). We hypothesized that BDNF would differentiate between ES and psychogenic nonepileptic seizures (PNES). METHODS: We assessed plasma [corrected] BDNF immunoreactivity in 15 patients with ES, 12 patients with PNES, and 17 healthy volunteers. Plasma [corrected] BDNF levels were measured using an enzyme-linked immunoassay. RESULTS: Healthy controls showed higher BDNF levels (4,289 ± 1,810 pg/mL) compared to patients with PNES (1,033 ± 435 pg/mL) (p < 0.001). However, unexpectedly, healthy controls also showed higher levels of BDNF compared to patients with ES without comorbid MDD (977 ± 565 pg/mL) (p < 0.001). CONCLUSIONS: Unlike children, adults with epilepsy appear to have decreased levels of plasma [corrected] BDNF. Reduced plasma [corrected] BDNF levels can be used to differentiate adult patients with ES or PNES from healthy controls. Further human studies are needed to better understand the pathophysiology explaining the decreased plasma [corrected] BDNF levels found in epilepsy and in PNES.

Pilot pharmacologic randomized controlled trial for psychogenic nonepileptic seizures.

OBJECTIVE: There have been few treatment trials for psychogenic nonepileptic seizures (PNES). Some psychotherapies have been shown to improve PNES and comorbid symptom outcomes. We evaluated a pharmacologic intervention to test the hypothesis that sertraline would reduce PNES. METHODS: We conducted a pilot, double-blind, randomized, placebo-controlled trial in an academic medical hospital with epilepsy center outpatients. Subjects aged 18 to 65 years diagnosed with video-EEG-confirmed PNES were treated with flexible-dose sertraline or placebo over 12 weeks. Seizure calendars and symptom scales were charted prospectively. Secondary outcome measures included psychiatric symptom scales and psychosocial variables. RESULTS: Thirty-eight subjects enrolled, and 26 (68%) completed the trial. Thirty-three subjects with nonzero nonepileptic seizure rates at baseline were included in intent-to-treat analysis of the primary outcome. Subjects assigned to the sertraline arm experienced a 45% reduction in seizure rates from baseline to final visit (p = 0.03) vs an 8% increase in placebo (p = 0.78). Secondary outcome scales revealed no significant between-group differences in change scores from baseline to final visit, after adjustment for differences at baseline. CONCLUSIONS: PNES were reduced in patients treated with a serotonin selective reuptake inhibitor, whereas those treated with placebo slightly increased. This study provides feasibility data for a larger-scale study. LEVEL OF EVIDENCE: This study provides Class II evidence that flexible-dose sertraline up to a maximum dose of 200 mg is associated with a nonsignificant reduction in PNES rate compared with a placebo control arm (risk ratio 0.51, 95% confidence interval 0.25-1.05, p = 0.29), adjusting for differences at baseline.

Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use.

OBJECTIVE: To determine whether 1) combined oral contraceptive (COC) use affects serum levels of valproate (VPA) as well as lamotrigine (LTG) and 2) the naturally occurring high (mid-luteal) and low (early-mid follicular) reproductive steroid level phases of the menstrual cycle might affect antiepileptic drug levels as well. METHODS: This investigation compared serum antiepileptic drug levels at two timepoints during a single menstrual cycle in four groups of women with epilepsy: 12 on VPA, 12 on VPA plus COC (VPA-COC), 12 on LTG, and 12 on LTG plus COC (LTG-COC). RESULTS: Both VPA and LTG levels were lower (p < 0.01) on active COC than on inactive pill with median declines of 23.4% for the VPA-COC group and 32.6% for the LTG-COC group. Serum LTG levels showed a notable but not significant 31.3% median decline during the mid-luteal phase compared to the early-mid follicular phase in the non-COC group. The non-COC valproate group showed the least change of any group between the two measured timepoints with a decline of 8.3% (p = NS). CONCLUSIONS: The findings suggest that valproate (VPA), like lamotrigine (LTG), has substantially and significantly lower serum levels while women take active combined oral contraceptives as compared to inactive pills. Larger sample sizes will be required to determine whether LTG levels may drop significantly also during the luteal (high steroid) phase of natural menstrual cycles and whether VPA levels may show greater stability in levels across the phases of the menstrual cycle.

Oxygen desaturations triggered by partial seizures: implications for cardiopulmonary instability in epilepsy.

