cover image European Journal of Neurology

European Journal of Neurology

2020 - Volume 27
Issue 1 | January 2020
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Article first published online:
06 Dec 2019 | DOI: 10.1111/ene.13991

Original Article

Background and purpose

Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are three of the most common neurodegenerative disorders. Up to 20% of these patients have the wrong diagnosis, due to overlapping symptoms and shared pathologies. A cerebrospinal fluid (CSF) biomarker panel for AD is making its way into the clinic, but an equivalent panel for PD and DLB and for improved differential diagnoses is still lacking. Using well‐defined, community‐based cohorts and validated analytical methods, the diagnostic value of CSF total‐α‐synuclein (t‐α‐syn) alone and in combination with total tau (t‐tau) in newly diagnosed patients with PD, DLB and AD was determined.

Methods

Cerebrospinal fluid concentrations of t‐α‐syn were assessed using our validated in‐house enzyme‐linked immunosorbent assay in 78 PD patients, 20 AD patients, 19 DLB patients and 32 controls. t‐tau was measured using a commercial assay. Diagnostic performance was assessed by receiver operating characteristic curve analysis.

Results

Compared to controls (mean 517 pg/ml), significantly lower levels of CSF t‐α‐syn in patients with PD (434 pg/ml, 16% reduction, 0.036), DLB (398 pg/ml, 23% reduction, 0.009) and AD (383 pg/ml, 26% reduction, 0.014) were found. t‐α‐syn levels did not differ significantly between PD, DLB and AD. The t‐tau/t‐α‐syn ratio showed an improved performance compared to the single markers.

Conclusion

This is the first study to compare patients with PD, DLB and AD at the time of diagnosis. It was found that t‐α‐syn can contribute as a teammate with tau in a CSF biomarker panel for PD and DLB, and strengthen the existing biomarker panel for AD.

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Authors:
M. G. Førland, O.‐B. Tysnes, D. Aarsland, J. Maple‐Grødem, K. F. Pedersen, G. Alves and J. Lange
Article first published online:
24 Jul 2019 | DOI: 10.1111/ene.14032

Original Article

Background and purpose

Next‐generation sequencing has greatly improved the diagnostic success rates for genetic neuromuscular disorders (NMDs). Nevertheless, most patients still remain undiagnosed, and there is a need to maximize the diagnostic yield.

Methods

A retrospective study was conducted on 72 patients with NMDs who underwent exome sequencing (ES), partly followed by genotype‐guided diagnostic reassessment and secondary investigations. The diagnostic yields that would have been achieved by appropriately chosen narrow and comprehensive gene panels were also analysed.

Results

The initial diagnostic yield of ES was 30.6% ( = 22/72 patients). In an additional 15.3% of patients ( = 11/72) ES results were of unknown clinical significance. After genotype‐guided diagnostic reassessment and complementary investigations, the yield was increased to 37.5% ( = 27/72). Compared to ES, targeted gene panels (<25 kilobases) reached a diagnostic yield of 22.2% ( = 16/72), whereas comprehensive gene panels achieved 34.7% ( = 25/72).

Conclusion

Exome sequencing allows the detection of pathogenic variants missed by (narrowly) targeted gene panel approaches. Diagnostic reassessment after genetic testing further enhances the diagnostic outcomes for NMDs.

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Authors:
M. Krenn, M. Tomschik, J. Rath, H. Cetin, A. Grisold, G. Zulehner, I. Milenkovic, E. Stogmann, A. Zimprich, T. M. Strom, T. Meitinger, M. Wagner and F. Zimprich
Article first published online:
13 Aug 2019 | DOI: 10.1111/ene.14033

Original Article

Background and purpose

The cost of medication overuse headache (MOH) is underestimated. Our aim was to address the cost‐effectiveness of a structured treatment protocol and to present annual cost estimates.

Methods

Patients were enrolled on the occasion of a structured treatment protocol, were administered a research protocol addressing direct and indirect costs and were followed up for 3 months.

Results

Of 176 enrolled patients, 138 completed the study. The 3‐month cost per patient fell from €2989 to €1160: the difference was €696 per month for patients treated in the ward and €466 for those treated in day‐hospital; thus it takes 2–3 months to compensate for the protocol's cost. The per‐person annual costs of MOH were €10 533 (95% confidence interval €8700–12 406): direct healthcare costs accounted for 44.8% and indirect costs for 51.5% of the total MOH cost. The annual MOH cost for Italy is estimated at €13.5 billion (95% confidence interval €11.1–15.9 billion).

Conclusion

The cost of MOH around the period of a structured treatment protocol is much higher compared to previous estimates. Our protocol is cost‐effective for reducing the economic burden of MOH.

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Authors:
A. Raggi, M. Leonardi, E. Sansone, M. Curone, L. Grazzi and D. D'Amico
Article first published online:
29 Jul 2019 | DOI: 10.1111/ene.14034

Original Article

Background and purpose

Assessment of the severity of chronic peripheral neuropathy during oxaliplatin treatment is based on symptoms. Efforts to adjust the total dose of oxaliplatin to prevent severe neuropathy can be complicated by the worsening of neuropathy symptoms following treatment. Objective measures of the structure and function of peripheral nerves during early phases of treatment may aid in determining the optimal oxaliplatin dose in individual patients. Intraepidermal nerve fibre density (IENFD) has been suggested as an early marker of peripheral neuropathy.

Methods

Sixty patients were examined before treatment and following 25% and 50% of the total planned oxaliplatin dose. Fifty‐five of them were also examined at completion of chemotherapy and 6 months later. IENFD in skin biopsies from the distal leg, nerve conduction studies and quantitative sensory testing at the dorsum of the foot were performed. Forty‐six healthy subjects were examined at baseline and after 6 and 52 weeks for comparison.

