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1.  Clinical, genetic, neurophysiological and functional study of new mutations in episodic ataxia type 1 
Background and objective
Heterozygous mutations in KCNA1 cause episodic ataxia type 1 (EA1), an ion channel disorder characterised by brief paroxysms of cerebellar dysfunction and persistent neuromyotonia. This paper describes four previously unreported families with EA1, with the aim of understanding the phenotypic spectrum associated with different mutations.
Methods
15 affected individuals from four families underwent clinical, genetic and neurophysiological evaluation. The functional impact of new mutations identified in the KCNA1 gene was investigated with in vitro electrophysiology and immunocytochemistry.
Results
Detailed clinical documentation, dating back to 1928 in one family, indicates that all patients manifested episodic ataxia of varying severity. Four subjects from three families reported hearing impairment, which has not previously been reported in association with EA1. New mutations (R167M, C185W and I407M) were identified in three out of the four families. When expressed in human embryonic kidney cells, all three new mutations resulted in a loss of Kv1.1 channel function. The fourth family harboured a previously reported A242P mutation, which has not been previously described in association with ataxia.
Conclusions
The genetic basis of EA1 in four families is established and this report presents the earliest documented case from 1928. All three new mutations caused a loss of Kv1.1 channel function. The finding of deafness in four individuals raises the possibility of a link between Kv1.1 dysfunction and hearing impairment. Our findings broaden the phenotypic range associated with mutations in KCNA1.
doi:10.1136/jnnp-2012-304131
PMCID: PMC4332158  PMID: 23349320
Cerebellar Ataxia; Epilepsy; Neurogenetics; Neuromuscular; Neurophysiol, Clinical
2.  DIAGNOSIS AND MANAGEMENT OF MARCHIAFAVA-BIGNAMI DISEASE: A REVIEW OF CT/MRI CONFIRMED CASES 
Objective
Marchiafava-Bignami disease (MBD) is a rare condition mainly associated with alcoholism, although it may be mimicked by several other disorders that cause corpus callosum lesions. Our objective was to identify helpful features for differential diagnosis and assess whether any treatment can be recommended.
Methods
We reviewed 122 reports containing data on 153 subjects with confirmed MBD that was associated with either alcoholism or malnutrition and 20 reports with data on 53 subjects with conditions mimicking MBD. All the cases had been verified ante mortem by brain imaging. Unconditional logistic regression was used to demonstrate factors that were associated with the outcome of MBD.
Results
The mimicking conditions were differentiated from MBD by the occurrence of solitary and rapidly disappearing splenial lesions; fewer signs and symptoms with exception of seizures, hemiparesis, and tetraparesis; nystagmus; and rapid, complete recovery. MBD occurred most frequently among alcoholics, but it was also reported in 11 non-alcoholics (7·2% of all the MBD cases). A better outcome was observed among those who were treated within two weeks after onset of symptoms with parenteral thiamine (p=0·033).
Conclusions
As thiamine deficiency is frequently associated with alcoholism, malnutrition and prolonged vomiting, we recommend prompt treatment of MBD with parenteral thiamine in such subjects. Recovery should be followed by repeated neuropsychological and MRI examinations, preferably using diffusion tensor imaging.
doi:10.1136/jnnp-2013-305979
PMCID: PMC4160728  PMID: 23978380
Marchiafava-Bignami disease; outcome; treatment; thiamine; differential diagnosis
5.  Cognitive decline in prodromal Huntington Disease: Implications for Clinical Trials 
Controversy exists regarding the feasibility of preventive clinical trials in prodromal Huntington disease (HD). A primary limitation is a lack of outcome measures for persons with the gene mutation who have not yet been diagnosed with HD. Many longitudinal studies of cognitive decline in prodromal HD have not stratified samples based on disease progression, thereby obscuring differences between symptomatic and nonsymptomatic individuals. Prodromal participants from PREDICT-HD were stratified by disease progression into one of three groups: those having a High, Medium, or Low probability of motor manifestation within the next five years. Data from a total of N = 1299 participants with up to 5950 data points were subjected to linear mixed effects regression on 29 longitudinal cognitive variables, controlling for age, education, depression, and gender. Performance of the three prodromal HD groups was characterized by insidious and significant cognitive decline over time. Twenty-one variables from 19 distinct cognitive tasks revealed evidence of a disease progression gradient, meaning that the rate of deterioration varied as a function of progression level, with faster deterioration associated with greater disease progression. Nineteen measures showed significant longitudinal change in the High group, nine showed significant change in the Medium group and four showed significant cognitive decline in the Low group. Results indicate that clinical trials may be conducted in prodromal HD using the outcome measures and methods specified. The findings may help inform interventions in HD as well as other neurodegenerative disorders.
