Modified automatic R-peak detection algorithm for patients with epilepsy using a portable electrocardiogram recorder.

Earlier studies have shown that short term heart rate variability (HRV) analysis of ECG seems promising for detection of epileptic seizures. A precise and accurate automatic R-peak detection algorithm is a necessity in a real-time, continuous measurement of HRV, in a portable ECG device. We used the portable CE marked ePatch® heart monitor to record the ECG of 14 patients, who were enrolled in the videoEEG long term monitoring unit for clinical workup of epilepsy. Recordings of the first 7 patients were used as training set of data for the R-peak detection algorithm and the recordings of the last 7 patients (467.6 recording hours) were used to test the performance of the algorithm. We aimed to modify an existing QRS-detection algorithm to a more precise R-peak detection algorithm to avoid the possible jitter Qand S-peaks can create in the tachogram, which causes error in short-term HRVanalysis. The proposed R-peak detection algorithm showed a high sensitivity (Se = 99.979%) and positive predictive value (P+ = 99.976%), which was comparable with a previously published QRS-detection algorithm for the ePatch® ECG device, when testing the same dataset. The novel R-peak detection algorithm designed to avoid jitter has very high sensitivity and specificity and thus is a suitable tool for a robust, fast, real-time HRV-analysis in patients with epilepsy, creating the possibility for real-time seizure detection for these patients.

Lack of interaction between sertraline and lamotrigine in psychiatric patients: a retrospective study.

INTRODUCTION: This study evaluates the pharmacokinetic interaction between sertraline and lamotrigine in psychiatric patients. METHODS: We identifi ed patients with at least 1 measurement of trough lamotrigine plasma concentration (at steady-state) during lamotrigine therapy and compared dose and plasma concentrations between patients who received lamotrigine with sertraline and patients who received lamotrigine without sertraline. RESULTS: The dose corrected concentration of lamotrigine in patients receiving lamotrigine in combination with sertraline was 60.4 µmol/L × 1,000/mg/day (SD: 31.1) (N = 7) compared to 51.1 µmol/L × 1 000/mg/day (SD: 27.6) (N = 44) in patients using lamotrigine without sertraline (p = 0.42). DISCUSSION: The slightly slower metabolism of lamotrigine in patients receiving lamotrigine with sertraline compared with those receiving lamotrigine alone is not believed to be of clinical signifi cance. However, due to the limited power, we may have overlooked a diff erence that could be clinically relevant.

Lamotrigine-induced rash--worth a rechallenge.

OBJECTIVES: The only serious adverse event associated with lamotrigine (LTG) treatment is a hypersensitivity reaction primarily presenting as a rash. Despite this concern, LTG is an antiepileptic drug (AED) with one of the most favorable efficacy/tolerability ratio compared with the new as well as the old AEDs. Thus, this study aimed to evaluate the results of rechallenge with LTG after the initial rash. MATERIAL AND METHODS: A total of 688 patients (350 as monotherapy, and 338 as add-on therapy) with either idiopathic generalized epilepsy or focal epilepsy were treated with LTG. The patients with LTG-induced rash were rechallenged to LTG. The dosage schedule was: 5 mg every day or every second day for 14 days, increased by 5 mg every 14th day to 25 mg a day. After achieving the daily dosage of 25 mg/day, the up-titration was completed following the current guidelines. RESULTS: A total of 52 patients developed a rash. The LTG-induced rash occurred in 6%, where 12 (1.8%) developed a rash shown to be coincidentally associated with the initiation of LTG therapy. In their cases LTG was continued with success without intermission. Nineteen (38%) of the initial cohort were rechallenged with LTG, with a success rate of 84%. CONCLUSION: This study is the first one to provide a successful recipe verified in time for the rechallenge with LTG after the initial drug-induced rash. Importantly, the concurrent use of valproate (VPA) was not found in this study to represent an additional risk factor for the occurrence of the rash during rechallenge with LTG. Our results agree with previous findings that women are more likely to develop the rash (P < 0.009).