PURPOSE: The occurrence of hypoxemia in adults with partial seizures has not been systematically explored. Our aim was to study in detail the temporal dynamics of this specific type of ictal-associated hypoxemia. METHODS: During long-term video/EEG monitoring (LTM), patients underwent monitoring of oxygen saturation using a digital Spo2 (pulse oximeter) transducer. Six patients (nine seizures) were identified with oxygen desaturations after the onset of partial seizure activity. RESULTS: Complex partial seizures originated from both left and right temporal lobes. Mean seizure duration (+/-SD) was 73 +/- 18 s. Mean Spo2 desaturation duration was 76 +/- 19 s. The onset of oxygen desaturation followed seizure onset with a mean delay of 43 +/- 16 s. Mean (+/-SD) Spo2 nadir was 83 +/- 5% (range, 77-91%), occurring an average of 35 +/- 12 s after the onset of the desaturation. One seizure was associated with prolonged and recurrent Spo2 desaturations. CONCLUSIONS: Partial seizures may be associated with prominent oxygen desaturations. The comparable duration of each seizure and its subsequent desaturation suggests a close mechanistic (possibly causal) relation. Spo2 monitoring provides an added means for seizure detection that may increase LTM yield. These observations also raise the possibility that ictal ventilatory dysfunction could play a role in certain cases of sudden unexpected death in epilepsy in adults with partial seizures.

Postictal heart rate oscillations in partial epilepsy.

We report postictal heart rate oscillations in a heterogeneous group of patients with partial epilepsy. This pattern is marked by the appearance of transient but prominent low-frequency heart rate oscillations (0.01 to 0.1 Hz) immediately after 5 of 11 seizures recorded in 5 patients. This finding may be a marker of neuroautonomic instability and, therefore, may have implications for understanding perturbations of heart rate control associated with partial seizures.

Focal status epilepticus: clinical features and significance of different EEG patterns.

PURPOSE: Focal status epilepticus is typically diagnosed by the observation of continuous jerking motor activity, but many other manifestations have been described. EEG evidence of focal status may take several forms, and their interpretation is controversial. We detailed the clinical spectrum of focal status in patients diagnosed by both clinical deficit and EEG criteria and contrasted clinical manifestations in patients with different EEG patterns. METHODS: Patients were diagnosed with a neurologic deficit and discrete recurrent focal electrographic seizures or rapid, continuous focal epileptiform discharges on EEG. Clinical findings were determined by chart review. RESULTS: Of 41 patients with focal status, acute vascular disease was the cause in 21; 10 of 41 had exacerbations of prior epilepsy. A variety of clinical seizure types occurred, both before and after the EEG diagnosis, but the diagnosis was not expected in 28 patients before the EEG. Three had no obvious clinical seizures. Focal motor seizures and an abnormal mental status were the most common manifestations at the time of the EEG. With antiepileptic drugs, almost all had control of clinical seizures, and most improved in mental status. Patients with rapid continuous focal epileptiform discharges were nearly identical in presentation, likelihood of diagnosis, subsequent seizures, response to medication, and outcome to those with discrete seizures on EEG. CONCLUSIONS: Focal status epilepticus may be seen with a wide variety of clinical seizure types or without obvious clinical seizures. The diagnosis is often delayed or missed and should be considered after strokes or clinical seizures when patients do not stabilize or improve as expected. The diagnosis should be made equally whether patients have discrete electrographic seizures or continuous rapid focal epileptiform discharges on the EEG, and the same response to medications and outcome should be anticipated for the two groups.

Heat sensitivity of sensory fibers in carpal tunnel syndrome.

Elevations in temperature may produce conduction block in demyelinated neurons. A well-described phenomenon in multiple sclerosis, it has also been reported in some patients with inflammatory demyelinating polyneuropathies. We used carpal tunnel syndrome (CTS) as a model to study the effect of heat on nerves with focal demyelination secondary to chronic compression. Compound motor and sensory responses were measured in 12 CTS patients and 12 normal subjects at 32 degrees C and with heating to 42 degrees C. Changes in relative motor response amplitude and area were similar for both normal subjects and CTS patients. In CTS patients, however, sensory response amplitude and area decreased 34.3% and 48.9%, significantly more than the 25.2% and 39.1% reductions in normal subjects (P=0.021 and P=0.018 respectively). We hypothesize that these reductions in response amplitude are secondary to the occurrence of heat-induced conduction block in demyelinated sensory neurons.

The role of the interventional radiologist in central venous access.

The role of the interventional radiologist in the care of patients requiring placement of central venous access devices is rapidly evolving. With experience gained from diagnosing and treating central venous catheter-related complications, interventional radiologists are assuming an increasing role in the placement of these devices. With imaging guidance, catheter and guidewire skills, and a commitment to providing a clinical service that includes management of catheter malfunctions and complications, central venous access by the interventional radiologist has proven a safe and effective alternative to standard surgical techniques.