doi:10.1136/jnnp-2013-305114
PMCID: PMC3795884  PMID: 23911948
6.  Exome sequencing identifies a significant variant in methionyl-tRNA synthetase (MARS) in a family with late-onset CMT2 
Charcot–Marie–Tooth (CMT) disease is a genetically heterogeneous condition with >50 genes now being identified. Thanks to new technological developments, namely, exome sequencing, the ability to identify additional rare genes in CMT has been drastically improved. Here we present data suggesting that MARS is a very rare novel cause of late-onset CMT2. This is supported by strong functional and evolutionary evidence, yet the absence of additional unrelated cases warrant future studies to substantiate this conclusion.
doi:10.1136/jnnp-2013-305049
PMCID: PMC3796032  PMID: 23729695
7.  Advances in epilepsy surgery 
This review summarises exciting recent and forthcoming advances that will impact on the surgical management of epilepsy in the near future. This does not cover the current accepted diagnostic methodologies or surgical treatments that are routinely practiced today. The content of this review was derived from a PubMed literature search, using the key words ‘Epilepsy Surgery’, ‘Neuromodulation’, ‘Neuroablation’, ‘Advances’, between 2010 and November 2013.
doi:10.1136/jnnp-2013-307069
PMCID: PMC4215277  PMID: 24719180
EPILEPSY, SURGERY; NEUROSURGERY
8.  Apolipoprotein E ε2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort 
Background
Results conflict concerning the relevance of APOE alleles on the development of dementia with Lewy bodies (DLB), though they are well established in connection with Alzheimer's disease (AD). The role of APOE alleles in a Norwegian cohort of patients with DLB was therefore examined compared with patients with AD and healthy control individuals.
Methods
The study included 156 patients with DLB diagnosed according to the consensus criteria guidelines, 519 patients diagnosed with AD according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ARDRA) criteria and 643 healthy elderly volunteers. Patients were recruited through hospitals, outpatient clinics, nursing homes or from local care authorities in central and south-western parts of Norway. Healthy individuals were recruited from caregivers and societies for retired people.
Results
Subjects carrying an APOE ε2 allele had a reduced risk for developing DLB (OR 0.4, CI 0.3 to 0.8, p=0.004), and the onset of disease was delayed by 4 years (p=0.01, Mann–Whitney U test). Conversely, the APOE ε4 allele increased the risk for development of DLB (OR 5.9, CI 2.7 to 13.0, p<0.0005 for homozygotes). Similar results were found for patients with AD regarding the effect of APOE ε2, though the protective effect appeared to be slightly less pronounced than in DLB. This study is one of the largest regarding DLB and APOE to date.
Conclusion
The results indicate that APOE ε2, a protective factor in AD, has a clear beneficial effect on the development of DLB also.
doi:10.1136/jnnp-2013-307228
PMCID: PMC4215279  PMID: 24639435
Dementia; Genetics; Alzheimer's disease
9.  A zebrafish model exemplifies the long preclinical period of motor neuron disease 
doi:10.1136/jnnp-2014-308288
PMCID: PMC4215267  PMID: 24970908
ALS; Motor Neuron Disease; Clinical Neurology; Genetics; Neurobiology
10.  Oral ponesimod in relapsing–remitting multiple sclerosis: a randomised phase II trial 
Objective
This double-blind, placebo-controlled, dose-finding phase IIb study evaluated the efficacy and safety of ponesimod, an oral selective S1P1 receptor modulator, for the treatment of patients with relapsing–remitting multiple sclerosis (RRMS).