Epilepsy and pregnancy: lamotrigine as main drug used.

OBJECTIVES: To study the risk of teratogenicity in infants of women with epilepsy. MATERIAL AND METHODS: Prospective data from 1996 to 2000 comprised 147 pregnancies. The most frequent antiepileptic drugs (AEDs) used were lamotrigine (LTG) 35% (n = 51), oxcarbazepine (OXC) 25% (n = 37) and valproate (VPA) 20% (n = 30). Seventy-four per cent (n = 109) received monotherapy. Folic acid supplementation was taken during first trimester by 118 patients (80%). RESULTS: The overall risk of malformations among newborns in the AED-exposed group was 3.1% (n = 4). Two children were born with multiple malformations (VPA monotherapy), two children had ventricular septal defects (one OXC monotherapy, and one OXC and LTG). The risk of malformations was 2.0% in women treated with LTG and 6.7% in women treated with VPA (NS). CONCLUSION: Despite the small number of cases in the study these data indicate that treatment with LTG during pregnancy might be relatively safe. Larger prospective studies are needed to obtain adequate power for statistical analysis.

Redistribution of axoplasm in the motor root in experimental diabetes.

Early experimental diabetes is associated with a reduction in axonal caliber. To elucidate the changes of nerve caliber further, we investigated the proximal and distal regions of the anterior root of rats after 5 weeks of streptozocin-induced diabetes. After vascular perfusion fixation, the fifth lumbar motor root was excised and two 3-mm segments were isolated, one at the level of the spinal cord and one at the dorsal root ganglion. The areas of myelinated fibers and their axons were measured by point counting. Axons from diabetic mice were enlarged proximally as compared to the controls, and reduced distally. It has been hypothesized that the reduction in axonal caliber is caused by an impairment of axonal transport of structural proteins rather than by osmotic shrinkage. Our findings indicate a redistribution of axoplasm in the nerves of the diabetic mice and support the hypothesis that changes in the axonal transport of neurofilaments are responsible for the structural changes seen in early diabetes. Similar changes could also play a role in the development of neuropathy in man.

Nerve conduction velocity in man: influence of glucose, somatostatin and electrolytes.

Insufficient metabolic control in diabetes mellitus is associated with a reversible reduction in nerve conduction velocity, but the mechanism behind this phenomenon is unknown. To examine the effect of acute hyperglycaemia on nerve conduction eight non-diabetic men (20-49 years of age) with no signs of peripheral neuropathy were studied before and after 3 h of hyperglycaemic clamping (plasma glucose approximately 15 mmol/l), while insulin secretion was suppressed by somatostatin [Study 1]. Nerve conduction velocity, as determined in the proximal part of the median nerve, fell by 2.8 +/- 3.0 m/s (2p-value: 0.033). However, during euglycaemic clamping (plasma glucose approximately 5 mmol/l) in five non-diabetic men (19-38 years of age) infused solely with somatostatin [Study 2], a comparable decrement in nerve conduction velocity was found (1.7 +/- 1.3 m/s, 2p-value: 0.043). In both studies relative hypoinsulinaemia was present. Serum-sodium decreased significantly (143 +/- 1 mmol/l vs 137 +/- 1 mmol/l [Study 1] and 143 +/- 1 mmol/l vs 142 +/- 2 mmol/l [Study 2]), while serum-potassium increased. In conclusion, the slight but significant reduction in nerve conduction velocity observed in both studies appears to be correlated to electrolyte changes. However, an effect of hypersomatostatinaemia or the hormonal changes associated with this cannot be excluded, while short-term hyperglycaemia per se seems to be without effect on nerve conduction velocity.

Diabetic neuropathy.

