Unbalanced Peptidergic Inhibition in Superficial Neocortex Underlies Spike and Wave Seizure Activity.

Slow spike and wave discharges (0.5-4 Hz) are a feature of many epilepsies. They are linked to pathology of the thalamocortical axis and a thalamic mechanism has been elegantly described. Here we present evidence for a separate generator in local circuits of associational areas of neocortex manifest from a background, sleep-associated delta rhythm in rat. Loss of tonic neuromodulatory excitation, mediated by nicotinic acetylcholine or serotonin (5HT3A) receptors, of 5HT3-immunopositive interneurons caused an increase in amplitude and slowing of the delta rhythm until each period became the "wave" component of the spike and wave discharge. As with the normal delta rhythm, the wave of a spike and wave discharge originated in cortical layer 5. In contrast, the "spike" component of the spike and wave discharge originated from a relative failure of fast inhibition in layers 2/3-switching pyramidal cell action potential outputs from single, sparse spiking during delta rhythms to brief, intense burst spiking, phase-locked to the field spike. The mechanisms underlying this loss of superficial layer fast inhibition, and a concomitant increase in slow inhibition, appeared to be precipitated by a loss of neuropeptide Y (NPY)-mediated local circuit inhibition and a subsequent increase in vasoactive intestinal peptide (VIP)-mediated disinhibition. Blockade of NPY Y1 receptors was sufficient to generate spike and wave discharges, whereas blockade of VIP receptors almost completely abolished this form of epileptiform activity. These data suggest that aberrant, activity-dependent neuropeptide corelease can have catastrophic effects on neocortical dynamics.

Thoracolumbar hydrated nucleus pulposus extrusion and intervertebral disc extrusion in dogs: Comparison of clinical presentation and magnetic resonance imaging findings.

Thoracolumbar hydrated nucleus pulposus extrusion (TL-HNPE) is an increasingly recognised pathology with a substantial lack of literature describing its features. The aim of this retrospective case-control study was to analyse the clinical and magnetic resonance imaging (MRI) features of dogs with TL-HNPE compared to dogs affected with thoracolumbar intervertebral disc extrusion (TL-IVDE). Data from dogs diagnosed with TL-HNPE and TL-IVDE via MRI at two referral hospitals, were retrospectively collected and compared in terms of clinical signs and MRI features. Cases diagnosed with TL-IVDE were deemed controls. The MRI features of the affected IVD space, herniated IVD material, affected overlying spinal cord and local epaxial musculature were evaluated for each group. Fifty-one cases with TL-HNPE and 105 randomly selected cases of TL-IVDE were included. Several signalment and neurological signs were identified as statistically distinct between groups in univariate analysis. Multivariate analysis identified that dogs affected with TL-HNPE were typically older, less likely to be chondrodystrophic (62.2 % vs. 91 %), more frequently experiencing a peracute onset (90.2 % vs. 61.9 %) often attributed to a suspected trauma linked with exercise (37.3 % vs. 10.5 %), being less frequently progressive (41.2 % vs. 86.5 %) and with herniated disc material less frequently lateralised (72.6 % vs. 89.5 %) than cases with TL-IVDE. MRI-identifiable intervertebral disc degeneration was found in every TL-IVDE case but only in 60 % of TL-HNPE cases. TL-HNPEs were associated to significantly less spinal cord compression and less hyperalgesia than TL-IVDE.

Frequency and risk factors for naturally occurring Cushing's syndrome in dogs attending UK primary-care practices.

