Decreasing the risk of sudden unexpected death in epilepsy: structured communication of risk factors for premature mortality in people with epilepsy.

BACKGROUND AND PURPOSE: Good practice guidelines highlight the importance of making people with epilepsy aware of the risk of premature mortality in epilepsy particularly due to sudden unexpected death in epilepsy (SUDEP). The SUDEP and Seizure Safety Checklist ('Checklist') is a structured risk communication tool used in UK clinics. It is not known if sharing structured information on risk factors allows individuals to reduce SUDEP and premature mortality risks. The aim of this study was to ascertain if the introduction of the Checklist in epilepsy clinics led to individual risk reduction. METHODS: The Checklist was administered to 130 consecutive people with epilepsy attending a specialized epilepsy neurology clinic and 129 attending an epilepsy intellectual disability (ID) clinic within a 4-month period. At baseline, no attendees at the neurology clinic had received formal risk advice, whereas all those attending the ID clinic had received formal risk advice on multiple occasions for 6 years. The Checklist was readministered 1 year later to each group and scores were compared with baseline and between groups. RESULTS: Of 12 risk factors considered, there was an overall reduction in mean risk score for the general (P = 0.0049) but not for the ID (P = 0.322) population. Subanalysis of the 25% of people at most risk in both populations showed that both sets had a significant reduction in risk scores (P < 0.001). CONCLUSION: Structured discussion results in behavioural change that reduces individual risk factors. This impact seems to be higher in those who are at current higher risk. It is important that clinicians share risk information with individuals as a matter of public health and health promotion.

Extra-hepatic manifestations of autochthonous hepatitis E infection.

BACKGROUND: Autochthonous (locally acquired) hepatitis E is increasingly recognised in developed countries, and is thought to be a porcine zoonosis. A range of extra-hepatic manifestations of hepatitis E infection have been described, but have never been systematically studied. AIM: To report the extra-hepatic manifestations of hepatitis E virus. METHODS: Retrospective review of data of 106 cases of autochthonous hepatitis E (acute n = 105, chronic n = 1). RESULTS: Eight (7.5%) cases presented with neurological syndromes, which included brachial neuritis, Guillain-Barré syndrome, peripheral neuropathy, neuromyopathy and vestibular neuritis. Patients with neurological syndromes were younger (median age 40 years, range 34-92 years, P = 0.048) and had a more modest transaminitis (median ALT 471 IU/L, P = 0.015) compared to cases without neurological symptoms [median age 64 years (range 18-88 years), median ALT 1135 IU/L]. One patient presented with a cardiac arrhythmia,twelve patients (11.3%) presented with thrombocytopenia, fourteen (13.2%) with lymphocytosis and eight (7.5%) with a lymphopenia, none of which had any clinical consequence. Serum electrophoresis was performed in 65 patients at presentation, of whom 17 (26%) had a monoclonal gammopathy of uncertain significance. Two cases developed haematological malignancies, acute myeloid leukaemia and duodenal plasmacytoma, 18 and 36 months after presenting with acute hepatitis E infection. CONCLUSIONS: A range of extra-hepatic manifestations can occur with hepatitis E. Neurological and haematological features of hepatitis E infection are relatively frequent in this UK cohort, and result in significant morbidity which warrants further study.

Campath 1-H treatment in patients with aggressive relapsing remitting multiple sclerosis.

Campath 1-H (Alemtuzumab) is a humanised monoclonal antibody which targets the CD52 antigen, a low molecular weight glycoprotein present on the surface of most lymphocyte lineages, causing complement mediated lysis and rapid and prolonged T lymphocyte depletion. Following encouraging initial data from other centres we report our open label experience of using Campath 1-H as a treatment in aggressive relapsing multiple sclerosis in a consecutive series of 39 highly selected patients treated across three regional centres and followed for a mean of 1.89 years. The mean annualised relapse rate fell from 2.48 pre treatment to 0.19 post treatment with 29% of documented relapses observed in the 12 weeks following initial infusion. Mean change in EDSS was -0.36 overall and -0.15 in those patients completing > or =1 year of follow- up. Eighty-three per cent of patients had stable or improved disability following treatment. Infusion related side effects were common including rash, headache and pyrexia but were usually mild and self limiting. Transient worsening of pre-existing neurological deficits during infusion was observed in 3 patients. 12 patients developed biochemical evidence of autoimmune dysfunction, 2 patients developed thyroid disease and 1 patient autoimmune skin disease. We conclude that relapse rates fall following Campath 1-H. Whilst side effects were common these were normally self limiting or easily managed, suggesting Campath 1-H may be of use in the treatment of very active relapsing remitting multiple sclerosis.

