"Neurophobia": More Nurture than Nature?

AIM: "Neurophobia" is the fear of neurology experienced by medical students. The aim of this study was to investigate if neurology now has a stigma attached to it causing a preconceived negative perception of neurology by students. METHODS: An online questionnaire was distributed to medical students via social media and email. Questions focused on students' perceptions of neurology before and after exposure to the subject. RESULTS: There were one hundred and thirty-seven responses. Twenty percent of preclinical students, twenty-six percent of early clinical students and fifty-six percent of clinical students said that they would not consider neurology as a speciality in the future. Neurophysiology and neuroanatomy were considered to be the most difficult aspects of neurology. Integration of preclinical academic training with clinical training was highlighted as a point of difficulty for students. DISCUSSION: Contrary to our initial hypothesis, "neurophobia" does not appear to be innate in medical students but is acquired during the course of their medical training.

A Life-Saving Palsy: Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) Presenting As Hand Weakness during Cardiopulmonary Resuscitation (CPR) Training

Aim To describe a case of acute and transient hand weakness that developed during cardiopulmonary resuscitation (CPR) training. Hereditary neuropathy with liability to pressure palsies (HNPP) should be considered in patients with recurrent, painless motor or sensory neuropathies at sites of peripheral nerve compression. Methods Nerve conduction studies confirmed neuropraxia of the distal ulnar nerve with a mild background demyelinating peripheral neuropathy. Results A positive family history emerged and HNPP was confirmed by genetic testing. HNPP is most reliably diagnosed by molecular testing for peripheral myelin protein 22 (PMP22) gene deletion or point mutation on chromosome 17p11.2. Conclusion CPR, a procedure carried out by medical professionals on a daily basis, is a high-energy manual task and provides multiple opportunities for nerve compression. This case demonstrates the importance of having a high index of clinical suspicion of this disorder in patients. Recognising a diagnosis of HNPP may prevent unnecessary surgical decompression.

An Audit of the Effectiveness of Large Group Neurology Tutorials for Irish Undergraduate Medical Students.

The aim of this audit was to determine the effectiveness of large group tutorials for teaching neurology to medical students. Students were asked to complete a questionnaire rating their confidence on a ten point Likert scale in a number of domains in the undergraduate education guidelines from the Association of British Neurologists (ABN). We then arranged a series of interactive large group tutorials for the class and repeated the questionnaire one month after teaching. In the three core domains of neurological: history taking, examination and differential diagnosis, none of the students rated their confidence as nine or ten out of ten prior to teaching. This increased to 6% for history taking, 12 % in examination and 25% for differential diagnosis after eight weeks of tutorials. This audit demonstrates that in our centre, large group tutorials were an effective means of teaching, as measured by the ABN guidelines in undergraduate neurology.

Myasthenia gravis: a population-based epidemiological study.

Myasthenia Gravis (MG) is a disorder affecting components of the neuromuscular junction. Epidemiological studies show rising incidence and prevalence rates. The aim of this study was to determine the incidence and prevalence of MG in the Republic of Ireland. Data sources included patient lists from consultant neurologists and ophthalmologists, a neuroimmunology laboratory, general practitioners and the Myasthenia Gravis Association. A total of 1715 cases were identified, of which 706 definite, probable or possible autoimmune and congenital MG cases were included. The overall prevalence rate from the data obtained is 15.38/100,000. The study demonstrated a female preponderance (female:male of 1.3: 1) and some geographical variation within Ireland. The average incidence rate for the years 2000 to 2009 was 11.3 per year; the rate for the current decade is 18 per year. The increasing number of diagnoses may be due to improved access to diagnostic investigations and increasing awareness of the clinical manifestations.

Headaches, neurologists and the emergency department.

This study explores the claim that headache management can be improved by evaluating current emergent care. A retrospective chart review investigated primary complaints of headache during a three-month period. Two hundred and twenty seven patients were identified for review and three-month follow-up using fully available records and imaging. A total of 543/8,759 had a neurological condition. The most common conditions were headaches (42% or 227 cases), cerebrovascular problems (26%) and seizures (17%). No 'usual headache' patterns showed abnormal imaging. In contrast, those with 'sudden-onset' type or clinical findings had an abnormal scan 17% of the time. Of the MRIs ordered, one-quarter changed management. On discharge, 39% of patients left without a specific headache diagnosis. In the discussion, we evaluate how well a tertiary referral ED treats its most common neurological complaint, focusing on the controversial topics of when to investigate and prevention of re-attendance.

