Brendan McLean

Elevated serum levels of tumor necrosis factor-α in Guillain-Barré syndrome

Activated T lymphocytes and macrophages play a putative role in the pathogenesis of Guillian-Barre syndrome. Both cell types secrete tumor necrosis factor-α, a cytokine that has well-recognized toxi effects on myelin, Schwann cells, and endothelial cells. We determined serum and cerebrospinal fluid concentrations of tumor necrosis factor α in 26 patients with Guillain-Barre syndrome, 27 patients with other polyneuropathies, 30 patients with neurological diseases of the central nervous system, and 14 helthy control subjects. Markedly increased serum levels were detected in 14 patients(54%) with Guillian-Barre syndrome and to a significantly lesser extent, in patients with other polyneuropathies (26%) and in neurological control subjects(23%). Tumor necrosis factor-α was not detected in the cerebrospinal fluid of patients with Guillain-Barre syndrome or other polyneuropathies. Increased serum concentrations in patients with Guillain-Barre syndrome or other polyneuropathies. Increased serum concentrations in patients with Guillain-Barre syndrome correlated directly with disease severity and these concentrations returned to normal in parallel with clinical recovery. These findings emphasize the complexity of the immune response in patients with Guillain-Barre syndrome and suggest that tumor necrosis factor-αL may be important in the pathogenesis of peripheral demylination in this disorder.

Neuralgic amyotrophy and hepatitis E virus infection

Objective: To determine whether there is an association between an acute preceding hepatitis E virus (HEV) infection and neuralgic amyotrophy (NA), and if so, whether patients with HEV-related NA differ from patients without an associated HEV infection. Methods: HEV testing was conducted in a retrospective cohort of 28 Cornish patients with NA (2011–2013) and a prospective cohort of 38 consecutive Dutch patients with NA (2004–2007). Acute-phase serum samples were analyzed for the presence of anti-HEV immunoglobulin (Ig) M and IgG and HEV RNA (quantitative real-time PCR). Results: Five cases (10.6%) of acute hepatitis E infection were identified in a total group of 47 patients with NA of whom serum samples were available. In 4 patients, HEV RNA was detected in serum samples taken at presentation. All patients with HEV-associated NA had clinical and electrophysiologic evidence of bilateral brachial plexus involvement. Anti-HEV IgM positivity was not related to age, sex, disease severity, disease course, or outcome. Conclusions: Acute hepatitis E is found in 10% of patients with NA from the United Kingdom and the Netherlands. Further research is required to investigate the role of HEV in NA in other geographical locations and to determine pathophysiologic mechanisms.

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 ≥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.

Hepatitis E virus and neurological injury

Hepatitis E is hyperendemic in many developing countries in Asia and Africa, and is caused by hepatitis E virus (HEV) genotypes 1 and 2, which are spread via the faecal–oral route by contaminated water. Recent data show that HEV infection is also endemic in developed countries. In such geographical settings, hepatitis E is caused by HEV genotypes 3 and 4, and is mainly a porcine zoonosis. In a minority of cases, HEV causes acute and chronic hepatitis, but infection is commonly asymptomatic or unrecognized. HEV infection is associated with a number of extrahepatic manifestations, including a range of neurological injuries. To date, 91 cases of HEV-associated neurological injury — most commonly, Guillain–Barré syndrome, neuralgic amyotrophy, and encephalitis/myelitis — have been reported. Here, we review the reported cases, discuss possible pathogenic mechanisms, and present our perspectives on future directions and research questions.

Elevated serum levels of tumor necrosis factor-alpha in Guillain-Barré syndrome.