Results

Intraepidermal nerve fibre density was not reduced during treatment. Sural nerve amplitude and conduction velocity, vibration detection thresholds, mechanical detection threshold and cold detection threshold were significantly reduced during treatment. Compared to reference values and spontaneous changes in healthy subjects, the largest proportions of patients with deterioration were found for vibration detection thresholds followed by nerve conduction studies, mechanical detection threshold, cold detection threshold and IENFD.

Conclusions

Significant changes were most pronounced for measures of large nerve fibre function, especially vibration sensation. Skin biopsies do not seem to provide a clinically relevant objective measure of peripheral nerve deterioration during oxaliplatin treatment.

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Authors:
T. Krøigård, T. K. Svendsen, M. Wirenfeldt, H. D. Schrøder, C. Qvortrup, P. Pfeiffer, D. Gaist and S. H. Sindrup
Article first published online:
02 Aug 2019 | DOI: 10.1111/ene.14035

Original Article

Background and purpose

The aim of this study was to assess the prevalence of cancer and its characteristics in patients with ischemic stroke and to compare this with cancer prevalence in the general population.

Methods

This was a multicenter cohort study with 2736 patients presenting with ischemic stroke or transient ischemic attack. The prevalence of cancer was assessed by interview and verified by reviewing all medical records. In stroke patients with a history of cancer, we studied the subtype of cancer and its treatment characteristics. We used the national database of The Netherlands Cancer Registry to calculate population‐based age and sex cancer standardized prevalence ratios (SPRs) for patients with ischemic stroke.

Results

Cancer prevalence in ischemic stroke patients was 12%, corresponding to an SPR of 1.2 [95% confidence interval (CI), 1.0–1.3]. Increased SPRs were observed for cancer of the central nervous system (SPR, 18.2; 95% CI, 9.0–27.4), head and neck (SPR, 3.4; 95% CI, 2.3–4.6), lower respiratory tract (SPR, 2.4; 95% CI, 1.5–3.3) and urinary tract (SPR, 2.1; 95% CI, 1.4–2.9), but not for other cancer types. Cardiovascular risk factors, stroke etiology, treatment and outcome were not different between patients with or without a history of cancer.

Conclusions

In stroke patients, the prevalence of cancer, most prominently cancer of the central nervous system, head and neck, lower respiratory and urinary tract, was higher than in the general population. Medical treatment for the prevention of stroke in cancer survivors deserves further study.

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Authors:
J. Wilbers, L. Sondag, S. Mulder, B. Siegerink and E. J. van Dijk
Article first published online:
29 Jul 2019 | DOI: 10.1111/ene.14037

Original Article

Background and purpose

The cervical and thoracic cross‐sectional spinal cord area (CS‐SCA) in multiple sclerosis (MS) correlates with disability, whilst such a correlation remains to be established in neuromyelitis optica spectrum disorder (NMOSD). Our aim was to clarify differences between MS and NMOSD in spinal cord segments where CS‐SCA is associated with disability.

Methods

The CS‐SCA at C2/C3, C3/C4, T8/T9 and T9/T10 vertebral disc levels was measured in 140 MS patients (111 with relapsing–remitting MS and 29 with progressive MS) and 42 NMOSD patients with anti‐aquaporin‐4 immunoglobulin G. Disability was evaluated by Expanded Disability Status Scale (EDSS) scores. Multivariate associations between CS‐SCA and disability were assessed by stepwise forward multiple linear regression.

Results

Thoracic CS‐SCA was significantly smaller in NMOSD patients than in MS patients even after adjusting for age, sex and disease duration (=0.002 at T8/T9), whilst there was no difference in cervical CS‐SCA between the two diseases. Cervical and thoracic CS‐SCA had a negative correlation with EDSS scores in MS patients (<0.0001 at C3/C4 and =0.0002 at T8/T9) whereas only thoracic CS‐SCA correlated with EDSS scores in NMOSD patients (=0.0006 at T8/T9). By multiple regression analyses, predictive factors for disability in MS were smaller cervical CS‐SCA, progressive course, older age and a higher number of relapses, whilst those in NMOSD were smaller thoracic CS‐SCA and older age.

Conclusions

Thoracic CS‐SCA is a useful predictive marker for disability in patients with NMOSD whilst cervical CS‐SCA is associated with disability in patients with MS.

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Authors:
Y. Nakamura, Z. Liu, S. Fukumoto, K. Shinoda, A. Sakoda, T. Matsushita, S. Hayashida, N. Isobe, M. Watanabe, A. Hiwatashi, R. Yamasaki and J. ‐i. Kira
Article first published online:
02 Aug 2019 | DOI: 10.1111/ene.14038

Original Article

Background and purpose

Tapering immunosuppressants is desirable in patients with well‐controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction‐associated exacerbation is not known. The aim of this study was to clarify the frequency of reduction‐associated exacerbation when tacrolimus is tapered in stable patients with anti‐acetylcholine receptor antibody‐positive MG, and to determine the factors that predict exacerbations.

Methods

We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction‐associated exacerbation was defined as the appearance or worsening of one or more MG symptoms <3 months after the reduction.

Results

Tacrolimus dosage was successfully tapered in 110 patients (96%) without any exacerbation. Five patients (4%) experienced an exacerbation, but symptoms were reversed in all patients when the tacrolimus dose was increased to the previous maintenance level. No patient developed an MG crisis. The age at onset was significantly earlier (30 vs. 56 years,  = 0.025) and the reduction in dosage was significantly larger (2.0 vs. 1.0 mg/day,  = 0.002) in patients with reduction‐associated exacerbation than in those without exacerbation. The cut‐off values determined in a receiver‐operating characteristic curve analysis were 52 years (sensitivity, 57%; specificity, 100%) for the age at onset and 1.5 mg (sensitivity, 80%; specificity, 100%) for the dose reduction.

