Anthony L. Johnson

Mortality from epilepsy : results from a prospective population-based study

Patients with epilepsy may be subject to an increased risk of premature death from the underlying cause, or from the epilepsy itself. The extent and nature of this risk has been insufficiently investigated. Standard mortality ratios (SMRs) of patients with newly diagnosed epilepsy were determined in a prospective national population-based study. 1091 patients with newly diagnosed or suspected epilepsy were ascertained who were attending one of 275 UK general practices from 1984-1987. 1091 patients were classified after 6 months as definite epilepsy (564), possible epilepsy (228), febrile seizures (220), or not epilepsy (79). Over a median follow up of 6.9 years the SMR for patients with definite or possible epilepsy was 2.5 (95% CI 2.1-2.9), and 3.0 (2.5-3.7) for definite epilepsy. The SMR was highest during the first year after diagnosis 5.1 (3.8-6.5), declined to 2.5 (1.5-3.9) at 3 years, and 1.3 (0.7-2.0) at 5 years. The commonest causes of death were pneumonia (SMR 7.2), cancer (3.5), and stroke (3.7). The SMR for patients with idiopathic epilepsy was 1.6 (1.0-2.4), remote symptomatic epilepsy 4.3 (3.3-5.5), and acute symptomatic epilepsy 2.9 (1.7-4.5). Mortality in patients with newly-diagnosed epilepsy was high, mainly due to the underlying cause. The SMR for idiopathic epilepsy was also raised, suggesting that epilepsy per se may carry a small risk of death.

National general practice study of epilepsy : newly diagnosed epileptic seizures in a general population

The National General Practice Study of Epilepsy is a prospective population-based cohort study of 1195 patients with newly diagnosed or suspected epileptic seizures. At the time of initial classification (6 months after notification), 104 patients were excluded. Of the remaining 1091 patients, 220 (20% [95% confidence interval 18-23%]) had febrile seizures, 564 (52% [49-55%]) definite epileptic seizures, and 228 (21% [19-23%]) possible epilepsy. In the definite epilepsy group the proportions of males and females were similar, 25% (21-28%) were younger than 15 years and 24% (21-28%) were 60 years or older. The definite seizures were classified as cryptogenic in 62% (58-66%), remote symptomatic in 21% (18-25%), and acute symptomatic in 15% (12-18%). The aetiology of epilepsy was vascular disease in 15% (12-18%) and tumour in 6% (4-8%). Among older subjects the proportion with an identifiable cause was much higher: 49% (41-58%) were due to vascular disease and 11% (6-16%) to tumour. Only 252 (45% [41-49%]) of the 564 patients with definite epileptic seizures were registered at the time of their first seizure. 52% (48-56%) of the patients had partial or secondarily generalised seizures, and only 39% (35-43%) seizures generalised from the outset.

Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial

BACKGROUND The relative risks and benefits of starting or withholding antiepileptic drug treatment in patients with few or infrequent seizures are unclear. We sought to compare policies of immediate versus deferred treatment in such patients and to assess the effects of these policies on short-term recurrence and long-term outcomes. METHODS We undertook an unmasked, multicentre, randomised study of immediate and deferred antiepileptic drug treatment in 1847 patients with single seizures and early epilepsy. Outcomes comprised time to first, second, and fifth seizures; time to 2-year remission; no seizures between years 1 and 3 and between years 3 and 5 after randomisation; and quality of life. Analysis was by intention to treat. FINDINGS 404 patients invited to join the trial did not consent to randomisation; 722 were subsequently assigned immediate treatment with antiepileptic drugs and 721 were assigned deferred treatment. Immediate treatment increased time to first seizure (hazard ratio 1.4 [95% CI 1.2 to 1.7]), second seizure (1.3 [1.1 to 1.6]), and first tonic-clonic seizure (1.5 [1.2 to 1.8]). It also reduced the time to achieve 2-year remission of seizures (p=0.023). At 5-years follow-up, 76% of patients in the immediate treatment group and 77% of those in the deferred treatment group were seizure free between 3 and 5 years after randomisation (difference -0.2% [95% CI -5.8% to 5.5%]). The two policies did not differ with respect to quality of life outcomes or serious complications. INTERPRETATION Immediate antiepileptic drug treatment reduces the occurrence of seizures in the next 1-2 years, but does not affect long-term remission in individuals with single or infrequent seizures.

Randomised study of antiepileptic drug withdrawal in patients in remission

A prospective multicentre randomised study of continued antiepileptic treatment vs slow withdrawal was conducted in 1013 patients who had been free of seizures for at least 2 years. Comparison of randomised and eligible, but non-randomised, patients suggests the results should be applicable to a wider patient population. By 2 years after randomisation, 78% of patients in whom treatment was continued and 59% of those in whom it was withdrawn remained seizure free, but thereafter the differences between the two groups diminished. Non-compliance with continued treatment accounted for only a small proportion of the risk to the group continuing with treatment. The most important factors determining outcome were longer seizure-free periods (reducing the risk) and more than one antiepileptic drug and a history of tonic-clonic seizures (increasing the risk). Other factors (eg, history of neonatal seizures, specific electroencephalographic features) seemed to have smaller effects, but even in such a large study the confidence intervals for these observations were wide.