Sudden death in epilepsy recorded in ambulatory EEG.

A woman with epilepsy died during a seizure and the event was recorded on ambulatory EEG. The circumstances were typical of sudden death in epilepsy (SUDEP). The EEG revealed that the patient had suffered a generalised seizure that abruptly ended with cessation of all cerebral electrical activity. Two other cases recorded on videotelemetry demonstrating similar EEG features were reported in the literature. We postulate that abrupt irreversible cerebral electrical shutdown during a seizure may be the primary mechanism of SUDEP.

Allgrove or 4 "A" syndrome: an autosomal recessive syndrome causing multisystem neurological disease.

Allgrove's or "4 A" syndrome is a rare autosomal recessive condition with alacrima, achalasia, autonomic disturbance, and ACTH insensitivity among other features. Recent studies have identified mutations in the AAAS, a candidate gene on chromosome 12q13 in such patients. Manifestations in adult patients are rarely reported. The syndrome usually presents during the first decade of life with dysphagia or severe (occasionally fatal) hypoglycaemic or hypotensive attacks, related to adrenocortical insufficiency. Onset of adrenal insufficiency or other features may be delayed to adulthood. In contrast with paediatric patients, adult patients with Allgrove's syndrome may present with multisystem neurological disease; the childhood history of achalasia or alacrima may be overlooked. The authors describe two families with two affected siblings and a further unrelated patient with typical clinical features of Allgrove's syndrome, who exhibit signs of multisystem neurological disease including hyperreflexia, muscle wasting, dysarthria, ataxia, optic atrophy, and intellectual impairment. None of the cases have developed adrenal insufficiency but all have progressive neurological disability. Autonomic dysfunction was a significant cause of morbidity in two cases. The three index cases represent the longest described follow up of Allgrove's syndrome into adulthood. It is speculated that they represent a subgroup of patients who follow an often undiagnosed chronic neurological course. Recognition of the syndrome presenting in adult life permits treatment of unrecognised autonomic dysfunction, adrenal insufficiency and dysphagia, and appropriate genetic advice.

A new defect of peroxisomal function involving pristanic acid: a case report.

AN adult onset novel disorder of peroxisomal function is described, characterised by retinitis pigmentosa resulting in progressive visual failure, learning difficulties, a peripheral neuropathy, and hypogonadism. The defect results in accumulation of pristanic acid, and the bile acid intermediates, dihydroxycholestanoic and trihydroxycholestanoic acid, and is due to a deficiency of alpha-methylacyl-CoA racemase, making this the first fully characterised description of this defect. Screening of patients with retinitis pigmentosa should be extended to include pristanic acid and/or bile acid intermediate concentrations, as dietary measures offer a potential treatment for the disorder.

Local synthesis of IgA in the cerebrospinal fluid of patients with neurological diseases.

To date qualitative studies of IgA in the cerebrospinal fluid in neurological disease, particularly multiple sclerosis, have been few and given mixed results. The aim of this study was to identify local synthesis of IgA by detection of clonal IgA bands, in a large cohort of patients with a variety of neurological disorders, using polyacrylamide gel electrophoresis, transfer of protein to nitrocellulose membranes and specific staining. Of 2,097 sequentially analysed patients with suspected neurological disease 54 (2.6%) had locally synthesised IgA; most notably, IgA was present in 39 of 291 (13%) patients with suspected multiple sclerosis. The latter group also had a significant excess of light-chain production, particularly free kappa, when compared to multiple sclerosis patients without local synthesis of IgA. Locally synthesised IgA was also demonstrated in inflammatory, infectious and autoimmune diseases of the central nervous system. This qualitative technique is simple and suitable for routine analysis of cerebrospinal fluid, and further qualitative studies of IgA may be useful in investigating the pathophysiology of certain neurological disorders.

Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy.

Sensory motor neuropathy is associated with various inherited disorders including Charcot-Marie-Tooth disease, X-linked adrenoleukodystrophy/adrenomyeloneuropathy and Refsum disease. In the latter two, the neuropathy is thought to result from the accumulation of specific fatty acids. We describe here three patients with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and C27-bile-acid intermediates. Two of the patients suffered from adult-onset sensory motor neuropathy. One patient also had pigmentary retinopathy, suggesting Refsum disease, whereas the other patient had upper motor neuron signs in the legs, suggesting adrenomyeloneuropathy. The third patient was a child without neuropathy. In all three patients we discovered a deficiency of alpha-methylacyl-CoA racemase (AMACR). This enzyme is responsible for the conversion of pristanoyl-CoA and C27-bile acyl-CoAs to their (S)-stereoisomers, which are the only stereoisomers that can be degraded via peroxisomal beta-oxidation. Sequence analysis of AMACR cDNA from the patients identified two different mutations that are likely to cause disease, based on analysis in Escherichia coli. Our findings have implications for the diagnosis of adult-onset neuropathies of unknown aetiology.

Neurological involvement in systemic lupus erythematosus.

The aetiology of neurological involvement in systemic lupus erythematosus (SLE) still remains largely uncertain, but there are some recent reports of retrovirus activity linked to human and mouse models of SLE. Antiribosomal P antibodies appear specific to SLE and tend to be associated with psychiatric disease, but not exclusively so. The role of antiphospholipid antibodies in the pathogenesis of SLE may not be solely to cause thrombotic events, but also to act directly on neuronal tissue. The importance of another group of antibodies, those against Beta 2 glycoprotein I, a phospholipid binding protein, is now being recognized. Amongst the many neurological manifestations of SLE, cognitive impairment is becoming increasingly recognized and appears not to be simply a response to chronic disease or its treatment. Of the newer imaging techniques applied to SLE, positron emission tomography has proved inconsistent and somewhat disappointing but single photon emission computed tomography in active disease appears more sensitive compared to MRI, although it still remains a nonspecific technique. The treatment of SLE remains disappointing and no controlled trials for neurological disease have been published to date but a number of experimental approaches do offer hope for the future.

A study of oligoclonal band negative multiple sclerosis.

OBJECTIVES: To determine whether oligoclonal band (OCB) negative multiple sclerosis is a reliable diagnosis and, if so, whether it has a distinctive prognosis. METHODS: Retrospective and matched prospective comparison of the clinical and laboratory features of patients with clinical definite multiple sclerosis with and without intrathecal synthesis of oligoclonal IgG. RESULTS: Thirty four patients were identified with apparent OCB negative clinically definite multiple sclerosis. The results of oligoclonal banding proved to have been equivocal in 14 of 34; the clinical diagnosis of multiple sclerosis was questionable in 8 of 34. The remaining 12 patients with "true" OCB negative multiple sclerosis were significantly less disabled than matched OCB positive controls. Re-examination of CSF-serum pairs from six OCB negative patients showed that three remained OCB negative while three showed evidence of intrathecal synthesis of OCBs. CONCLUSIONS: OCB negative clinically definite multiple sclerosis is rare and should be diagnosed with caution; in unequivocal cases it seems to have a relatively benign prognosis.

Oligoclonal banding of IgG in CSF, blood-brain barrier function, and MRI findings in patients with sarcoidosis, systemic lupus erythematosus, and Behçet's disease involving the nervous system.