Conclusion

Tapering of tacrolimus was possible in most patients with well‐controlled anti‐acetylcholine receptor antibody‐positive MG. Early age at onset and a large reduction from maintenance dosage were associated with exacerbation. Reductions ≤1.5 mg/day from the maintenance dosage should be considered for patients with late‐onset disease.

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Authors:
Y. Nishida, Y. K. Takahashi, T. Kanai, Y. Nose, S. Ishibashi, N. Sanjo, A. Uzawa, F. Oda, Y. Ozawa, S. Kuwabara, E. Noguchi, S. Suzuki, J. Nakahara, N. Suzuki, T. Ogawa, K. Yokoyama, N. Hattori, S. Konno, T. Fujioka, N. Kawaguchi, Y. Hatanaka, M. Sonoo, J. Kaneko, M. Ogino, K. Nishiyama, K. Nomura and T. Yokota
Article first published online:
08 Aug 2019 | DOI: 10.1111/ene.14039

Original Article

Background and purpose

We aimed to determine the burden of comorbidities at the time of diagnosis of multiple sclerosis (MS), the risk of developing new comorbidities after diagnosis and the effect of comorbidities on mortality in patients with MS.

Methods

This study used data from 2526 patients with incident MS and 9980 age‐, sex‐ and physician‐matched controls without MS identified from the UK Clinical Practice Research Datalink.

Results

Before the MS diagnosis, the adjusted odds ratio for the association between MS and a Charlson comorbidity index score of 1–2, 3–4 or ≥5 was 131 [95% confidence interval (CI), 1.17–1.47], 1.65 (95% CI, 1.20–2.26) or 3.26 (95% CI, 1.58–6.70), respectively. MS was associated with increased risks of cardiovascular and neurological/mental diseases. After diagnosis, the adjusted hazard ratio for the association between MS and an increased risk of developing comorbidities was 1.13 (95% CI, 1.00–1.29). The risk of developing any comorbidity in terms of neoplasms, musculoskeletal/connective tissue diseases or neurological/mental diseases was higher in MS. Patients with MS had a higher mortality risk compared with controls, with a hazard ratio of 2.29 (95% CI, 1.81–2.73) after adjusting for comorbidities. There was a dose effect of pre‐existing comorbidities on mortality.

Conclusions

Patients with MS have an increased risk of developing multiple comorbidities both before and after diagnosis and pre‐existing comorbidities have an impact on survival.

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Authors:
I. J. Chou, C. F. Kuo, R. Tanasescu, C. R. Tench, C. G. Tiley, C. S. Constantinescu and W. P. Whitehouse
Article first published online:
31 Jul 2019 | DOI: 10.1111/ene.14040

Original Article

Background and purpose

Systemic lupus erythematosus (SLE) is an immune‐mediated disease that may affect the nervous system. We explored the topographical organization of structural and functional brain connectivity in patients with SLE and its correlation with neuropsychiatric (NP) involvement and autoantibody profiles.

Methods

Graph theoretical analysis was applied to diffusion tensor magnetic resonance imaging (MRI) and resting‐state functional MRI data from 32 patients with SLE and 32 age‐ and sex‐matched healthy controls. Structural and functional connectivity matrices between 116 cortical/subcortical brain regions were estimated using a bivariate correlation analysis, and global and nodal network metrics were calculated.

Results

Structural, but not functional, global network properties (strength, transitivity, global efficiency and path length) were abnormal in patients with SLE versus controls (<0.0001), especially in patients with anti‐double‐stranded DNA (ADNA) autoantibodies (=0.03). No difference was found according to NP involvement or anti‐phospholipid autoantibody status. Patients with SLE and controls shared identical structural hubs and the majority of functional hubs. In patients with SLE, all structural hubs showed reduced strength and clustering coefficient compared with controls ( from 0.001 to <0.0001), especially in patients with ADNA autoantibodies. Only a few differences in functional hub properties were found between patients with SLE and controls. Structural and functional hub measures did not differ according to NP involvement or anti‐phospholipid autoantibody status. Significant correlations were found between clinical, MRI and network measures ( from −0.56 to 0.60, from 0.0003 to 0.05).

Conclusions

Abnormalities of global and nodal structural connectivity occur in patients with SLE, especially with ADNA autoantibodies, with a diffuse disruption of structural integrity. Functional network integrity may contribute to preserve clinical functions.

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Authors:
P. Preziosa, M. A. Rocca, G. A. Ramirez, E. P. Bozzolo, V. Canti, E. Pagani, P. Valsasina, L. Moiola, P. Rovere‐Querini, A. A. Manfredi and M. Filippi
Article first published online:
08 Aug 2019 | DOI: 10.1111/ene.14041

Original Article

Background and purpose

Considerable functional reorganization takes place in amyotrophic lateral sclerosis (ALS) in face of relentless structural degeneration. This study evaluates functional adaptation in ALS patients with lower motor neuron predominant (LMNp) and upper motor neuron predominant (UMNp) dysfunction.

Methods

Seventeen LMNp ALS patients, 14 UMNp ALS patients and 14 controls participated in a functional magnetic resonance imaging study. Study‐group‐specific activation patterns were evaluated during preparation for a motor task. Connectivity analyses were carried out using the supplementary motor area (SMA), cerebellum and striatum as seed regions and correlations were explored with clinical measures.

Results

Increased cerebellar, decreased dorsolateral prefrontal cortex and decreased SMA activation were detected in UMNp patients compared to controls. Increased cerebellar activation was also detected in UMNp patients compared to LMNp patients. UMNp patients exhibit increased effective connectivity between the cerebellum and caudate, and decreased connectivity between the SMA and caudate and between the SMA and cerebellum when performing self‐initiated movement. In UMNp patients, a positive correlation was detected between clinical variables and striato‐cerebellar connectivity.

