cover image European Journal of Neurology

European Journal of Neurology

2016 - Volume 23
Issue 6 | June 2016
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CME Article

Background and purpose

Multiple sclerosis (MS) patients can present with atypical cavitary lesions mimicking vanishing white matter disease (VWMD). Our objective was to identify brain magnetic resonance imaging (MRI) findings that differentiate these two disorders.

Methods

A cross‐sectional study was performed including 14 patients with MS with cavitary lesions and 14 patients with VWMD. Two neuroradiologists retrospectively reviewed the MRI including at least T1‐, T2‐ and fluid‐attenuated inversion recovery weighted images.

Results

The main differences included ovoid lesions perpendicular to the lateral ventricle, punctate isolated juxtacortical lesions (both 100% in MS versus 0% in VWMD) and symmetrical infratentorial hyperintensities (0% in MS versus 50% in VWMD). Other statistically significant differences included midbrain (79% in MS versus 29% in VWMD) and thalamus lesions (71% vs. 7%) as well as extensive external capsule involvement (29% vs. 86%) and extensive corpus callosum lesions (64% vs. 100%). Cavitary lesions usually had periventricular predominance in MS (36% vs. 0%) whereas they were more frequently anterior in VWMD (0% in MS versus 57% in VWMD).

Conclusion

Despite many similar MRI findings, our results suggest that a careful analysis of the morphology and the location of the lesions is helpful to differentiate these distinct disorders.

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Authors:
X. Ayrignac, N. Menjot de Champfleur, S. Menjot de Champfleur, C. Carra‐Dallière, J. Deverdun, A. Corlobe and P. Labauge
Article first published online:
04 Jan 2016 | DOI: 10.1111/ene.12931

Original Article

Background and purpose

Peripheral neuropathy in mitochondrial diseases (MDs) may vary from a subclinical finding in a multisystem syndrome to a severe, even isolated, manifestation in some patients.

Methods

To investigate the involvement of the peripheral nervous system in MDs extensive electrophysiological studies were performed in 109 patients with morphological, biochemical and genetic diagnosis of MD [12 A3243G progressive external ophthalmoplegia (PEO)/mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS), 16 myoclonic epilepsy with ragged‐red fibres (MERRF), four mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), 67 PEO with single or multiple deletions of mitochondrial DNA, 10 others].

Results

A neuropathy was found in 49 patients (45%). The incidence was very high in MNGIE (100%), MELAS (92%) and MERRF (69%), whilst 28% of PEO patients had evidence of peripheral involvement. The most frequent abnormality was a sensory axonal neuropathy found in 32/49 patients (65%). A sensory‐motor axonal neuropathy was instead detected in 16% of the patients and sensory‐motor axonal demyelinating neuropathy in 16%. Finally one Leigh patient had a motor axonal neuropathy. It is interesting to note that the great majority had preserved tendon reflexes and no sensory disturbances.

Conclusions

In conclusion, peripheral involvement in MD is frequent even if often mild or asymptomatic. The correct identification and characterization of peripheral neuropathy through electrophysiological studies represents another tile in the challenge of MD diagnosis.

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Authors:
M. Luigetti, D. Sauchelli, G. Primiano, C. Cuccagna, D. Bernardo, M. Lo Monaco and S. Servidei
Article first published online:
29 Jan 2016 | DOI: 10.1111/ene.12954

Original Article

Background and purpose

Brain derived neurotrophic factor (BDNF) is suggested to play a neuroprotective role in multiple sclerosis (MS). However, the BDNF response to long‐term exercise in MS remains unknown. Our objective was to compare resting BDNF profiles of healthy controls (HCs) and persons with relapsing−remitting MS (RRMS) and to investigate the impact of a 24‐week exercise intervention on serum BDNF release in MS.