It has been generally accepted that diabetic neuropathy is associated with substantial morbidity and increased mortality, and that aldose reductase inhibitors are of potential therapeutic value, whereas the beneficial effect of strict insulin treatment is questionable. Contrary to these expectations, population-based studies now report only 6% occurrence of severe neuropathy among insulin-dependent diabetes mellitus patients. Also, intensified insulin treatment preserved conduction velocity for 5 years in a large group of insulin-dependent diabetes mellitus patients and reduced neuropathy development by 60%, whereas studies on aldose reductase inhibitors failed to produce any convincing therapeutic effect.

No effect of growth hormone treatment on axonal transport of slow component a in diabetic and nondiabetic rats.

A decreased axonal transport of slow component a (SCa), i.e., neurofilaments, is an early event in experimental diabetes as well as hypothyroidism, and common to these metabolic derangements are decreased levels of serum insulin-like growth factor I (IGF-I). To evaluate the possible connection between these facts, we investigated the effect of growth hormone (GH), which stimulates IGF-I production, on axonal transport of SCa in diabetic and nondiabetic rats. Serum concentrations of IGF-I fell from about 1500 micrograms/L in controls to about 600 micrograms/L in diabetics. GH treatment (100 mu/rat twice daily) normalized IGF-I for the first week of diabetes, after which the level decreased to the level of the untreated diabetics. The SCa transport velocity was found to be decreased in the diabetic nerves as previously reported [0.91 +/- 0.07 = mm/day, n = 9; (mean +/- SD) versus 1.01 +/- 0.09 mm/day, n = 8, in controls, 2 p less than 0.05). No changes were seen for the GH-treated groups (1.03 +/- 0.06 mm/day, (n = 11) in GH-treated controls). The lack of effect of GH treatment can be due to blockage of IGF-I synthesis or the decreased level of thyroid hormone, triiodothyronine (T3), in the diabetic rats.

Slow axonal transport of structural polypeptides in rat, early changes in streptozocin diabetes, and effect of insulin treatment.

The synthesis and transport of slowly transported polypeptides in sciatic nerves of rats was investigated by [35S]methionine pulse labeling and gel electrophoresis in control, diabetic, and insulin-treated diabetic rats. To detect very early changes diabetes was induced by streptozocin only 5 days prior to the labeling of the dorsal root ganglion cells. Fourteen days were allowed for axonal transport. In this experimental system, the neurofilament triplet is transported at an apparent velocity of 1.1 +/- 0.1 mm/day (mean +/- SD). The actin-related complex, including actin and two polypeptides of 87 kilodaltons and 37 kilodaltons, was transported at a velocity of 2.6 +/- 0.2 mm/day. For alpha- and beta-tubulin we found an apparent transport velocity of 2.2 +/- 0.1 mm/day, placing it between actin and the neurofilament triplet. The diabetic rats had a selective 32% decrease in the amount of the heaviest neurofilament subunit: 0.47 +/- 0.19% of trichloroacetic acid-insoluble radioactivity versus 0.69 +/- 0.17% in controls; 2p less than 0.05. This decrease was associated with a proximal accumulation of the two lighter neurofilament subunits. Insulin treatment of a diabetic group failed to normalize the changes of axonal transport and additional changes suggesting a hypoglycemic injury was observed.

Prazosin treatment of neurological patients with detrusor hyperreflexia and bladder emptying disability.

In a placebo-controlled clinical trial with cross-over design the effect of alpha-adrenoceptor blockade with prazosin was studied in 18 neurological patients with detrusor hyperreflexia and bladder emptying disability. During active treatment both the distance to maximal urethral closure pressure (MUCP) and MUCP were significantly reduced. In addition, the volume at first bladder contraction was increased. The urodynamic parameters measured during voiding were unaffected. We conclude that prazosin decreases detrusor hyperreflexia but only in rare cases may benefit bladder emptying in these patients.

Axonal transport of slow component a in sciatic nerves of hypo- and hyperthyroid rats.

