Tuberous Sclerosis: A Rare Disease with an Orphan Complex.

Introduction In the Republic of Ireland, there are no tuberous sclerosis complex (TSC) specialist clinics. Methods A clinical audit was carried out to assess the care received by patients attending two specialist adult epilepsy specialist centres, measuring their care against the UK guidelines. Results Although many baseline investigations are carried out, only one-third of patients had diagnostic genetic testing results available. Neuropsychiatry is largely neglected, and the completion of neuropsychiatric assessments checklists is inadequate. Discussions concerning SUDEP are not happening and access to treatment is limited. Reporting of radiological findings in TSC is inconsistent and the number of adults with TSC accessing specialist epilepsy services appear to be low. Discussion TSC care in the Republic of Ireland is fragmented, difficult to navigate and wasteful of resources due to the complex nature of the disease and no formal clinical setting to manage it. The service gaps echo the demand for an improved care system including consistent radiological reporting of TSC pathology. The absence of a specialist TSC clinic compounds the complexity of navigating care for individuals with TSC, families and healthcare professionals. Extending this audit nationally will give a more complete picture and highlight the resources required to bring care of these patients in line with recommended guidelines.

Increased thrombin generation potential in symptomatic versus asymptomatic moderate or severe carotid stenosis and relationship with cerebral microemboli.

INTRODUCTION: The importance of thrombin generation in the pathogenesis of TIA or stroke and its relationship with cerebral microembolic signals (MES) in asymptomatic and symptomatic carotid stenosis has not been comprehensively assessed. METHODS: Plasma thrombin generation parameters from patients with moderate or severe (≥ 50%) asymptomatic carotid stenosis were compared with those from patients with symptomatic carotid stenosis in the early (≤ 4 weeks) and late phases (≥ 3 months) after TIA or stroke in this prospective, pilot observational study. Thrombin generation profile was longitudinally assessed in symptomatic patients with data at each time point. Bilateral transcranial Doppler ultrasound monitoring of the middle cerebral arteries was performed whenever possible to classify patients as MES-positive or MES-negative. RESULTS: Data from 31 asymptomatic, 46 'early symptomatic' and 35 'late symptomatic' patients were analysed. Peak thrombin (344.2 nM vs 305.3 nM; p = 0.01) and endogenous thrombin potential (1772.4 vs 1589.7; p = 0.047) were higher in early symptomatic than asymptomatic patients. Peak thrombin production decreased in symptomatic patients followed up from the early to late phase after TIA or stroke (339.7 nM vs 308.6 nM; p = 0.02). Transcranial Doppler ultrasound data were available in 25 asymptomatic, 31 early symptomatic and 27 late symptomatic patients. Early symptomatic MES-positive patients had a shorter 'time-to-peak thrombin' than asymptomatic MES-positive patients (p=0.04), suggesting a more procoagulant state in this early symptomatic subgroup. DISCUSSION: Thrombin generation potential is greater in patients with recently symptomatic than asymptomatic carotid stenosis, and decreases over time following TIA or stroke associated with carotid stenosis. These data improve our understanding of the haemostatic/thrombotic biomarker profile in moderate-severe carotid stenosis.

Increased endothelial activation in recently symptomatic versus asymptomatic carotid artery stenosis and in cerebral microembolic-signal-negative patient subgroups.