Methods

At baseline, blood BDNF levels were assessed in MS ( = 22, mean Expanded Disability Status Scale 2.6 ± 0.2, mean age 43 ± 2 years) and HCs ( = 19, mean age 47 ± 1 year). Next, persons with MS were randomized to an exercise intervention group (EX, = 15) or a sedentary control group (SED, = 7) completing a 24‐week randomized controlled trial. In persons with MS, muscle strength, exercise tolerance and body composition were assessed, as compliance measures, at baseline and after 24 weeks.

Results

At baseline, the BDNF concentration of persons with RRMS was 21% lower than HCs. Following 24 weeks of intervention, changes in BDNF concentrations differed significantly between EX and SED. In particular, within EX BDNF concentrations increased 13.9% ± 8.8%, whereas it decreased 10.5% ± 4.1% within SED. Furthermore, 24 weeks of exercise induced changes in the compliance measures between EX and SED. In addition, within EX muscle strength, exercise tolerance and lean tissue mass improved, whereas these remained stable within SED.

Conclusion

In conclusion, BDNF concentration of persons with RRMS was lower compared to HCs and increased after 24 weeks of exercise in persons with MS, compared to the non‐exercise MS control group.

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Authors:
I. Wens, C. Keytsman, N. Deckx, N. Cools, U. Dalgas and B. O. Eijnde
Article first published online:
16 Mar 2016 | DOI: 10.1111/ene.12976

Original Article

Background and purpose

Although abnormal sleep duration is positively associated with increased risk for cardiovascular disease and mortality, the specific impact on intracerebral haemorrhage (ICH) risk remains unclear. The relationship between sleep duration and the risk of ICH was investigated in our study.

Methods

A nationwide, multicentre matched case−control study was performed to investigate the risk factors for haemorrhagic stroke, using patients from 33 hospitals in Korea. In all, 490 patients with ICH and 980 age‐ and sex‐matched controls were enrolled. Detailed information regarding sleep, sociodemographic factors, lifestyle and medical history before ICH onset was obtained using qualified structured questionnaires. Sleep duration was categorized and the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a conditional logistic regression with 7 h as the reference duration.

Results

The number of subjects with long sleep duration, more than 8 h, was significantly greater in the ICH group than in the control group (≥8 h, 30.4% vs. 22.6%, = 0.002). After controlling for relevant confounding factors, longer sleep duration was found to be independently associated with the risk of ICH in a dose−response manner (8 h, OR 1.57, 95% CI 1.00–2.47; ≥9 h, OR 5.00, 95% CI 2.18–11.47).

Conclusions

Our study suggested that long sleep duration is positively associated with an increased ICH risk in a dose‐dependent manner. Further studies on the relationship linking long sleep duration with increased risk of ICH are required.

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Authors:
T. J. Kim, C. K. Kim, Y. Kim, S. Jung, H.‐G. Jeong, S. J. An, S.‐B. Ko and B.‐W. Yoon
Article first published online:
04 Mar 2016 | DOI: 10.1111/ene.12978

Original Article

Background and purpose

Enlarged perivascular spaces (EPVS) have been recently considered a feature of cerebral small vessel disease. They have been related to aging, hypertension and dementia but their relationship with hypertension related variables (i.e. target organ damage, treatment compliance) and mild cognitive impairment (MCI) is not fully elucidated. Our aims were to investigate the relation between basal ganglia (BG) and centrum semiovale (CSO) EPVS with vascular risk factors, hypertension related variables and MCI.

Methods

In all, 733 hypertensive individuals free of stroke and dementia from the Investigating Silent Strokes in Hypertensives, a magnetic resonance imaging Study (ISSYS) underwent brain magnetic resonance imaging and cognitive testing to diagnose MCI or normal cognitive aging.