Conclusions

Our findings indicate that, despite the dysfunction of SMA–striatal and SMA–cerebellar networks, cerebello‐striatal connectivity increases in ALS indicative of compensatory processes. The coexistence of circuits with decreased and increased connectivity suggests concomitant neurodegenerative and adaptive changes in ALS.

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Authors:
M. Abidi, G. de Marco, A. Couillandre, M. Feron, E. Mseddi, N. Termoz, G. Querin, P. ‐F. Pradat and P. Bede
Article first published online:
13 Aug 2019 | DOI: 10.1111/ene.14042

Original Article

Background and purpose

Data on epilepsy in dementia, particularly on its risk factors, are scarce. Confounding comorbidities and the rising incidence of epilepsy in older age have hampered studies in this field. The occurrence and risk factors for epilepsy in the Swedish Dementia Registry (SveDem), a large cohort of patients with dementia, have been examined.

Methods

Information on epilepsy and seizure‐related diagnoses, comorbidities and survival were extracted for all individuals in SveDem (=81 192) and three randomly selected age‐ and gender‐matched controls from the population register, excluding all with a dementia diagnosis (=223 933). The risk of epilepsy following dementia diagnosis was estimated with Kaplan–Meier curves, and Cox proportional hazard modelling was used to identify risk factors and adjust for comorbidities.

Results

A diagnosis of epilepsy was found more frequently amongst dementia patients [4.0%, 95% confidence interval (CI) 3.8–4.1] than controls (1.9%, 95% CI 1.9–2.0). The risk of incident epilepsy after dementia was 2.1% (95% CI 1.9–2.3) at 5 years and 4.0% (95%CI 3.4–4.6) at 10 years, compared to 0.8% (95% CI 0.8–0.8) and 1.6% (95% CI 1.4–1.8) respectively for controls. The risk was greatest for early‐onset Alzheimer's disease. In multivariate analysis, dementia was associated with a hazard ratio of 2.52 (95% CI 2.31–2.74) for epilepsy. Young age, male sex, stroke, brain trauma, brain tumour and low Mini‐Mental State Examination score significantly increased the risk.

Conclusions

Dementia, particularly young‐onset Alzheimer's disease, increases the risk of subsequent epilepsy. Further studies are needed to determine optimal management and the impact of epilepsy on prognosis.

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Authors:
J. Zelano, F. Brigo and S. Garcia‐Patek
Article first published online:
13 Aug 2019 | DOI: 10.1111/ene.14043

Original Article

Background and purpose

The role of lifestyle and dietary habits and antecedent events has not been clearly identified in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

Methods

Information was collected about modifiable environmental factors and antecedent infections and vaccinations in patients with CIDP included in an Italian CIDP Database. Only patients who reported not having changed their diet or the lifestyle habits investigated in the study after the appearance of CIDP were included. The partners of patients with CIDP were chosen as controls. Gender‐matched analysis was performed with randomly selected controls with a 1:1 ratio of patients and controls.

Results

Dietary and lifestyle data of 323 patients and 266 controls were available. A total of 195 cases and 195 sex‐matched controls were used in the analysis. Patients eating rice at least three times per week or eating fish at least once per week appeared to be at decreased risk of acquiring CIDP. Data on antecedent events were collected in 411 patients. Antecedent events within 1–42 days before CIDP onset were reported by 15.5% of the patients, including infections in 12% and vaccinations in 1.5%. Patients with CIDP and antecedent infections more often had an acute onset of CIDP and cranial nerve involvement than those without these antecedent events.

Conclusions

The results of this preliminary study seem to indicate that some dietary habits may influence the risk of CIDP and that antecedent infections may have an impact on the onset and clinical presentation of the disease.

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Authors:
P. E. Doneddu, E. Bianchi, D. Cocito, F. Manganelli, R. Fazio, M. Filosto, A. Mazzeo, G. Cosentino, A. Cortese, S. Jann, A. M. Clerici, G. Antonini, G. Siciliano, M. Luigetti, G. A. Marfia, C. Briani, G. Lauria, T. Rosso, G. Cavaletti, M. Carpo, L. Benedetti, E. Beghi, G. Liberatore, L. Santoro, E. Peci, S. Tronci, S. Cotti Piccinelli, A. Toscano, L. Piccolo, E. P. Verrengia, L. Leonardi, E. Schirinzi, G. Mataluni, M. Ruiz, P. Dacci and E. Nobile‐Orazio
Article first published online:
09 Aug 2019 | DOI: 10.1111/ene.14044

Original Article

Background and purpose

The occurrence of intermediate uveitis, which is characterized by the presence of vitreous haze (VH), in patients with multiple sclerosis (MS) may be a sign of coexistent inflammatory central nervous system (CNS) disease activity. Using an automated algorithm to quantify VH on optical coherence tomography (OCT) scans, the aim was to investigate whether VH in MS patients is associated with signs of inflammatory CNS disease activity.

Methods

Vitreous haze was quantified on OCT macular volume scans of 290 MS patients and 85 healthy controls (HCs). The relationship between VH and clinical, retinal OCT and magnetic resonance imaging parameters of inflammatory disease activity was investigated using generalized estimating equations.

Results

Mean VH scores did not differ between patients and HCs ( = 0.629). Six patients (2.1%) showed values higher than the highest of the controls by HCs. VH scores did not differ between the different disease types or between eyes with and without a history of optic neuritis ( = 0.132). VH was not associated with inner nuclear layer volume on OCT ( = 0.233), cerebral T2 lesion load on magnetic resonance imaging ( = 0.416) or the development of new relapses ( = 0.205).

