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1.  Dual-task interference and brain structural connectivity in people with Parkinson’s disease who freeze 
Background
Freezing of gait in people with Parkinson’s disease (PD) is likely related to attentional control (ie, ability to divide and switch attention). However, the neural pathophysiology of altered attentional control in individuals with PD who freeze is unknown. Structural connectivity of the pedunculopontine nucleus has been related to freezing and may play a role in altered attentional control; however, this relationship has not been investigated. We measured whether dual-task interference, defined as the reduction in gait performance during dual-task walking, is more pronounced in individuals with PD who freeze, and whether dual-task interference is associated with structural connectivity and/or executive function in this population.
Methods
We measured stride length in 13 people with PD with and 12 without freezing of gait during normal and dual-task walking. We also assessed asymmetry of pedunculopontine nucleus structural connectivity via diffusion tensor imaging and performance on cognitive tests assessing inhibition and set-shifting, cognitive domains related to freezing.
Results
Although stride length was not different across groups, change in stride length between normal and dual-task gait (ie, dual-task interference) was more pronounced in people with PD who freeze compared to non-freezers. Further, in people with PD who freeze, dual-task interference was correlated with asymmetry of pedunculopontine nucleus structural connectivity, Go-NoGo target accuracy (ability to release a response) and simple reaction time.
Conclusions
These results support the hypothesis that freezing is related to altered attentional control during gait, and suggest that differences in pedunculopontine nucleus connectivity contribute to poorer attentional control in people with PD who freeze.
doi:10.1136/jnnp-2014-308840
PMCID: PMC4363035  PMID: 25224677
2.  Re-evaluating the treatment of acute optic neuritis 
Clinical case reports and prospective trials have demonstrated a reproducible benefit of hypothalamic-pituitary-adrenal (HPA) axis modulation on the rate of recovery from acute inflammatory central nervous system (CNS) demyelination. As a result, corticosteroid preparations and adrenocorticotrophic hormones are the current mainstays of therapy for the treatment of acute optic neuritis (AON) and acute demyelination in multiple sclerosis.
Despite facilitating the pace of recovery, HPA axis modulation and corticosteroids have failed to demonstrate long-term benefit on functional recovery. After AON, patients frequently report visual problems, motion perception difficulties and abnormal depth perception despite ‘normal’ (20/20) vision. In light of this disparity, the efficacy of these and other therapies for acute demyelination require re-evaluation using modern, high-precision paraclinical tools capable of monitoring tissue injury.
In no arena is this more amenable than AON, where a new array of tools in retinal imaging and electrophysiology has advanced our ability to measure the anatomic and functional consequences of optic nerve injury. As a result, AON provides a unique clinical model for evaluating the treatment response of the derivative elements of acute inflammatory CNS injury: demyelination, axonal injury and neuronal degeneration.
In this article, we examine current thinking on the mechanisms of immune injury in AON, discuss novel technologies for the assessment of optic nerve structure and function, and assess current and future treatment modalities. The primary aim is to develop a framework for rigorously evaluating interventions in AON and to assess their ability to preserve tissue architecture, re-establish normal physiology and restore optimal neurological function.
doi:10.1136/jnnp-2014-308185
PMCID: PMC4414747  PMID: 25355373
3.  Re-evaluating the treatment of acute optic neuritis 
Clinical case reports and prospective trials have demonstrated a reproducible benefit of hypothalamic-pituitary-adrenal (HPA) axis modulation on the rate of recovery from acute inflammatory central nervous system (CNS) demyelination. As a result, corticosteroid preparations and adrenocorticotrophic hormones are the current mainstays of therapy for the treatment of acute optic neuritis (AON) and acute demyelination in multiple sclerosis.
Despite facilitating the pace of recovery, HPA axis modulation and corticosteroids have failed to demonstrate long-term benefit on functional recovery. After AON, patients frequently report visual problems, motion perception difficulties and abnormal depth perception despite ‘normal’ (20/20) vision. In light of this disparity, the efficacy of these and other therapies for acute demyelination require re-evaluation using modern, high-precision paraclinical tools capable of monitoring tissue injury.
