Margaret Jackson

The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial

BACKGROUND Carbamazepine is widely accepted as a drug of first choice for patients with partial onset seizures. Several newer drugs possess efficacy against these seizure types but previous randomised controlled trials have failed to inform a choice between these drugs. We aimed to assess efficacy with regards to longer-term outcomes, quality of life, and health economic outcomes. METHODS SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm A recruited 1721 patients for whom carbamazepine was deemed to be standard treatment, and they were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Primary outcomes were time to treatment failure, and time to 12-months remission, and assessment was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS For time to treatment failure, lamotrigine was significantly better than carbamazepine (hazard ratio [HR] 0.78 [95% CI 0.63-0.97]), gabapentin (0.65 [0.52-0.80]), and topiramate (0.64 [0.52-0.79]), and had a non-significant advantage compared with oxcarbazepine (1.15 [0.86-1.54]). For time to 12-month remission carbamazepine was significantly better than gabapentin (0.75 [0.63-0.90]), and estimates suggest a non-significant advantage for carbamazepine against lamotrigine (0.91 [0.77-1.09]), topiramate (0.86 [0.72-1.03]), and oxcarbazepine (0.92 [0.73-1.18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) is 0 (-8 to 7) and 5 (-3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine. INTERPRETATION Lamotrigine is clinically better than carbamazepine, the standard drug treatment, for time to treatment failure outcomes and is therefore a cost-effective alternative for patients diagnosed with partial onset seizures.

The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.

BACKGROUND Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. METHODS SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1.57 [95% CI 1.19-2.08]), but there was no significant difference between valproate and lamotrigine (1.25 [0.94-1.68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1.55 [1.07-2.24] and topiramate (1.89 [1.32-2.70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0.76 [0.62-0.94]), and for the subgroup with an idiopathic generalised epilepsy 0.68 (0.53-0.89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. INTERPRETATION Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

Multi-system neurological disease is common in patients with OPA1 mutations

Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal ‘dominant optic atrophy plus’ variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44–6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08–4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.

Population based, prospective study of the care of women with epilepsy in pregnancy

This prospective, population based study in the former Northern health region was designed to establish the proportion of pregnant women with a history of epilepsy; doctors supervising their care; effectiveness of preconceptional counselling and control of epilepsy; and use of medication and pregnancy outcomes. The project had approval from regional ethics committees. Pregnant women with epilepsy were recruited to the study, predominantly by community midwives. Women who consented were interviewed by using a standard questionnaire. Hospital notes were reviewed after the women had given birth. General practice and hospital notes were checked in one area to confirm the womens response regarding preconceptional advice. Between 1 January 1997 and 31 December 1998, 400 notifications of pregnancies to women with epilepsy were received (the total number of livebirths, stillbirths, and medical terminations for this period was 65 478, giving a proportion of all pregnancies to women with epilepsy of 6.1/1000). View this table: Malformations seen in relation to use of drugs Three hundred women were interviewed, 60 did not consent …

A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast

Whereas the majority of disease‐related mitochondrial DNA mutations exhibit significant biochemical and clinical heterogeneity, mutations within the mitochondrially encoded human cytochrome b gene (MTCYB) are almost exclusively associated with isolated complex III deficiency in muscle and a clinical presentation involving exercise intolerance. Recent studies have shown that a small number of MTCYB mutations are associated with a combined enzyme complex defect involving both complexes I and III, on account of the fact that an absence of assembled complex III results in a dramatic loss of complex I, confirming a structural dependence between these two complexes. We present the biochemical and molecular genetic studies of a patient with both muscle and brain involvement and a severe reduction in the activities of both complexes I and III in skeletal muscle due to a novel mutation in the MTCYB gene that predicts the substitution (Arg318Pro) of a highly conserved amino acid. Consistent with the dramatic biochemical defect, Western blotting and BN‐PAGE experiments demonstrated loss of assembled complex I and III subunits. Biochemical studies of the equivalent amino‐acid substitution (Lys319Pro) in the yeast enzyme showed a loss of enzyme activity and decrease in the steady‐state level of bc1 complex in the mutant confirming pathogenicity.

Biochemical and Molecular Studies of Mitochondrial Function in Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness

OBJECTIVE To determine if diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD) combined with a cerebellar syndrome is associated with a systemic disorder of respiratory chain function as found in similar genetic syndromes. CASE A muscle biopsy was taken from a patient with DIDMOAD, and a mitochondrial fraction was prepared. Respiratory chain function was assessed by analysis of intermediary metabolites, histochemical analysis of muscle biopsy, measurement of the activity of individual respiratory chain complexes, oxidative flux through the respiratory chain, and cytochrome concentration and compared with a population with normal respiratory chain function. Mitochondrial DNA from skeletal muscle, brain, and pancreas was examined for major rearrangements and specific point mutations. Brain tissue was examined neuropathologically for abnormalities, particularly those previously described in association with DIDMOAD. RESULTS No abnormality was found in mitochondrial oxidation, individual complex activity, or cytochrome concentration. Histochemical analysis and electron microscopy showed no abnormality known to be associated with mitochondrial dysfunction. A single-base substitution at position 12308 of the mitochondrial genome was found, but no major rearrangement of mitochondrial DNA was demonstrated. Neuropathological examination revealed severe demyelination and gliosis in the optic nerves and loss of Purkinje cells associated with gliosis in the white matter in the cerebellum. CONCLUSIONS We have found no evidence that DIDMOAD is associated with a systemic abnormality of respiratory chain function. The mitochondrial DNA single-base substitution noted is likely to be a polymorphism rather than a pathogenic point mutation. We have confirmed that DIDMOAD may be associated with a neurodegenerative disorder, but the cause of this remains undetermined.

