Late-life terminal seizure freedom in drug-resistant epilepsy: "Burned-out epilepsy".

The course of established epilepsy in late life is not fully known. One key question is whether the resolution of an epileptic diathesis is a natural outcome in some people with long-standing epilepsy. We investigated this with a view to generating a hypothesis. We retrospectively explored whether terminal seizure-freedom occurs in older people with previous drug-resistant epilepsy at the Chalfont Centre for Epilepsy over twenty years. Of the 226 people followed for a median period of 52 years, 39 (17%) achieved late-life terminal seizure-freedom of at least two years before death, which occurred at a median age of 68 years with a median duration of 7 years. Multivariate analysis suggests that a high initial seizure frequency was a negative predictor (p < 0.0005). Our findings indicate that the 'natural' course of long-standing epilepsy in some people is one of terminal seizure freedom. We also consider the concept of "remission" in epilepsy, its definition challenges, and the evolving terminology used to describe the state of seizure freedom. The intersection of ageing and seizure freedom is an essential avenue of future investigation, especially in light of current demographic trends. Gaining mechanistic insights into this phenomenon may help broaden our understanding of the neurobiology of epilepsy and potentially provide targets for therapeutic intervention.

Is a separate clinical pathway for first seizures justified? Appraisal of the first seizure pathway at a tertiary neuroscience centre.

OBJECTIVES: To investigate the clinical characteristics, final diagnosis, investigation results, management, response to anti-seizure medications (ASMs) and clinical outcomes of individuals assessed in a First Seizure service over a 5-year period. METHODS: Retrospective analysis of 772 individuals who were clinically assessed in a dedicated First Seizure service at National Hospital for Neurology & Neurosurgery (NHNN), Queen Square over a 5-year period. RESULTS: 772 individuals were assessed following a suspected or reported first seizure (median age of 54, average age of 39.4, range 16-96). 393 (50.9 %) were ultimately diagnosed with a definite seizure of which 183 (46.5 %) had experienced seizures previously which had not been recognised or diagnosed. 250 (32 %) had vasovagal syncope and 69 (18.2 %) were diagnosed with psychogenic non-epileptic seizures. EEGs in 16.6 % of individuals who had a first unprovoked seizure demonstrated epileptiform discharges, whilst 33.6 % had abnormal MRI findings felt to be clinically relevant. CONCLUSIONS: Seizure mimics represent a significant proportion of attendees to a 'first seizure' service. Improved recognition and more education of this issue could facilitate earlier management of these other diagnostic entities and ensure that only appropriate cases are referred to the first seizure service. Almost half of 'first seizure' cases had previous seizures, highlighting the importance of obtaining this relevant history and in reviewing ASM-naive individuals in a timely manner with the primary aim of preventing further recurrences.

Effectiveness, retention, and safety of modified ketogenic diet in adults with epilepsy at a tertiary-care centre in the UK.

With the rising demand for ketogenic diet therapy in adult epilepsy, there is a need for research describing the real-life effectiveness, retention, and safety of relevant services. In this 1-year prospective cohort study we present outcomes of the first 100 referrals for modified ketogenic diet (MKD) at the UK's largest tertiary-care epilepsy centre, where patients received dietetic review up to twice per week. Of the first 100 referrals, 42 (31 females, 11 males; mean age 36.8 [SD ± 11.4 years]) commenced MKD, having used a mean of 4 (SD ± 3) previous antiepileptic drugs. Retention rates were: 60% at 3 months, 43% at 6 months, and 29% at 12 months. 60% of patients reported an improvement in seizure frequency, 38% reported a > 50% reduction, and 13% reported a period of seizure freedom; 30% reported a worsening in seizure frequency at some point during MKD therapy. The most common reasons for discontinuing MKD were side effects and diet restrictiveness. The most common side effects were weight loss, gastrointestinal symptoms and low mood. The likelihood of discontinuing MKD was significantly decreased by experiencing an improvement in seizure frequency (p ≤ 0.001). This study demonstrates that MKD can be effective in adults, although, even with regular dietetic support, retention rates remain low, and periods of worsening seizure frequency are common.

Haemorrhagic cerebral air embolism from an atrio-oesophageal fistula following atrial fibrillation ablation.

We report the case of a man found unconscious three weeks following atrial fibrillation (AF) ablation. Cranial and thoracic imaging demonstrated multiple areas of pneumo-embolic infarction secondary to an atrio-oesophageal fistula (AEF). AEF is a recognised, but rare, complication of AF ablation.(1-8) Early recognition is critical as the mortality is 100% without surgical intervention. We consider the postulated mechanisms of AEF formation, the spectrum of clinical presentation, investigations and treatment.

Muscle weakness, palpitations and a small chin: the Andersen-Tawil syndrome.