In no arena is this more amenable than AON, where a new array of tools in retinal imaging and electrophysiology has advanced our ability to measure the anatomic and functional consequences of optic nerve injury. As a result, AON provides a unique clinical model for evaluating the treatment response of the derivative elements of acute inflammatory CNS injury: demyelination, axonal injury and neuronal degeneration.
In this article, we examine current thinking on the mechanisms of immune injury in AON, discuss novel technologies for the assessment of optic nerve structure and function, and assess current and future treatment modalities. The primary aim is to develop a framework for rigorously evaluating interventions in AON and to assess their ability to preserve tissue architecture, re-establish normal physiology and restore optimal neurological function.
doi:10.1136/jnnp-2014-308185
PMCID: PMC4414747  PMID: 25355373
NEUROOPHTHALMOLOGY; MULTIPLE SCLEROSIS; VISION
5.  Amyloid imaging in Alzheimer's disease: comparison of Florbetapir and Pittsburgh Compound-B PET 
Amyloid imaging provides in vivo detection of the fibrillar amyloid-β (Aβ) plaques of Alzheimer's Disease (AD). The PET ligand Pittsburgh Compound-B (PiB-C11) is the most well studied amyloid imaging agent, but the short half-life of carbon-11 limits its clinical viability. Florbetapir-F18 recently demonstrated in vivo correlation with post-mortem Aβ histopathology, but has not been directly compared with PiB-C11. Fourteen cognitively normal adults and 12 AD patients underwent PiB-C11 and florbetapir-F18 PET scans within a 28 day period. Both ligands displayed highly significant group discrimination and correlation of regional uptake, supporting the hypothesis that florbetapir-F18 provides comparable information with PiB-C11.
doi:10.1136/jnnp-2012-302548
PMCID: PMC4479493  PMID: 22791901
7.  The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey 
Recent advances in understanding amyotrophic lateral sclerosis (ALS) have delivered new questions. Disappointingly, the initial enthusiasm for transgenic mouse models of the disease has not been followed by rapid advances in therapy or prevention. Monogenic models may have inadvertently masked the true complexity of the human disease. ALS has evolved into a multisystem disorder, involving a final common pathway accessible via multiple upstream aetiological tributaries. Nonetheless, there is a common clinical core to ALS, as clear today as it was to Charcot and others. We stress the continuing relevance of clinical observations amid the increasing molecular complexity of ALS.
doi:10.1136/jnnp-2014-308946
PMCID: PMC4453495  PMID: 25644224
MOTOR NEURON DISEASE; CLINICAL NEUROLOGY; GENETICS; MOLECULAR BIOLOGY; PRION
8.  Neuronal antibodies in patients with suspected or confirmed sporadic Creutzfeldt-Jakob disease 
Objectives
There have been reports of patients with antibodies to neuronal antigens misdiagnosed as sporadic Creutzfeldt-Jakob disease (sCJD). Conversely, low levels of antibodies to neuronal proteins have been reported in patients with sCJD. However, the frequency of misdiagnoses, or of antibodies in patients with subsequently confirmed sCJD, is not clear.
Methods
We reviewed 256 consecutive cases of sCJD seen in the National Prion Clinic, of whom 150 had sera previously referred for selected antibody tests. Eighty-two available samples were retested for antibodies to N-methyl-d-aspartate receptor (NMDAR), the glycine receptor (GlyR), voltage-gated potassium channel (VGKC)-complex and the associated proteins, leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2).
Results
Four of the initial 150 sera referred were positive; two had antibodies to NMDAR, and two to the VGKC-complex, one of which was also positive for GlyR antibodies. Of the 82 sCJD sera retested, one had VGKC-complex antibodies confirming the previous result, two had CASPR2 and GlyR antibodies and one had CASPR2 and NMDAR antibodies; all antibodies were at low levels. Over the same period three patients with autoimmune encephalitis and high VGKC-complex antibodies were initially referred as sCJD.