A retrospective study of CSF and serum analysis from a total of 43 patients with sarcoidosis, 20 with systemic lupus erythematosus, and 12 with Behçet's disease with neurological involvement found local synthesis of oligoclonal IgG using isoelectric focusing and immunoblotting in 51%, 25%, and 8% respectively at some stage in their disease. Blood-brain barrier breakdown, when assessed with an albumin ratio found 47% of patients with sarcoidosis, 30% of those with systemic lupus erythematosus, and 42% of patients with Behçet's disease exhibiting abnormal barrier function at some time. Serial CSF analysis showed that clinical relapses were associated with worsening barrier function and in some patients the development of local oligoclonal IgG synthesis; conversely steroid treatment led to a statistically significant improvement in barrier function, and in two patients a loss of oligoclonal IgG bands. A higher proportion of patients had MRI abnormalities than oligoclonal IgG or blood-brain barrier breakdown, MRI being abnormal in 16 of 19 patients with sarcoidosis, three of four patients with systemic lupus erythematosus, and seven of nine patients with Behçet's disease, although this may have been due to temporal factors. In the differential diagnosis of chronic neurological disorders, locally synthesised oligoclonal IgG cannot distinguish between diseases, but the loss of bands seen in two patients contrasts with what is seen in multiple sclerosis, and thus may be a useful diagnostic clue.

Hairy leukaemic cell influx into the cerebrospinal fluid secondary to encephalomyelitis.

A case report of a 53 year old male with hairy cell leukaemia is presented in whom encephalomyelitis caused by toxoplasmosis resulted in an influx of hairy cells into the cerebrospinal fluid following disruption of the blood-brain barrier. These cells subsequently disappeared as the barrier reformed. It is suggested that the presence of hairy cells in the cerebrospinal fluid is a secondary self-limiting phenomenon.

Patterns of blood-brain barrier impairment and clinical features in multiple sclerosis.

Seventy four patients with clinically definite multiple sclerosis were studied by using polyacrylamide gel electrophoresis of cerebrospinal fluid to assess blood-brain barrier function. Blood-brain barrier impairment was associated with recent clinical relapses of multiple sclerosis and worsened across a spectrum from the relapsing-remitting type of multiple sclerosis to secondary and primary progressive disease. The association between blood-brain barrier impairment and primary progressive disease is particularly interesting in the light of recent evidence that focal gadolinium enhancement on MRI is relatively unusual in patients with this disease.

Intrathecal baclofen in severe spasticity.

Control of severe spasticity and its associated features with administration of baclofen directly into the CSF via an intrathecal pump has radically improved the management of patients resistant to oral therapy. This article reviews the rationale and clinical indications for this technique, and the outcome and complications encountered.

Dural sinus thrombosis.

The outlook for cerebral venous and sinus thrombosis, once considered a uniformly fatal disorder, has been dramatically improved by the advent of sophisticated neuroradiology and effective management. Many potentially treatable underlying disorders are now recognized. Presentation is often nonspecific and a high index of suspicion is necessary to make an early diagnosis.

Local synthesis of specific IgG in the cerebrospinal fluid of patients with neurosarcoidosis detected by antigen immunoblotting using Kveim material.

The technique of antigen immunoblotting for detection of specific immunoglobulin G (IgG), using Kveim material as antigen, was applied to paired sera and cerebrospinal fluid from 11 patients with definite neurosarcoidosis, 9 patients with definite sarcoidosis and suspected neurosarcoidosis, 22 patients with possible neurosarcoidosis and 16 patients with other neurological disorders, including multiple sclerosis and optic neuritis. Six of the 11 (55%) patients with neurosarcoidosis, none of the 9 patients with definite sarcoidosis and suspected neurosarcoidosis, 5 of the 22 (23%) with possible neurosarcoidosis, and none of the control patients had local synthesis of specific IgG reacting with Kveim material at some stage in the disease. Six of the 8 (75%) patients with definite neurosarcoidosis who had never received steroids or immunosuppressants had local synthesis of Kveim-specific IgG. Local synthesis of Kveim-specific IgG was not found in patients who had received in the past, or were still receiving, immunomodulating agents, and local synthesis was abolished when such treatment was introduced to those patients who had been positive. Those patients whose cerebrospinal fluid showed local synthesis of oligoclonal total IgG were more likely to have local synthesis of Kveim-specific IgG, but not necessarily in an oligoclonal fashion. Immunoblotting, using Kveim material, may thus be a useful adjunct for the investigation of suspected neurosarcoidosis.

A study of immunoglobulin G in the cerebrospinal fluid of 1007 patients with suspected neurological disease using isoelectric focusing and the Log IgG-Index. A comparison and diagnostic applications.

