Brivaracetam efficacy and tolerability in clinical practice: A UK-based retrospective multicenter service evaluation.

PURPOSE: This multicenter service evaluation explores the efficacy and tolerability of brivaracetam (BRV) in an unselected, consecutive population in 'real-life' clinical settings. METHOD: We retrospectively collected data from patient records at 11 UK hospitals and epilepsy centers. Consecutive patients prescribed BRV with at least 3 months of follow-up (FU) were included. Apart from reporting effectiveness and tolerability of BRV across the whole cohort, we compared treatment outcomes depending on previous levetiracetam use (LEV+ versus LEV-), comorbid learning disability (LD+ versus LD-), and epilepsy syndrome (focal versus generalized epilepsy). RESULTS: Two hundred and ninety patients (46% male, median age: 38 years, range: 15 to 77) with ≥3 months of FU were included. The median duration of BRV exposure was 12 months (range: 1 day to 72 months). Overall BRV retention was 71.1%. While 56.1% of patients improved in terms of seizure frequency category (daily, weekly, monthly, yearly seizures), 23.1% did not improve on this measure and 20.8% deteriorated. In terms of seizure frequency, 21% of patients experienced a ≥50% reduction, with 7.0% of all patients becoming seizure-free. Treatment-emergent adverse events (AEs) were reported by 107 (36.9%) patients, but there were no serious AEs. The commonest AEs were sedation/fatigue (18.3%), mood changes (9.0%), and irritability/aggression (4.8%). There were no significant differences in drug retention, seizure frequency outcomes, or AEs between the LEV+ and LEV- subgroups, or between patients with generalized or focal epilepsies. Although 15.5% of patients in the LD+ group achieved a ≥50% reduction, this rate was lower than in the LD- group. CONCLUSIONS: This 'real-life' evaluation suggests that reductions in seizure frequency can be achieved with BRV in patients with highly refractory epilepsy. Brivaracetam may be a useful treatment option in patients who have previously failed to respond to or tolerate LEV, those with LD, or (off-label) those with generalized epilepsies.

Decreasing the risk of sudden unexpected death in epilepsy: structured communication of risk factors for premature mortality in people with epilepsy.

BACKGROUND AND PURPOSE: Good practice guidelines highlight the importance of making people with epilepsy aware of the risk of premature mortality in epilepsy particularly due to sudden unexpected death in epilepsy (SUDEP). The SUDEP and Seizure Safety Checklist ('Checklist') is a structured risk communication tool used in UK clinics. It is not known if sharing structured information on risk factors allows individuals to reduce SUDEP and premature mortality risks. The aim of this study was to ascertain if the introduction of the Checklist in epilepsy clinics led to individual risk reduction. METHODS: The Checklist was administered to 130 consecutive people with epilepsy attending a specialized epilepsy neurology clinic and 129 attending an epilepsy intellectual disability (ID) clinic within a 4-month period. At baseline, no attendees at the neurology clinic had received formal risk advice, whereas all those attending the ID clinic had received formal risk advice on multiple occasions for 6 years. The Checklist was readministered 1 year later to each group and scores were compared with baseline and between groups. RESULTS: Of 12 risk factors considered, there was an overall reduction in mean risk score for the general (P = 0.0049) but not for the ID (P = 0.322) population. Subanalysis of the 25% of people at most risk in both populations showed that both sets had a significant reduction in risk scores (P < 0.001). CONCLUSION: Structured discussion results in behavioural change that reduces individual risk factors. This impact seems to be higher in those who are at current higher risk. It is important that clinicians share risk information with individuals as a matter of public health and health promotion.

Managing anti-epileptic drug treatment in adult patients with intellectual disability: a serious conundrum.