BACKGROUND AND PURPOSE: von Willebrand factor propeptide (VWF:Ag II) is potentially a more sensitive marker of acute endothelial activation than von Willebrand factor antigen (VWF:Ag). These biomarkers have not been simultaneously assessed in asymptomatic versus symptomatic carotid stenosis patients. The relationship between endothelial activation and cerebral microembolic signals (MESs) detected on transcranial Doppler ultrasound is unknown. METHODS: In this multicentre observational analytical study, plasma VWF:Ag and VWF:Ag II levels in patients with ≥50% asymptomatic carotid stenosis were compared with those from patients with ≥50% symptomatic carotid stenosis in the 'early' (≤4 weeks) and 'late' (≥3 months) phases after transient ischaemic attack or ischaemic stroke. Endothelial activation was also longitudinally assessed in symptomatic patients during follow-up. Transcranial Doppler ultrasound monitoring classified patients as MES-positive or MES-negative. RESULTS: Data from 31 asymptomatic patients were compared with those from 46 early symptomatic and 35 late phase symptomatic carotid stenosis patients, 23 of whom had undergone carotid intervention. VWF:Ag II levels were higher in early (12.8 µg/ml; P < 0.001), late (10.6 µg/ml; P = 0.01) and late post-intervention (10.6 µg/ml; P = 0.038) symptomatic patients than asymptomatic patients (8.9 µg/ml). VWF:Ag levels decreased in symptomatic patients followed up from the early to late phase after symptom onset (P = 0.048). Early symptomatic MES-negative patients had higher VWF: Ag II levels (13.3 vs. 9.0 µg/ml; P < 0.001) than asymptomatic MES-negative patients. CONCLUSIONS: Endothelial activation is enhanced in symptomatic versus asymptomatic carotid stenosis patients, in early symptomatic versus asymptomatic MES-negative patients, and decreases over time in symptomatic patients. VWF:Ag II levels are a more sensitive marker of endothelial activation than VWF:Ag levels in carotid stenosis. The potential value of endothelial biomarkers and concurrent cerebral MES detection at predicting stroke risk in carotid stenosis warrants further study.

Widespread service fragmentation for patients and families with tuberous sclerosis complex (TSC) in the Republic of Ireland.

Background: Tuberous sclerosis complex (TSC) is a rare approximate 1:6000 birth incidence, a genetic disease with a wide variability of physical and neuropsychiatric symptoms. Patients require lifelong care from multiple healthcare specialities, for which International and United Kingdom (UK) TSC consensus recommendations exist. Personalised care delivered by a centralised coordinated team of TSC experts is recommended. There is no such service for the estimated 600 TSC patients in the Republic of Ireland (ROI) and there is a paucity of information regarding the healthcare of this group. Purpose: Evaluate the baseline care of patients with TSC attending epilepsy services in the Republic of Ireland (ROI) against UK TSC consensus recommendations. Methods: Patients with a diagnosis of TSC attending 12 adult and paediatric epilepsy centres in the ROI were identified. Clinical audits measured the baseline care of a subset of these patients against UK, TSC clinical recommendations. Data was anonymised and analysed at Trinity College Dublin. Results: One hundred thirty-five TSC patients attending twelve epilepsy centres were identified. Adults (n = 67) paediatric (n = 68). The care of 83 patients was audited (n = 63 ≥ 18 years) and (n = 20 < 18 years). Many baseline tests were completed, however, they required intra or interhospital referral. Care appears fragmented and there was no evidence of formal disease surveillance plans. Conclusions: The number of TSC patients attending epilepsy services is lower than expected (n = 135). Specialist services and treatments for TSC are available through informal referral pathways. Although UK, TSC consensus baseline recommendations are roughly adhered to, care is fragmented. Increased coordination of care could benefit disease management. Supplementary Information: The online version contains supplementary material available at 10.1007/s44162-024-00049-8.

Patient safety ward round checklist via an electronic app: implications for harm prevention.

INTRODUCTION: Patient safety is a value at the core of modern healthcare. Though awareness in the medical community is growing, implementing systematic approaches similar to those used in other high reliability industries is proving difficult. The aim of this research was twofold, to establish a baseline for patient safety practices on routine ward rounds and to test the feasibility of implementing an electronic patient safety checklist application. METHODS: Two research teams were formed; one auditing a medical team to establish a procedural baseline of "usual care" practice and an intervention team concurrently was enforcing the implementation of the checklist. The checklist was comprised of eight standard clinical practice items. The program was conducted over a 2-week period and 1 month later, a retrospective analysis of patient charts was conducted using a global trigger tool to determine variance between the experimental groups. Finally, feedback from the physician participants was considered. RESULTS: The results demonstrated a statistically significant difference on five variables of a total of 16. The auditing team observed low adherence to patient identification (0.0%), hand decontamination (5.5%), and presence of nurse on ward rounds (6.8%). Physician feedback was generally positive. CONCLUSIONS: The baseline audit demonstrated significant practice bias on daily ward rounds which tended to omit several key-proven patient safety practices such as prompting hand decontamination and obtaining up to date reports from nursing staff. Results of the intervention arm demonstrate the feasibility of using the Checklist App on daily ward rounds.