Mortality in epilepsy in the first 11 to 14 years after diagnosis: Multivariate analysis of a long-term, prospective, population-based cohort

The United Kingdom National General Practice Study of Epilepsy is a prospective, population‐based study of newly diagnosed epilepsy. A cohort of 792 patients has now been followed for up to 14 years (median follow‐up [25th, 75th percentiles] 11.8 years, range 10.6–11.7 years), a total of 11,400 person‐years. These data are sufficient for a detailed analysis of mortality in this early phase of epilepsy. Over 70% of patients in this cohort have developed lasting remission from seizures, although the mortality rate in the long term was still twice that of the general population. The standardized mortality ratio (SMR), the number of observed deaths per number of expected deaths, was 2.1 (95% confidence interval [CI] = 1.8, 2.4). Patients with acute symptomatic epilepsy (SMR 3.0; 95% CI = 2.0, 4.3), remote symptomatic epilepsy (SMR 3.7; 95% CI = 2.9, 4.6), and epilepsy due to congenital neurological deficits (SMR 25; 95% CI = 5.1, 73.1) had significantly increased long‐term mortality rates, whereas patients with idiopathic epilepsy did not (SMR 1.3; 95% CI = 0.9, 1.9). This increase in mortality rate was noted particularly in the first few years after diagnosis. Multivariate Cox regression and time‐dependent co‐variate analyses were utilized for the first time in a prospective study of mortality in epilepsy. The former showed that patients with generalized tonic‐clonic seizures had an increased risk of mortality. The hazard ratio (HR), or risk of mortality in a particular group with a particular risk factor compared to another group without that particular risk factor, was 6.2 (95% CI = 1.4, 27.7; p = 0.049). Cerebrovascular disease (HR 2.4; 95% CI = 1.7, 3.4; p < 0.0001), central nervous system tumor (HR 12.0; 95% CI = 7.9, 18.2; p < 0.0001), alcohol (HR 2.9; 95% CI = 1.5, 5.7; p = 0.004), and congenital neurological deficits (HR 10.9; 95% CI = 3.2, 36.1; p = 0.003) as causes for epilepsy and older age at index seizure (HR 1.9; 95% CI = 1.7,2.0; p < 0.0001) were also associated with significantly increased mortality rates. These hazard ratios suggest that epilepsy due to congenital neurological deficits may carry almost the same risk of mortality as epilepsy due to central nervous system tumors and that epileptic seizures subsequent to alcohol abuse may carry almost the same risk of mortality as epilepsy due to cerebrovascular disease. The occurrence of one or more seizures before the index seizure (the seizure that led to the diagnosis of epilepsy and enrolment in the study) was associated with a significantly reduced mortality rate (HR 0.57; 95% CI = 0.42, 0.76; p = 0.00001). Time‐dependent co‐variate analysis was used to examine the influence of ongoing factors, such as seizure recurrence, remission, and antiepileptic drug use, on mortality rates in the cohort. Seizure recurrence (HR 1.30; 95% CI = 0.84, 2.01) and antiepileptic drug treatment (HR 0.97; 95% CI = 0.67, 1.38) did not influence mortality rate. There were only 5 epilepsy‐related deaths (1 each of sudden unexpected death in epilepsy, status epilepticus, burns, drowning, and cervical fracture), suggesting that death directly due to epileptic seizures is uncommon in a population‐based cohort with epilepsy. Ann Neurol 2001;49:336–344

Screening of Maternal Serum for Fetal Down's Syndrome in the First Trimester

BACKGROUND Screening of maternal serum to identify fetuses with Downs syndrome is now routinely offered during the second trimester of pregnancy. Prenatal screening by means of serum assays or ultrasonographic measurements, either alone or in combination, may also be possible in the first trimester. METHODS We measured serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin (hCG), the free beta subunit of hCG, and pregnancy-associated protein A in 4412 women (82 percent of whom were 35 years of age or older) who came to 16 prenatal diagnostic centers for chorionic-villus sampling or early amniocentesis at 9 to 15 weeks of gestation. Ultrasound measurements of fetal nuchal translucency were also reported. Fetal chromosomal analysis was performed in all pregnancies. Altogether, there were 61 fetuses with Downs syndrome. RESULTS A total of 48 pregnancies affected by Downs syndrome and 3169 unaffected pregnancies were identified before 14 weeks of gestation; the rates of detection of Downs syndrome for the five serum markers were as follows: 17 percent for alpha-fetoprotein, 4 percent for unconjugated estriol, 29 percent for hCG, 25 percent for the free beta subunit of hCG, and 42 percent for pregnancy-associated protein A, at false positive rates of 5 percent. The results of the measurements of serum hCG and its free beta subunit were highly correlated. When used in combination with the serum concentration of pregnancy-associated protein A and maternal age, the detection rate was 63 percent for hCG (95 percent confidence interval, 47 to 76 percent) and 60 percent for its free beta subunit (95 percent confidence interval, 45 to 74 percent). Measurements of nuchal translucency varied considerably between centers and could not be reliably incorporated into our calculations. CONCLUSIONS Screening for Downs syndrome in the first trimester is feasible, with use of measurements of pregnancy-associated protein A and either hCG or its free beta subunit in maternal serum.