A proposed modification to the McDonald 2010 criteria for the diagnosis of primary progressive multiple sclerosis.

BACKGROUND: The diagnostic criteria for primary-progressive multiple sclerosis (PPMS) have undergone revision over the last 20 years. Cerebrospinal fluid oligoclonal bands (CSFOBs) have received less emphasis in recent revisions of the McDonald criteria. The aim of this study was to examine the sensitivity of the diagnostic criteria for PPMS with particular reference to spinal cord criteria and examine the utility of CSFOBs in a cohort of PPMS patients. METHODS: All new PPMS diagnoses between 1990 and 2011 were identified. Baseline clinical details and paraclinical evaluations including MRI of the brain, spinal cord, CSF and visually evoked responses (VERs) were assessed. The proportion of patients who met the requirements for diagnosis of PPMS on the basis of Thompson's and the McDonald Criteria (2001, 2005, 2010) were determined. RESULTS: There were 88/95 PPMS patients who had at least two diagnostic investigations. The sensitivity of Thompson's and the McDonald 2001 criteria was 64%; the McDonald 2010 revisions gave the highest sensitivity (77%); the McDonald 2005 criteria had intermediate sensitivity (74%). The combination of CSFOBs and MRI of the brain yielded the greatest number of patients demonstrating dissemination in space (DIS) on only two investigations. VERs did not aid diagnosis. Reducing requirements for the number of spinal cord lesions (symptomatic or not) to one increased diagnostic sensitivity to 84%. CONCLUSION: An alternative criterion requiring two of: i) MRI of the brain with one or more lesions in two of three regions typical for demyelination; ii) the presence of one T2-weighted spinal cord plaque (typical for demyelination); iii) CSFOBs; would increase the diagnostic sensitivity for PPMS.

A web-based electronic neurology referral system: a solution for an overburdened healthcare system?

Ireland has the lowest number of consultant neurologists per capita in Europe. This results in long waiting lists, overbooked clinics, unnecessary emergency department presentations and patient frustration. In 2006, the neurology department in St. Vincent's University Hospital and the National Healthlink project, launched an internet referral system (Neurolink) for GPs, to alleviate the administrative burden on staff, reduce unnecessary visits for patients, shorten waiting lists and improve patient care. 710 electronic referrals from GPs between December 2006 and January 2011 were analysed. The average time taken to for a consultant to reply to a GP referral was 19hours 8minutes. When asked their opinion as to the suspected aetiology 33.7% (239/710) of GPs selected the option "unknown", followed by epilepsy 12.1% (86/710), migraine 12% (85/710), and multiple sclerosis 7.6% (54/710). Significantly, 19% (127/662) of referrals did not require a neurology outpatient appointment and the GP was given advice. The results highlight the benefits of using an electronic communication system with primary care; allowing prompt response to GP enquires, early initiation of treatment and reducing the number of patients attending hospital clinics.

Longitudinal stability of JCV antibody index in Natalizumab treated people with multiple sclerosis.

OBJECTIVE: The aim of this study was to evaluate the evolution of JCV index over time in Natalizumab treated people with multiple sclerosis. MATERIALS AND METHODS: We retrospectively reviewed antibody index values from pwMS who were treated with Natalizumab for greater than six months and had at least two antibody results available between 2011 and 2019. Survival analysis was performed on those who were JCV index value negative at baseline to evaluate time to seroconversion. In pwMS who had index values available at 48 and/or 96 months post Natalizumab initiation, t-tests were performed to evaluate change in index over time. RESULTS: 1144 JCV antibody index results were available for 132 pwMS. Median time to seroconversion based on survival analysis was 103 months. Annualised seroconversion rate was 5.8%. Initial antibody index and rate of seroconversion did not differ with regards to age or gender. Antibody index increased significantly over time on treatment for the cohort as a whole, initial antibody index (0.27) to final antibody testing (0.86), t(131)=6.45, p<.0005. There was a significant increase in those with initial positive index value, between first (0.95) and final index (2.14), t(33) = 4.85, p<.0005 over a median of 77 months. CONCLUSIONS: In those who were seronegative at baseline there is a long median duration of treatment with Natalizumab prior to seroconversion. In individuals with positive JCV antibody index at treatment initiation, antibody index increases over time.