Methods
464 patients were randomised to receive once-daily oral ponesimod 10, 20 or 40 mg, or placebo for 24 weeks. The primary endpoint was the cumulative number of new T1 gadolinium-enhanced (T1 Gd+) lesions per patient recorded every 4 weeks from weeks 12 to 24 after study drug initiation. Secondary endpoints were the annualised confirmed relapse rate (ARR) and time to first confirmed relapse. Safety and tolerability were also evaluated.
Results
The mean cumulative number of new T1 Gd+ lesions at weeks 12–24 was significantly lower in the ponesimod 10 mg (3.5; rate ratio (RR) 0.57; p=0.0318), 20 mg (1.1; RR 0.17; p<0.0001) and 40 mg (1.4; RR 0.23; p<0.0001) groups compared with placebo (6.2). The mean ARR was lower with 40 mg ponesimod versus placebo, with a maximum reduction of 52% (0.25 vs 0.53; p=0.0363). The time to first confirmed relapse was increased with ponesimod compared with placebo. The proportion of patients with ≥1 treatment-emergent adverse events (AEs) was similar across ponesimod groups and the placebo group. Frequently reported AEs with higher incidence in the three ponesimod groups compared with placebo were anxiety, dizziness, dyspnoea, increased alanine aminotransferase, influenza, insomnia and peripheral oedema.
Conclusions
Once-daily treatment with ponesimod 10, 20 or 40 mg significantly reduced the number of new T1 Gd+ lesions and showed a beneficial effect on clinical endpoints. Ponesimod was generally well tolerated, and further investigation of ponesimod for the treatment of RRMS is under consideration.
Trial registration number
NCT01006265.
doi:10.1136/jnnp-2013-307282
PMCID: PMC4215282  PMID: 24659797
Multiple Sclerosis
11.  Long-term impact of interferon beta-1b in patients with CIS: 8-year follow-up of BENEFIT 
Objective
To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in patients with a first event suggestive of multiple sclerosis (MS).
Methods
In the original placebo-controlled phase of BENEFIT, patients were randomised to IFNB1b 250 μg or placebo subcutaneously every other day. After 2 years or diagnosis of clinically definite MS (CDMS), all patients were offered open-label IFNB1b treatment for a maximum duration of 5 years. Thereafter, patients were enrolled in an observational extension study for up to 8.7 years.
Results
Of the initial 468 patients, 284 (60.7%; IFNB1b: 178 (61.0% of the original arm), placebo: 106 (60.2% of original arm)) were enrolled in the extension study. 94.2% of patients were receiving IFNB1b. Patients originally randomised to IFNB1b had a reduced risk of developing CDMS by 32.2% over the 8-year observation period (HR 0.678; 95% CI 0.525 to 0.875; p=0.0030), a longer median time to CDMS by 1345 days (95% CI 389 to 2301), and a lower annualised relapse rate (0.196 (95% CI 0.176 to 0.218) versus 0.255 (95% CI 0.226 to 0.287), p=0.0012), with differences mainly emerging in the first year of the study. Cognitive outcomes remained higher in the early treated patients. EDSS remained low over time with a median of 1.5 in both arms.
Conclusions
These 8-year results provide further evidence supporting early initiation of treatment with IFNB1b in patients with a first event suggestive of MS.
doi:10.1136/jnnp-2013-306222
PMCID: PMC4215285  PMID: 24218527
MULTIPLE SCLEROSIS; INTERFERON; INTERVENTIONAL; RANDOMISED TRIALS
12.  Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results 
Background
Clinical trials established the efficacy and safety of natalizumab. Data are needed over longer periods of time and in the clinical practice setting.
Objective
To evaluate long-term safety of natalizumab and its impact on annualised relapse rate and Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting multiple sclerosis (RRMS).