Conclusions
This study indicates that <5% patients with sCJD develop serum antibodies to these neuronal antigens and, when positive, only at low titres. By contrast, three patients referred with possible prion disease had a clinical picture in keeping with autoimmune encephalitis and very high VGKC-complex/LGI1 antibodies. Low titres of neuronal antibodies occur only rarely in suspected patients with sCJD and when present should be interpreted with caution.
doi:10.1136/jnnp-2014-308695
PMCID: PMC4453627  PMID: 25246643
PRION; NMDA; NEUROIMMUNOLOGY; IMMUNOLOGY; LIMBIC SYSTEM
9.  Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex antibodies: experience from a tertiary referral centre 
Background
Voltage-gated potassium channel (VGKC)-complex antibodies can be associated with a range of immunotherapy-responsive clinical presentations including limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. However, there are patients with positive levels in whom the significance is uncertain.
Objective
To evaluate the clinical significance associated with positive (>100 pM) VGKC-complex antibodies.
Methods
Over a 4-year period, 1053 samples were sent for testing of which 55 were positive. The clinical presentations, final diagnoses and responses to immunotherapies, when given, were assessed retrospectively and the likelihood of autoimmunity was categorised as definite, possible, unlikely or undetermined (modified from Zuliani et al 2012).
Results
Only 4 of the 32 patients with low-positive (100–400 pM) levels were considered definitely autoimmune, 3 with peripheral nerve hyperexcitability and 1 with a thymoma; 3 were given immunotherapies. Of the remaining 28 with low-positive levels, 13 (3 of whom had tumours) were considered possibly autoimmune, and 15 were unlikely or undetermined; 1 was given immunotherapy unsuccessfully. Of the 23 patients with high-positive (>400 pM) levels, 12 were given immunotherapies, 11 of whom showed a good response. 11 were considered definitely autoimmune, 10 with limbic encephalitis (antibody specificity: 5 LGI1, 1 contactin2, 2 negative, 2 untested) and 1 with a tumour. In the remaining 12, autoimmunity was considered possible (n=9; most had not received immunotherapies), or unlikely (n=3).
Conclusions
As antibody testing becomes more widely available, and many samples are referred from patients with less clear-cut diagnoses, it is important to assess the utility of the results. VGKC-complex antibodies in the range of 100–400 pM (0.1–0.4 nM) were considered clinically relevant in rare conditions with peripheral nerve hyperexcitability and appeared to associate with tumours (12.5%). By contrast high-positive (>400 pM; >0.4 nM) levels were considered definitely (38%) or possibly (49%) clinically relevant, but not all patients had a ‘classical’ limbic encephalitis and some did not receive immunotherapies.
doi:10.1136/jnnp-2013-305218
PMCID: PMC4451115  PMID: 23757422
NEUROIMMUNOLOGY; LIMBIC SYSTEM; EPILEPSY
11.  Long-term outcome of subthalamic nucleus deep brain stimulation for Parkinson's disease using an MRI-guided and MRI-verified approach 
Background
Subthalamic nucleus (STN) deep brain stimulation (DBS) represents a well-established treatment for patients with advanced Parkinson's disease (PD) insufficiently controlled with medical therapies. This study presents the long-term outcomes of patients with PD treated with STN-DBS using an MRI-guided/MRI-verified approach without microelectrode recording.
Methods
A cohort of 41 patients who underwent STN-DBS were followed for a minimum period of 5 years, with a subgroup of 12 patients being followed for 8–11 years. Motor status was evaluated using part III of the Unified Parkinson's Disease Rating Scale (UPDRS-III), in on- and off-medication/on-stimulation conditions. Preoperative and postoperative assessments further included activities of daily living (UPDRS-II), motor complications (UPDRS-IV), neuropsychological and speech assessments, as well as evaluation of quality of life. Active contacts localisation was calculated and compared with clinical outcomes.