Conclusion

In this study, OCT‐based automated VH estimation did not detect increased vitreous inflammation in MS patients compared to HCs and did not find an association with CNS inflammatory burden.

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Authors:
D. Coric, G. Ometto, G. Montesano, P. A. Keane, L. J. Balk, B. M. J. Uitdehaag, A. Petzold, D. P. Crabb and A. K. Denniston
Article first published online:
18 Aug 2019 | DOI: 10.1111/ene.14048

Original Article

Background and purpose

Our purpose was to study the association between country of birth and incident epilepsy in second‐generation immigrants in Sweden.

Methods

The study population included all children ( = 4 023 149) aged up to 18 years in Sweden. Epilepsy was defined as at least one registered diagnosis of epilepsy in the National Patient Register. The incidence of epilepsy, using individuals with Swedish‐born parents as referents, was assessed by Cox regression, expressed in hazard ratios (HRs) and 95% confidence interval (95% CI). All models were stratified by sex and adjusted for age, geographical residence in Sweden, educational level, marital status, neighbourhood socioeconomic status and comorbid conditions, also using data from the Total Population Register.

Results

A total of 26 310 individuals had a registered epilepsy event, i.e. 6.5/1000 (6.6/1000 amongst boys and 6.3/1000 amongst girls). After adjustment, the risk of epilepsy was lower than in children of Swedish‐born parents. Amongst girls the significant HR was 0.85 (95% CI 0.81–0.88), but in boys only when adjusting also for comorbidity (HR 0.96, 95% CI 0.92–0.99). Amongst specific immigrant groups, a higher incidence of epilepsy was observed amongst boys with parents from Turkey and Africa, but not when adjusting for comorbidity, and a lower risk was observed in many other groups (boys with parents from Latvia, girls with parents from Finland, Iceland, Southern Europe, countries from the former Yugoslavia, and Asia).

Conclusion

The risk of epilepsy was lower in second‐generation immigrant children compared to children with Swedish‐born parents, but with substantial differences between different immigrant groups.

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Authors:
P. Wändell, S. Fredrikson, A. C. Carlsson, X. Li, D. Gasevic, J. Sundquist and K. Sundquist
Article first published online:
19 Aug 2019 | DOI: 10.1111/ene.14049

Original Article

Background and purpose

Orthostatic hypotension is frequent with aging with a prevalence of 20%–30% in people aged 65 or older and is considered to increase the risk for coronary events, strokes and dementia. Our objective was to characterize the association of orthostatic hypotension and cognitive function longitudinally over 6 years in a large cohort of the elderly aged over 50 years.

Methods

In all, 495 participants were assessed longitudinally with the Schellong test and comprehensive cognitive testing using the extended CERAD neuropsychological test battery at baseline and after 6 years. In a subgroup of 92 participants, cerebral magnetic resonance imaging was evaluated for white matter changes using a modified version of the Fazekas score.

Results

The prevalence of orthostatic hypotension increases with aging reaching up to 30% in participants aged >70 years. Participants with orthostatic hypotension presented with a higher vascular burden index (1.03 vs. 0.69,  ≤ 0.001), tended to have a higher prevalence of cerebral white matter hyperintensities (91.7% vs. 68.8%,  = 0.091) and showed a faster deterioration in executive and memory function (Trail Making Test B 95 vs. 87 s,  ≤ 0.001; word list learning sum −0.53 vs. 0.38,  = 0.002) compared to participants without orthostatic hypotension.

Conclusion

Orthostatic hypotension seems to be associated with cognitive decline longitudinally.

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Authors:
M. Zimmermann, I. Wurster, S. Lerche, B. Roeben, G. Machetanz, U. Sünkel, A.‐K. von Thaler, G. Eschweiler, A. J. Fallgatter, W. Maetzler, D. Berg and K. Brockmann
Article first published online:
26 Aug 2019 | DOI: 10.1111/ene.14050

Original Article

Background and purpose

Acute ischemic stroke treatment with intravenous thrombolysis (IVT) is restricted to a time window of 4.5 h after known or presumed onset. Recently, magnetic resonance imaging‐guided treatment decision‐making in wake‐up stroke (WUS) was shown to be effective. The aim of this study was to determine the safety and outcome of IVT in patients with a time window beyond 4.5 h selected by computed tomography perfusion (CTP) imaging.

Methods

We analyzed all consecutive patients last seen well beyond 4.5 h after stroke onset treated with IVT based on CTP between January 2015 and October 2018. CTP was visually assessed to estimate the mismatch between cerebral blood flow and cerebral blood volume maps. Early infarct signs were documented according to Alberta Stroke Program Early CT Score (ASPECTS). Safety data were obtained for mortality and symptomatic intracerebral hemorrhage (sICH). Follow‐up was assessed with the modified Rankin Scale (mRS).

Results

A total of 70 patients fulfilled the inclusion criteria (mean age ± SD 77.6 ± 11.5 years, 50.0% female). Median National Institutes of Health Stroke Scale score on admission was 8.0 [interquartile range (IQR), 4–14]. The most frequent reasons for an extended time window were WUS (60.0%) and delayed hospital admission (27.1%). Median time from last seen well to IVT was 11.4 h. Median ASPECTS was 10 (IQR, 9–10) and CTP mismatch 90% (IQR, 80%–100%). A total of 24 patients (34.3%) underwent additional mechanical thrombectomy. sICH occurred in four patients (5.7%). At follow‐up, 49.3% had an mRS score of 0–2 and 22.4% had an mRS score of 0–1.

Conclusions

In patients presenting in an extended time window beyond 4.5 h, IVT treatment with decision‐making based on CTP might be a safe procedure. Further evaluation in clinical trials is needed.