BACKGROUND AND PURPOSE: About a quarter of people with epilepsy have intellectual disability (ID). This group has communication issues, premature mortality, more treatment resistance, difficulties in making informed choices and greater risks of physical and mental health comorbidities. There is no specific prescribing guidance for this large and vulnerable group. The literature on prescribing for epilepsy in this group was reviewed, in particular examining how antiepileptic drugs (AEDs) work regarding their side effect profiles, effects on specific epilepsy syndromes associated with ID and their individual strengths and weaknesses based on the nature and degree of ID. METHOD: This is a narrative review for which a comprehensive search was conducted to identify evidence for prescribing commonly used AEDs to people with ID including genetic syndromes specifically associated with epilepsy. RESULTS: A detailed analysis of the results has highlighted the urgent requirement for suitable and reliable evidence in AED prescribing amongst adults with epilepsy and ID as no studies taking account of the response to AEDs of the ID populations based on the WHO Diagnostic and Statistical Manual of Mental Disorders criteria of clinical severity of ID were identified. CONCLUSION: There is a significant shortfall in suitably powered studies to provide sufficient evidence for safe prescribing of AEDs to people with ID.

Does somatosensation change with age in children and adolescents? A systematic review.

BACKGROUND: Somatosensory modalities, such as touch, proprioception and haptic ability, greatly influence the achievement of developmental milestones for children. Describing somatosensory impairment, natural variability and typical or expected developmental changes across age groups will help establish frameworks for intervention in clinical populations. This systematic review aimed to determine how different somatosensory modalities develop across childhood into adolescence to use as a point of reference for children at risk of somatosensory impairment. METHODS: Searches of five electronic databases were undertaken through EBSCO-host (MEDLINE, CINAHL, PsycINFO, SPORTDiscus and ERIC) for studies measuring at least one somatosensory modality in typically developing individuals between birth and 18 years and analysed by age. Characteristics of studies were collected including country of origin, sample size, demographics and outcome measure used. Quality assessment and data extraction were performed by two independent reviewers. RESULTS: Twenty three cross-sectional studies were included from a total of 188 articles retrieved: 8 examined aspects of touch, 5 proprioception and 10 haptic ability. Variability of study designs and variation in assessment tools precluded any formal meta-analysis. CONCLUSIONS: Somatosensation matures through childhood into adolescence; however, the present review found the pattern of somatosensory development varied depending on the assessment tool used and the aspect of somatosensation being measured, making it difficult to describe typical performance. There is a need for comprehensive assessment batteries to measure the somatosensation, including touch, proprioception and haptic ability, of children at risk of somatosensory impairment to aid in the development of effective interventions.

Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy.

Sensory motor neuropathy is associated with various inherited disorders including Charcot-Marie-Tooth disease, X-linked adrenoleukodystrophy/adrenomyeloneuropathy and Refsum disease. In the latter two, the neuropathy is thought to result from the accumulation of specific fatty acids. We describe here three patients with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and C27-bile-acid intermediates. Two of the patients suffered from adult-onset sensory motor neuropathy. One patient also had pigmentary retinopathy, suggesting Refsum disease, whereas the other patient had upper motor neuron signs in the legs, suggesting adrenomyeloneuropathy. The third patient was a child without neuropathy. In all three patients we discovered a deficiency of alpha-methylacyl-CoA racemase (AMACR). This enzyme is responsible for the conversion of pristanoyl-CoA and C27-bile acyl-CoAs to their (S)-stereoisomers, which are the only stereoisomers that can be degraded via peroxisomal beta-oxidation. Sequence analysis of AMACR cDNA from the patients identified two different mutations that are likely to cause disease, based on analysis in Escherichia coli. Our findings have implications for the diagnosis of adult-onset neuropathies of unknown aetiology.

Rapid switching from levetiracetam to brivaracetam in pharmaco-resistant epilepsy in people with and without intellectual disabilities: a naturalistic case control study.