Methods
The Tysabri (natalizumab) Observational Program (TOP) is an open-label, multinational, 10-year prospective study in clinical practice settings.
Results
In this 5-year interim analysis, 4821 patients were enrolled. Follow-up for at least 4 years from natalizumab commencement in 468 patients and at least 2 years in 2496 patients revealed no new safety signals. There were 18 cases of progressive multifocal leucoencephalopathy reported, following 11–44 natalizumab infusions. Mean annualised relapse rate decreased from 1.99 in the 12 months prior to baseline to 0.31 on natalizumab therapy (p<0.0001), remaining low at 5 years. Lower annualised relapse rates were observed in patients who used natalizumab as first MS therapy, in patients with lower baseline EDSS scores, and in patients with lower prenatalizumab relapse rates. Mean EDSS scores remained unchanged up to 5 years.
Conclusions
Interim TOP data confirm natalizumab's overall safety profile and the low relapse rate and stabilised disability levels in natalizumab-treated patients with RRMS in clinical practice.
Trial registration number
NCT00493298.
doi:10.1136/jnnp-2013-306936
PMCID: PMC4215289  PMID: 24532785
Multiple Sclerosis
13.  Sitting-up vertigo and trunk retropulsion in patients with benign positional vertigo but without positional nystagmus 
Background
Presently, the unambiguous diagnosis of benign paroxysmal positioning vertigo (BPPV) requires the detection of positioning or positional nystagmus provoked by Dix–Hallpike (for vertical semicircular canals) or supine roll (for horizontal semicircular canals) manoeuvres, which indicates canalo- or cupolithiasis of affected semicircular canals. There are patients, however, in whom—despite typical complaints of BPPV—no positional nystagmus can be documented; this is called ‘subjective BPPV’ (sBPPV). These patients usually complain of short vertigo spells during and after sitting up, sometimes with abnormal retropulsion of the trunk.
Aim
In this study, the authors aimed to ascertain whether these patients in fact demonstrate abnormal sitting-up trunk oscillations when measured by posturography. Of 200 unselected patients with vertigo or dizziness, 43% had sBPPV with vertigo spells while sitting up, and 20% classical BPPV.
Methods
Posturographic recordings were performed in 20 patients with sBPPV and sitting-up vertigo.
Results and discussion
Seven of the 20 patients had trunk oscillations during the act of sitting up and for a short time immediately afterwards. Based on their findings, the authors propose a new type of BPPV, the so-called Type 2 BPPV (typical complaints of BPPV, no nystagmus in Dix–Hallpike positions but short vertigo spell while sitting up), which may be the result of chronic canalolithiasis within the short arm of a posterior canal. Furthermore, the authors suggest that Type 2 BPPV, which could be identical to sBPPV or constitute a major subgroup of it, occurs frequently among patients with vertigo. For therapy, the authors recommend repetitive sit-ups from the Dix–Hallpike positions to liberate the short arm of the posterior canal from canaloliths.
doi:10.1136/jnnp.2009.199208
PMCID: PMC4196320  PMID: 20660923
14.  Bone health in Parkinson's disease: a systematic review and meta-analysis 
Objective
Parkinson's disease (PD) and osteoporosis are chronic diseases associated with increasing age. Single studies have reported associations between them and the major consequence, namely, increased risk of fractures. The aim of this systematic review and meta-analysis was to evaluate the relationship of PD with osteoporosis, bone mineral density (BMD) and fracture risk.
Methods
A literature search was undertaken on 4 September 2012 using multiple indexing databases and relevant search terms. Articles were screened for suitability and data extracted where studies met inclusion criteria and were of sufficient quality. Data were combined using standard meta-analysis methods.