Results
STN-DBS significantly improved the off-medication UPDRS-III scores, compared with baseline. However, UPDRS scores increased over time after DBS. Dyskinesias, motor fluctuations and demands in dopaminergic medication remained significantly reduced in the long term. Conversely, UPDRS-III on-medication scores deteriorated at 5 and 8 years, mostly driven by axial and bradykinesia subscores. Quality of life, as well as depression and anxiety scores, did not significantly change at long-term follow-up compared with baseline. In our series, severe cognitive decline was observed in 17.1% and 16.7% of the patients at 5 and 8 years respectively.
Conclusions
Our data confirm that STN-DBS, using an MRI-guided/MRI-verified technique, remains an effective treatment for motor ‘off’ symptoms of PD in the long term with low morbidity.
doi:10.1136/jnnp-2013-306907
PMCID: PMC4451170  PMID: 24790212
PARKINSON'S DISEASE; NEUROSURGERY
12.  Rapidly progressive atypical parkinsonism associated with frontotemporal lobar degeneration and motor neuron disease 
Objective
To report the rare but distinct clinical and neuropathological phenotype of non-familial, rapidly progressive parkinsonism and dementia associated with frontotemporal lobar degeneration with motor neuron disease (FTLD-MND).
Methods
Subjects included two 70-year-old women presenting with rapidly progressive severe postural instability, axial-predominant parkinsonism, oculomotor dysfunction and frontal-predominant dementia with language impairment and pseudobulbar palsy. One had diffuse weakness without signs of lower motor neuron disease. Post-mortem evaluations included immunohistochemistry with antiphospho-TAR DNA-binding protein 43 (TDP-43) and genetic analysis of the TARDBP and PGRN genes.
Results
Subjects died within 14 months from symptom onset. TDP-43-positive neuronal intracytoplasmic inclusions were prominent in the primary motor cortex, granule cell layer of the hippocampus, and several cranial and spinal cord nuclei. TDP-43 globular glial inclusions (GGI) were identified in one case. There were no mutations in PGRN or TARDBP genes.
Conclusions
FTLD-MND due to TDP-43-proteinopathy should be considered in patients with rapidly progressive parkinsonism and dementia phenotype, especially when aphasia and/or weakness are also present.
doi:10.1136/jnnp.2009.201608
PMCID: PMC4449730  PMID: 20587488
13.  The grey matter correlates of impaired decision-making in multiple sclerosis 
Objective
People with multiple sclerosis (MS) have difficulties with decision-making but it is unclear if this is due to changes in impulsivity, risk taking, deliberation or risk adjustment, and how this relates to brain pathology.
Methods
We assessed these aspects of decision-making in 105 people with MS and 43 healthy controls. We used a novel diffusion MRI method, diffusion orientational complexity (DOC), as an index of grey matter pathology in regions associated with decision-making and also measured grey matter tissue volumes and white matter lesion volumes.
Results
People with MS showed less adjustment to risk and slower decision-making than controls. Moreover, impaired decision-making correlated with reduced executive function, memory and processing speed. Decision-making impairments were most prevalent in people with secondary progressive MS. They were seen in patients with cognitive impairment and those without cognitive impairment. On diffusion MRI, people with MS showed DOC changes in all regions except the occipital cortex, relative to controls. Risk adjustment correlated with DOC in the hippocampi and deliberation time with DOC in the medial prefrontal, middle frontal gyrus, anterior cingulate and caudate parcellations and with white matter lesion volumes.
Conclusions
These data clarify the features of decision-making deficits in MS, and provide the first evidence that they relate to grey and white matter abnormalities seen using MRI.
doi:10.1136/jnnp-2014-308169
PMCID: PMC4413680  PMID: 25006208
Multiple Sclerosis; MRI
14.  MRI in Leber's hereditary optic neuropathy: the relationship to multiple sclerosis 
Background
Leber's hereditary optic neuropathy (LHON) and a multiple sclerosis (MS)-like illness appear to coexist 50 times more frequently than would be expected by chance. This association of LHON and MS (LMS) raises an important question about whether there could be a common pathophysiological mechanism involving mitochondrial dysfunction.
Objective
The primary aim was to define MRI features of LMS and LHON, and to assess the proportions of individuals displaying features typical of MS. Secondarily, we investigated the effect of gender on the risk of developing white matter lesions in the context of LHON.