OBJECTIVES: To estimate the frequency and risk factors for Cushing's syndrome in dogs under UK primary veterinary care. MATERIALS AND METHODS: Dogs with Cushing's syndrome were identified by searching electronic patient records of primary-care veterinary practices. Pre-existing and incident cases of Cushing's syndrome during 2016 were included to estimate the 1-year period prevalence. Incident cases were used to estimate the annual incidence and to identify demographic risk factors for the diagnosis of Cushing's syndrome in dogs, through multivariable logistic regression. RESULTS: Analysis included 970 pre-existing and 557 incident cases of Cushing's syndrome from a population of 905,544 dogs. The estimated 1-year period prevalence for Cushing's syndrome in dogs under veterinary care was 0.17% (95% confidence interval 0.16 to 0.18) and incidence was 0.06% (95% confidence interval 0.05 to 0.07). In multivariable logistic regression modelling, the Bichon frise (odds ratio=6.17, 95% confidence interval 4.22 to 9.00), Border terrier (5.40, 95% confidence interval 3.66 to 7.97) and Miniature schnauzer (3.05, 95% confidence interval 1.67 to 5.57) had the highest odds of Cushing's syndrome. The Golden retriever (0.24, 95% confidence interval 0.06 to 0.98) and Labrador retriever (0.30, 95% confidence interval 0.17 to 0.54) were the most protected breeds. Increasing age, bodyweight greater than the breed-sex mean and being insured also showed increased odds of Cushing's syndrome. CLINICAL SIGNIFICANCE: As Cushing's syndrome is predominately diagnosed and managed in primary-care practice, this study provides valuable new information of its epidemiology in this setting. Demographics reported are supportive of previous work and additional novel associations identified, such as the Border terrier, could enhance the index of suspicion for veterinarians.

Incidence and risk factors for feline lymphoma in UK primary-care practice.

OBJECTIVES: The study aimed to estimate the incidence and prevalence of feline lymphoma in cats attending primary-care practices across the UK and to identify patient-based and environmental (radon and pesticide exposure) risk factors. MATERIALS AND METHODS: Case records from the VetCompass programme from primary-care veterinary practices in the UK were searched for a diagnosis of lymphoma in cats in 2016. Cases were required to have had an external laboratory confirmed diagnosis based on cytology and/or histopathology. A nested case-control study design was used to identify risk factors for lymphoma using multivariable logistic regression. RESULTS: From a cohort of 562,446 cats under veterinary care at VetCompass participating practices in 2016, a total of 271 lymphoma cases were identified (prevalence: 48/100,000, 95% confidence interval (CI) 44 to 56/100,000; incidence 32/100,000, 95% CI 26 to 35/100,000). There were 180 incident lymphoma cases and 803 controls, all aged 2 years and older. Male (odds ratio (OR) 1.7, 95% CI 1.2 to 2.4), insured (OR 3.6, 95% CI 2.3 to 5.6) and older cats (compared to cats 2 to <5 years, OR 5.0, 95% CI 2.8 to 8.8) were associated with increased odds of lymphoma diagnosis. Vaccinated cats were associated with decreased odds (OR 0.7, 95% CI 0.5 to 1.0) compared to unvaccinated cats, although the type of vaccination received was not statistically significant. Breed and environmental factors studied were not associated with a diagnosis of lymphoma. CLINICAL SIGNIFICANCE: This is the first study to estimate the frequency and report risk factors for lymphoma in cats attending UK primary-care practice.

Hypoadrenocorticism in dogs under UK primary veterinary care: frequency, clinical approaches and risk factors.

OBJECTIVES: To estimate the frequency, clinical approaches and risk factors of hypoadrenocorticism in dogs under UK primary veterinary care. MATERIALS AND METHODS: Dogs diagnosed with hypoadrenocorticism were identified from the UK VetCompass™ programme by searching anonymised electronic patient records. Pre-existing and newly diagnosed cases of disease during 2016 were included. Cases were further sub-categorised as having a laboratory-confirmed or presumed diagnosis of hypoadrenocorticism based on the information recorded in the electronic patient records. Descriptive data were manually extracted. Multivariable logistic regression methods were used to identify demographic risk factors. RESULTS: There were 177 hypoadrenocorticism cases identified from 905,543 dogs in 2016; 72 laboratory-confirmed and 105 presumed. The 1-year period prevalence for hypoadrenocorticism in all dogs was 0.06% (95% confidence interval: 0.05-0.07%). The most common presenting clinical signs in laboratory-confirmed dogs were lethargy (51/66, 77.3%), anorexia (48/66, 66.7%) and vomiting (48/66, 66.7%). Hyperkalaemia was reported in 47 of 53 (88.7%), hyponatraemia in 46 of 53 (86.8%). Median sodium: potassium ratio was 19.00 (interquartile range: 16.20-20.60). Breed, age, neuter status and insurance status were associated with a laboratory-confirmed diagnosis of hypoadrenocorticism. No sex association with hypoadrenocorticism was observed in the multivariable model. The standard poodle had 51.38 times the odds (95% CI: 14.49-182.18) of hypoadrenocorticism compared with crossbreeds. The labradoodle and West Highland white terrier also had increased odds. CLINICAL SIGNIFICANCE: This is the first epidemiological study to report on hypoadrenocorticism in dogs within the UK primary-care population. These results provide benchmark data of current veterinary activity relating to hypoadrenocorticism in primary-care practices.