Activated T lymphocytes and macrophages play a putative role in the pathogenesis of Guillian-Barre syndrome. Both cell types secrete tumor necrosis factor-α, a cytokine that has well-recognized toxi effects on myelin, Schwann cells, and endothelial cells. We determined serum and cerebrospinal fluid concentrations of tumor necrosis factor α in 26 patients with Guillain-Barre syndrome, 27 patients with other polyneuropathies, 30 patients with neurological diseases of the central nervous system, and 14 helthy control subjects. Markedly increased serum levels were detected in 14 patients(54%) with Guillian-Barre syndrome and to a significantly lesser extent, in patients with other polyneuropathies (26%) and in neurological control subjects(23%). Tumor necrosis factor-α was not detected in the cerebrospinal fluid of patients with Guillain-Barre syndrome or other polyneuropathies. Increased serum concentrations in patients with Guillain-Barre syndrome or other polyneuropathies. Increased serum concentrations in patients with Guillain-Barre syndrome correlated directly with disease severity and these concentrations returned to normal in parallel with clinical recovery. These findings emphasize the complexity of the immune response in patients with Guillain-Barre syndrome and suggest that tumor necrosis factor-αL may be important in the pathogenesis of peripheral demylination in this disorder.

A dominantly inherited mutation in collagen IV A1 (COL4A1) causing childhood onset stroke without porencephaly

We describe a three generation family with recurrent strokes and cataracts. The index case, a 14 year old boy presented with stroke at the age of 14 years and again 6 months later. His mother had long standing episodic headaches diagnosed as migraine. Grandmother was initially diagnosed with multiple sclerosis and had recurrent strokes at age 18 years and 49 years. MRI scanning showed a diffuse leukoencephalopathy with microhaemorrhages in all three individuals. All of the family members had cataracts but did not have retinal arterial changes. Sequence analysis of COL4A1 revealed the heterozygous missense mutation c.2263G-->A in exon 30, responsible for a glycine-to-arginine substitution (p.Gly755Arg) in both the index case and mother. Grandmother died at the age of 73 years and DNA analysis was not possible. Mutation in COL4A1 should be considered in families with a history of autosomal dominant cerebral vasculopathy, even in the absence of porencephaly.

Sudden unexpected death in epilepsy (SUDEP): Development of a safety checklist

PURPOSE The incidence of sudden death appears to be 20 times higher in patients with epilepsy compared with the general population. Epilepsy-related death, particularly sudden unexpected death in epilepsy (SUDEP), is still underestimated by healthcare professionals and this may reflect the mistaken belief that epilepsy is a benign condition. The risk of death associated with epilepsy appeared rarely to have been discussed with patients or their families. It appears the decision to discuss SUDEP and also to peg SUDEP risk is arbitrary and clinical. Unfortunately there is no structured evidenced mechanism at present to represent person centered risk of SUDEP and there is currently no easy manner or template to have this discussion with the family and the patient. METHODS We conducted a detailed literature review in Medline, Embase and Psychinfo databases to extract the common risk factors as evidenced from literature till date. Research into risk factors has identified a number of risk factors for SUDEP, some of which are potentially modifiable. RESULTS Based on the literature review, we believe that the ascertained risk factors could be employed in clinical practice as a checklist to reduce an individual patients risk of SUDEP. The SUDEP safety checklist may be of practical use in reducing risks in some individuals and is definitely of use in helping communication. CONCLUSIONS An evidence based checklist identifying the major risk factors can help both clinicians and patients to focus on minimizing certain risk factors and promote safety by focusing on the modifiable factors and guide treatment. It can be a tool to open a person centered discussion with patients and to outline how individual behaviors could impact on risk.