Axonal transport of slow component a was studied in dorsal root afferents of the sciatic nerves of hypo- and hyperthyroid rats. Three experimental groups of rats were made hypothyroid at the age of 12 weeks by the administration of 131I. From the age of 22 weeks to the end of the study, the groups were treated with daily subcutaneous injections of thyroxine in various doses to make them hypo-(0 microgram/100 g), normo- (1 microgram/100 g), and hyperthyroid (6 micrograms/100 g), respectively. The hypothyroid group had a moderate thyroid hormone deficiency (a serum triiodothyronine level of 0.19 +/- 0.10 nmol/L and a heart/body weight ratio of 1.87 +/- 0.09 g/kg at time of killing compared with 0.60 +/- 0.09 nmol/L and 2.18 +/- 0.06 g/kg, respectively, for the control group). The hyperthyroid group was severely deranged, with serum triiodothyronine being 3.30 +/- 0.37 nmol/L and a heart/body weight ratio of 3.11 +/- 0.16 g/kg. The hypothyroid rats showed a reduction in mean velocity for the transport of slow component a (0.80 +/- 0.07 mm/day compared with 0.91 +/- 0.05 mm/day in the controls). The width of the wave of activity was smaller for the hyperthyroid group than for the control group (6.6 +/- 0.7 mm compared with 8.1 +/- 1.2 mm), suggesting an increased clearance of the axonally transported activity in the proximal axon. A decrease in transport of slow component a in hypothyroidism may be the explanation of peripheral neuropathy with axonal degeneration occasionally seen in patients with severe myxoedema.

Anterograde fast component of axonal transport during insulin-induced hypoglycemia in nondiabetic and diabetic rats.

To elucidate the pathogenesis of the peripheral neuropathy associated with hypoglycemia the anterograde fast component (aFC) of axonal transport was studied in nondiabetic rats during acute and prolonged insulin-induced hypoglycemia and in streptozocin-diabetic (STZ-D) rats with acute hypoglycemia. [35S]methionine and [3H]fucose were injected into the dorsal root ganglion (L5) to label protein and glycoprotein, respectively. During the 4 h of transport, thigh temperature was maintained constant. Acute severe hypoglycemia (1.5 +/- 0.2 mM) was associated with a 36% decrease in the amount of aFC (2.3 +/- 0.7% in the test group vs. 3.6 +/- 0.8% in the controls), whereas transport velocity was unaffected. Prolonged hypoglycemia, obtained by pretreatment with insulin for 3 days, prevented the decrease in amount of aFC. In STZ-D rats, acute severe hypoglycemia (1.5 +/- 0.6 mM) produced a similar but less-pronounced decrease of aFC. We conclude that hypoglycemia is associated with alterations in axonal transport that could play a role in development of neuropathy. Prolonged hypoglycemia protects axonal transport against the effects of glucopenia, and an untreated diabetic state maintained for several days has a partially protective effect against episodes of hypoglycemia.

Diabetes decreases Na+-K+ pump concentration in skeletal muscles, heart ventricular muscle, and peripheral nerves of rat.

Na+-K+-ATPase or the Na+-K+ pump is essential for some specific properties of muscle and nerve tissue such as contractility and excitability. Previous studies have shown conflicting variations in Na+-K+-ATPase activity or Na+-K+ pump concentration of muscle cells in experimental diabetes. Our study demonstrates that early untreated diabetes in rats induced by injection of streptozocin is associated with decreases in [3H]ouabain binding-site concentration of 24-48% in various skeletal muscles and 16% in peripheral nerves as well as a decrease in K+-dependent 3-O-methylfluorescein phosphatase activity of 21% in the heart ventricle. These effects could be prevented by insulin treatment. They probably represent a decrease in the concentration of Na+-K+ pumps. There was no evidence for more than one population of Na+-K+ pumps in intact samples of skeletal muscle and nerves from normal, diabetic, and insulin-treated animals. The decrease in Na+-K+ pump concentration in nerve cells may be due to atrophy of the axons. In skeletal muscles, myocardium, and peripheral nerves, the observed decrease in Na+-K+ pump concentration may be important for the pathophysiology of diabetes. We emphasize that quantification of Na+-K+-ATPase or the Na+-K+ pump in muscle and nerve tissue from diabetic animals should preferably be performed with either intact samples or crude homogenates of whole tissue.