Cerebrospinal fluid and serum immunoglobulin G from 1007 patients with suspected neurological disease were analysed by 2 methods: isoelectric focusing for the detection of oligoclonal banding, and quantitative measurement of IgG and albumin for the formulation of a Log IgG-Index. A comparison of the 2 methods in the detection of local synthesis of IgG showed that isoelectric focusing not only gave a much higher yield overall, with 282 patients showing local synthesis versus 225 for the Log IgG-Index, but also a higher specificity, with a false positive rate of 0% versus 3.5%. In addition, of the 282 patients positive by isoelectric focusing only 163 (58%) were positive by the Log IgG-Index. Of the 1007 patients studied, 206 had multiple sclerosis (MS), and isoelectric focusing showed local synthesis in 95% of clinically definite cases, with a 90% detection rate overall. The Log IgG-Index was positive in only 67% of clinically definite cases, with an overall 59% detection rate. Thus with the exceptions noted above, local synthesis of IgG as defined by isoelectric focusing is confined to demyelinating, inflammatory, infectious and postinfectious disorders. Our results compare very favourably with the published sensitivities of magnetic resonance imaging in the detection of abnormalities in multiple sclerosis, and better than those for evoked potentials. Where both these investigations are readily available isoelectric focusing provides a useful adjunct. For the majority of physicians and neurologists who do not have ready access to magnetic resonance imaging, isoelectric focusing is an excellent alternative. We would also recommend that it become the standard for the measurement of IgG abnormalities in the cerebrospinal fluid and that the use of quantitative data be abandoned for routine purposes.

Isoelectric focusing versus quantitative measurements in the detection of intrathecal local synthesis of IgG.

Specimens from 1007 patients with suspected neurological disturbances had quantitative and qualitative measurements made of cerebrospinal fluid and serum to investigate the presence of locally synthesised IgG. Qualitative measurement was recorded as the presence or absence of oligoclonal banding, and the quantitative measurement was derived by the use of the IgG index, the log index and the Reiber, Schuller and Tourtellotte formulae. The patients were divided into two categories, on the basis of banding: those with local synthesis and those without. The sensitivity, specificity and efficiency for each of the quantitative measurements were then calculated. Receiver-operator curves were also constructed for each of the quantitative measurements. 282 samples showed local synthesis of IgG by isoelectric focusing, whereas the best quantitative assay (log index) could only detect 198. Therefore, we conclude that oligoclonal banding should be adopted as the standard laboratory measurement of local synthesis of IgG in the diagnosis of neurological disorders, and that the diagnostic use of quantitative measurements should be abandoned for routine purposes. Furthermore, we suggest that quantitative analysis, at its current level, is misleading and has little value in the understanding of neurological disorders, but may be of use in serially monitoring individual patients as part of their therapeutic trials.

Antibodies against the paramyxovirus SV5 are not specific for cerebrospinal fluid from multiple sclerosis patients.

An aetiological agent for multiple sclerosis has not yet been identified. The paramyxovirus SV5 (Simian virus 5) has been suggested as an important cause in some cases. Using antigen immunoblotting with SV5 virus, we confirmed the binding to SV5 of immunoglobulin G from the cerebrospinal fluid of 58% of multiple sclerosis patients, but also found binding in 70% of patients with a variety of neurological disorders where oligoclonal banding was present. This suggests that the antibodies present are not specific for multiple sclerosis and that the SV5 virus is thus unlikely to be of aetiological significance.

Viral specific IgG and IgM antibodies in the CSF of patients with tropical spastic paraparesis.

The cerebrospinal fluid (CSF) from seven West Indian migrants to the United Kingdom with tropical spastic paraparesis were studied by antigen immunoblotting for specific anti-HTLV1 oligoclonal IgG and IgM. Eight CSFs from five patients were positive for specific IgG and negative for IgM; three CSFs from two patients were positive for IgM and negative for IgG. No patient had both IgG- and IgM-positive CSF. Those patients with IgM only had disease of the shortest duration. When looking for evidence that neurological damage is caused by HTLV1, both IgM and IgG should be examined.