Technical implementation and clinical findings/results of monitoring oxygen saturation in patients referred for long-term EEG monitoring.

Recent technical developments allow the recording of a patient's oxygen saturation (SpO2) simultaneously with intensive long-term EEG monitoring (LTM). Clinically significant information from this enhanced multi-system physiological monitoring device can contribute to more accurate diagnoses in patients referred for LTM. This report covers the technical usage of combined SpO2/EEG recordings in a small group of patients. Clinically, the findings on the SpO2 monitor helped to define the diagnosis in many of these patients. In a few, the SpO2 changes were diagnostic in their own right and prompted referral to our Sleep Disorders Laboratory. From a research aspect, the details of the morphology and timing of the oxygen desaturations and EEG show several interesting relationships with respect to the dynamics of seizure semiology and respiratory physiology.

Nonconvulsive status epilepticus in thrombotic thrombocytopenic purpura.

Fluctuating neurologic symptoms, including confusion, stupor, and convulsions, are common signs in thrombotic thrombocytopenic purpura (TTP). We describe a patient with TTP who had a clinical seizure, intermittent stupor, and a declining course despite aggressive treatment. An EEG showed continuous rhythmic epileptiform discharges, and she improved with anticonvulsants. Fluctuating stupor in TTP has generally been attributed to microvascular occlusive disease, but nonconvulsive status epilepticus is a treatable condition that can cause similar symptoms.

Low-dose zalcitabine-related toxic neuropathy: frequency, natural history, and risk factors.

We studied the features and frequency of sensory neuropathy among 79 HIV-1-infected individuals participating in a multicenter clinical trial of zalcitabine (2'3'-dideoxycytidine, or ddC) antiretroviral therapy. The trial compared zalcitabine monotherapy (2.25 mg/day) versus combination therapy (2.25 mg/day ddC) with zidovudine (ZDV, formerly AZT) versus monotherapy with ZDV alone. Neuropathy developed in 34% of ddC recipients but in only 4% of comparable patients treated with ZDV alone--a 7.9-fold increase in the attack rate of neuropathy. Using risk factor analysis, we found that diabetes mellitus was significantly associated with the development of toxic neuropathy (p = 0.02), and weight loss may contribute to its appearance. Like HIV-associated sensory neuropathy, ddC-related toxic neuropathy is a predominantly sensory, length-dependent, symmetric, painful neuropathy. Dose reduction lessened the severity of symptoms, although objective signs of neuropathy persisted. Patients with subclinical neuropathies or significant neuropathy risks such as diabetes may be poor candidates for ddC therapy.

Developmental regulation of ganglioside antigens recognized by the JONES antibody.

The JONES monoclonal antibody has been immunocytochemically associated with regions of the developing rat brain where cell and axon migrations are occurring (Mendez-Otero et al., 1986, 1988). In the present study the antigens recognized by the JONES antibody were analyzed in a variety of brain regions and at developmental ages selected to correspond to the preceding immunocytochemical observations. In accordance with earlier results from retina, JONES binding could not be detected in SDS gels from developing brain. Binding of the antibody was, however, prominent in chloroform/methanol extracts of the same tissues, and it was completely removed from tissue sections by brief chloroform/methanol form/methanol treatment. Enzymatic analyses of chloroform/methanol extracts indicated that the JONES epitope was sensitive to neuraminidase but insensitive to proteases. Overlay assays on developed high-performance thin-layer chromatographic plates (HPTLC) indicate that in all regions the JONES epitope resides on 2 or 3 ganglioside bands, depending on the age examined. These bands migrate between ganglioside standards GD 1a and GM2 on HPTLC plates and have been designated GJ1, GJ2, and GJ3, with the higher number designating the more rapidly migrating species. Occasionally, additional bands migrating in the range of polysialogangliosides were observed. The pattern of expression of GJ species was studied in forebrain, retina, and cerebellar tissue taken from embryonic day 18 (E18), postnatal day 0 (P0), P7, P14, and adult animals. Both region-specific differences in the relative prominence of each band and stage-specific differences in the total amount of the JONES gangliosides were detected. The stage-specific differences in the amount of JONES antigens are well correlated with the developmental periods of maximal cell migration in each region. While the JONES gangliosides are most prominent in forebrain before birth, in they are most prominent during the first 2 postnatal weeks. In cerebellum, JONES antigen expression is more pronounced during the 2 periods of cell migration in this tissue. In retina, the more rapidly migrating GJ3 band was the most prominent band at all stages examined, and this same band is retained in the adult. In cerebellum and forebrain GJ3 is also the most pronounced band during development. However, in contrast to the retina, the more slowly migrating GJ1 band is retained in adult forebrain and cerebellum. A variety of non-brain tissues have also been examined for the presence of the JONES antigens.(ABSTRACT TRUNCATED AT 400 WORDS)

O-acetylation of a cell-surface carbohydrate creates discrete molecular patterns during neural development.