Incidence and risk factors for the diagnosis of lymphoma in dogs in UK primary-care practice.

OBJECTIVES: To identify the incidence, risk factors and presenting signs of lymphoma in dogs presenting to primary-care practice in the UK using analysis of data within the VetCompass™ programme. MATERIALS AND METHODS: Case records from the VetCompass™ programme from primary-care practices in the UK were searched for newly diagnosed lymphoma in dogs within a 1-year period: 2013. Diagnosis was based on clinical records with or without laboratory confirmation. Signalment was evaluated as risk factors for lymphoma diagnosis using multivariable logistic regression. RESULTS: There were 286 presumed newly diagnosed cases identified during 2013 from 455,553 dogs (overall incidence risk 63 of 100,000 dogs per year) of which 193 (67%) were laboratory confirmed (42 of 100,000 dogs per year). Advanced age, dogs older than 12 years, dogs weighing more than 30 kg and some specific breeds were significantly associated with lymphoma diagnosis. Only 18 dogs (6%) of the population identified were referred to a specialist clinic. CLINICAL SIGNIFICANCE: This study concurs with others that age, bodyweight and breed are significant risk factors for lymphoma. Results of this study highlight: (1) the low number of dogs with lymphoma that are referred to specialists in the UK and (2) that few dogs undergo immunophenotyping (which can carry prognostic importance), emphasising the importance of epidemiological programmes that evaluate diseases presented to primary-care veterinarians.

Geographic distribution and environmental risk factors of lymphoma in dogs under primary-care in the UK.

OBJECTIVES: To integrate external data sources with VetCompass postcode data to explore the spatial distribution and examine potential associations with environmental risk factors in dogs diagnosed with lymphoma at primary care veterinary practices. MATERIALS AND METHODS: Cases of lymphoma were identified from electronic patient records of 455,553 dogs under primary veterinary care during 2013 in the UK. Cases were defined as either laboratory-confirmed or non-laboratory-confirmed. Disease maps at the postcode-district level were used to define the geographic distribution of lymphoma incidence and spatial clustering was explored. Environmental risk factors from external data sources were transferred to a compatible format and logistic regression modelling was used to examine associations between environmental herbicide, fungicide and radon concentrations with lymphoma. RESULTS: From the denominator population of 455,553 dogs, 279 lymphoma cases (187 with laboratory confirmation and 93 without) were identified. Heterogeneous geographic variation was observed with weak evidence of clustering around London and the south-west of England. Herbicide and fungicide exposures were weakly associated with a diagnosis of lymphoma in the univariable analysis. After accounting for the age at diagnosis and breed in the multivariable analysis, herbicide exposure was associated with a diagnosis of lymphoma. CLINICAL SIGNIFICANCE: The heterogeneous distribution of lymphoma in UK dogs provides further evidence for geographic variation of lymphoma, perhaps in part associated with underlying environmental risk factors. The results suggest an association between environmental herbicide and canine lymphoma.

Diagnostic criteria for amyotrophic lateral sclerosis: A multicentre study of inter-rater variation and sensitivity.