Multiple sclerosis prevalence in Ireland: relationship to vitamin D status and HLA genotype.

BACKGROUND: The relationship between prevalence of multiple sclerosis (MS) and latitude may be due to both genetic and environmental factors. The hypothesis that, in Ireland, MS prevalence is increasing and that north-south differences relate to variation in serum 25-hydroxyvitamin D (25(OH)D) levels was tested in this study. PATIENTS AND METHODS: Patients and matched control subjects were identified in counties Donegal, Wexford and South Dublin through multiple sources. Prevalence was determined. Blood samples were taken for serum 25(OH)D and serum intact parathyroid hormone measurement, and DNA was extracted. RESULTS: Prevalence in 2007 was significantly greater in Donegal (northwest) (290.3/105, 95% CI 262.3 to 321.7) compared with 2001 (184.6/105; 162 to 209.5). In Wexford (southeast), there was a non-significant increase in prevalence in 2007 compared with 2001. Prevalence was significantly higher in Donegal than in Wexford (144.8/105; 126.7 to 167.8, p<0.0001) and South Dublin (127.8/105; 111.3 to 148.2, p<0.0001). Overall, mean 25(OH)D levels were low and did not differ between patients (38.6 nmol/l) and controls (36.4 nmol/l) However, significantly more patients than controls had 25(OH)D levels <25 nmol/l (deficiency) (p=0.004). Levels of 25(OH)D (mean 50.74 nmol/l) were significantly higher in South Dublin (area with lowest prevalence) (p<0.0001) than in Donegal or Wexford. HLA DRB1*15 occurred most frequently in Donegal (greatest MS prevalence) and least frequently in South Dublin. CONCLUSION: Vitamin D deficiency is common in Ireland. Latitudinal variation in MS probably relates to an interaction between genetic factors and environment (25(OH)D levels), and MS risk may be modified by vitamin D in genetically susceptible individuals.

Multiple sclerosis, from referral to confirmed diagnosis: an audit of clinical practice.

BACKGROUND: The National Institute for Health and Clinical Excellence (NICE) guidelines recommend a timeline of 6 weeks from referral to neurology consultation and then 6 weeks to a diagnosis of multiple sclerosis (MS). OBJECTIVES: We audited the clinical management of all new outpatient referrals diagnosed with MS between January 2007 and May 2010. METHODS: We analysed the timelines from referral to first clinic visit, to MRI studies and lumbar puncture (LP) (if performed) and the overall interval from first visit to the time the diagnosis was given to the patient. RESULTS: Of the 119 diagnoses of MS/Clinically Isolated Syndrome (CIS), 93 (78%) were seen within 6 weeks of referral. MRI was performed before first visit in 61% and within 6 weeks in a further 27%. A lumbar puncture (LP) was performed in 83% of all patients and was done within 6 weeks in 78%. In total, 63 (53%) patients received their final diagnosis within 6 weeks of their first clinic visit, with 57 (48%) patients having their diagnosis delayed. The main rate-limiting steps were the availability of imaging and LP, and administrative issues. CONCLUSIONS: We conclude that, even with careful scheduling, it is difficult for a specialist service to obtain MRI scans and LP results so as to fulfil NICE guidelines within the optimal six-week period. An improved service would require MRI scans to be arranged before the first clinic visit in all patients with suspected MS.

Preliminary evidence for correlation between PASAT performance and P3a and P3b amplitudes in progressive multiple sclerosis.