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Authors:
K. Feil, P. Reidler, W. G. Kunz, C. Küpper, J. Heinrich, C. Laub, K. Müller, J. Vöglein, T. Liebig, M. Dieterich and L. Kellert
Article first published online:
21 Aug 2019 | DOI: 10.1111/ene.14051

Original Article

Background and purpose

Thymectomy is an effective treatment for myasthenia gravis (MG) with anti‐acetylcholine receptor (AChR) antibodies. We rarely encounter patients who develop MG after surgery for thymic tumors. This study aimed to investigate the characteristics and frequency of post‐thymectomy onset (PostTx) MG.

Methods

We reviewed the clinical information of thymoma‐associated MG in 158 patients. Of these, 18 (11%) patients with PostTx MG were identified.

Results

The presence of anti‐AChR antibodies (82%) and electrophysiological abnormalities (50%) was confirmed before thymectomy in patients with PostTx MG. The clinical characteristics of PostTx MG were similar to those of pre‐thymectomy onset (PreTx) MG. In PostTx MG, the duration between thymectomy and MG onset were distributed as < 6 months (early‐onset PostTx MG) and ≥ 6 months (late‐onset PostTx MG). Notably, some patients with late‐onset PostTx MG were associated with thymoma relapse.

Conclusion

Our results suggest that approximately 11% of patients with thymoma‐associated MG were PostTx MG and pre‐surgical assessment of anti‐AChR antibody titer or electrophysiological testing may predict PostTx MG development. However, no difference in clinical manifestation and prognosis was observed between PreTx MG and PostTx MG.

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Authors:
A. Uzawa, T. Kanai, F. Oda, Y. Ozawa, M. Yasuda, N. Kawaguchi, K. Himuro, I. Yoshino and S. Kuwabara
Article first published online:
12 Aug 2019 | DOI: 10.1111/ene.14052

Original Article

Background and purpose

Hypertrophy/signal hyperintensity and/or gadolinium enhancement of plexus structures on magnetic resonance imaging (MRI) are observed in two‐thirds of cases of typical chronic inflammatory demyelinating polyneuropathy (CIDP). The objective of our study was to determine the additional benefit of plexus MRI in patients referred to tertiary centers with baseline clinical and electrophysiological characteristics suggestive of typical or atypical CIDP.

Methods

A total of 28 consecutive patients with initial suspicion of CIDP were recruited in nine centers and followed for 2 years. Plexus MRI data from the initial assessment were reviewed centrally. Physicians blinded to the plexus MRI findings established the final diagnosis (CIDP or neuropathy of another cause). The proportion of patients with abnormal MRI was analyzed in each group.

Results

Chronic inflammatory demyelinating polyneuropathy was confirmed in 14 patients (50%), as were sensorimotor CIDP (=6), chronic immune sensory polyradiculoneuropathy (=2), motor CIDP (=1) and multifocal acquired demyelinating sensory and motor neuropathy (=5). A total of 37 plexus MRIs were performed (17 brachial, 19 lumbosacral and 8 in both localizations). MRI was abnormal in 5/37 patients (14%), all of whom were subsequently diagnosed with CIDP [5/14(36%)], after an atypical baseline presentation. With plexus MRI results masked, non‐invasive procedures confirmed the diagnosis of CIDP in all but one patient [1/14 (7%)]. Knowledge of the abnormal MRI findings in the latter could have prevented nerve biopsy being performed.

Conclusion

Systematic plexus MRI in patients with initially suspected CIDP provides little additional benefit in confirming the diagnosis of CIDP.

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Authors:
F. Jomier, V. Bousson, K. Viala, Y. Péréon, A. Magot, C. Cauquil, F. Bouhour, C. Vial, A.‐L. Bedat‐Millet, F. Taithe, S. Bresch, A. Siri, N. Kubis and P. Lozeron
Article first published online:
12 Aug 2019 | DOI: 10.1111/ene.14053

Original Article

Background and purpose

Cholesterol is an important structural component of myelin and essential for brain homeostasis. Our objective was to investigate whether longitudinal changes in cholesterol biomarkers are associated with neurodegeneration in multiple sclerosis (MS).

Methods

This prospective, longitudinal study (=154) included 41 healthy controls, 76 relapsing–remitting MS subjects and 37 progressive MS subjects. Neurological examination, brain magnetic resonance imaging and blood samples were obtained at baseline and at 5‐year follow‐up visits. Cholesterol biomarkers measured included plasma total cholesterol, high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol and the apolipoproteins ApoA‐I, Apo‐II, ApoB, ApoC‐II and ApoE. Key cholesterol pathway single nucleotide polymorphisms were genotyped.

Results

Greater percentage increases in HDL‐C and ApoA‐I levels were associated with a lower rate of gray matter and cortical volume loss. Greater percentage increases in low‐density lipoprotein cholesterol were associated with increases in new T2 lesions. The percentage increases in HDL‐C (=0.032) and ApoA‐I (=0.007) were smaller in patients with relapsing–remitting MS at baseline who converted to secondary progressive MS during the 5‐year follow‐up period. Changes in HDL‐C and ApoA‐I were associated with lipoprotein lipase rs328 genotype status.

Conclusions

Increases in HDL‐C and ApoA‐I have protective associations with magnetic resonance imaging measures of neurodegeneration in MS.