OBJECTIVE: This study assesses inter-rater agreement and sensitivity of diagnostic criteria for amyotrophic lateral sclerosis (ALS). METHODS: Clinical and electrophysiological data of 399 patients with suspected ALS were collected by eleven experienced physicians from ten different countries. Eight physicians classified patients independently and blinded according to the revised El Escorial Criteria (rEEC) and to the Awaji Criteria (AC). Inter-rater agreement was assessed by Kappa coefficients, sensitivity by majority diagnosis on 350 patients with follow-up data. RESULTS: Inter-rater agreement was generally low both for rEEC and AC. Agreement was best on the categories "Not-ALS", "Definite", and "Probable", and poorest for "Possible" and "Probable Laboratory-supported". Sensitivity was equal for rEEC (64%) and AC (63%), probably due to downgrading of "Probable Laboratory-supported" patients by AC. However, AC was significantly more effective in classifying patients as "ALS" versus "Not-ALS" (p < 0.0001). CONCLUSIONS: Inter-rater variation is high both for rEEC and for AC probably due to a high complexity of the rEEC inherent in the AC. The gain of AC on diagnostic sensitivity is reduced by the omission of the "Probable Laboratory-supported" category. SIGNIFICANCE: The results highlight a need for initiatives to develop simpler and more reproducible diagnostic criteria for ALS in clinical practice and research.

Generalised sensory system abnormalities in amyotrophic lateral sclerosis: a European multicentre study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is defined as a disease of the motor neurones, although several studies indicate involvement of the sensory nervous system. AIM: To evaluate the sensory nerve conduction studies (NCS) in 88 patients with ALS as part of a European multicentre study. METHODS: Seven European clinical neurophysiologists examined consecutive series of ALS patients. The examinations were peer reviewed, and the diagnosis of ALS was confirmed clinically. RESULTS: 20 (22.7%) patients with ALS had sensory NCS abnormalities in at least one nerve. Of those, 11 (12.5% of all patients) obtained an additional peer review diagnosis of electrophysiological polyneuropathy. There was no difference between the subgroups of patients with normal versus abnormal sensory NCS findings with respect to age, duration and region of onset. CONCLUSION: The findings support previous reports of sensory involvement in ALS, and raise the question of whether patients with ALS with sensory nerve abnormalities represent a variant of ALS. ALS associated with generalised sensory system abnormalities may be consistent with degeneration of motor neurones and dorsal root ganglion cells.

Added value of electromyography in the diagnosis of myopathy: A consensus exercise.

OBJECTIVE: Currently, neurologists may primarily rely on blood biomarkers, muscle biopsy, MRI, and genetics in the diagnostic work-up of suspected myopathy. Using expert consensus as diagnostic reference standard, this study addressed the added value of electrodiagnostic medicine (EDX) in diagnosis of myopathies. METHODS: One hundred ninety-four EDX evaluations of patients with a peer-review consensus diagnosis of myopathy were collected by seven European centres. Each patient was given three different consensus diagnoses: (1) the EDX diagnosis solely based on EDX results, (2) the pure clinical diagnosis based on all available information except EDX results, and (3) the final diagnosis including EDX and all additional information. The myopathies were grouped as muscular dystrophy (45), inflammatory myopathy (46), other aetiology (36) or unknown aetiology (67). RESULTS: Higher diagnostic probabilities for myopathy were seen in the final diagnosis compared to the pure clinical diagnosis (p<0.001). Adding EDX information increased the diagnostic probability of myopathy in 67 patients (34.4%). The greatest increase was seen for myopathies of unknown aetiology. CONCLUSIONS: EDX has a major impact in the diagnosis of myopathies of unknown aetiology. In genetically or biopsy proven myopathies, EDX generally supports the diagnosis. SIGNIFICANCE: EDX is still a useful tool in the diagnostic work-up of most patients with suspected myopathy.

Amplitude, area and duration of the compound muscle action potential change in different ways over the length of the ulnar nerve.