Results

The numbers of participants presenting high grade (>10) EPVS at the BG and CSO were 23.3% and 40.0%, respectively. After controlling for vascular risk factors, high grade BG EPVS were associated with age (odds ratio 1.68; 95% confidence interval 1.37, 2.06), poor antihypertensive compliance (1.49; 1.03, 2.14) and the presence of microalbuminuria (1.95; 1.16, 3.28), whereas in the CSO only age (1.38; 1.18, 1.63) and male sex were associated with EPVS (1.73; 1. 24, 2.42). MCI was diagnosed in 9.3% of the participants and it was predicted by EPVS in the BG (1.87; 1.03, 3.39) but not in the CSO. This last association was greatly attenuated after correction for lacunes and white matter hyperintensities.

Conclusions

Basal ganglia EPVS are associated with the presence of microalbuminuria and poor adherence to antihypertensive drugs. The BG EPVS relation with MCI is not independent of the presence of other cerebral small vessel disease markers.

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Authors:
I. Riba‐Llena, C. Nafría, X. Mundet, A. López‐Rueda, I. Fernández‐Cortiñas, C. I. Jarca, J. Jiménez‐Balado, M. Domingo, J. L. Tovar, F. Orfila, F. Pujadas, J. Álvarez‐Sabín, O. Maisterra, J. Montaner and P. Delgado
Article first published online:
10 Mar 2016 | DOI: 10.1111/ene.12979

Original Article

Background and purpose

Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for 90 days was recommended as the secondary prevention of minor ischaemic strokes or transient ischaemic attacks (TIAs) in 2014. However, whether the duration of 90 days is optimal for each patient remains unclear. Therefore, the efficacy and safety of short‐term (≤3 months) and prolonged (≥1 year) DAPT after stroke or TIA were assessed via a systematic review and meta‐analysis.

Methods

The Cochrane Library, Clinical Trials.gov and PubMed were searched up to December 2014 and nine randomized controlled trials were included involving 21 923 patients.

Results

Short‐term DAPT significantly reduced the risk of ischaemic stroke recurrence by 41% and major vascular events by 30%, without increasing the risk of intracranial haemorrhage. Prolonged DAPT reduced the risk of ischaemic stroke recurrence by 12% and major vascular events by 10%. However, the risk of major bleeding and intracranial haemorrhage increased.

Conclusions

Short‐term DAPT appears to be superior to prolonged DAPT. However, the difference in efficacy outcome needs to be carefully explained and confirmed by further well‐designed randomized controlled trials.

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Authors:
F. Ge, H. Lin, Y. Liu, M. Li, R. Guo, Z. Ruan and T. Chang
Article first published online:
28 Mar 2016 | DOI: 10.1111/ene.12982

Original Article

Background and purpose

Fisher syndrome (FS) may overlap with Guillain–Barré syndrome (GBS), in particular the pharyngeal–cervical–brachial variant form (PCB‐GBS), or Bickerstaff brainstem encephalitis (BBE). Our aim was to elucidate the frequency of this overlap and the patterns of clinical progression in patients with FS.

Methods

Sixty consecutive patients with FS were studied. FS/PCB‐GBS was diagnosed when the patients developed pharyngeal, cervical and/or brachial weakness. Patients with flaccid tetraparesis were diagnosed as having FS/conventional GBS. FS/BBE was defined as the development of consciousness disturbances.

Results

All 60 patients initially developed the FS clinical triad alone (pure FS). Of these, 30 (50%) patients had pure FS throughout their course, whereas the remaining 50% of patients showed an overlap: PCB‐GBS in 14 (23%) patients, conventional GBS in nine (15%) patients and BBE in seven (12%) patients. The median (range) durations from FS onset to progression to FS/PCB‐GBS, FS/GBS or FS/BBE were 5 (1–7), 3 (1–4) and 3 (1–5) days, respectively. Patients with overlap syndromes more frequently received immune‐modulating treatment, and the outcomes were generally favourable. The frequencies of positivity for anti‐GQ1b, GT1a, GD1a, GD1b, GalNAc‐GD1a and GM1 antibodies were not significantly different amongst the four groups.