A community study in Cornwall UK of sudden unexpected death in epilepsy (SUDEP) in a 9-year population sample

PURPOSE Epilepsy-related death, particularly sudden unexpected death in epilepsy (SUDEP), is underestimated by healthcare professionals. One argument that physicians use to justify the failure to discuss SUDEP with patients and their families is that there is a lack of evidence for any protective interventions. However, there is growing evidence of potentially modifiable risk factors for SUDEP; although large-scale trials of interventions are still lacking. We determined the main risk factors associated with SUDEP in a comprehensive community sample of epilepsy deaths in Cornwall UK from 2004 to 2012. METHODS We systemically inspected 93 cases of all epilepsy and epilepsy associated deaths which occurred in Cornwall between 2004 and 2012 made available to us by the HM Cornwall coroner. These are the deaths where epilepsy was a primary or a secondary cause. RESULTS 48 cases met the criteria for SUDEP and we elicited associated relevant risk factors. Many findings from our study are comparable to what has been reported previously. New points such as most of the population had increase in either or both seizure frequency/intensity within six months of death and majority did not have an epilepsy specialist review in the last one year to demise were noted. CONCLUSION This study is the first epidemiological study in England occurring in a whole population identifying systemically all deaths and the first large scale review in UK of SUDEP deaths since 2005. Being a community based study a key issue which was highlighted was that in the SUDEPs examined many might have been potentially preventable.

Does intellectual disability increase sudden unexpected death in epilepsy (SUDEP) risk

PURPOSE An estimated 1.4 million people in the United Kingdom (UK) have intellectual disability (ID) with 210,000 having severe or profound ID. Of these, approximately 125,000 have epilepsy, representing one quarter of all patients with epilepsy in the UK. For those with full scale intellectual quotients (FSIQs) of less than 50, half have epilepsy, with half of these having treatment resistant epilepsy. One of the two major causes of mortality within this population is sudden unexpected death in epilepsy (SUDEP). METHODS We performed a literature review exploring the extent to which ID was considered as a risk factor for SUDEP. We also considered whether there was any relationship between the types of health care system in which the studies were conducted and whether ID was considered in studies of SUDEP. RESULTS We identified 49 studies which had explored risk factors for SUDEP, of which, approximately 50% (n=23) considered ID in the planning stages. Of these studies 60% (n=14) found ID was a risk factor for SUDEP. 60% of all the studies were conducted in countries where the health care system was publicly funded. CONCLUSIONS Overall we found ID definitions and specified standardized mortality rates and impact of institutionalization to be quite poorly presented.

Hepatitis E virus infection and acute non-traumatic neurological injury: A prospective multicentre study

BACKGROUND & AIMS Hepatitis E virus (HEV) has been associated with a number of neurological syndromes, but causality has not yet been established. The aim of this study was to explore the relationship between HEV and neurological illness by prospective HEV testing of patients presenting with acute non-traumatic neurological injury. METHODS Four hundred and sixty-four consecutive patients presenting to hospital with acute non-traumatic neurological illnesses were tested for HEV by serology and PCR from four centres in the UK, France and the Netherlands. RESULTS Eleven of 464 patients (2.4%) had evidence of current/recent HEV infection. Seven had HEV RNA identified in serum and four were diagnosed serologically. Neurological cases in which HEV infection was found included neuralgic amyotrophy (n=3, all PCR positive); cerebral ischemia or infarction (n=4); seizure (n=2); encephalitis (n=1); and an acute combined facial and vestibular neuropathy (n=1). None of these cases were clinically jaundiced and median ALT at presentation was 24IU/L (range 8-145). Cases of HEV-associated neuralgic amyotrophy were found in each of the participating countries: all were middle-aged males with bilateral involvement of the brachial plexus. CONCLUSIONS In this cohort of patients with non-traumatic neurological injury, 2.4% had evidence of HEV infection. Symptoms of hepatitis were mild or absent and no patients were jaundiced. The cases of HEV-associated neuralgic amyotrophy had similarities with other HEV-associated cases described in a large retrospective study. This observation supports a causal relationship between HEV and neuralgic amyotrophy. To further understand the relevance of HEV infection in patients with acute neurological illnesses, case-control studies are warranted. Lay summary: Hepatitis E virus (HEV), as its name suggests, is a hepatotropic virus, i.e. it causes damage to the liver (hepatitis). Our findings show that HEV can also be associated with a range of injury to the nervous system.