OBJECTIVE: To study physiological changes of the compound muscle action potential (CMAP) obtained from stimulation at different sites over the full length of a motor nerve and to study possible effects of anthropometrical factors. METHODS: Multicentre study of ulnar motor nerve conduction in five segments to Erb's point performed bilaterally on 100 healthy subjects aged 17-83 years. RESULTS: CMAP amplitude decreased linearly with conduction distance (0.31%/cm) from wrist to Erb's point. CMAP area decreased with the square of conduction distance. Decrease in area was smaller than decrease in amplitude especially distally. CMAP duration increased linearly (0.17%/cm). Amplitude decay correlated with age, height and BMI and dispersion correlated with age and height. There were no correlations between area decay and anthropometrical factors. There was no significant inter-examiner variation. CONCLUSIONS: Area decay may be preferred to amplitude decay in the evaluation of conduction block over short segments due to smaller physiological changes and independence of anthropometrical factors. The absence of inter-examiner variation indicates that the results are robust and may be used by other laboratories. SIGNIFICANCE: This study provides knowledge of physiological changes of CMAP parameters that may be of importance in the evaluation of nerve pathology, in particular conduction block.

Variation in diagnostic strategy of the EMG examination--a multicentre study.

OBJECTIVES: In order to improve the universal quality of the EMG examination, knowledge about the variation among physicians is needed. METHODS: The variation among physicians in diagnostic strategy or criteria for diagnosing was analysed from a multicentre database with 940 EMG examinations sampled by seven physicians from six laboratories in Europe. RESULTS: For the whole group of patients as well as for the subgroup of patients with polyneuropathy, variation among physicians in examination techniques, number of examined structures per patient and number of abnormal structures per patient required for a diagnosis was found. Some of the variation may be explained by use of different techniques, which showed differences in sensitivity, while some of the variation may be due to differences in diagnostic strategy and criteria for diagnosing. CONCLUSIONS: The study indicates a need for development and revision of international guidelines for EMG practice although implementation of standards requires caution.

Variation in the classification of polyneuropathies among European physicians.

OBJECTIVE: Considerable debate still exists regarding the classification of polyneuropathies (PNPs) into predominantly demyelinating, predominantly axonal loss, mixed or unclassified. This study was designed to determine the variation among physicians in the classification of PNPs by using the European Standardized Telematic tool to Evaluate Electromyography knowledge-based systems and Methods (ESTEEM) multicenter database. METHODS: Seven physicians from 6 laboratories in Europe sent a total of 156 prospectively collected cases of PNP with electromyography (EMG) data including diagnosis (examination diagnosis) to the database. Each physician interpreted the electrophysiological data from all cases (interpretation diagnosis) and a final diagnosis was given at the consensus meetings of the group (consensus diagnosis). RESULTS: Comparison of each physician's examination diagnosis with his/her interpretation diagnosis, i.e. intra-physician variation, showed a change towards less classified PNPs (P < 0.05). Interpretation diagnoses showed large inter-physician variation in the classification of PNPs. The consensus group was more cautious than individual physicians in classifying PNPs as mixed and axonal. The probability of the consensus diagnosis increased with increasing number of abnormal motor and sensory segments tested. CONCLUSIONS: Recognition of variation in classification of PNP as shown in this study and suggesting standards of good clinical practice developed by a consensus group may increase the quality of EMG practice.

Comparison of electrophysiological and histochemical methods for assessing the spatial distribution of muscle fibres of a motor unit within muscle.

The spatial distribution of muscle fibres of a motor unit has been examined in patients with a variety of neuromuscular disorders using the fibre density (FD) technique of single fibre EMG and the enclosed fibre count (EFC) method, and the results of the two approaches compared. Agreement between the findings occurred in 64% of cases; an increase in both parameters was seen only in neurogenic conditions. FD was found to be more sensitive to minor disturbances of motor unit architecture as seen in myopathies and mild neurogenic states, and this factor together with sampling differences accounted for most of the discrepancies between the two methods. The finding of normal FD and EFC values in the presence of fibre type disproportion helped to exclude reinnervation as the cause by confirming the predominantly diffuse distribution of muscle fibres.

Solitary extranodal lymphoma of sciatic nerve.