Conclusions

Of the patients with pure FS, 50% later developed an overlap with PCB‐GBS, conventional GBS or BBE. The overlap occurred within 7 days of FS onset; thus, physicians should pay attention to the possible development of this overlap during the first week after FS onset.

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Authors:
Y. Sekiguchi, M. Mori, S. Misawa, S. Sawai, N. Yuki, M. Beppu and S. Kuwabara
Article first published online:
11 Mar 2016 | DOI: 10.1111/ene.12983

Original Article

Background and purpose

Our objective was to study the association between serum levels of anti Epstein–Barr virus nuclear antigen 1 (EBNA‐1) antibody and 25‐hydroxyvitamin D (25(OH)D) in a prospective cohort of patients with relapsing−remitting multiple sclerosis.

Method

The study comprised 90 patients with relapsing−remitting multiple sclerosis, all participants in a randomized clinical trial of ω‐3 fatty acids (the OFAMS study). Repeated, paired measurements of serum 25(OH)D and serum EBNA‐1 immunoglobulin G (IgG) levels were obtained at baseline and every 6 months for 24 months. The association between serum EBNA‐1 IgG and serum 25(OH)D levels was analysed using generalized linear models for hierarchical data.

Results

There was a significant variation in EBNA‐1 IgG antibody level between sampling months ( = 1.8, = 0.043, one‐way ). There was a negative association between EBNA‐1 IgG and 25(OH)D [ = −0.230, 95% confidence interval (CI) (−0.440, −0.023), = 0.030] and a positive association between EBNA‐1 IgG and HLA‐DRB1*15 positive status [ = 94.7, 95% CI (2.423, 186.9), = 0.044]. The association between 25(OH)D and EBNA‐1 IgG remained significant after adjusting for the patient's age, gender, HLA‐DRB1*15, retinol levels and interferon β‐1a treatment.

Conclusion

Our study demonstrates monthly differences in EBNA‐1 IgG levels and an association between EBNA‐1 IgG, 25(OH)D levels and HLA‐DRB1*15. These results indicate that EBNA‐1 IgG serum levels are affected by genetic and environmental factors that also modulate multiple sclerosis risk.

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Authors:
S. Wergeland, K.‐M. Myhr, K. I. Løken‐Amsrud, A. G. Beiske, K. S. Bjerve, H. Hovdal, R. Midgard, S. S. Kvistad, T. Holmøy, T. Riise and Ø. Torkildsen
Article first published online:
21 Mar 2016 | DOI: 10.1111/ene.12986

Original Article

Background and purpose

John Cunningham virus (JCV) seropositivity is a risk factor for the development of natalizumab‐associated progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients. When JCV seronegative patients seroconvert, their risk of developing PML increases. Limited longitudinal data exist about the seroconversion rate amongst natalizumab‐treated relapsing−remitting MS (RRMS) patients. Our objective was to evaluate the seroconversion rate in a large Dutch cohort of natalizumab‐treated RRMS patients. Seroconversion was defined as at least two consecutive seropositive serum samples (or cessation of therapy after a single seropositive sample because of seropositivity) after initial seronegative testing.

Methods and results

In our study of 179 patients for whom longitudinal blood samples were available over a long period (median 4.2 years), anti‐JCV antibody indices were measured in 933 available samples. Eighty‐six patients (48.0%) tested seronegative initially. Of these 86 seronegative patients, 23 patients (26.7%) seroconverted during follow‐up. The annualized seroconversion rate was 7.1%. Seroconversion occurred between 9 and 90 months (median 43 months) of treatment. The rate of seroconversion was independent of follow‐up duration. No significant increase was seen in the anti‐JCV antibody index in the non‐converting patients during the follow‐up.

Conclusion

The annualized seroconversion rate of 7.1% in patients using natalizumab, cumulatively leading to more than 25% of seronegative patients becoming seropositive in 4 years, is of clinical relevance and should be taken into account in the risk assessment when considering the start of natalizumab therapy.