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Authors:
N. Murali, R. W. Browne, K. Fellows Maxwell, M. L. Bodziak, D. Jakimovski, J. Hagemeier, N. Bergsland, B. Weinstock‐Guttman, R. Zivadinov and M. Ramanathan
Article first published online:
19 Aug 2019 | DOI: 10.1111/ene.14055

Original Article

Background and purpose

Chronic inflammatory demyelinating polyneuropathy (CIDP) causes weakness which adversely impacts function and quality of life (QOL). CIDP often requires long‐term management with intravenous or subcutaneous immunoglobulin. The Polyneuropathy and Treatment with Hizentra® (PATH) study showed that subcutaneous immunoglobulin (SCIG) was efficacious in CIDP maintenance. Here, patient‐reported outcomes in patients on SCIG are assessed.

Methods

Subjects stabilized on intravenous immunoglobulin were randomly allocated to receive weekly 0.2 or 0.4 g/kg bodyweight of 20% SCIG (IgPro20) or placebo. Overall QOL/health status was assessed using the EuroQoL 5‐Dimension (EQ‐5D) health profile and visual analog scale, treatment satisfaction was assessed with the Treatment Satisfaction Questionnaire for Medicine (TSQM) and work‐related impact was assessed with the Work Productivity and Activity Impairment Questionnaire for General Health (WPAI‐GH). The EQ‐5D health profile was assessed in terms of the percentage of subjects maintained or improved at week 25 of SCIG therapy on each of the EQ‐5D domains versus baseline after intravenous immunoglobulin stabilization. TSQM and WPAI‐GH were assessed by median score changes from baseline to week 25.

Results

In total, 172 subjects were randomized to placebo (=57), 0.2 g/kg IgPro20 (=57) and 0.4 g/kg IgPro20 (=58). Significantly higher proportions of IgPro20‐treated subjects improved/maintained their health status on the EQ‐5D usual activities dimension, and in additional dimensions (mobility and pain/discomfort) in sensitivity analyses. TSQM and WPAI‐GH scores were more stable with IgPro20 treatment compared with placebo.

Conclusions

 IgPro20 maintained or improved QOL in most subjects with CIDP, consistent with the PATH study findings that both IgPro20 doses were efficacious in maintaining CIDP.

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Authors:
H.‐P. Hartung, R. Mallick, V. Bril, R. A. Lewis, G. Sobue, J.‐P. Lawo, O. Mielke, B. L. Durn, D. R. Cornblath, I. S. J. Merkies and I. N. van Schaik
Article first published online:
23 Sep 2019 | DOI: 10.1111/ene.14056

Original Article

Background and purpose

Stress is a known risk factor for the onset and modulation of disease activity in autoimmune disorders. The aim of this cross‐sectional study was to determine any associations between myasthenia gravis (MG) severity and chronic stress, depression and personality type.

Methods

In all, 179 consecutive adult patients with confirmed MG attending the Neuromuscular Clinic between March 2017 and December 2017 were included. At baseline, patients were assessed clinically and they completed self‐administered scales for disease severity, perceived stress, depression and personality type.

Results

Higher disease severity [Myasthenia Gravis Impairment Index (MGII)] showed a moderate correlation with depression score (Beck's Depression Inventory, Second Edition,  = 0.52,  < 0.001) and a lower correlation with chronic stress (Trier Inventory for Assessment of Chronic Stress,  = 0.28,  = 0.001). Chronic stress scores were different according to personality types (, = 0.02). The linear regression model with MGII score as the dependent variable showed = 0.34, likelihood ratio chi‐squared 74.55, with  < 0.0001. The only variables that predicted disease severity were depression scores ( < 0.0001) and female sex ( = 0.003).

Conclusions

A significant association of MG severity with depression and chronic stress was found, as well as with female gender. These findings should raise awareness that the long‐term management of MG should address depression and potential stress and consider behavioural management to prevent stress‐related immune imbalance.

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Authors:
A. Bogdan, C. Barnett, A. Ali, M. AlQwaifly, A. Abraham, S. Mannan, E. Ng and V. Bril
Article first published online:
05 Sep 2019 | DOI: 10.1111/ene.14057

Original Article

Background and purpose

Limited research has been dedicated to upper limb (UL) rehabilitation in progressive multiple sclerosis (PMS). The objective in this pilot study was to investigate the effect of task‐oriented UL rehabilitation in PMS and to perform explorative analyses of the magnetic resonance imaging (MRI) correlates of changes in motor performance.

Methods

Twenty‐six PMS patients with mild UL impairment were prospectively enrolled and randomized into two groups: an active treatment group (ATG,  = 13) and a passive treatment group (PTG,  = 13). At baseline and after training, patients underwent MRI scans with structural and functional imaging and were evaluated with the action research arm test, the nine‐hole peg test, the ABILHAND scale and the modified fatigue impact scale (MFIS). Measures of motor finger performance were obtained by engineered glove measuring.

Results

After rehabilitation, the ATG improved in several finger motor tasks (0.001 ≤ ≤0.03, 0.72 ≤ Cohen's  ≤ 1.22) and showed reduced MFIS scores compared with the PTG (=0.03). The ATG showed increased functional connectivity within the cerebellar and thalamic resting state networks compared with the PTG (<0.05). Correlations were found between several measures of motor improvement and thalamic and sensorimotor networks (0.87 ≤ ≤0.93, 0.001 ≤ ≤0.03). No changes in cerebral volumes and diffusion tensor imaging derived measures were detected.

Conclusions

Progressive multiple sclerosis patients with mild UL dysfunction benefit from task‐oriented UL rehabilitation, which seems to be more efficient than simple passive mobilization. Despite a high burden of disability and brain damage, functional adaptive capacities seem to be preserved, thus providing a rationale for the use of rehabilitative treatments in late PMS.

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Authors:
G. Boffa, A. Tacchino, E. Sbragia, S. Schiavi, A. Droby, N. Piaggio, G. Bommarito, G. Girardi, G. L. Mancardi, G. Brichetto and M. Inglese
Article first published online:
20 Sep 2019 | DOI: 10.1111/ene.14059

Letter to the Editor

Do longitudinal cerebrospinal fluid profiles correspond to postmortem brain pathology in Parkinson's disease?