BACKGROUND: Approximately one quarter of people with an intellectual disability (PwID) have epilepsy of whom nearly three-quarters are pharmaco-resistant. There are higher reported neuropsychiatric side-effects to anti-seizure medication (ASM) in this group. Levetiracetam (LEV) is a first-line ASM with a stronger association with neuropsychiatric symptoms for PwID than other ASMs. Brivaracetam (BRV) is a newer ASM. Recent studies suggest a beneficial effect of swapping people who experience neuropsychiatric events with LEV to BRV. However, there is limited evidence of this for PwID. This evaluation analyses real world outcomes of LEV to BRV swap for PwID compared to those without ID. METHODS: We performed a multicentre, retrospective review of clinical records. Demographic, clinical characteristics and reported adverse events of patients switched from LEV to BRV (2016-2020) were recorded at 3 months pre and 6- and 12-month post-BRV initiation. Outcomes were compared between PwID and those without and summarised using cross-tabulations and logistic regression models. A Bonferroni correction was applied. RESULTS: Of 77 participants, 46 had ID and 52% had a past psychiatric illness. 71% participants switched overnight from LEV to BRV. Seizure reduction of > 50% was seen in 40% patients. Psychiatric illness history was predictive of having neuropsychiatric side-effects with LEV but not BRV (p = 0.001). There was no significant difference for any primary outcomes between PwID versus without ID. CONCLUSIONS: Switching from LEV to BRV appears as well tolerated and efficacious in PwID as those without ID with over 90% still on BRV after 12 months.

Campath 1-H treatment in patients with aggressive relapsing remitting multiple sclerosis.

Campath 1-H (Alemtuzumab) is a humanised monoclonal antibody which targets the CD52 antigen, a low molecular weight glycoprotein present on the surface of most lymphocyte lineages, causing complement mediated lysis and rapid and prolonged T lymphocyte depletion. Following encouraging initial data from other centres we report our open label experience of using Campath 1-H as a treatment in aggressive relapsing multiple sclerosis in a consecutive series of 39 highly selected patients treated across three regional centres and followed for a mean of 1.89 years. The mean annualised relapse rate fell from 2.48 pre treatment to 0.19 post treatment with 29% of documented relapses observed in the 12 weeks following initial infusion. Mean change in EDSS was -0.36 overall and -0.15 in those patients completing > or =1 year of follow- up. Eighty-three per cent of patients had stable or improved disability following treatment. Infusion related side effects were common including rash, headache and pyrexia but were usually mild and self limiting. Transient worsening of pre-existing neurological deficits during infusion was observed in 3 patients. 12 patients developed biochemical evidence of autoimmune dysfunction, 2 patients developed thyroid disease and 1 patient autoimmune skin disease. We conclude that relapse rates fall following Campath 1-H. Whilst side effects were common these were normally self limiting or easily managed, suggesting Campath 1-H may be of use in the treatment of very active relapsing remitting multiple sclerosis.

Sudden death in epilepsy recorded in ambulatory EEG.

A woman with epilepsy died during a seizure and the event was recorded on ambulatory EEG. The circumstances were typical of sudden death in epilepsy (SUDEP). The EEG revealed that the patient had suffered a generalised seizure that abruptly ended with cessation of all cerebral electrical activity. Two other cases recorded on videotelemetry demonstrating similar EEG features were reported in the literature. We postulate that abrupt irreversible cerebral electrical shutdown during a seizure may be the primary mechanism of SUDEP.

Cell-to-cell movement of plant viruses.

To establish an infection, most plant viruses move from cell to cell in the plant. Virus-encoded movement proteins mediate this process and appear to use two mechanisms for transport. Both mechanisms involve interaction with and potential modification of plant intercellular connections, the plasmodesmata. Thus, although viral movement proteins are a diverse group, they share an ability to interact with specific plant components.

The rapidity of drug dose escalation influences blood pressure response and adverse effects burden in patients with hypertension: the Quinapril Titration Interval Management Evaluation (ATIME) Study. ATIME Research Group.