Coordinated regulation of gene expression by the cell cycle transcription factor SWI4 and the protein kinase C MAP kinase pathway for yeast cell integrity

Specific transcription in late G1, mediated by the transcription factors SBF (Swi4p‐Swi6p) and MBF (Mbp1p‐Swi6p), is crucial for cell cycle progression in budding yeast. In order to better understand the G1/S transition, we initiated a search for conditional mutations synthetic lethal with swi4delta. One of the isolated mutants, rsf8swi4delta, showed a growth defect due to cell lysis. rsf8 is allelic to PKC1, encoding a protein kinase C homologue which controls cell integrity. In the presence of the rsf8/(pkc1–8) mutation, a functional SBF but not MBF is required for viability. Importantly, swi4delta and swi6delta strains are hypersensitive to calcofluor white and SDS, indicating that they possess a weakened cell wall. Overexpression or ectopic expression of CLN did not suppress the pkc1–8swi4delta mutant phenotype, thus SBF must control cell integrity independently, rather than acting through CLN expression. We found that at least six genes involved in cell wall biosynthesis are periodically expressed at the G1/S phase boundary. In all six cases, cell cycle‐regulated expression is due mainly to Swi4p. Finally, we found that the PKC1 MAP kinase pathway is a positive regulator of five of these cell wall genes, these genes being novel targets of regulation by this pathway. We suggest that SBF and the PKC1 MAP kinase pathway act in concert to maintain cell integrity during bud formation.

Prognosis of epilepsy : A review and further analysis of the first nine years of the British National General Practice Study of Epilepsy, a prospective population-based study

Summary: Purpose: To understand the prognosis of newly diagnosed epilepsy to provide rational therapy and advice for patients and their physicians.

The Prognosis for Seizure Control in Newly Diagnosed Epilepsy

We assessed the prognosis for seizure control in 106 patients who were referred to an adult neurology clinic with previously untreated tonic-clonic, partial, or mixed seizures and were followed prospectively for a median of 66 months (range, 6 to 96). Twenty-six patients remained completely free of seizures for as long as they were followed. Actuarial analysis showed that 35 per cent of patients could be expected to enter a seizure-free period of at least two years at the start of treatment, 73 per cent would have had a two-year seizure-free period at the end of four years, and 82 per cent would have had a two-year seizure-free period at the end of eight years. Of 79 patients whose seizures were completely controlled for at least two years, 51 subsequently remained seizure-free. If seizures continued for up to two years after the start of treatment, the probability of subsequent seizure control fell by half. The presence of partial seizures; a high frequency of tonic-clonic seizures before treatment; a neurologic, social, or psychiatric handicap; and a family history of epilepsy each indicated a worse prognosis. We conclude that the long-term pattern of seizure control is largely established during the first two years of treatment.

The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial

BACKGROUND Infantile spasms is a severe infantile seizure disorder that is difficult to treat and has a high morbidity. Absence of spasms on days 13 and 14 after randomisation is more common in infants allocated hormone treatments than in those allocated vigabatrin. We sought to assess whether early control of spasms is associated with improved developmental or epilepsy outcomes. METHODS Infants enrolled in the United Kingdom Infantile Spasms Study (UKISS) were randomly assigned hormone treatment (n=55) or vigabatrin (n=52) and were followed up until clinical assessment at 12-14 months of age. We assessed neurodevelopment with the Vineland adaptive behaviour scales (VABS) at 14 months of age on an intention to treat basis. FINDINGS Of 107 infants enrolled, five died and 101 survivors reached both follow-up assessments. Absence of spasms at final clinical assessment (hormone 41/55 [75%] vs vigabatrin 39/51 [76%]) was similar in each treatment group (difference 1.9%, 95% CI -18.3% to 14.4%; chi(2)=0.05; p=0.82). Mean VABS score did not differ significantly (hormone 78.6 [SD 16.8] vs vigabatrin 77.5 [SD 12.7]; difference 1.0, 95% CI -4.9 to 7.0; t(99)=0.35, p=0.73). In infants with no identified underlying aetiology, the mean VABS score was higher in those allocated hormone treatment than in those allocated vigabatrin (88.2 [17.3] vs 78.9 [14.3]; difference 9.3, 95% CI 1.2 to 17.3; t(95)=2.28, p=0.025). INTERPRETATION Hormone treatment controls spasms better than does vigabatrin initially, but not at 12-14 months of age. Better initial control of spasms by hormone treatment in those with no identified underlying aetiology may lead to improved developmental outcome.