Refractory Epilepsy: Natural History and Pathogenesis

Despite antiepileptic drug (AED) treatment, up to one third of patients continue to have seizures. Refractory epilepsy is a poorly understood subject, both in terms of its development and pathogenesis. Outcome studies have focused on terminal remission, but little is known about the natural history of epilepsy in terms of its progression to eventual remission or persistent refractoriness. Such an understanding is essential to the formulation of a rational management approach. Natural history of treated epilepsy Long-term outcome of newly diagnosed patients was investigated longitudinally for up to 15 years. Response to the first drug and successive substitution monotherapy or polytherapy was analysed. Outcome among patients with different neuropathologies was compared in a separate study. Among 470 newly diagnosed patients, 64% became seizure-free for at least a year. Patients with high numbers of pre-treatment seizures were less likely to become seizure- free. Epilepsy was controlled by the first AED in 47% of patients. Patients with symptomatic or cryptogenic epilepsy were less likely to become seizure-free on the first AED, partly because they were more likely to develop intolerable side-effects compared to those with idiopathic epilepsy. The majority of such withdrawals occurred at low doses of the three most commonly prescribed AEDs, carbamazepine (CBZ), sodium valproate (VPA) and lamotrigine (LTG). Over 90% of seizure-free patients also required only a moderate daily dose (up to 800mg CBZ, ISOOmg VPA, 300mg LTG). The probability of attaining seizure-freedom declined progressively with successive AED regimens. While 47% became seizure-free on the first drug, only 10% did so on the second drug and 1% on the third monotherapy. Three percent became seizure-free on a combination of two AEDs. The subsequent seizure-free rate was 41% among those failing the first drug due to intolerable side effects, but only 11% among those in whom the first AED was well tolerated but did not control the seizures completely. Among patients with inadequate seizure control on the first well tolerated AED, those who received substituted monotherapy and those who received add-on treatment had similar seizure-free rates and incidence of intolerable side effects. More patients became seizure- free on combinations involving an AED that blocked sodium channels and one with multiple mechanisms of action than on other combinations. Combination treatment was more effective when prescribed immediately after the first drug failed due to inadequate seizure control than w'hen it was delayed until a substitution also proved unsuccessful. In a separate study, compared with other pathologies identified on magnetic resonance imaging, mesial temporal sclerosis (MTS) was associated with the worst prognosis, although 42% did become seizure-free on AED treatment. Pathogenesis of refractory epilepsy Two candidate biological mechanisms in the pathogenesis of refractory epilepsy were studied. Glutamic acid decarboxylase (GAD) autoantibody titres were compared between patients with controlled and uncontrolled epilepsy. GAD catalyses the conversion of glutamate to y-aminobutyric acid, the major inhibitory neurotransmitter. Autoantibodies against GAD are prevalent in insulin dependent diabetes mellitus, and have been documented in anecdotal cases of refractory epilepsy. The drug transporter P-glycoprotein (P-gp) was investigated in a series of laboratory-based pilot experiments. Encoded by the multidrug resistance gene family (MDRl in man and mdrla and lb in rodents), P-gp actively extrudes a wide range of xenobiotics out of cells. Its over-expression is thought to underlie the resistance of some cancers to multiple chemotherapeutics. P-gp is physiologically expressed at high level in the cerebral capillary endothelium where it contributes to the integrity of the blood-brain barrier. Overexpression of P-gp in brain tissues resected from patients with refractory epilepsy has been reported in surgical case series. Mdrla(-/-) mice devoid of cerebral P-gp were used to determine whether AEDs were substrates of the drug transporter. The pharmacokinetic profiles of four established and four new AEDs in mdrla(-/-) mice and wild-type mice were compared. The technique of quantitative reverse transcriptase-polymerase chain reaction was developed and validated to determine tissue concentration of mdrl mRNA as an indicator of gene expression. Expression was determined in different regions of the normal rat brain, and in brains of genetically epilepsy-prone rats (GEPRs) subject to a single audiogenic seizure. To explore the effect of tissue damage, a laser beam was impinged upon the cerebral cortex of rats. Mdrl expression was measured in tissues surrounding the focal necrosis. Human brain tissues resected during epilepsy surgery were also analysed for MDRl gene expression. There was no difference in GAD autoantibody titres between patients with controlled and uncontrolled epilepsy. (Abstract shortened by ProQuest.)