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Authors:
A. Vennegoor, J. A. van Rossum, C. Leurs, M. P. Wattjes, T. Rispens, J. L. A. N. Murk, B. M. J. Uitdehaag and J. Killestein
Article first published online:
27 Mar 2016 | DOI: 10.1111/ene.12988

Original Article

Background and purpose

Camptocormia is a marked anterior curvature of the thoracolumbar spine that may be caused by parkinsonism, amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG) and muscle disease. The interest of a systematic muscle biopsy has not been evaluated until now. In our study, the aim was to prospectively evaluate the proportion of patients with isolated camptocormia without ALS, MG and parkinsonism who have an underlying myopathy.

Methods

Twenty consecutive patients (75% female, mean age 70 years) with isolated camptocormia were enrolled in a single centre in this 5‐year prospective study. ALS, MG and parkinsonism had been excluded in all cases. A left deltoid muscle biopsy was performed in all patients and processed with standard techniques for histology and immunohistochemistry. Additional biochemical and genetic studies were performed when pathological analysis was consistent with myopathy.

Results

A myopathy was identified in seven patients (35%). Three patients presented with mitochondrial myopathy, including two patients harbouring a heterozygous gene pathogenic variant and one patient with a heterozygous gene pathogenic variant. Two patients presented with an inflammatory myopathy, including one with anti‐PM/Scl antibodies. One patient presented with facioscapulohumeral muscular dystrophy and one patient with an gene‐related myofibrillar myopathy. No obvious myopathy was found in the 13 remaining cases.

Discussion

In this prospective study, an underlying myopathy was found in 35% of patients with isolated camptocormia. These results suggest that a muscle biopsy should be systematically performed in patients with isolated camptocormia when ALS, MG and parkinsonism have been excluded.

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Authors:
J.‐B. Chanson, B. Lannes and A. Echaniz‐Laguna
Article first published online:
10 Mar 2016 | DOI: 10.1111/ene.12989

Original Article

Background and purpose

Much clinical knowledge about multiple sclerosis (MS) has been gained from patients who attend MS specialty clinics. However, there is limited information about whether these patients are representative of the wider MS population. The objective of this study was to compare incident MS cases who were MS clinic users to non‐users of the specialty MS clinics in British Columbia, Canada.

Methods

This was a retrospective record‐linkage cohort study using prospectively collected data from the British Columbia Multiple Sclerosis database and province‐wide health administrative databases.

Results

There were 2841 incident MS cases between 1996 and 2004 including 1648 (58%) that had registered at an MS clinic (‘clinic cases’) and 1193 (42%) that had not (‘non‐clinic cases’). Gender and socioeconomic status distributions were similar; however, non‐clinic cases were older, accessed health services more frequently and had a higher burden of comorbidity than clinic cases. Only 1% of the non‐clinic cases had filled a prescription for an MS‐specific disease‐modifying therapy, compared to 51% of the clinic cases.

Conclusions

Our findings have several important implications: even within a publicly funded healthcare system, a high proportion of individuals with MS may not access a specialty MS clinic; the needs of MS patients managed in the community may differ from those referred to an MS clinic; findings from studies involving clinic‐based MS cohorts may not always be generalizable to the wider MS population; and access to population‐based health administrative data offers the opportunity to gain a broader understanding of MS.

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Authors:
K. A. McKay, H. Tremlett, F. Zhu, L. Kastrukoff, R. A. Marrie and E. Kingwell
Article first published online:
15 Mar 2016 | DOI: 10.1111/ene.12990

Original Article

Background and purpose

Cerebrospinal fluid (CSF) analysis supports the clinical diagnosis of sporadic Creutzfeldt−Jakob disease (sCJD) when applied within an adequate clinical context. A diagnostic potential has been attributed to CSF proteins such as 14‐3‐3, but also tau protein, phosphorylated tau (181P) (p‐tau) protein, amyloid β, S100B and neuron‐specific enolase (NSE). There has been only limited information available about the contribution of CSF analysis in the differentiation of various molecular sCJD subtypes.