Predicting drug-resistant patients who respond to add-on therapy with levetiracetam.

INTRODUCTION: Levetiracetam (LEV) is approved for use as add-on therapy in adult patients with partial epilepsy. It is apparent from clinical trials that up to 8% of previously drug-resistant patients may be rendered seizure-free by adding-on levetiracetam. As yet there is no way of predicting these unexpectedly responsive patients. We set out to identify our previously refractory patients who had demonstrated unexpected responsiveness to add-on therapy with levetiracetam, and compared these to patients who had not responded to the drug. We then attempted to characterise any clinical features that differentiated these groups of patients. METHODS: We included all patients with a history of present or previous exposure to levetiracetam who had been unresponsive to at least two other prior anti-epileptic drugs (AEDs) and recorded their demographic and clinical data. We divided response into (a) 'seizure-free' (seizure-free for a minimum of 6 months after commencing LEV); (b) 'partial > 50%' (greater than 50% reduction in seizures for a minimum of 6 months after commencing LEV); (c) 'honeymoon' (seizure-free for less than 6 months after commencing LEV and then returned towards baseline frequency); and (d) 'no-response'. For the purpose of analysis we considered the 'seizure-free' and 'partial > 50%' groups as 'responders', and the 'no response' group as 'non responders'. RESULTS: 344 patients were included in the analysis. Fifty-six patients (16.3%) were rendered seizure-free on levetiracetam. Idiopathic generalised epilepsy and post-traumatic partial epilepsy were more common in the responder than the non-responder group (p = 0.005 and 0.05 respectively). Lamotrigine was used significantly more often in combination with levetiracetam in responders than non-responders (p = 0.003). The mean daily dose of levetiracetam was lower in responders than non-responders. DISCUSSION: A higher than expected number of previously drug resistant patients was rendered seizure-free by add-on therapy with levetiracetam. Those who respond best appear to do so at relatively low doses and our data suggest the possibility of a beneficial pharmacodynamic interaction between levetiracetam and lamotrigine. We were unable to identify any clinical factors that clearly predicted which patients would become seizure-free and we hypothesise that response may be determined by genetic or molecular factors. All drug-resistant patients, including those being assessed for surgery, should be considered for a trial of levetiracetam, regardless of their epilepsy classification.

Zinc and rehabilitation from severe protein-energy malnutrition: higher-dose regimens are associated with increased mortality.

A randomized, double-blind trial was undertaken to measure the effects of zinc supplementation on catch-up growth in severe protein-energy malnutrition, with particular reference to linear growth. One hundred forty-one children between the ages of 6 mo and 3 y were enrolled after admission to a nutritional rehabilitation unit in Dhaka, Bangladesh, and randomly assigned to receive elemental zinc by mouth, 1.5 mg/kg for 15 d, 6.0 mg/kg for 15 d, or 6.0 mg/kg for 30 d, and thereafter they were followed for a total of 90 d. Anthropometric outcome measures included change in knee-heel length, midupper arm circumference, subscapular and triceps skinfold thicknesses, and change in height-for-age, weight-for-age, and weight-for-height z scores. Higher zinc doses were not associated with significant change in any anthropometric measurement, but mortality was significantly greater in children who received high-dose zinc (6.0 mg/kg) initially as opposed to those who received low-dose zinc supplementation (1.5 mg/kg) (Yates-corrected chi-square P value of 0.033 and a risk ratio of 4.53; 95% CI: 1.09 < risk ratio < 18.8). We conclude that there is no benefit to using high-dose zinc supplementation regimens and that they could contribute to increased mortality in severely malnourished children.

Radiological determination of the posterior limits of the temporal lobe for volumetric analysis.