Methods
A blinded standardised review of conventional brain MRIs of 30 patients with MS, 31 patients with LHON and 11 patients with LMS was conducted by three independent experts in the field. MS-like MRI features were assessed.
Results
All patients with LMS and 26% of patients with LHON had white matter lesions. Of these, all patients with LMS and 25% with LHON were found to have an MRI appearance typical of MS. Female patients with LHON had a significantly greater risk of having white matter lesions consistent with MS compared with male patients (relative risk 8.3).
Conclusions
A blinded review of conventional brain MRIs shows that patients with LMS have a scan appearance indistinguishable from MS. Mitochondrial dysfunction could be a common pathophysiological pathway in the formation of white matter lesions. There appears to be a strong female influence on the radiological appearance as well as clinical development of MS in patients with LHON.
doi:10.1136/jnnp-2014-308186
PMCID: PMC4413690  PMID: 25053773
Leber Heredit Optic Atropy; MRI; Multiple Sclerosis; Neurogenetics
15.  Brief intervention for medication-overuse headache in primary care. The BIMOH study: a double-blind pragmatic cluster randomised parallel controlled trial 
Background
Medication-overuse headache (MOH) is common in the general population. We investigated effectiveness of brief intervention (BI) for achieving drug withdrawal in primary care patients with MOH.
Methods
The study was double-blind, pragmatic and cluster-randomised controlled. A total of 25 486 patients (age 18–50) from 50 general practitioners (GPs) were screened for MOH. GPs defined clusters and were randomised to receive BI training (23 GPs) or to continue business as usual (BAU; 27 GPs). The Severity of Dependence Scale was applied as a part of the BI. BI involved feedback about individual risk of MOH and how to reduce overuse. Primary outcome measures were reduction in medication and headache days/month 3 months after the intervention and were assessed by a blinded clinical investigator.
Results
42% responded to the postal screening questionnaire, and 2.4% screened positive for MOH. A random selection of up to three patients with MOH from each GP were invited (104 patients), 75 patients were randomised and 60 patients included into the study. BI was significantly better than BAU for the primary outcomes (p<0.001). Headache and medication days were reduced by 7.3 and 7.9 (95% CI 3.2 to 11.3 and 3.2 to 12.5) days/month in the BI compared with the BAU group. Chronic headache resolved in 50% of the BI and 6% of the BAU group.
Conclusions
The BI method provides GPs with a simple and effective instrument that reduces medication-overuse and headache frequency in patients with MOH.
Trial registration number
NCT01314768.
doi:10.1136/jnnp-2014-308548
PMCID: PMC4413802  PMID: 25112307
HEADACHE; MIGRAINE; PAIN
16.  Pregnancy outcomes in patients exposed to interferon beta-1b 
doi:10.1136/jnnp-2014-308113
PMCID: PMC4413804  PMID: 25185209
MULTIPLE SCLEROSIS; INTERFERON; PAEDIATRIC
17.  Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study 
Objective
To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS).
Methods
A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression.
Results
Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products.
Conclusions
Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progression.
Trail registration number
NIHRID6160.
doi:10.1136/jnnp-2014-307672
PMCID: PMC4413806  PMID: 25009280
ALS; Motor Neuron Disease; Neuroimmunology
19.  An observational study of asymmetry in CMT1A 
doi:10.1136/jnnp-2014-309096
PMCID: PMC4413808  PMID: 25313262
NEUROPATHY; CLINICAL NEUROLOGY; NEUROGENETICS
20.  GNE Myopathy: current update and future therapy 
GNE myopathy is an autosomal recessive muscle disease due to biallelic mutations in GNE, a gene encoding for a single protein with key enzymatic activities in sialic acid biosynthetic pathway. The diagnosis should be considered primarily in patients presenting with distal weakness (foot drop) in early adulthood (other onset symptoms are possible too). The disease slowly progresses to involve other lower and upper extremities’ muscles, with marked sparing of the quadriceps. Characteristic findings found in biopsies of affected muscles include “rimmed” (autophagic) vacuoles, aggregation of various proteins, and fiber size variation. The diagnosis is confirmed by sequencing of the GNE gene. Note that we use a new mutation nomenclature based upon the longest transcript (GenBank: NM_001128227), which encodes a 31-amino-acid longer protein than the originally described one (GenBank: NM_005476), which has been used previously in most papers. Given the pathophysiology of the disease, recent clinical trials have evaluated the use of sialic acid or ManNAc (a precursor of sialic acid) in patients with GNE myopathy as well as early gene therapy trials. Now that therapies are under investigation, it is critical that a timely and accurate diagnosis is made in patients with GNE myopathy.