Methods

The CSF levels of the aforementioned proteins from 73 sCJD patients with distinct molecular subtypes were determined.

Results

Differences in tau values were significant amongst the homozygous patients (MM and VV genotype) compared to the heterozygous group ( = 0.07 and = 0.02 respectively). Significantly higher CSF tau levels ( = 0.003) and NSE ( = 0.02) but lower p‐tau/tau ratio ( = 0.01) were observed in MM1 compared to MM2 patients. The p‐tau/tau ratio enabled the differentiation of MV genotype with higher levels in PrP type 2 ( = 0.04). Elevation of S100B ( < 0.001) and NSE ( = 0.03) was observed in VV2 compared to VV1 subtype. codon 129 genotype, PrP isotype, disease duration and clinical stage influenced the test sensitivity in all proteins.

Conclusions

Cerebrospinal fluid protein levels might be useful in the pre‐mortem differentiation of molecular sCJD subtypes when the codon 129 genotype is known.

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Authors:
K. Gmitterová, U. Heinemann, A. Krasnianski, J. Gawinecka and I. Zerr
Article first published online:
31 Mar 2016 | DOI: 10.1111/ene.12991

Original Article

Background and purpose

The long‐term benefit of natalizumab on brain atrophy progression in multiple sclerosis (MS) patients is unknown. Our aim was to investigate its effect over 5 years.

Methods

This prospective study included 60 relapsing MS patients who started natalizumab treatment in years 2006−2007.

Results

At the 5‐year follow‐up, 20 patients discontinued natalizumab after an average of 29.5 cycles, 27 continued natalizumab treatment with some periods of honeymoon (average of 38.4 infusions) and 13 never stopped natalizumab (average of 60.6 infusions). In multiple linear regression analysis, adjusted for age, sex and baseline magnetic resonance imaging (MRI) status, the number of natalizumab infusions was associated with decrease of relapse rate (adjusted = 0.037), but no association was found with the progression of disability, accumulation of lesion burden or brain volume loss. However, only one (8%) patient in the continuous monthly group experienced disability progression compared to 10 (37%) in the non‐continuous and seven (35%) in the discontinuation natalizumab groups. At the follow‐up, two patients had died [one from a fatal case of progressive multifocal leukoencephalopathy (PML) and one from a car accident] and 15 patients were lost to follow‐up. There was another case of non‐fatal PML over the follow‐up.

Conclusions

In line with previous reports, MS patients with longer and continuous use of natalizumab had fewer relapses and remained stable in their disability status. No difference in lesion burden accumulation or brain atrophy development was found in relation to the duration of natalizumab use. PML occurred in 2.5% of patients in this small sample cohort. Given the increased risk of PML and uncertain benefit of prolonged natalizumab use on clinical and MRI outcomes of disease progression found in this study, a careful risk−benefit therapeutic assessment is mandatory.

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Authors:
R. Zivadinov, D. Hojnacki, N. Bergsland, C. Kennedy, J. Hagemeier, R. Melia, D. P. Ramasamy, J. Durfee, E. Carl, M. G. Dwyer and B. Weinstock‐Guttman
Article first published online:
21 Mar 2016 | DOI: 10.1111/ene.12992

Original Article

Background and purpose

Our aim was to study not only the prevalence but more importantly the severity and the correlation between sleep quality and restless legs syndrome (RLS) in a large population of well‐defined migraine patients as poor sleep presumably triggers migraine attacks.

Methods

In a large cross‐sectional and observational study, data on migraine and RLS were collected from 2385 migraine patients (according to the International Classification of Headache Disorders ICHD‐IIIb) and 332 non‐headache controls. RLS severity (International RLS Study Group severity scale) and sleep quality (Pittsburgh Sleep Quality Index) were assessed. Risk factors for RLS and RLS severity were calculated using multivariable‐adjusted regression models.