BACKGROUND: Antihypertensive medication doses are typically increased within several weeks after initiation of therapy because of inadequate blood pressure (BP) control and/or adverse effects. METHODS: We conducted a parallel-group clinical trial with 2935 subjects (53% women, n=1547) aged 21 to 75 years, with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VI stages 1 to 2 hypertension, recruited from 365 physician practices in the southeastern United States. Participants were randomized either to a fast (every 2 weeks; n=1727) or slow (every 6 weeks; n=1208) drug titration. Therapy with quinapril, an angiotensin-converting enzyme inhibitor, was initiated at 20 mg once daily. The dose was doubled at the next 2 clinic visits until the BP was lower than 140/90 mm Hg or a dose of 80 mg was reached. RESULTS: Pretreatment BP averaged 152/95 mm Hg. Patients with stage 2 hypertension reported more symptoms than those with stage 1. The BP averaged 140/86, 137/84, and 134/83 mm Hg in the slow group compared with 141/88, 137/85, and 135/84 mm Hg in the fast group at the 3 respective clinic visits. The BP control rates to lower than 140/90 mm Hg at the 3 clinic visits were (slow, fast, respectively) 41.3%, 35.7% (P<.001); 54.3%, 51.5% (P=.16); and 68%, 62.3% (P=.02). In the fast group, 10.7% of participants experienced adverse events vs 10.8% in the slow group; however, 21.0% of adverse events in the fast group were "serious" vs only 12% in the slow group. CONCLUSION: Slower dose escalation of the angiotensin-converting enzyme inhibitor quinapril provides higher BP control rates and fewer serious adverse events than more rapid drug dose escalation.

Cytologic observations on axotomized feline Betz cells. II. Quantitative ultrastructural findings.

Quantitative electron microscopic examination was made of Betz cells of two unoperated cats as well as cats subjected to left lateral funiculotomy 5, 10, 28 and 49 days before sacrifice. The percent cytoplasmic composition of chromatolyzed, right-sided Betz cells contributed by cisternal elements of RER, Golgi apparatus and dense bodies and the percent perikaryal membrane apposed by subsurface cisterns were unchanged from the normal despite marked qualitative alterations of the cytoplasm. However, 49 days postoperatively mitochondrial numerical density of axotomized, right-sided Betz cells was significantly less than at 0, 10 and 28 days post funiculotomy. Importantly, normal-appearing Betz cells ipsilateral to corticospinal tract section showed an increase in mitochondrial numerical density 5 days postoperatively. Operation did not induce change in the % perikaryal coverage by axosomatic boutons. Retraction of axosomatic boutons, though often reported for other neuronal populations undergoing axon reaction, is not a necessary feature of the axon reaction of feline Betz cells.

Cholinergic control of the nocturnal prolactin surge in the pseudopregnant rat.

The possible involvement of cholinergic mechanisms in the control of rhythmic secretion of prolactin has been examined in the pseudopregnant rat. Baseline data were obtained in decapitated animals in which the diuranl surge was observed in the 1430--2030 h range and the nocturnal surge during the 2330-0530 h interval. Atrial cannulation permitted a faithful reproduction of the prolactin pattern seen in decapitated rats if at least 3 days elapsed between the cannulation operation and bleeding, while cardiac puncture, under light ether anesthesia, appeared to suppress the diurnal surge. This latter observation appeared to depend on the time of sampling in relation to the onset of the dark phase of the daily lighting cycle. Atropine (35 or 70 mg/100 g BW) was found to inhibit the nocturnal surge in animals bled by either the cardiac puncture or cannulation techniques --an effect which was reversed by pretreatment with eserine (50 or 100 mug/100 g BW). Nicotine (0.75 mg/100 g BW) was found to delay, but not completely to inhibit, the nocturnal surge. When evaluated in the light of other available information, these observations suggest that a complex cholinergic mechanism is involved in control of the nocturnal rhythm of prolactin in pseudopregnancy and that the two surges, diurnal and nocturnal, are differentially controlled.