Quantitative changes of cerebral neocortical structure in insulin-treated long-term streptozocin-induced diabetes in rats.

The brains of rats with streptozocin-induced diabetes treated with a low-dose insulin regimen (1 IU/day) were studied with morphometric techniques. After 1 yr of diabetes, brain weight decreased slightly (1350 +/- 71 vs. 1521 +/- 55 mg, 2P less than .01) as did the volume of the neocortex (498 +/- 36 vs. 567 +/- 40 mm3, 2P less than .05). A significant loss of neocortical neurons occurred (38 +/- 2 X 10(6) vs. 46 +/- 3 X 10(6), 2P less than .01), and the length of the capillary network in the neocortical tissue shortened disproportionately (405 +/- 102 vs. 631 +/- 47 m, 2P less than .01), leading to increased diffusion distance. The mechanisms underlying cerebral loss in this model are unknown, but abnormalities of the vascular supply with prolongation of the route of diffusion might play a role.

The effect of doxorubicin on slow and fast components of the axonal transport system in rats.

The study was designed to investigate the changes in axonal transport that result from disturbances in protein synthesis. Doxorubicin, an antineoplastic drug which interferes with the function of DNA, has a selective effect on peripheral sensory nerves because of the high vascular permeability in the dorsal root ganglia. After the intravenous administration of a moderate dose (4 mg/kg) to male Wistar rats, the transport of slow component a (SCa) was found to be retarded, transport velocity being decreased by 17% (0.85 +/- 0.06 mm/day vs 1.03 +/- 0.06 mm/day in controls). The transport kinetics of the fast anterograde and retrograde components (aFC and rFC) were unchanged after the administration of a dose of 6 mg/kg, although the relative amount of aFC was decreased by 27% (3.2 +/- 0.9% vs 4.4 +/- 1.1% in controls). It is suggested that the neuronopathy induced by doxorubicin is mediated by changes in axonal transport.

A proposal for a classification of neuropathies according to their axonal transport abnormalities.

Recent studies on axonal transport in experimental neuropathy are reviewed and the following combinations of pathological changes and underlying axonal transport abnormalities are proposed for a classification of polyneuropathies. Alterations of the anterograde transport of slow component a(SCa) leads to changes of the dimensions of the axon calibre without the occurrence either of overt neuropathy or fibre loss. Thus damming of SCa in beta,beta'-iminodiproprionitrile (IDPN) intoxication results in axonal swelling in nerve roots whereas decrease of SCa leads to atrophy distal to the swellings in IDPN intoxication and in streptozotocin induced diabetes as well. Decrease in the amount of material conveyed within the anterograde fast component (aFC) leads to acute axonal degeneration including break down of axons and fibre loss. This state occurs in acute hypoglycaemia and in doxorubicin intoxication. The most frequent type of polyneuropathy, namely distal axonopathy with accumulation of axon organelles leading to distal fibre loss, is associated with decrease in amount of the retrograde fast component (rFC). The transport is impaired before the appearance of symptoms and electrophysiological signs of neuropathy develop in the intoxications induced by parabromophenylacetylurea, acrylamide and 2.5 hexanedione, and the severity of neuropathy is proportional to the rFC impairment.

The retrograde fast component of axonal transport in motor and sensory nerves of the rat during administration of 2,5-hexanedione.