The posterior peri-Sylvian area is the most highly lateralized part of the human brain due to its specialised role in language. Currently, there is no clearly defined posterior boundary of the temporal lobe which takes account of language lateralization and which can be reliably determined radiologically. However, there have been a number of recent advances in magnetic resonance technology including volume visualisation techniques which have as their goal the realistic three-dimensional representation of the brain which is acquired in two-dimensional slices. These have enabled the identification of precise macroanatomical and cytoarchitectural boundaries from which an efficient and reproducible posterior limit may be demarcated. Such limit standardisation is important for volumetric investigations of both neurological and psychiatric disease. Magnetic resonance imaging (MRI) scans of 20 normal subjects (10 male and 10 female), aged between 18 and 42 years, were acquired as part of a study of normal temporal lobe volume variation. In order to demonstrate the method of posterior limit placement, a thin slice (1.5 mm) 3D spoiled gradient magnetic resonance image of the brain of a 30 year-old right-handed male, without neurological disease, was acquired on a 1.5 tesla GE magnetic resonance machine. The data set was transferred via network to the hard disk of a 166 MHz Pentium processor PC. A software package called MEASURE allowed reformation of the data set in all three orthogonal planes. Then, using a high resolution algorithm, the brain was aligned along the newly proposed posterior plane which runs from the limit of the Sylvian fissure, identified on a 3D rendering, to the posterior/inferior splenium. It is hoped that this procedure will be utilised as a standard method for radiological determination of the limit of the posterior temporal lobe in order to allow volumetric measurements of this structure to be compared in a meaningful way.

Accuracy and validity of stereology as a quantitative method for assessment of human temporal lobe volumes acquired by magnetic resonance imaging.

The object of this study was to compare the accuracy and validity of stereology as a method for determining whole temporal lobe volume with the more established technique of semi-automated thresholding and tracing. Ten, fixed, post-mortem human brains, were imaged using a three dimensional (3D) acquisition protocol. The volume of the left temporal lobe, dissected from each brain, was determined by fluid displacement. Each volume was compared to measurements obtained from magnetic resonance images (MRI) of the post-mortem brain using each of the two segmentation methods. Post-acquisition processing was performed using MEASURE software. Three investigators performed each measurement three times using each method, yielding a total of 180 measurements. Stereology took, on average, half the time of thresholding/tracing. Using a clinically acceptable variation for 95% of repeat measures; both intra-observer and inter-observer variation were acceptable for each technique. However, validity, as demonstrated by graphs of agreement against water displacement showed that the "limits of agreement" using stereology were within the acceptable range, while those using the thresholding/tracing technique were not. Quantitative estimates of variation and a graphical representation of the limits of agreement show that stereology is at least as precise as the thresholding/tracing method but is superior in terms of speed and validity. This has broad implications for published estimates of brain region volumes in human diseases such as epilepsy, dementia and other neurodegenerative disorders.

Increased platelet activation in early symptomatic vs. asymptomatic carotid stenosis and relationship with microembolic status: results from the Platelets and Carotid Stenosis Study.

BACKGROUND: Cerebral microembolic signals (MES) may predict increased stroke risk in carotid stenosis. However, the relationship between platelet counts or platelet activation status and MES in symptomatic vs. asymptomatic carotid stenosis has not been comprehensively assessed. SETTING: University teaching hospitals. METHODS: This prospective, pilot observational study assessed platelet counts and platelet activation status, and the relationship between platelet activation and MES in asymptomatic vs. early (≤ 4 weeks after TIA/stroke) and late phase (≥ 3 months) symptomatic moderate or severe (≥ 50%) carotid stenosis patients. Full blood count measurements were performed, and whole blood flow cytometry was used to quantify platelet surface activation marker expression (CD62P and CD63) and circulating leucocyte-platelet complexes. Bilateral simultaneous transcranial Doppler ultrasound monitoring of the middle cerebral arteries was performed for 1 h to classify patients as MES positive or MES negative. RESULTS: Data from 31 asymptomatic patients were compared with 46 symptomatic patients in the early phase, and 35 of these patients were followed up to the late phase after symptom onset. The median platelet count (211 vs. 200 × 10(9)  L(-1) ; P = 0.03) and the median percentage of lymphocyte-platelet complexes was higher in early symptomatic than asymptomatic patients (2.8 vs. 2.4%; P = 0.001). The percentage of lymphocyte-platelet complexes was higher in early symptomatic than in asymptomatic patients with ≥ 70% carotid stenosis (P = 0.0005) and symptomatic patients recruited within 7 days of symptom onset (P = 0.028). Complete TCD data were available in 25 asymptomatic, 31 early phase symptomatic and 27 late phase symptomatic patients. Twelve per cent of asymptomatic vs. 32% of early phase symptomatic (P = 0.02) and 19% of late phase symptomatic patients (P = 0.2) were MES positive. Early symptomatic MES-negative patients had a higher percentage of lymphocyte-platelet complexes than asymptomatic MES-negative patients (2.8 vs. 2.3%; P = 0.0085). DISCUSSION: Recently, symptomatic carotid stenosis patients have had higher platelet counts (potentially reflecting increased platelet production, mobilization or reduced clearance) and platelet activation status than asymptomatic patients. MES were more frequently detected in early symptomatic than asymptomatic patients, but the differences between late symptomatic and asymptomatic groups were not significant. Increased lymphocyte-platelet complex formation in recently symptomatic vs. asymptomatic MES-negative patients indicates enhanced platelet activation in this early symptomatic subgroup. Platelet biomarkers, in combination with TCD, have the potential to aid risk-stratification in asymptomatic and symptomatic carotid stenosis patients.