Ovarian steroids directly alter luteinizing hormone (LH) release by pituitary homografts.

The direct role of estradiol and progesterone in sensitizing the adenohypophysis to the releasing action of LHRH (luteinizing hormone-releasing hormone) has been examined in rats bearing pituitary homografts. Groups (10-14/group) of virgin female rats (CDF) strain) were hypophysectomized, ovariectomized, and pituitaries obtained from long-term ovariectomized donors were implanted under the kidney capsule. The animals were treated on the sixth day after transplantation with sesame oil vehicle, estradiol (1.6 mug/100 g BW), progesterone (0.6 mg/100 g BW), or estradiol plus progesterone. This injection regimen was repeated 12 h later. Ninety minutes after the steroid injection on day 7 half of the animals in each group received LHRH (ip) and half received saline. Basal levels of LH in the steroid-treated groups not injected with LHRH were, in general, elevated as compared to the oil-injected group. Following LHRH, blood samples were collected by cardiac puncture under light ether anesthesia at 5, 15, 30, 60, and 90 min postinjection. Animals receiving LHRH responded with significant elevations of LH both in the presence and absence of steroids while saline was without effect. However, the magnitude of the LH peak was found to be significantly blunted by estrogen treatment. Moreover, the peak LH response to LHRH occurred 30 min following injection in all groups except the progesterone primed animals. In this group the peak LH was delayed by 30 min. These results suggest that estradiol directly inhibits the release of LH at the level of the pituitary and that the ovarian steroids, estradiol and progesterone probably interact to determine the time of optimal pituitary sensitivity to LHRH.

Prolactin: the initial luteotropic stimulus of pseudopregnancy in the rat.

The luteotropic stimuli necessary to transform the corpus luteum of the estrous cycle into a corpus luteum of psuedopregnancy on the morning of diestrus-2 (Day 2), as reflected by a dramatic divergence in progesterone secretion, were studied (Day 1 was taken as the first day of diestrus of pseudopregnancy). The requirement of prolactin (PRL) as a luteotropic stimulus was determined by inhibiting the diurnal and nocturnal PRL surges that occur immediately before and during the divergence in progesterone. Following cervical stimulation, 1 mg of 2-Br-alpha-ergocryptine (EC) was injected at 1100 and 2300 h on Day 1 (lights on 0600-1800 h), and the animals were decapitated at 2-4 h intervals from 1100 h on Day 1 to 1700 h on Day 2. In the control animals, the PRL surges on Day 1 and Day 2 were associated with an increase in progesterone secretion on Day 2. However, the regimen of EC treatment resulted in an inhibition of PRL surges, prolactin remaining at baseline values from 1100 h on Day 1 to 1700 h on Day 2. The inhibition of PRL secretion was associated with a fall in progesterone concentration to reach baseline values by 1700h on Day 2. Furthermore, a group of animals similarly treated with EC returned to vaginal estrus 2 days later. LH concentrations did not differ in control and EC-treated animals. The effect of EC on corpus luteum function could be completely reversed by the simultaneous administration of PRL. In addition, if PRL was administered at 1100 h and 2300 h on diestrus-1 of the estrous cycle, in an attempt to mimic the surges os pseudopregnancy, regression of the corpora lutea did not occur. Progesterone levels increased to reach values comparable to those observed in pseudopregnancy on diestrus-2. The role of LH was studied by administering a dose of LH antiserum at 110 and 2300 h on Day 1 of pseudopregnancy. This treatment failed to inhibit the increase in progesterone observed on Day 2. These results demonstrate that the surges of plasma PRL initiated by cervical stimulation are responsible for transforming a corpus luteum of the estrous cycle into a corpus luteum of pseudopregnancy, as reflected by an increase in progesterone secretion of Day 2. LH seems to have a minor role in maintaining corpus luteum function beyond that observed during the estrous cycle.

The differential effects of exposure to tobacco smoke on the secretion of luteinizing hormone and prolactin in the proestrous rat.