Results
23 studies were used in the final analysis. PD patients were at higher risk of osteoporosis (OR 2.61; 95% CI 1.69 to 4.03) compared with healthy controls. Male patients had a lower risk for osteoporosis and osteopenia than female patients (OR 0.45; 95% CI 0.29 to 0.68). PD patients had lower hip, lumbar spine and femoral neck BMD levels compared with healthy controls; mean difference, −0.08, 95% CI −0.13 to −0.02 for femoral neck; −0.09, 95% CI −0.15 to −0.03 for lumbar spine; and −0.05, 95% CI −0.07 to −0.03 for total hip. PD patients were also at increased risk of fractures (OR 2.28; 95% CI 1.83 to 2.83).
Conclusions
This systematic review and meta-analysis demonstrate that PD patients are at higher risk for both osteoporosis and osteopenia compared with healthy controls, and that female patients are at greater risk than male patients. Patients with PD also have lower BMD and are at increased risk of fractures.
doi:10.1136/jnnp-2013-307307
PMCID: PMC4173751  PMID: 24620034
15.  Transcranial Direct Current Stimulation for the Treatment of Parkinson’s Disease 
Background
Progression of Parkinson’s disease (PD) is characterized by motor deficits, which eventually respond less to dopaminergic therapy and, thus, pose a therapeutic challenge. Deep brain stimulation has proven efficacy, but carries risks and is not possible in all patients. Non-invasive brain stimulation has shown promising results and may provide a therapeutic alternative.
Objective
To investigate the efficacy of transcranial direct current stimulation (tDCS) in the treatment of PD
Design
Randomized, double blind, sham-controlled study.
Setting
Research institution
Methods
We investigated efficacy of anodal tDCS applied to the motor and prefrontal cortices in 8 sessions over 2.5 weeks. Assessment over a 3-month period included timed tests of gait (primary outcome measure) and bradykinesia in the upper extremities, UPDRS, Serial Reaction Time Task, Beck Depression Inventory, Health Survey and self-assessment of mobility.
Results
Twenty-five PD patients were investigated, 13 receiving tDCS and 12 sham stimulation. TDCS improved gait by some measures for a short time and improved bradykinesia in both the on- and off-states for longer than 3 months. Changes in UPDRS, reaction time, physical and mental well-being, and self-assessed mobility did not differ between tDCS and sham intervention.
Conclusion
TDCS of the motor and prefrontal cortices may have therapeutic potential in PD, but better stimulation parameters need to be established to make the technique clinically viable.
doi:10.1136/jnnp.2009.202556
PMCID: PMC4162743  PMID: 20870863
transcranial direct current stimulation (tDCS); non-invasive brain stimulation; therapeutic study; Parkinson’s disease
16.  Anterior choroidal artery ischaemic patterns predict outcome of carotid occlusion 
Objective
To investigate whether anterior choroidal artery (AChA) territory sparing or AChA infarction restricted to the medial temporal lobe (MT), implying good collateral status, predicts good outcome, defined as modified Rankin Scale 0–2, at discharge in acute internal carotid artery (ICA) occlusion.
Methods
The authors studied consecutive patients with acute ICA occlusion admitted to an academic medical centre between January 2002 and August 2010, who underwent MRI followed by conventional angiography. The pattern of AChA involvement on initial diffusion-weighted imaging was dichotomised as spared or MT only versus other partial or full. The association of AChA infarct patterns and good outcome at discharge was calculated by multivariate logistic regression with adjustment.
Results
For the 60 patients meeting entry criteria, mean age was 68.3 years and median admission NIH Stroke Scale score was 19. AChA territory was spared or restricted to the MT in 27 patients and other partially involved or fully involved in 33 patients. AChA territory spared or ischaemia restricted to MT only, compared with other partial infarct patterns or full infarct, was independently associated with good discharge outcome (44.4% vs 12.1%, OR 7.24, 95% CI 1.32 to 39.89, p=0.023).
Conclusion
In acute ICA occlusion, the absence of AChA infarction or restriction to the MT is an independent predictor of good discharge outcome. Analysis of AChA infarct patterns may improve early prognostication and decision-making.
doi:10.1136/jnnp-2011-301493
PMCID: PMC4157912  PMID: 22492212
17.  TDP-43 Frontotemporal Lobar Degeneration and Autoimmune Disease 
Journal of neurology, neurosurgery, and psychiatry  2013;84(9):10.1136/jnnp-2012-304644.