Results

Restless legs syndrome prevalence in migraine was higher than in controls (16.9% vs. 8.7%; multivariable‐adjusted odds ratio 1.83; 95% confidence interval 1.18–2.86; = 0.008) and more severe (adjusted severity score 14.5 ± 0.5 vs. 12.0 ± 1.1; = 0.036). Poor sleepers were overrepresented amongst migraineurs (50.1% vs. 25.6%; < 0.001). Poorer sleep quality was independently associated with RLS occurrence (odds ratio 1.08; < 0.001) and RLS severity ( < 0.001) in migraine patients.

Conclusion

Restless legs syndrome is not only twice as prevalent but also more severe in migraine patients, and associated with decreased sleep quality.

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Authors:
W. P. J. van Oosterhout, E. J. W. van Someren, M. A. Louter, G. G. Schoonman, G. J. Lammers, R. M. Rijsman, M. D. Ferrari and G. M. Terwindt
Article first published online:
21 Mar 2016 | DOI: 10.1111/ene.12993

Original Article

Background and purpose

A strong association between time to generalization (TTG), considered as the time of spreading of the clinical signs from spinal or bulbar localization to both, and survival was recently identified in patients with amyotrophic lateral sclerosis (ALS). Thus, TTG may be used as an early to intermediate end‐point in survival studies. The aim of the present study was to test TTG as a predictor of survival in ALS.

Methods

This was an observational retrospective study of ALS patients from a tertiary referral centre over a 5‐year follow‐up period.

Results

In 212 ALS patients, TTG was associated with time to death/tracheostomy [R 0.62, 95% confidence interval (CI) 0.53–0.70; < 0.001]. In a time‐to‐event analysis, longer TTG resulted in lower risk to reach a composite outcome (death or tracheostomy) both in univariate [hazard ratio (HR) 0.98, 95% CI 0.97–0.99] and multivariate Cox analyses (HR 0.98, 95% CI 0.96–0.99). TTG predicted death/tracheostomy at 4 years (‐statistic 0.58; 95% CI 0.53–0.63) and at 5 years (‐statistic 0.58; 95% CI 0.53–0.62).

Conclusions

Based on the present results from a large clinical cohort, TTG may be used as a new early to intermediate end‐point to describe the ALS natural history. TTG may be potentially useful as a new primary outcome measure for clinical trials.

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Authors:
R. Tortelli, M. Copetti, F. Panza, A. Fontana, R. Cortese, R. Capozzo, A. Introna, E. D'Errico, S. Zoccolella, S. Arcuti, D. Seripa, I. L. Simone and G. Logroscino
Article first published online:
25 Mar 2016 | DOI: 10.1111/ene.12994

Original Article

Background and purpose

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition for which there is no single diagnostic test or biomarker. The level of the creatine kinase (CK) enzyme in serum may be mild to moderately elevated in some patients with ALS, the precise cause of which and its behaviour with disease progression is unknown. The aim of this study was to examine the usefulness of monitoring CK serially during the ALS disease trajectory and to determine whether CK levels mirror disease progression.

Methods

This was a prospective observational cohort study, using the clinical database of the olesoxime (TRO19622) investigational medicinal product trial.

Results

The baseline CK was raised in 52% of the trial participants with the mean CK ± SD being 257 ± 239 U/l. The mean CK was significantly higher in male participants than in female participants ( < 0.001) and amongst participants with limb onset ALS compared to participants with bulbar onset ALS ( < 0.001). There was no significant difference in the CK levels between upper limb and lower limb onset disease ( = 0.746). The CK level co‐related positively with serum creatinine and estimated lean body mass but there was no relationship between CK and muscle scores and limb function. A higher CK was associated with significantly better survival, even when adjusted for prognostic co‐variants ( = 0.013).