doi:10.1136/jnnp-2013-307051
PMCID: PMC4394625  PMID: 25002140
GNE myopathy; hereditary inclusion body myopathy; distal myopathy with rimmed vacuoles; sialic acid; N-acetylmannosamine (ManNAc)
21.  Effect of subthalamic nucleus deep brain stimulation on dual-task cognitive and motor performance in isolated dystonia 
Objective
Subthalamic nucleus (STN) deep brain stimulation (DBS) can improve motor complications of Parkinson's disease (PD) but may worsen specific cognitive functions. The effect of STN DBS on cognitive function in dystonia patients is less clear. Previous reports indicate that bilateral STN stimulation in patients with PD amplifies the decrement in cognitive-motor dual-task performance seen when moving from a single-task to dual-task paradigm. We aimed to determine if the effect of bilateral STN DBS on dual-task performance in isolated patients with dystonia, who have less cognitive impairment and no dementia, is similar to that seen in PD.
Methods
Eight isolated predominantly cervical patients with dystonia treated with bilateral STN DBS, with average dystonia duration of 10.5 years and Montreal Cognitive Assessment score of 26.5, completed working memory (n-back) and motor (forced-maintenance) tests under single-task and dual-task conditions while on and off DBS.
Results
A multivariate, repeated-measures analysis of variance showed no effect of stimulation status (On vs Off) on working memory (F=0.75, p=0.39) or motor function (F=0.22, p=0.69) when performed under single-task conditions, though as working memory task difficulty increased, stimulation disrupted the accuracy of force-tracking. There was a very small worsening in working memory performance (F=9.14, p=0.019) when moving from single-task to dual-tasks when using the ‘dual-task loss’ analysis.
Conclusions
This study suggests the effect of STN DBS on working memory and attention may be much less consequential in patients with dystonia than has been reported in PD.
doi:10.1136/jnnp-2014-307942
PMCID: PMC4392192  PMID: 25012202
Dystonia; Cognition; Memory
22.  Patterns of cerebral and cerebellar white matter degeneration in ALS 
doi:10.1136/jnnp-2014-308172
PMCID: PMC4392231  PMID: 25053771
ALS; MRI; Cerebellar Disease; Neuroradiology; Motor Neuron Disease
23.  The Safety of Airplane Travel in Patients with Symptomatic Carotid Occlusion 
Objective
Patients with carotid stenosis or occlusion may be at increased risk for stroke during air travel. Records from the Carotid Occlusion Surgery Study (COSS), a randomized trial of surgical revascularization for complete carotid artery occlusion and hemodynamic ischemia, were examined for evidence of stroke related to air travel.
Methods
COSS subjects who travelled by airplane to a regional Positron Emission Tomography (PET) center for a screening cerebrovascular hemodynamic evaluation were identified. Maximum altitude and total flight time were estimated based on the distance between origin and destination. Ischemic events were determined by a structured telephone interview within 24 hours of travel. Patient demographics, co-morbidities, OEF data and 24-hour interview responses were recorded.
Results
Seventy-seven patients with symptomatic carotid occlusion travelled by airplane to a single PET center (174 flights). Fifty two (67.5%) were male and 25 (32.5%) were females. The average age was 58.7 ± 1.4 years. Twenty-seven patients (35.1%) demonstrated evidence of ipsilateral hemodynamic cerebral ischemia as measured by PET OEF, while 50 (64.9%) had normal OEF. Patients flew an average distance of 418.9 ± 25.9 miles for 107.1 ± 4.7 minutes per trip. No patient reported symptoms of a transient ischemic attack or stroke during or within 24 hours after airplane travel (95% CI 0 – 2.0%).