Medium-term Outcomes of Myocarditis and Pericarditis following BNT162b2 Vaccination among Adolescents in Hong Kong

In this study, we examined the clinical and electrophysiological outcomes of adolescents in Hong Kong who developed myocarditis or pericarditis following BNT162b2 vaccination for COVID-19, and followed-up for 60 to 180 days after their initial diagnosis. Clinical assessments included electrocardiogram (ECG) and echocardiogram at the initial admission and follow-up were compared. Treadmill testing was also performed in some cases. Between 14 June 2021 and 16 February 2022, 53 subjects were approached to participate in this follow-up study, of which 28 patients were followed up for >60 days with a median follow-up period of 100 days (range, 61-178 days) and were included in this study. On admission, 23 patients had ECG abnormalities but no high-grade atrioventricular block. Six patients had echocardiogram abnormalities, including reduced contractility, small rim pericardial effusions, and hyperechoic ventricular walls. All patients achieved complete recovery on follow-up. After discharge, 10 patients (35.7%) reported symptoms, including occasional chest pain, shortness of breath, reduced exercise tolerance, and recurrent vasovagal near-syncope. At follow-up, assessments, including ECGs, were almost all normal. Among the three patients with possible ECG abnormalities, all their echocardiograms or treadmill testings were normal. Sixteen patients (57.1%) underwent treadmill testing at a median of 117 days post-admission, which were also normal. However, at follow-up, there was a significant mean bodyweight increase of 1.81kg (95%CI 0.47-3.1 kg, p=0.01), possibly due to exercise restriction. In conclusion, most adolescents experiencing myocarditis and pericarditis following BNT162b2 vaccination achieved complete recovery. Some patients developed non-specific persistent symptoms, and bodyweight changes shall be monitored

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Cathodal transcranial direct-current stimulation for treatment of drug-resistant temporal lobe epilepsy:A pilot randomized controlled trial

Objective: To investigate the effect of cathodal transcranial direct-current stimulation (c-tDCS) on seizure frequency in patients with drug-resistant temporal lobe epilepsy (TLE). Method: Twenty-nine patients with drug-resistant TLE participated in this study. They were randomized to experimental or sham group. Twenty participants (experimental group) received within-session repeated c-tDCS intervention over the affected temporal lobe, and nine (sham group) received sham tDCS. Paired-pulse transcranial magnetic stimulation was used to assess short interval intracortical inhibition (SICI) in primary motor cortex ipsilateral to the affected temporal lobe. SICI was measured from motor evoked potentials recorded from the contralateral first dorsal interosseous muscle. Adverse effects were monitored during and after each intervention in both groups. A seizure diary was given to each participant to complete for 4 weeks following the tDCS intervention. The mean response ratio was calculated from their seizure rates before and after the tDCS intervention. Results: The experimental group showed a significant increase in SICI compared to the sham group (F = 10.3, p = 0.005). None of the participants reported side effects of moderate or severe degree. The mean response ratio in seizure frequency was -42.14% (standard deviation [SD] 35.93) for the experimental group and -16.98% (SD 52.41) for the sham group. Significance: Results from this pilot study suggest that tDCS may be a safe and efficacious nonpharmacologic intervention for patients with drug-resistant TLE. Further evaluation in larger double-blind randomized controlled trials is warranted

Smad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma

TGF-β stimulated tumor-associated neutrophils (TANs) can exert pro-tumoral functions. Here the authors show that Smad3 activation in TANs is associated with an N2-like polarization state and poor outcome in patients with non-small cell lung carcinoma and that Smad3 targeting reprograms TANs to an antitumor state suppressing tumor growth in preclinical lung cancer models

Donor-Derived Genotype 4 Hepatitis E Virus Infection, Hong Kong, China, 2018

Hepatitis E virus (HEV) genotype 4 (HEV-4) is an emerging cause of acute hepatitis in China. Less is known about the clinical characteristics and natural history of HEV-4 than HEV genotype 3 infections in immunocompromised patients. We report transmission of HEV-4 from a deceased organ donor to 5 transplant recipients. The donor had been viremic but HEV IgM and IgG seronegative, and liver function test results were within reference ranges. After a mean of 52 days after transplantation, hepatitis developed in all 5 recipients; in the liver graft recipient, disease was severe and with progressive portal hypertension. Despite reduced immunosuppression, all HEV-4 infections progressed to persistent hepatitis. Four patients received ribavirin and showed evidence of response after 2 months. This study highlights the role of organ donation in HEV transmission, provides additional data on the natural history of HEV-4 infection, and points out differences between genotype 3 and 4 infections in immunocompromised patients