The acute effects of tobacco smoke inhalation on the spontaneous proestrous rise in serum luteinizing hormone and prolactin have been investigated in the female Wistar rat. It was found that the surge of LH normally seen throughout the afternoon of proestrus was delayed by inhalation of tobacco smoke and that the delay was dose-related to the nicotine content of the cigarettes used in the experiment. In the case of prolactin neither the timing nor the magnitude of the surge was altered when compared with controls. These results suggest that under certain well-defined conditions inhalation of tobacco smoke of known nicotine content is capable of exerting profound influences on the hypothalamic-pituitary-gonadal axis.

The effect of hypercholesterolemia on aortic endothelium studied en face.

The aortic endothelium of rabbits fed a stock diet containing 1 or 2% cholesterol for intervals of 1 day to 21 weeks was compared with that of normal rabbits on a stock diet without cholesterol. The endothelium was examined en face using the Häutchen technique. The aortic endothelium of the experimental animals revealed an increase in stigmata and stomata, multinucleated giant cells and leukocytes particularly about sites of branching. These changes were also observed in the endothelium overlying lipid deposits but in addition, there was an increase in mitoses, an alteration in the orientation of endothelial cells and their nuclei, and a change in their argyrophilic staining properties. Closely related to the endothelium was an increasing number of foam cells which appeared to be derived from monocytic leukocytes.

Isolation of chlamydiae in untreated and Cytochalasin B treated McCoy cells.

A comparison was made between untreated McCoy cells and McCoy cells treated with Cytochalasin B for the isolation of chlamydiae of subgroup A. Chlamydiae were isolated in both cell systems from 125 specimens, whereas six agents were isolated only in untreated cultures and seven agents were isolated only in Cytochalasin B treated cultures.

Mannanase Man26A from Cellulomonas fimi has a mannan-binding module.

A modular mannanase (Man26A) from the bacterium Cellulomonas fimi contains a mannan-binding module (Man26Abm) that binds to soluble but not to insoluble mannans. Man26Abm does not bind to cellulose, chitin or xylan. The K(d) for binding of Man26Abm to locust bean gum (LBG) is approximately 0.2 microM. Man26A is the first mannanase reported to contain a mannan-binding module.

Viral specific IgG and IgM antibodies in the CSF of patients with tropical spastic paraparesis.

The cerebrospinal fluid (CSF) from seven West Indian migrants to the United Kingdom with tropical spastic paraparesis were studied by antigen immunoblotting for specific anti-HTLV1 oligoclonal IgG and IgM. Eight CSFs from five patients were positive for specific IgG and negative for IgM; three CSFs from two patients were positive for IgM and negative for IgG. No patient had both IgG- and IgM-positive CSF. Those patients with IgM only had disease of the shortest duration. When looking for evidence that neurological damage is caused by HTLV1, both IgM and IgG should be examined.

Local synthesis of IgA in the cerebrospinal fluid of patients with neurological diseases.

To date qualitative studies of IgA in the cerebrospinal fluid in neurological disease, particularly multiple sclerosis, have been few and given mixed results. The aim of this study was to identify local synthesis of IgA by detection of clonal IgA bands, in a large cohort of patients with a variety of neurological disorders, using polyacrylamide gel electrophoresis, transfer of protein to nitrocellulose membranes and specific staining. Of 2,097 sequentially analysed patients with suspected neurological disease 54 (2.6%) had locally synthesised IgA; most notably, IgA was present in 39 of 291 (13%) patients with suspected multiple sclerosis. The latter group also had a significant excess of light-chain production, particularly free kappa, when compared to multiple sclerosis patients without local synthesis of IgA. Locally synthesised IgA was also demonstrated in inflammatory, infectious and autoimmune diseases of the central nervous system. This qualitative technique is simple and suitable for routine analysis of cerebrospinal fluid, and further qualitative studies of IgA may be useful in investigating the pathophysiology of certain neurological disorders.