Background
The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored.
Objective
To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared to neurologically healthy normal controls (NC) and Alzheimer’s disease (AD) as dementia controls.
Design
Case control.
Setting
Academic medical centres.
Participants
129 svPPA, 39 PGRN, 186 NC, and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN, and NC cohorts underwent serum analysis for tumor necrosis factor α (TNF-α) levels.
Outcome Measures
Chi-square comparison of autoimmune prevalence and follow up logistic regression.
Results
There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders, and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared to NC.
Conclusions
svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared to NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 (TDP-43) aggregation.
doi:10.1136/jnnp-2012-304644
PMCID: PMC3840954  PMID: 23543794
18.  APOE associations with severe CAA-associated vasculopathic changes – collaborative meta-analysis 
Objectives
Cerebral amyloid angiopathy (CAA) is associated with lobar intracerebral haemorrhage (ICH). While only the ε4 allele of the apolipoprotein E gene (APOE) is associated with the presence of CAA, both APOE-ε4 and ε2 are associated with lobar ICH. The generally accepted explanation is that APOE-ε4 promotes vascular amyloid deposition, while APOE-ε2 promotes progression to severe CAA with associated vasculopathic changes that cause vessel rupture and ICH. We assessed the evidence for these allele-specific effects.
Methods
We systematically identified published studies with data on APOE genotype and histopathological assessment of post-mortem brains for CAA severity. We obtained unpublished data from these for meta-analyses of the effects of ε4-containing (ε4+) and ε2-containing (ε2+) genotypes on progression to severe CAA.
Results
Of six eligible studies (543 eligible participants), data were available from five (497 participants, 353 with CAA). Meta-analyses showed a possible association of ε4+ genotypes with severe CAA (ε4+ versus ε4-: severe versus mild/moderate CAA, odds ratio [OR] 2.5, 95% confidence interval [CI] 1.4 to 4.5, p=0.002; severe versus moderate CAA, OR 1.7, 95%CI 0.9 to 3.1, p=0.11). For ε2+ versus ε2-genotypes, there was no significant association, but the very small number of participants with ε2+ genotypes (22) precluded reliable estimates.
Conclusions
We found a possible association of severe CAA with APOE-ε4 but not APOE-ε2. However, our findings do not exclude a biologically meaningful association between APOE-ε2 and severe CAA. Further work is needed to elucidate fully the allele-specific associations of APOE with CAA and their mechanisms.
doi:10.1136/jnnp-2013-306485
PMCID: PMC4018226  PMID: 24163429
Cerebral Amyloid Angiopathy; Apolipoproteins E; Cerebral Hemorrhage; Systematic Review
20.  The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs 
The aim of this study was to compare the prevalence of diagnosed neurodevelopmental disorders in children exposed, in utero, to different antiepileptic drug (AED) treatments.
A prospective cohort of women with epilepsy and a control group of women without epilepsy were recruited from antenatal clinics. The children of this cohort were followed longitudinally until six years of age (n=415). Diagnosis of a neurodevelopmental disorder was made independently of the research team.
Multiple logistic regression analysis revealed an increase in risk of neurodevelopmental disorders in children exposed to monotherapy sodium valproate (6/50, 12.0%; aOR 6.05, 95%CI 1.65–24.53; p=0.007) and in those exposed to polytherapy with sodium valproate (3/20, 15.0%; aOR 9.97, 95%CI 1.82–49.40; p=0.005) compared to control children (4/214; 1.87%). Autistic spectrum disorder was the most frequent diagnosis. No significant increase was found amongst children exposed to carbamazepine (1/50) or lamotrigine (2/30).