BACKGROUND: The no-go P3a event-related potential (ERP) is a measure of attentional engagement and the P3b is a measure of context updating. The aim of this study was to compare ERP topographies: (i) to Paced Auditory Serial Addition Test (PASAT) results, (ii) of visual and auditory P3a and P3b of patients with primary progressive multiple sclerosis (PPMS) versus patients with secondary-progressive multiple sclerosis (SPMS) and (iii) of both progressive subtypes to healthy controls. METHODS: Thirty subjects (10 PPMS, 10 SPMS and 10 age-matched controls) completed visual and auditory no-go P3a and P3b tasks whilst data were recorded from a 128-scalp channel electroencephalography (EEG) array. Data from scalp channels were converted into continuous interpolated images (incorporating the entire scalp and time). Topographical differences and correlations were then tested using statistical parametric mapping. RESULTS: For the patients with multiple sclerosis (MS), PASAT score correlated significantly with parietal regions in the auditory P3b, auditory P3a and visual P3b conditions, and with central regions in the visual P3a condition. Patients with PPMS had significantly lower amplitude than patients with SPMS in the auditory P3b condition over the parietal area. The control group had greater amplitude than the patients with MS in all the P3 tasks, with the exception of the auditory P3b. CONCLUSIONS: These data suggest that PASAT performance and P3 ERPs correlate for MS progressive subtypes and that PPMS and SPMS differ in electrophysiological responses during auditory P3b tasks.

T cells in multiple sclerosis and experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4(+) T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting γδ T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, γδ, CD8(+) and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.

The 'hidden work' of a hospital neurologist: 1000 consults later.

BACKGROUND: A new Web-based, internal neurology referral service was introduced in our department to expedite inpatient review for other departments and to allow assessment of the impact of neurology consults on patient care throughout the hospital, especially in the emergency department (ED). The results of the analysis of the first 1000 referrals using the new system are presented. METHODS: An intranet referral system was designed by the consultant neurologists. The previous method of referral was by handwritten letter. The electronic template included 'drop-down' menus and mandatory fields to help guide referring teams. An outcome section is completed by the neurology team. RESULTS: An average of 17 referrals was seen weekly. Seventy-seven per cent were seen within 24 h of referral. A consultant neurologist saw 87% of the referrals directly; 13% were first seen by a registrar and later discussed with a consultant. Forty per cent were seen in the ED of which a one-third of the patients were discharged following assessment. The most common reason for referral was seizure(s) or an episode of collapse (28%). Patients presenting with stroke/transient ischaemic attack represented 13.5%, and 12.5% presented with headaches. The management of 79% of referred cases was deemed to have been significantly changed after neurology review. DISCUSSION: The introduction of a neurology consultant-designed and consultant-led intranet referral service has greatly enhanced the delivery of the consult service to patients in our hospital. This referral system contributes significantly to hospital efficiency and to access for patients to specialist assessment.

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.

Posterior reversible encephalopathy syndrome with Lilliputian hallucinations secondary to Takayasu's arteritis.

Posterior Reversible Encephalopathy Syndrome (PRES) is a rare complication of Takayasu's Arteritis. A 54-year-old, right-handed woman presented with Lilliputian visual hallucinations, postprandial abdominal pain, blurred vision and headaches. She then had a tonic-clonic seizure. Neuroimaging revealed characteristic white matter oedema of the occipital lobes, in keeping with PRES. Renal infarcts and abnormalities of the abdominal aorta, subclavian, mesenteric, and internal carotid arteries were demonstrated on further imaging. The combination of hypertension, absent peripheral pulses, postprandial claudication, and imaging abnormalities of the aorta as well as its branches, lead to the diagnosis of PRES secondary to Takayasu's Arteritis. Treatment with oral steroids resulted in complete resolution of the patient's symptoms and abnormalities found on CT and MRI brain imaging. Takayasu's Arteritis is a rare vasculitis, more common in women and PRES is an unusual complication. Symptoms of PRES may include headache, seizures, hallucinations, confusion, and altered consciousness. Risk factors for PRES include; pregnancy, immunosuppression, renal disease, hypertension and rheumatological disorders. Vasogenic oedema in affected lobes, most often occipital, is characteristic of PRES on neuroimaging. Prompt treatment of PRES can avoid catastrophic consequences such as death and can achieve complete resolution of symptoms and imaging abnormalities.

HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis.