Conclusions

The serum CK level seems to be an independent prognostic factor for survival in ALS. The cellular mechanism of CK enzyme suggests that it may be upregulated to provide energy in the face of metabolic stress in ALS.

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Authors:
M. K. Rafiq, E. Lee, M. Bradburn, C. J. McDermott and P. J. Shaw
Article first published online:
31 Mar 2016 | DOI: 10.1111/ene.12995

Editorial

Abstract

Click to view the accompanying paper in this issue.

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Authors:
D. Hilton‐Jones
Article first published online:
01 Apr 2016 | DOI: 10.1111/ene.12999

Editorial

Abstract

Click to view the accompanying paper in this issue.

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Authors:
J. P. Klaas
Article first published online:
01 Apr 2016 | DOI: 10.1111/ene.13000

Short Communication

Background and purpose

Disease severity varies considerably among patients with Spinal and Bulbar Muscular Atrophy (SBMA). Our aim was to investigate the role of androgen receptor () polymorphic repeats in SBMA phenotype.

Methods

We analyzed the length of polyQ and polyG tracts in 159 SBMA patients.

Results

No relationship between polyG size or polyG/polyQ haplotypes and clinical phenotype was found. An independent negative correlation between polyQ‐length and onset of weakness was confirmed ( < 0.001).

Conclusions

The negative results of our study prompt to continue the search for potential disease modifiers in SBMA outside the gene.

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Authors:
C. Bertolin, G. Querin, E. Da Re, A. Sagnelli, L. Bello, M. Cao, M. Muscas, M. Pennuto, M. Ermani, E. Pegoraro, C. Mariotti, C. Gellera, M. G. Hanna, D. Pareyson, P. Fratta and G. Sorarù
Article first published online:
03 May 2016 | DOI: 10.1111/ene.13001

Review Article

Abstract

Depression, anxiety and apathy are common mood disturbances in Parkinson's disease (PD) but their pathophysiology is unclear. Advanced neuroimaging has been increasingly used to unravel neural substrates linked to these disturbances. A systematic review is provided of neuroimaging findings in depression, anxiety and apathy in PD. A PubMed, MEDLINE and EMBASE search of peer‐reviewed original research articles on these mood disturbances in PD identified 38 studies on depression, eight on anxiety and 14 on apathy in PD. Most of the imaging studies used either position emission tomography or single‐photon emission computed tomography techniques. These studies generally suggest increased neural activity in the prefrontal regions and decreased functional connectivity between the prefrontal−limbic networks in depressed patients. Functional imaging studies revealed an inverse correlation between dopaminergic density in the caudate and putamen with the severity of anxiety in PD. There was no consistent correlation between dopaminergic density of thalamus and anxiety. Studies demonstrated both positive and inverse correlations between apathy and metabolism or activity in the striatum, amygdalar, prefrontal, temporal and parietal regions. The clinical variability of study subjects and differences in image pre‐processing and analytical strategies may contribute to discrepant findings in these studies. Both nigrostriatal and extra‐nigrostriatal pathways (in particular the frontal region and its connecting areas) are affected in mood disorders in PD. Identifying the relative contributions of these neural pathways in PD patients with overlapping motor and mood symptoms could provide new pathophysiological clues for the development of better therapeutic targets for affected patients.

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Authors:
M.‐C. Wen, L. L. Chan, L. C. S. Tan and E. K. Tan
Article first published online:
03 May 2016 | DOI: 10.1111/ene.13002

Letter to the Editor

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Authors:
J. Finsterer and M. Frank
Article first published online:
03 May 2016 | DOI: 10.1111/ene.13007

Editorial

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Authors:
M. R. Camilo and O. M. Pontes‐Neto
Article first published online:
03 May 2016 | DOI: 10.1111/ene.13018

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Article first published online:
03 May 2016 | DOI: 10.1111/ene.13045