An accumulation of evidence demonstrates that the risks associated with prenatal sodium valproate exposure include an increased prevalence of neurodevelopmental disorders. Whether such disorders are discrete or represent the severe end of a continuum of altered neurodevelopmental functioning requires further investigation. Replication and extension of this research is required to investigate the mechanism(s) underpinning the relationship. Finally, the increased likelihood of neurodevelopmental disorders should be communicated to women for whom sodium valproate is a treatment option.
doi:10.1136/jnnp-2012-304270
PMCID: PMC4115188  PMID: 23370617
Epilepsy; Pregnancy; Neurodevelopment; Antiepileptic drugs; Autistic spectrum disorder
21.  Verbal memory is associated with structural hippocampal changes in newly diagnosed Parkinson’s disease 
Background and objective
Cognitive impairment, including impairment of episodic memory, is frequently found in newly diagnosed Parkinson’s disease (PD). In this longitudinal observational study we investigated whether performance in memory encoding, retention, recognition and free recall is associated with reduced hippocampal radial distance.
Methods
We analysed baseline T1-weighted brain MRI data from 114 PD subjects without cognitive impairment, 29 PD subjects with mild cognitive impairment and 99 normal controls from the ParkWest study. Age- and education-predicted scores for the California Verbal Learning Test 2 (CVLT-2) and tests of executive function were regressed against hippocampal radial distance while adjusting for imaging centre.
Results
There was no association between encoding or performance on executive tests and hippocampal atrophy in the PD group. In the full PD sample we found bilaterally significant associations between lower delayed free recall scores and hippocampal atrophy in the CA1, CA3 and subiculum area (left, p=0.0013; right, p=0.0082). CVLT-2 short delay free recall scores were associated with bilateral hippocampal CA1 and subicular atrophy in the full PD sample (left, p=0.013; right, p=0.047). CVLT-2 recognition scores showed a significant association with right-sided subicular and CA1 atrophy in the full PD sample (p=0.043).
Conclusions
At the time of PD diagnosis, subjects’ verbal memory performance in recall and recognition are associated with atrophy of the hippocampus, while encoding is not associated with hippocampal radial distance. We postulate that impaired recall and recognition might reflect deficient memory consolidation at least partly due to structural hippocampal changes.
doi:10.1136/jnnp-2012-303054
PMCID: PMC4041694  PMID: 23154124
22.  Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations 
Background
Spinocerebellar ataxia syndromes presenting in adulthood have a broad range of causes, and despite extensive investigation remain undiagnosed in up to ~50% cases. Mutations in the mitochondrially-encoded MTATP6 gene typically cause infantile-onset Leigh syndrome and occasionally have onset later in childhood. We report two families with onset of ataxia in adulthood (with pyramidal dysfunction and/or peripheral neuropathy variably present), who are clinically indistinguishable from other spinocerebellar ataxia patients.
Methods
Genetic screening study of the MTATP6 gene in 64 pedigrees with unexplained ataxia, and case series of two families who had MTATP6 mutations.
Results
Three pedigrees had mutations in MTATP6, two of which have not been reported previously and are detailed in this report. These families respectively had the m.9185T>C and m.9035T>C mutations, which have not previously been associated with adult-onset cerebellar syndromes. Other investigations including muscle biopsy and respiratory chain enzyme activity were nonspecific or normal.
Conclusions
MTATP6 sequencing should be considered in the workup of undiagnosed ataxia, even if other investigations do not suggest a mitochondrial DNA disorder.
doi:10.1136/jnnp-2012-302568
PMCID: PMC4034166  PMID: 22577227
MTATP6; ATPase; mitochondria; ataxia; spinocerebellar ataxia; neuropathy; adult-onset
23.  Is phonophobia associated with cutaneous allodynia in migraine? 
Objective
To determine whether phonophobia and dynamic mechanical (brush) allodynia are associated in episodic migraine (EM).