The cell-surface antigen detected by the monoclonal antibody JONES is expressed in the retina and a number of other central nervous system regions of the rat during the latter part of embryonic development and the early postnatal period. In addition to the expression on certain neuroblast populations it is found on some but not all axons and is also expressed at high levels on the end feet of radial glia in regions through which axons actively grow. In the perinatal rat retina, almost all the antigenic activity was carried on a ganglioside migrating between GM1 and GM2. The epitope recognized by antibody JONES was base labile and treatment with 0.1 M sodium carbonate or ammonia vapor converted the antigen into GD3. Resistance to oxidation by sodium periodate and reformation of the epitope by chemical acetylation of base-treated gangliosides with N-acetylimidazole identify the antigen as 9-O-acetyl GD3. The acetylation of GD3 seems to be regulated independently from GD3 expression itself since acetylated and nonacetylated GD3 do not have identical immunocytochemical distributions in the developing central nervous system. In addition, five independent human melanoma cell lines varied substantially in their expression of 9-O-acetyl GD3, even though they all expressed high levels of GD3. Acetylation of ganglioside-linked sialic acid provides a mechanism for generating unique patterns of surface carbohydrates, which may influence cell interactions in development.

Bone density in myelomeningocele: the effects of ambulatory status and other factors.

Measurements were made of distal radius, mid-radius, tibia and metatarsal bone-density of 80 patients with myelomeningocele (17 thoracic, six L1/L2, 13 L3, 30 L4, 14 L5/sacral). For the upper extremity the bone density primarily was low in the thoracic patients, but in the tibia and metatarsal it showed a more linear correlation with neurological levels. The effect of age was highly significant at all sites; after controlling for this, the neurological level was a significant determinant of bone density at all sites, and this effect was greater in older children. Patients with impaired ambulation had decreased bone-density in the distal radius, tibia and metatarsal, but not in the mid-radius. Race had no significant effect on density after accounting for differences in neurological level. Weight for height and multiple fractures did not correlate with bone density. Although ambulatory status (weight-bearing stresses) and neurological status (muscle stresses) are both important factors in bone density, this study suggests that the latter is a more important determinant.

A cell surface molecule distributed in a dorsoventral gradient in the perinatal rat retina.

Brain topography may have its earliest expression as spatial gradients of molecules controlling the deposition of neurones and neuronal processes. In the vertebrate visual system there is evidence that the stereotyped alignment of central retinal projections relies on an initial spatially organized distribution of molecules in both the retina and its central target nuclei. We used an immunological approach to look for molecules that are so organized and produced a monoclonal antibody (JONES) which shows a pronounced dorsal to ventral gradient of binding in the rat retina throughout the period when retinal ganglion cell axons are forming topographically organized projections within the central nervous system (CNS). Binding is present throughout the radial thickness of the retinal epithelium in regions where postmitotic neurones are generated but is not associated with any consistent histological characteristic of the tissue. The antibody was shown to bind on the cell surface of freshly dissociated retinal cells, and dorsal retinal quadrants were found in vitro to have nearly twice as much antigen as ventral retinal quadrants. Initial biochemical characterization of the target epitope reveals that it is a lipid present in chloroform/methanol extracts from perinatal retina and is sensitive to neuraminidase digestion.

Computer evaluation of statistical procedures, and a new quality-control statistical procedure.

I describe a program for definitive comparison of different quality-control statistical procedures. A microcomputer simulates quality-control results generated by repetitive analytical runs. It applies various statistical rules to each result, tabulating rule breaks to evaluate rules as routinely applied by the analyst. The process repeats with increasing amounts of random and systematic error. Rate of false rejection and true error detection for currently popular statistical procedures were comparatively evaluated together with a new multirule procedure described here. The nature of the analyst's response to out-of-control signals was also evaluated. A single-rule protocol that is as effective as the multirule protocol of Westgard et al. (Clin Chem 27:493, 1981) is reported.