'Ion channelopathies' have emerged in the past decade as a new cause of several neurological diseases. These Mendelian disorders are caused by mutations in genes that encode ion channel subunits and are often characterised by paroxysmal attacks of brain or muscle dysfunction, interspersed with periods of clinical normality. Andersen-Tawil syndrome is one of the rarest and is characterised clinically by the triad of periodic paralysis, cardiac dysrhythmias and skeletal abnormalities. Mutations in a potassium channel gene, KCNJ2 which encodes the potassium channel, Kir2.1, underlie the disorder. Here, the authors describe a patient and review the clinical spectrum and genetic features of the disorder.

Nongenetic factors influence severity of episodic ataxia type 1 in monozygotic twins.

OBJECTIVE: Episodic ataxia type 1 (EA1) is a monogenic channelopathy caused by mutations of the potassium channel gene KCNA1. Affected individuals carrying the same mutation can exhibit considerable variability in the severity of ataxia, neuromyotonia, and other associated features. We investigated the phenotypic heterogeneity of EA1 in 2 sets of identical twins to determine the contribution of environmental factors to disease severity. One of the mutations was also found in a distantly related family, providing evidence of the influence of genetic background on the EA1 phenotype. METHODS: We evaluated 3 families with an EA1 phenotype, 2 of which included monozygotic twins. We sequenced the KCNA1 gene and studied the biophysical consequences of the mutations in HEK cells. RESULTS: We identified a new KCNA1 mutation in each pair of twins. Both pairs reported striking differences in the clinical severity of symptoms. The F414S mutation identified in one set of twins also occurred in a distantly related family in which seizures complicated the EA1 phenotype. The other twins had an R307C mutation, the first EA1 mutation to affect an arginine residue in the voltage-sensor domain. Both mutants when expressed exerted a dominant-negative effect on wild-type channels. CONCLUSION: These results broaden the range of KCNA1 mutations and reveal an unexpectedly large contribution of nongenetic factors to phenotypic variability in EA1. The occurrence of epilepsy in 1 of 2 families with the F414S mutation suggests an interplay of KCNA1 with other genetic factors.

Large scale calcium channel gene rearrangements in episodic ataxia and hemiplegic migraine: implications for diagnostic testing.

BACKGROUND: Episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are autosomal dominant disorders characterised by paroxysmal ataxia and migraine, respectively. Point mutations in CACNA1A, which encodes the neuronal P/Q-type calcium channel, have been detected in many cases of EA2 and FHM1. The genetic basis of typical cases without CACNA1A point mutations is not fully known. Standard DNA sequencing methods may miss large scale genetic rearrangements such as deletions and duplications. The authors investigated whether large scale genetic rearrangements in CACNA1A can cause EA2 and FHM1. METHODS: The authors used multiplex ligation dependent probe amplification (MLPA) to screen for intragenic CACNA1A rearrangements. RESULTS: The authors identified five previously unreported large scale deletions in CACNA1A in seven families with episodic ataxia and in one case with hemiplegic migraine. One of the deletions (exon 6 of CACNA1A) segregated with episodic ataxia in a four generation family with eight affected individuals previously mapped to 19p13. In addition, the authors identified the first pathogenic duplication in CACNA1A in an index case with isolated episodic diplopia without ataxia and in a first degree relative with episodic ataxia. CONCLUSIONS: Large scale deletions and duplications can cause CACNA1A associated channelopathies. Direct DNA sequencing alone is not sufficient as a diagnostic screening test.

Peutz-Jeghers syndrome associated with primary malignant melanoma of the rectum.

An 85-year-old Chinese woman was found to have mucocutaneous pigmentation involving the lips, buccal mucosa, hard palate and the buttocks when she presented with primary malignant melanoma of the rectum. Multiple brown-black pigmentation was also noted in the anal canal and the adjacent mucosa surrounding the tumour. This is the first report of Peutz-Jeghers syndrome associated with malignant melanoma of the rectum.

Cutaneous leishmaniasis in Sri Lanka. An imported disease linked to the Middle East and African employment boom.

Cutaneous leishmaniasis acquired by two Sri Lankan nationals while they were employed in Iraq and Northern Nigeria respectively constitutes examples of an imported disease related to the 'Middle East and African employment boom'. In both cases the diagnoses were confirmed by demonstrating the parasites in smears from the lesions and in tissue sections, and by culturing the parasites in vitro. Since leishmaniasis, neither visceral nor cutaneous is prevalent in Sri Lanka the risks of 'introduced' diseases is discussed here in the context of these two cases.

Acute hepatic failure precipitated in a patient with subclinical liver disease by vibrionic and clostridial septicemia.

A case of fatal septicemia caused by Vibrio vulnificus and Clostridium bifermentans in a patient with subclinical liver disease is described. The patient appeared to recover from the infection initially after antibiotic therapy but finally succumbed to rapidly developing hepatic failure. Postmortem examination revealed hemochromatosis. The pathogenesis of the polymicrobial septicemia and hepatic failure is discussed in the light of the published literature.