What do people with epilepsy know about their condition? Evaluation of a subspecialty clinic population.

Knowledge and understanding of chronic disease has an important role to play in establishing good quality outcomes. A small number of studies have looked at a number of different aspects of patient knowledge and self-management strategies. This study used three previously published scales to assess for the first time both the patients' personal knowledge of their own condition and their fund of knowledge about epilepsy in general, its treatment and consequences. The subjects were all patients attending a specialist-led epilepsy service in a tertiary care teaching hospital in Dublin, Ireland. Fifty-two subjects successfully completed three knowledge-based surveys focusing on personal information and compliance, safety, driving and employment legalities. Patients were more knowledgeable about the particulars of their individual condition rather than about epilepsy in general. Anti-epileptic drug compliance scores were highest overall; safety and legal issues ranked lowest. Many patients with epilepsy are not well informed about their disorder. Thus, there is a need for educational intervention in this population in order to optimize self-management strategies.

No major role of common SV2A variation for predisposition or levetiracetam response in epilepsy.

Levetiracetam (LEV), a newer antiepileptic drug (AED) useful for several epilepsy syndromes, binds to SV2A. Identifying genetic variants that influence response to LEV may allow more tailored use of LEV. Obvious candidate genes are SV2A, SV2B and SV2C, which encode the only known binding site, synaptic vesicle protein 2 (SV2), with LEV binding to the SV2A isoform. SV2A is an essential protein as homozygous SV2A knockout mice appear normal at birth but fail to grow, experience severe seizures and die by 3 weeks. We addressed characterising AED response issues in pharmacogenetics and whether variation in these genes associates with response to LEV in two independent cohorts with epilepsy. We also investigated whether variation in these three genes associated with epilepsy predisposition in two larger cohorts of patients with various epilepsy phenotypes. Common genetic variation in SV2A, encoding the actual binding site of LEV, was fully represented in this study whereas SV2B and SV2C were not fully covered. None of the polymorphisms tested in SV2A, SV2B or SV2C influence LEV response or predisposition to epilepsy. We found no association between genetic variation in SV2A, SV2B or SV2C and response to LEV or epilepsy predisposition. We suggest this study design may be used in future pharmacogenetic work examining AED or LEV efficacy. However, different study designs would be needed to examine common variation with minor effect sizes, or rare variation, influencing AED or LEV response or epilepsy predisposition.

Typhoid fever, ciprofloxacin and growth in young children.