Human leucocyte antigen (HLA)-DRB1*1501 and other class II alleles influence susceptibility to multiple sclerosis (MS), but their contribution if any to the clinical course of MS remains uncertain. Here, we have investigated DRB1 alleles in a large sample of 1230 Australian MS cases, with some enrichment for subjects with primary progressive (PPMS) disease (n = 246) and 1210 healthy controls. Using logistic regression, we found that DRB1*1501 was strongly associated with risk (P = 7 x 10(-45)), as expected, and after adjusting for DRB1*1501, a predisposing effect was also observed for DRB1*03 (P = 5 x 10(-7)). Individuals homozygous for either DRB1*15 or DRB1*03 were considerably more at risk of MS than heterozygotes and non-carriers. Both the DRB1*04 and the DRB1*01/DRB1*15 genotype combination, respectively, protected against PPMS in comparison to subjects with relapsing disease. Together, these data provide further evidence of heterogeneity at the DRB1 locus and confirm the importance of HLA variants in the phenotypic expression of MS.

A pernicious leucoencephalopathy.

Pernicious anaemia may manifest various neurological symptoms and signs ranging from the subtle to the dramatic. We describe a young man with cobalamin deficiency presenting with sensorimotor deficits, ataxia, dysarthria, mild cognitive deterioration and altered mood of insidious onset. The MRI brain findings were in keeping with a leucoencephalopathy without evidence of MRI changes in the spinal cord. This constellation of features has been reported rarely. His response to treatment as well as the marked improvement of the leucoencephalopathy on imaging suggests at least partial reversibility of the neurological deficits.

Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians.

A recent genome-wide association study (GWAS) conducted by the International Multiple Sclerosis Genetics Consortium (IMSGC) identified a number of putative MS susceptibility genes. Here we have performed a replication study in 1134 Australian MS cases and 1265 controls for 17 risk-associated single nucleotide polymorphisms (SNPs) reported by the IMSGC. Of 16 SNPs that passed quality control filters, four, each corresponding to a different non-human leukocyte antigen (HLA) gene, were associated with disease susceptibility: KIAA0350 (rs6498169) P=0.001, IL2RA (rs2104286) P=0.033, RPL5 (rs6604026) P=0.041 and CD58 (rs12044852) P=0.042. There was no association (P=0.58) between rs6897932 in the IL7R gene and the risk of MS. No interactions were detected between the replicated IMSGC SNPs and HLA-DRB1*15, gender, disease course, disease progression or age-at-onset. We used a novel Bayesian approach to estimate the extent to which our data increased or decreased evidence for association with the six most-associated IMSGC loci. These analyses indicated that even modest P-values, such as those reported here, can contribute markedly to the posterior probability of 'true' association in replication studies. In conclusion, these data provide support for the involvement of four non-HLA genes in the pathogenesis of MS, and combined with previous data, increase to genome-wide significance (P=3 x 10(-8)) evidence of an association between KIAA0350 and risk of disease.

Long-term clinical relevance of criteria for designating multiple sclerosis as benign after 10 years of disease.

OBJECTIVES: To determine the long-term outcome of a cohort of 436 patients with multiple sclerosis (MS) seen in 1985 and long-term predictors of benign MS. METHODS: The initial 1985 group of 436 patients with possible MS, including 53 benign patients, were followed for 21 years. Disability was recorded using the Expanded Disability Status Scale (EDSS). Survival from disease onset was calculated. The indicators of benign MS in the initial 1985 cohort and in the survivors in 2006 were determined. RESULTS: Of the original 436 patients, the 21-year follow-up outcome in 397 (91%) was established. The diagnosis of MS was incorrect in 41/397 (10%) of the whole cohort and in 2/53 (4%) of the benign group. Median survival of 356 patients with MS was 43.6 years from disease onset. Of 47/51 (92%) patients with benign MS followed in 2006, 7 (15%) remained benign, 18 had died and 22 were disabled. Median survival advantage for the 47 benign patients in 1985 compared to the 88 non-benign patients, when corrected for age, was 6 years (p<0.08). In 2006, 40/356 (11%) patients had a benign outcome at a mean follow-up of 26.1 years. A benign course was significantly associated with female sex, younger age of onset and absence of motor symptoms at presentation. CONCLUSIONS: Although designating patients as having a benign course after 10 years has a poor predictive value, three factors at presentation indicate a better prognosis.