The retrograde and anterograde fast component of axonal transport (rFC and aFC) were examined in rats following intoxication with 2,5-hexanedione (1 g/kg/week) for 2, 4, 6 and 8 weeks. rFC and aFC were measured as accumulations distal and proximal to a double ligature after labeling of protein by injection of [35S]methionine into L5 spinal cord or L5 dorsal root ganglion. Clinical symptoms appeared after an accumulated dose of 6 g/kg of the toxin and was dominated by motor deficiencies. Abnormalities in retrograde build-up appeared earliest in motor nerves after an accumulated dose of 4 g/kg, while the sensory nerves showed a decreased retrograde build-up only after 6 g/kg. In motor nerves retrograde build-up for the short and the long accumulation interval (11.5-17.5 h and 11.5-25.5 h, respectively) was equally depressed, while in sensory nerves the retrograde build-up for the early accumulation interval (10-16 h) was less severely depressed as compared to the late collection interval (10-24 h). These findings point to a decreased amount of rFC, rather than a delay in turn-around. Furthermore, build-up was inversely correlated with the dose of 2,5-hexanedione and was most pronounced in motor nerves (82% vs 52% in motor and sensory nerves, respectively) at the final dose of 8 g/kg. When intoxication was stopped, rats improved in muscle-strength, but still showed atrophy of leg muscles. Coincidently, retrograde transport in motor nerves was normalized for the short accumulation interval, and improved for the longer collection interval, though not completely normalized.

Anterograde components of axonal transport in motor and sensory nerves in experimental 2,5-hexanedione neuropathy.

Anterograde slow and fast axonal transport was examined in rats intoxicated with 2,5-hexanedione (1 g/kg/week) for 8 weeks. Distribution of radioactivity was measured in 3-mm segments of the sciatic nerve after labelling of proteins with [35S]methionine or [3H]leucine and glycoproteins with [3H]fucose. The axonal transport of the anterograde slow components was examined after 25 (SCa) and 10 days (SCb), in motor and sensory nerves. SCa showed an increased transport velocity in motor (1.25 +/- 0.08 mm/day versus 1.01 +/- 0.05 mm/day) and in sensory nerves (1.21 +/- 0.13 mm/day versus 1.06 +/- 0.07 mm/day). The relative amount of labelled protein in the SCa wave in both fiber systems was also increased. SCb showed unchanged transport velocity in motor as well as in sensory nerves, whereas the amount of label was decreased in the motor system. Anterograde fast transport in motor nerves was examined after intervals of 3 and 5 h, whereas intervals of 2 and 4 h were used for sensory nerves. Velocities and amounts of labelled proteins of the anterograde fast component remained normal. We suggest that the increase in protein transport in SCa reflects axonal regeneration.

Slow component-a of axonal transport, nerve myo-inositol, and aldose reductase inhibition in streptozocin-diabetic rats.

This study measured sugars and polyols, weight/unit length, and slow component-a of axonal transport (SCa) in dorsal root afferents of the sciatic nerves of control rats and rats with streptozocin (STZ)-induced diabetes of 4-wk duration. The effects of two treatments--aldose reductase inhibition [Statil ("Statil" is a trademark; the property of Imperial Chemical Industries PLC.) ICI 128436 at 25 mg/kg/day, p.o.] and myo-inositol supplementation (650 mg/kg/day, p.o.)--were studied in control and diabetic groups. Inclusion of untreated controls and diabetics gave a total of six groups for the study. The treatments were begun on the day after injection of STZ and were maintained throughout the protocol. The sciatic nerves of the diabetic (untreated) rats showed accumulation of sorbitol and fructose, depletion of myo-inositol, and an 8% increase in weight/unit length. All of these abnormalities were prevented by treatment with Statil. Treatment of diabetic rats with myo-inositol prevented its depletion in the sciatic nerve, but did not affect the accumulation of sorbitol and fructose nor the increase in weight/unit length. Neither treatment exerted any apparent effect on body weight, blood glucose, nerve weight, or nerve sugars and polyols in the control rats. The diabetic rats showed a retardation of the wave of transported-labeled protein (shown as increased leftward skewness of the wave) and a reduction in mean transport velocity (calculated as the mean velocity for all segments contributing to the transport wave: 0.96 +/- 0.09 mm/day in diabetics versus 1.15 +/- 0.07 mm/day in controls).(ABSTRACT TRUNCATED AT 250 WORDS)