Spectrum of movement disorders in neuroferritinopathy

Neuroferritinopathy is a recently recognized, dominantly inherited movement disorder caused by a mutation of the ferritin light chain gene. We present video case reports of 4 individuals with neuroferritinopathy chosen to illustrate how this disorder can present and subsequently progress clinically. The clinical phenotype of this disorder is highly variable with symptoms beginning in the third to sixth decades. Chorea, dystonia, or an akinetic‐rigid syndrome can predominate in different individuals. Neuroferritinopathy is not restricted to the UK and it has been described in apparently sporadic cases. The diagnosis should therefore be considered in patients with a wide variety of different movement disorders. Characteristic neuroimaging assists in identifying affected individuals.

Prevalence of active epilepsy in rural Tanzania: A large community-based survey in an adult population

PURPOSE To estimate the prevalence of active epilepsy in adults in an established demographic surveillance site in rural Tanzania. To describe the clinical characteristics of epilepsy and to estimate the treatment gap in this population. METHODS A pilot study established that a previously validated screening questionnaire was sensitive for detecting cases of epilepsy in a Kiswahili-speaking Tanzanian population. A door-to-door census of the adult population (total 103,026) used the screening questionnaire to identify possible cases of epilepsy, who were then assessed by a research doctor to establish a diagnosis of epilepsy or otherwise. The prevalence of active epilepsy in this population was estimated with age-standardisation to the WHO standard population. Seizure types and epilepsies were classified according to current recommendations of the International League Against Epilepsy. The treatment gap for epilepsy was estimated based on antiepileptic drug use as reported by cases. RESULTS Two hundred and ninety-one cases of active epilepsy, all with convulsive seizures, were identified. The age-standardised prevalence was 2.91/1000 adults (95% CI 2.58-3.24); the crude prevalence adjusted for non-response was 3.84/1000 adults (95% CI 3.45-4.20). Focal-onset seizures accounted for 71.5% of all cases identified. The treatment gap was 68.4% (95% CI 63.0-73.7). CONCLUSIONS This is one of the largest community-based studies of the prevalence of epilepsy in adults conducted in sub-Saharan Africa to date. We identified a lower prevalence than has previously been described in this region. The high proportion of focal onset seizures points to a large burden of acquired, and possibly preventable, epilepsy in this population. A treatment gap of 68.4% confirms that interventions to raise awareness of the treatable nature of epilepsy are warranted in this and similar populations.

Cortical blindness during left internal mammary angiography

Two cases of transient cortical blindness during coronary and graft angiography are described. In both cases, the onset of blindness was immediately preceded by manipulation of a guidewire in the left subclavian artery during attempts to selectively engage the internal mammary artery. Vertebral angiography was performed in the first patient and the appearances were compatible with multiple emboli in the posterior circulation. This patient was anticoagulated with intravenous heparin. His vision recovered within 72 h, but a mild visual agnosia persisted and it was only after nearly 3 weeks that all neurological deficits had resolved. The second patient recovered fully within 15 min. We postulate that emboli occurring as a result of manipulation of the guidewire close to the origin of the left vertebral artery was the cause of the cortical blindness in both these patients, although vasospasm as a contributory factor cannot be excluded. With an increasing need for investigation of patients after coronary artery bypass grafting, angiographers should be aware that selective internal mammary graft angiography may carry a higher than normal risk of neurological complications. The use of a guidewire to manipulate the catheter in the subclavian artery may increase this risk.

INSULIN AND PROINSULIN SECRETION IN SUBJECTS WITH ABNORMAL GLUCOSE TOLERANCE AND A MITOCHONDRIAL TRNALEU(UUR) MUTATION

(2). In a study about contraception and other reproductive issues in consecutively chosen women with type I diabetes (age 16-46 years) on intensified insulin therapy, we had the opportunity to evaluate the use of IUDs among a large group of young diabetic women (n = 808; age 31 ± 7 years; duration of diabetes 14 ± 5 years; mean ± SD [4]). Through a multiple-choice questionnaire, the women were asked about current and previous contraception, satisfaction with their contraceptive method, and duration of use. If they were using or had previously used an IUD, the women were asked if they had pain, increased menstrual or additional bleeding, accidental pregnancies, or a PID. There were 94 current users (age 32 [20-45] years, 70% nullipara, HbAlc 8.0 ± 1.7%) who had used the IUD for 5 (0.1-20) years, a cumulated use of 466 person-years. Of those, there were nine who indicated less than full satisfaction because of pain and/or bleeding. There were 33 ex-users who had used the IUD for 6 (0.5-16) years, a cumulated use of 146 personyears. Among those, there were two accidental pregnancies, three cases of PID, and twelve cases of bleeding and/or pain. If we combine users and ex-users, one can evaluate 612 person-years in 127 type I diabetic women. The rate of accidental pregnancies per 100 person-years is 0.3 (Pearl index), the rate of PID per 100 person-years is 0.5, and the rate of pain and/or bleeding per 100 person-years is 3.4. These results are well within the corresponding rates seen in large prospective studies of the use of modern copper IUDs in nondiabetic women (5).