Mark Kellett

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.

Quality of life after epilepsy surgery

OBJECTIVE To assess the relation between seizure status and quality of life after surgery for drug resistant epilepsy, using a previously validated quality of life model developed for use in epilepsy. METHODS A retrospective postal survey was made on 94 patients who underwent surgery for epilepsy between 1986 and 1994, and 36 patients who after investigation during the same period were found to be unsuitable for surgery. A health related quality of life model was used containing validated measures of anxiety, depression, self esteem, mastery, impact of epilepsy, affect balance, stigma, overall health status, and overall quality of life, to examine the relation between postoperative seizure status and quality of life. RESULTS Overall 47.9% of patients were seizure free after surgery. On all measures seizure free patients scored significantly better than either patients deemed unsuitable for surgery or those having more than 10 seizures per year after surgery. Patients having less than 10 seizures per year obtained intermediate scores. There was no difference between the groups unsuitable for surgery or having more than 10 seizures per year postoperatively. Employment rates were significantly different between groups, 80% of seizure free and 53% of patients having less than 10 seizures per year in gainful employment postoperatively, compared with 28% and 27% of patients having greater than 10 seizures per year or those who were unsuitable for surgery. CONCLUSIONS Within broad categories, postoperative quality of life is clearly related to seizure outcome, but the study emphasises the importance of long term follow up in defining the tangible psychosocial effects of freedom from seizures.

Topiramate in clinical practice: first year's postlicensing experience in a specialist epilepsy clinic.

OBJECTIVE Topiramate became available for use in October 1995. Meta-analysis of its randomised controlled data suggested that it may be the most potent of the new antiepileptic drugs. The aim of this study was to assess the first year’s postlicensing experience in a specialist regional epilepsy clinic. METHODS The case notes of 174 of 178 patients who were prescribed topiramate in the 12 months between November 1995 and October 1996 were retrospectively reviewed. Data were collected on seizure type, classification of epilepsy, presence or absence of learning difficulties, depression, or behavioural problems, co-medication, dosage escalation, efficacy, adverse events, whether or not the patient was still on topiramate and, if not, the reason for withdrawal. Kaplan-Meier survival analysis was used to estimate the overall retention rate and log rank tests were used to determine factors associated with stopping topiramate. RESULTS Overall 90 of 174 patients had ceased taking topiramate at the end of the study. The median “survival time” was 427 days (95% CI 362.9–491.1). The cumulative probability for remaining on topiramate at 1 year was 0.549 (95% CI 0.475–0.623). The retention rate in patients in whom topiramate was substituted for another drug was significantly higher than in those in whom it was added to current therapy. Adverse events (CNS related) were the most common reason for stopping topiramate. Eight patients with partial and one patient with juvenile myoclonic epilepsy became seizure free. CONCLUSIONS There is a significant (20–25%) chance of being intolerant to topiramate at relatively low doses. Substituting topiramate for another antiepileptic drug may reduce the chances of drug withdrawal. If topiramate is tolerated there is a good chance of worthwhile improvement in seizure control. These data, although not derived from randomised controlled trials, represent pragmatic use of novel antiepileptic drugs in “real life” and may be helpful to non-specialists when prescribing topiramate.

Characterization of Corticobulbar Pharyngeal Neurophysiology in Dysphagic Patients With Parkinson's Disease