A solitary extranodal malignant lymphoma (non-Hodgkin's lymphoma, centrocytic type) of the sciatic nerve is described in a 64-year-old woman. Whereas previous reports of peripheral nervous system lymphoma have described multifocal lesions and generally an association with systemic lymphomas, in this case the lymphoma was confined to a segment of a peripheral nerve and was not associated with systemic lymphoma. The clinical presentation was a progressive weakness and sensory disturbance in the right leg. Clinical and electrophysiological examination indicated a lesion in the sciatic nerve, and computerised tomography of the right thigh revealed an enlarged distal segment of the sciatic nerve. On surgical exploration, a fusiform tumour of the sciatic nerve was resected. Pathological examination, including immunohistology and electron microscopy revealed a malignant lymphoma. An unusual histological feature was the presence in the tumour and infiltrated nerve of an extracellular eosinophilic non-amyloid material, similar to that occasionally seen in nodal lymphomas. The patient showed no evidence of lymphoma at other sites at the presentation and this has been confirmed at a 9-month review.

Osteosarcoma: an example of the thickended periodontal ligament space.

A case of osteosarcoma which displayed a widened PDL space in a dental radiograph was presented. Other causes for thickening of the PDL were reviewed and differentiated from the features seen in osteosarcoma.

Artificial neural nets in computer-aided macro motor unit potential classification.

The use of macro electromyography to obtain a macro motor unit potential (MMUP) is described. At least 20 potentials are measured from a single muscle to obtain a reasonable estimate of the parameters of an average motor unit potential. The MMUP data are analyzed by means of the peak-to-peak amplitude and the integral of the central 50 ms of the signal. The possibility of using artificial neural networks (ANNs) to analyze the macro data in a way that makes no assumptions about the relationships between the parameters and without recourse to conventional modeling methods is discussed. The results of an analysis carried out on 820 MMUPs recorded from 41 subjects who were classified on the basis of a clinical opinion and the appearance of a muscle biopsy are presented and discussed.

A morphological analysis of the macro motor unit potential.

The technique of macro EMG is used to investigate the motor unit architecture in a number of pathological conditions. Amplitude and area are the most commonly used criteria, but these parameters alone are not sufficient to assess the complexity of the macro MUP morphology. In an attempt to examine the morphology of the macro MUP in more detail, additional measures were investigated including, (i) average power, (ii) duration, and (iii) number of phases. Macro MUP duration was defined as the time parameter that contains a particular fraction (90%) of the total power of the potential. The above mentioned parameters were evaluated for normal subjects and for patients suffering with motor neuron disease (MND), spinal muscular atrophy (SMA), and Becker's muscular dystrophy (BMD). It is shown that high amplitude and average power macro MUPs give shorter macro MUP duration than macro MUPs with normal amplitude. In contrast, in low amplitude macro MUPs there is a tendency towards a higher duration measure, as compared with the duration of the normal amplitude macro MUPs. Also, t-test results for the duration measure gave a significant difference between the NOR-MND, and no significant difference between the NOR-BMD and NOR-SMA groups at P<0. 05. Significant difference between the NOR and the three disease groups investigated was obtained for the parameters log amplitude, log area, and log average power. The number of phases was not significantly different between the NOR and the rest of the groups. In conclusion, the average power and duration parameters can possibly be used as additional discriminators to detect abnormalities of the macro motor unit potential in both needle and surface EMG but further investigation is necessary.

Quality assurance in clinical neurophysiology: the ESTEEM project example.

This paper describes the current status of the utilisation of clinical practice guidelines (protocols) in the ESTEEM project as one form of the clinical quality assurance procedures considered in the project. The performance of electrodiagnostic studies, in terms of which types of conclusions need to be inferred during the examination plan, is briefly described. The main focus of the paper is a description of an European multicentre clinical audit in the field of Clinical Neurophysiology, using a common data-entry protocol for prospective EMG case collection and assessment with the ultimate objective of building up a multicentre reference database of EMG cases.

The need for specialist nurses to work with older people.

This article is based on a comprehensive literature review undertaken by the Royal College of Nursing gerontological nursing programme on the development of specialist gerontological nursing practice (Schofield et al, 1998). The scope of the original review covered the development of specialist nursing, frameworks for practice, accreditation and regulation, role components and competencies, methods of evaluating the specialist role and fields of practice. The literature review's purpose was to inform work on the development of a specialist gerontological nursing BSc (Hons) degree by distance learning. This article focuses on the key findings of the literature review, setting out the potential for the introduction of specialist gerontological nurses in the UK.