Conclusions
The risk of stroke as a consequence of air travel is low, even in a cohort of patients at high risk for future stroke owing to hemodynamic impairment. These patients with should not be discouraged from air travel.
doi:10.1136/jnnp-2013-306627
PMCID: PMC4245017  PMID: 24249780
PET; Stroke; Cerebrovascular Disease
24.  Atrophy in distinct corticolimbic networks in frontotemporal dementia relates to social impairments measured using the Social Impairment Rating Scale 
Patients with frontotemporal dementia (FTD) often exhibit prominent, early and progressive impairments in social behaviour. We developed the Social Impairment Rating Scale (SIRS), rated by a clinician after a structured interview, which grades the types and severity of social behavioural symptoms in seven domains. In 20 FTD patients, we used the SIRS to study the anatomic basis of social impairments. In support of hypotheses generated from a prior study of healthy adults, we found that the relative magnitude of brain atrophy in three partially dissociable corticolimbic networks anchored in the amygdala predicted the severity of distinct social impairments measured using the SIRS. Patients with the greatest atrophy in a mesolimbic, reward-related (affiliation) network exhibited the most severe socioemotional detachment, whereas patients with the greatest atrophy in an interoceptive, pain-related (aversion) network exhibited the most severe lack of social apprehension. Patients with the greatest atrophy in a perceptual network exhibited the most severe lack of awareness or understanding of others’ social and emotional behaviour. Our findings underscore observations that FTD is associated with heterogeneous social symptoms that can be understood in a refined manner by measuring impairments in component processes subserved by dissociable neural networks. Furthermore, these findings support the validity of the SIRS as an instrument to measure the social symptoms of patients with FTD. Ultimately, we hope it will be useful as a longitudinal outcome measure in natural history studies and in clinical trials of putative interventions to improve social functioning.
doi:10.1136/jnnp-2012-304656
PMCID: PMC4315506  PMID: 24133285
25.  Increased prevalence of ECG markers for sudden cardiac arrest in refractory epilepsy 
Background and aim
People with epilepsy are at increased risk of sudden cardiac arrest (SCA) due to ECG-confirmed ventricular tachycardia/fibrillation, as seen in a community-based study. We aimed to determine whether ECG-risk markers of SCA are more prevalent in people with epilepsy.
Methods
In a cross-sectional, retrospective study, we analysed the ECG recordings of 185 people with refractory epilepsy and 178 controls without epilepsy. Data on epilepsy characteristics, cardiac comorbidity, and drug use were collected, and general ECG variables (heart rate (HR), PQ and QRS intervals) assessed. We analysed ECGs for three markers of SCA risk: severe QTc prolongation (male >450 ms, female >470 ms), Brugada ECG pattern, and early repolarisation pattern (ERP). Multivariate regression models were used to analyse differences between groups, and to identify associated clinical and epilepsy-related characteristics.
Results
People with epilepsy had higher HR (71 vs 62 bpm, p<0.001) and a longer PQ interval (162.8 vs 152.6 ms, p=0.001). Severe QTc prolongation and ERP were more prevalent in people with epilepsy (QTc prolongation: 5% vs 0%; p=0.002; ERP: 34% vs 13%, p<0.001), while the Brugada ECG pattern was equally frequent in both groups (2% vs 1%, p>0.999). After adjustment for covariates, epilepsy remained associated with ERP (ORadj 2.4, 95% CI 1.1 to 5.5) and severe QTc prolongation (ORadj 9.9, 95% CI 1.1 to 1317.7).
Conclusions
ERP and severe QTc prolongation appear to be more prevalent in people with refractory epilepsy. Future studies must determine whether this contributes to increased SCA risk in people with epilepsy.
doi:10.1136/jnnp-2014-307772
PMCID: PMC4345521  PMID: 24946773
Anticonvulsants; Channels; Epilepsy; Sudden Death

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