BACKGROUND & AIMS Dysphagia in patients with Parkinsons disease, persisting despite dopaminergic treatment, affects intake of nutrients and medication, and reduces quality of life (QOL). We investigated the neurophysiologic mechanisms that contribute to dysphagia in these patients, on and off L-3,4-dihydroxyphenylalanine (levodopa), using transcranial magnetic stimulation. METHODS We studied 26 patients with Parkinsons disease (age, 65 ± 9 y; 10 men). Dysphagia and QOL were first assessed with qualitative questionnaires. Twelve hours after patients were taken off levodopa, they underwent cortical transcranial magnetic stimulation mapping of the pharyngeal musculature and trigeminal (bulbar) transcranial magnetic stimulation, as well as videofluoroscopy to examine swallowing. The analyses were repeated after administration of levodopa. RESULTS Eleven patients initially reported dysphagia and reduced QOL scores. Videofluoroscopy identified 10 patients with swallowing impairments on and off levodopa, and 6 patients with swallowing impairments only on levodopa; the remaining 10 subjects showed no swallowing impairments, on or off the drug. While patients were on levodopa, those with swallowing impairments had bilateral increases in pharyngeal cortical excitability compared with those with no swallowing impairment (P < .05). By contrast, with medication, amplitudes of brainstem reflexes were altered only in patients with swallowing impairments on levodopa; these were decreased compared with when the patients were off levodopa. CONCLUSIONS In patients with Parkinsons disease, dopaminergic medications such as levodopa can negatively affect swallowing. The increased cortical excitability observed in dysphagic patients after they begin taking levodopa likely results from compensatory mechanisms, perhaps secondary to subcortical disease, because we observed associated inhibition of brainstem reflexes in patients with affected swallowing on medication. UK clinical trials registration no., 9882.

The effect of gym training on multiple outcomes in Parkinson's disease: A pilot randomised waiting-list controlled trial

There is accumulating evidence for the benefits of exercise in Parkinsons disease (PD), but less is known about group exercise interventions. We evaluated the effect of gym-training programme on people with PD. Thirty-two adults with mild to moderate PD, not currently exercising formally, were randomised to an immediate 20-week biweekly gym training programme at a local leisure complex, or a 10-week programme starting 10 weeks later. Assessments at baseline (T1), 10 weeks (T2) and 20 weeks (T3) included reaction time, motor performance (UPDRS), quality of life and illness perceptions. Experiences of the programme were assessed via questionnaire and a focus group. Overall UPDRS motor function score did not change over time. However, gym training was associated with significant improvements in reaction times and some timed tests in the immediate training group (T1-T2). The delayed group showed similar improvements following gym training (T2-T3). Participants reported enjoyment, obtaining social benefits, and increased confidence. However, the questionnaire measures did not show improvements in subjective health ratings or illness perceptions. Although benefits were not apparent in the questionnaire measures or overall UPDRS scores, our findings suggest that a 10-week gym training programme in a community setting can provide some benefits for people with PD.

The response of spinal cord ependymomas to bevacizumab in patients with neurofibromatosis Type 2

OBJECTIVE People with neurofibromatosis Type 2 (NF2) have a genetic predisposition to nervous system tumors. NF2-associated schwannomas stabilize or decrease in size in over half of the patients while they are receiving bevacizumab. NF2 patients treated with bevacizumab for rapidly growing schwannoma were retrospectively reviewed with regard to ependymoma prevalence and response to treatment. METHODS The records of 95 NF2 patients receiving bevacizumab were retrospectively reviewed with regard to spinal ependymoma prevalence and behavior. The maximum longitudinal extent (MLE) of the ependymoma and associated intratumoral or juxtatumoral cysts were measured on serial images. Neurological changes and patient function were reviewed and correlated with radiological changes. RESULTS Forty-one of 95 patients were found to have ependymomas (median age 26 years; range 11-53 years). Thirty-two patients with a total of 71 ependymomas had scans appropriate for serial assessment with a mean follow-up of 24 months (range 3-57 months). Ependymomas without cystic components showed minimal change in MLE. Twelve patients had ependymomas with cystic components or syringes. In these patients, reductions in MLE were observed, particularly due to decreases in the cystic components of the ependymoma. Clinical improvement was seen in 7 patients, who all had cystic ependymomas. CONCLUSIONS Bevacizumab treatment in NF2 patients with spinal cord ependymomas results in a decrease in the size of intratumoral and juxtatumoral cysts as well as adjacent-cord syringes and a decrease in cord edema. This may provide clinical benefit in some patients, although the changes do not meet the current criteria for radiological tumor response.