Methods
Adult patients with EM were prospectively recruited. A structured questionnaire was used to obtain demographic and migraine related data. Phonophobia was tested quantitatively using a real time sound processor and psychoacoustic software. Sound stimuli were pure tones at frequencies of 1000 Hz, 4000 Hz and 8000 Hz, delivered to both ears at increasing intensities, until an aversive level was reached. Allodynia was assessed by brushing the patient’s skin with a gauze pad at different areas. Patients were tested both between and during acute attacks. Sound aversion thresholds (SATs) in allodynic and non-allodynic patients were compared.
Results
Between attacks, SATs were lower in allodynic compared with non-allodynic patients, with an average difference of −5.7 dB (p=0.04). During acute attacks, the corresponding average SAT difference (allodynic-non-allodynic) was −15.7 dB (p=0.0008). There was a significant negative correlation between allodynia scores and SATs, both within and between attacks.
Conclusions
The results support an association between phonophobia and cutaneous allodynia in migraine.
doi:10.1136/jnnp.2009.198481
PMCID: PMC4030377  PMID: 20562466
24.  Cortical atrophy in presymptomatic Alzheimer’s disease presenilin 1 mutation carriers 
Background
Sporadic late-onset Alzheimer’s disease (AD) dementia has been associated with a ‘signature’ of cortical atrophy in paralimbic and heteromodal association regions measured with MRI.
Objective
To investigate whether a similar pattern of cortical atrophy is present in presymptomatic presenilin 1 E280A mutation carriers an average of 6 years before clinical symptom onset.
Methods
40 cognitively normal volunteers from a Colombian population with familial AD were included; 18 were positive for the AD-associated presenilin 1 mutation (carriers, mean age=38) whereas 22 were non-carriers. T1-weighted volumetric MRI images were acquired and cortical thickness was measured. A priori regions of interest from our previous work were used to obtain thickness from AD-signature regions.
Results
Compared to non-carriers, presymptomatic presenilin 1 mutation carriers exhibited thinner cortex within the AD-signature summary measure (p<0.008). Analyses of individual regions demonstrated thinner angular gyrus, precuneus and superior parietal lobule in carriers compared to non-carriers, with trend-level effects in the medial temporal lobe.
Conclusion
Results demonstrate that cognitively normal individuals genetically determined to develop AD have a thinner cerebral cortex than non-carriers in regions known to be affected by typical late-onset sporadic AD. These findings provide further support for the hypothesis that cortical atrophy is present in preclinical AD more than 5 years prior to symptom onset. Further research is needed to determine whether this method could be used to characterise the age-dependent trajectory of cortical atrophy in presymptomatic stages of AD.
doi:10.1136/jnnp-2012-303299
PMCID: PMC3632663  PMID: 23134660
25.  Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia 
Objective
Mutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory neuropathy. We sought to investigate for SCN9A mutations in a clinically well-characterised cohort of patients with CIP and erythromelalgia.
Methods
We sequenced all exons of SCN9A in 19 clinically well-studied cases including 6 CIP and 13 erythromelalgia (9 with family history, 10 with small-fibre neuropathy). The identified variants were assessed in dbSNP135, 1K genome, NHLBI-Exome Sequencing Project (5400-exomes) databases, and 768 normal chromosomes.
Results
In erythromelalgia case 7, we identified a novel Q10>K mutation. In CIP case 6, we identified a novel, de novo splicing mutation (IVS8-2A>G); this splicing mutation compounded with a nonsense mutation (R523>X) and abolished SCN9A mRNA expression almost completely compared with his unaffected father. In CIP case 5, we found a variant (P610>T) previously considered causal for erythromelalgia, supporting recently raised doubt on its causal nature. We also found a splicing junction variant (IVS24-7delGTTT) in all 19 patients, this splicing variant was previously considered casual for CIP, but IVS24-7delGTTT was in fact the major allele in Caucasian populations.
Conclusions
Two novel SCN9A mutations were identified, but frequently polymorphism variants are found which may provide susceptibility factors in pain modulation. CIP and erythromelalgia are defined as genetically heterogeneous, and some SCN9A variants previously considered causal may only be modifying factors.
doi:10.1136/jnnp-2012-303719
PMCID: PMC3594382  PMID: 23129781

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