Typhoid fever remains a significant public health problem in Southern Asia, particularly with the emergence of multi-resistant strains of Salmonella typhi in the late 1980s. Use of ciprofloxacin in children, although discouraged, is increasing and we aimed to assess whether its use affects growth or the prevalence of joint symptomology. Children under 6 years of age diagnosed as typhoid fever on the basis of a positive Widal test were recruited in the outpatient department of a paediatric teaching hospital after treatment had been initiated. During 6 months follow-up, prevalences of arthritis/arthralgia and ponderal, linear and knemometric growth were recorded. Seventy-five children were recruited (mean age 32 months, mean weight-for-height Z-score--1.3, mean height-for-age Z-score 1.4) and 29 (39%) of them received ciprofloxacin. No significant adverse effects on ponderal, linear or knemometric growth, or on the incidence of arthritis/arthralgia were found to be associated with the use of ciprofloxacin. Knemometric and ponderal catch-up growth was demonstrable 30 days after diagnosis but linear growth was still declining 3 months after diagnosis with catch-up growth demonstrable only after 6 months. We conclude that ciprofloxacin is commonly used in typhoid fever and has no adverse effects on growth or joint symptomology.

Discrimination of prosody and music by normal children.

Prosody or the melody of speech is the process used to alter the meaning (linguistic prosody) or emotional force (affective prosody) of a sentence. The components of prosody are rhythm, pitch, tone and stress and they are articulated by modulation of the acoustic correlates of prosody; frequency, duration and amplitude. Little is known about the development of prosody in normal children other than that it appears to be a precursor to the further acquisition of normal language. In order to examine the development of the perception of prosody in normal children, a group of 40 neurologically normal children aged between 5 and 9 years were subjected to a number of prosodic recognition tasks. The objective was to modify a number of existing tasks and to devise a number of new ones to test both linguistic and affective prosody and the appreciation of affective cues in music. The results indicate a step-wise improvement in perceptual contours up to 8.5 years old. However the perception of emotion in music appears highly developed early on in development. This study provides normative data and is the first report of a comparison between the development of prosodic and musical appreciation in this age group of normal children.

Middle cerebral artery territory infarction sparing the precentral gyrus: report of three cases.

We report three patients with large middle cerebral artery infarctions in the non-dominant hemisphere, with striking recovery of motor function. In each case this excellent functional outcome correlated with selective sparing of the motor cortex in the precentral gyrus. We discuss some of the possible circulatory variants that might underlie this pattern of infarction.

Linear and knemometric growth in the early phase of rehabilitation from severe malnutrition.

The relationship between ponderal, linear and lower leg growth in children recovering from severe malnutrition remains unclear. We report on the early growth of 141 severely malnourished Bangladeshi children aged 6 to 36 months of age who were followed for 90 d. Mean (sd) weight for height (WHZ) and height for age (HAZ) catch-up growth z scores over the 90 d were 1.6 (0.85) and 0.47 (0.325) respectively. Mean (sd) lower leg length growth was 10.35 (4.5) mm. Change in HAZ was significantly associated with initial WHZ, but linear growth occurred in the presence of severe wasting and no threshold WHZ score was identified. Lower leg length gain correlated throughout with ponderal indices but with change in HAZ score only after day 45. Only initial WHZ score and maternal height predicted for linear growth and only accounted for 20 % of total variance. We conclude that linear growth occurs early in severely malnourished children but that knemometry behaves as a ponderal index acutely.

Prosodic preservation in Landau-Kleffner syndrome: a case report.

Landau-Kleffner syndrome (LKS) is a rare acquired condition of auditory verbal agnosia and convulsive disorder in children. It has been proposed that there is a functional relationship between electrical disturbance and the speech defect. Prosody or the melody of language, as described by Monrad-Krohn (1947), is one aspect of non-verbal communication which is distributed bilaterally in the brain. Prosodic parameters of expression and perception in one 7.5-year-old child were tested to see if they were preserved as a means of communication. The child was observed during video-electroencephalogram (EEG) monitoring over a 48-hour period. All utterances were recorded and subject to analysis for the salience and variation of acoustic correlates of prosody. Prosodic comprehension was measured using specific perceptual tasks previously presented to normal children between the ages of 5.5 and 8.5. Despite being unable to meaningfully use or perceive phonemes, the child was able to use variations in fundamental frequency, duration and intensity of utterances, to convey both emotional and propositional intent. Similarly, the child was able to discriminate prosodic contours of a male adult voice to an age equivalent to 5.5 to 6.5 years. This argues in favour of the notion for educating such children not only through the visual channel but also through the auditory channel.