Schwannomatosis: a genetic and epidemiological study

Objectives Schwannomatosis is a dominantly inherited condition predisposing to schwannomas of mainly spinal and peripheral nerves with some diagnostic overlap with neurofibromatosis-2 (NF2), but the underlying epidemiology is poorly understood. We present the birth incidence and prevalence allowing for overlap with NF2. Methods Schwannomatosis and NF2 cases were ascertained from the Manchester region of England (population=4.8 million) and from across the UK. Point prevalence and birth incidence were calculated from regional birth statistics. Genetic analysis was also performed on NF2, LZTR1 and SMARCB1 on blood and tumour DNA samples when available. Results Regional prevalence for schwannomatosis and NF2 were 1 in 126 315 and 50 500, respectively, with calculated birth incidences of 1 in 68 956 and 1 in 27 956. Mosaic NF2 causes a substantial overlap with schwannomatosis resulting in the misdiagnosis of at least 9% of schwannomatosis cases. LZTR1-associated schwannomatosis also causes a small number of cases that are misdiagnosed with NF2 (1%–2%), due to the occurrence of a unilateral vestibular schwannoma. Patients with schwannomatosis had lower numbers of non-vestibular cranial schwannomas, but more peripheral and spinal nerve schwannomas with pain as a predominant presenting symptom. Life expectancy was significantly better in schwannomatosis (mean age at death 76.9) compared with NF2 (mean age at death 66.2; p=0.004). Conclusions Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

Novel PTEN mutation with leukoencephalopathy, basal ganglia calcification and action tremor

A 36-year-old security officer presented with a 2.5-year history of left upper limb tremor, which worsened on pouring water. There was no slowing of movements, lower limb tremor, or improvement with alcohol. His four-year-old daughter was born prematurely and had been investigated for developmental delay in walking after her 2nd birthday, general clumsiness/dyspraxia and macrocephaly. Examination of the proband revealed relative macrocephaly (head circumference 98th centile), mild dystonic posturing and position-specific left upper limb action tremor. There was no evidence of Kayser-Fleischer rings, cervical dystonia, or bradykinesia. Neurological examination was otherwise normal. Thyroid function tests, parathyroid hormone and 24 hour urinary copper were normal. White cell enzymes and urinary organic acids were negative. Magnetic resonance imaging (MRI) of the brain revealed bilateral confluent deep white matter T2 hyperintensity (Fig. 1A, C). MRI in the probands daughter revealed similar white matter abnormalities (Fig. 1EeF). Gradient echo sequences showed low signal changes in the proband consistent with mineralisation of the globus pallidus bilaterally, confirmed on CT brain to be calcification (Fig. 1B, D). Genetic testing confirmed that the proband and his daughter were heterozygous for c.809T > C p. mutation in exon 8 of the PTEN gene, predicted to result in a substitution of a highly conserved amino acid (Methionine270 to Threonine). In silico analysis (supplementary material) suggests this substitution will be damaging to the PTEN protein. The PTEN hamartoma tumour syndromes (PHTS) are characterised by cellular overgrowth due tomutations in the PTEN (phosphatase and tensin homolog) gene. PTEN is a tumour suppressor gene, localised to chromosome 10q22-23, which encodes a lipid phosphatase that regulates cellular proliferation and apoptosis via the phosphoinositol-3-kinase/Akt pathway [1]. Impaired PTEN function, due to gene deletion, mutation or methylation, activates this pathway, thereby enhancing cellular proliferation [1]. PTEN mutations have been implicated in various malignancies, including brain, lung, colorectal, thyroid, bladder, kidney, prostate, breast

“Reverse Hoover's sign” demonstrated by neurophysiology in a patient with functional dystonia

A 36 year-old man presented with sudden onset of abnormal painful posturing of the left lower limb, worsening over seven years and exacerbated by walking. There were no obvious underlying psychological stressors. Aside from psoriasis, there was no other medical history. He described sudden exacerbations and remissions of the movements, which could last several months. Botulinum toxin injections to tibialis anterior and extensor hallucis were of limited and short-lived benefit. Examination revealed a fixed deformity of the left foot, which was held rigid at the ankle. This abnormality was fully reversible during examination under spinal anaesthesia. His symptoms further evolved over the following year, with ongoing painful movements of the left and right lower limbs, involving prolonged hip flexion movements, and fixed flexion of the left upper limb, with more subtle posturing of the right upper limb (video clip 1). The movements persisted on walking, with features of a “magnetic gait” and toe-walking (video clip 2). He was referred for neurophysiological studies to further examine his movement disorder and to exclude neurophysiological features of stiff person syndrome. Anti-GAD antibodies were negative. Supplementary video related to this article can be found at