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Authors:
I. Wurster, S. Lerche, A-K. Hauser, C. Schulte, I. Lachmann, R. Beschorner, M. Neumann and K. Brockmann
Article first published online:
10 Sep 2019 | DOI: 10.1111/ene.14060

Letter to the Editor

A man with sarcoidosis and slurred speech

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Authors:
T. Nicoletti, S. Gaudino, G. Colacicco, L. Ausili Cefaro, G. Tasca, V. Guglielmi, A. Modoni, M. Gessi, G. Silvestri and G. Frisullo
Article first published online:
18 Sep 2019 | DOI: 10.1111/ene.14067

Review Article

Abstract

The profile and trajectory of cognitive impairment in mitochondrial disease are poorly defined. This systematic review sought to evaluate the current literature on cognition in mitochondrial disease, and to determine future research directions. A systematic review was conducted, employing PubMed, Medline, Psycinfo, Embase and Web of Science, and 360‐degree citation methods. English language papers on adult patients were included. The literature search yielded 2421 articles, of which 167 met inclusion criteria. Case reports and reviews of medical reports of patients yielded broad diagnoses of dementia, cognitive impairment and cognitive decline. In contrast, systematic investigations of cognitive functioning using detailed cognitive batteries identified focal cognitive rather than global deficits. Results were variable, but included visuospatial functioning, memory, attention, processing speed and executive functions. Conclusions from studies have been hampered by small sample sizes, variation in genotype and the breadth and depth of assessments undertaken. Comprehensive cognitive research with concurrent functional neuroimaging and physical correlates of mitochondrial disease in larger samples of well‐characterized patients may discern the aetiology and progression of cognitive deficits. These data provide insights into the pattern and trajectory of cognitive impairments, which are invaluable for clinical monitoring, health planning and clinical trial readiness.

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Authors:
H. L. Moore, A. P. Blain, D. M. Turnbull and G. S. Gorman
Article first published online:
22 Oct 2019 | DOI: 10.1111/ene.14068

Review Article

Abstract

Stroke mimics form a significant proportion of cases in acute stroke services and some present with functional neurological disorder. Little is known about the prevalence or clinical characteristics of functional stroke mimics (FSMs). A systematic literature search and meta‐analysis were carried out on published studies reporting suspected stroke and stroke mimic rates; 114 papers met the inclusion criteria of which 70 provided an FSM rate. Random‐effects models estimated prevalence rates across settings and moderators of FSM rate. Pooled proportions indicated that 25% [95% confidence intervals (CI), 22–27%] of suspected stroke cases were stroke mimics. Within the 67 studies providing positive FSM rates, FSMs represented 15% (95% CI, 13–18%) of stroke mimics and 2% (95% CI, 2–3%) of suspected strokes. FSMs were younger and more likely to be female, and presented more with weakness/numbness but less with reduced consciousness or language problems. Stratified analyses suggested higher stroke mimic rates in primary care versus acute settings (38% vs. 12%) but higher FSM rates in stroke units compared with primary care (24% vs. 12%). Functional rates were higher in studies that were descriptive, retrospective and in patients receiving thrombolysis. Several studies reported the proportion of functional stroke patients presenting to stroke services. FSMs have discernible demographic and clinical characteristics, but there is a conspicuous lack of evidence on their presentation or guidance for treatment. The social and psychological mechanisms underlying FSM presentations need more accurate quantification to help inform stroke pathways and improve care for these patients.

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Authors:
A. T. Jones, N. K. O'Connell and A. S. David
Article first published online:
18 Sep 2019 | DOI: 10.1111/ene.14069

Short Communication

Background and purpose

The brain's cholinergic network has various interconnections with the cortical and subcortical structures. Disruption of cholinergic pathways by white matter hyperintensities (WMH) may cause pathologic changes within brain regions. Thus, WMH may represent an important pathological contributor to subcortical vascular cognitive impairment (scVCI). We aimed to investigate associations between the magnitude of WMH and volumetric changes in cortical and subcortical regions innervated by cholinergic neurons in patients with scVCI.

Methods

We enrolled patients with scVCI, defined as moderate to severe WMH or multiple (>2) lacunar infarcts outside the brainstem. Cholinergic Pathway HyperIntensities Scale (CHIPS) scores were used to quantify the magnitude of cholinergic pathway disruptions by WMH. We measured cortical thickness and subcortical volumes of 11 brain regions innervated by cholinergic neurons. Partial correlation of brain region volumes with total CHIPS scores was obtained using multiple linear regression.

Results

In total, 80 patients were enrolled. The mean age was 78.4 ± 6.5 years, median Mini‐Mental State Examination score was 17 (interquartile range, 13–20) and median CHIPS score was 11 (interquartile range, 7–17). CHIPS scores were positively correlated with subcortical volumes of the putamen (ʹ = 0.46,  = 0.002) and pallidum ( = 0.45,  = 0.002), and were negatively associated with inferior temporal (ʹ= −0.35,  = 0.002) and medial orbitofrontal (= −0.32,  = 0.002) cortical thickness.

Conclusion

Our study suggested that WMH in cholinergic pathways may contribute to volumetric structural changes in cortical and subcortical structures innervated by cholinergic neurons.

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Authors:
J.‐S. Lim, H.‐M. Kwon and Y.‐S. Lee
Article first published online:
05 Sep 2019 | DOI: 10.1111/ene.14073

Letter to the Editor

Spastic ataxia associated with colour vision deficiency due to mutations

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Authors:
P. Bogdanova‐Mihaylova, N. Austin, M. D. Alexander, L. Cassidy, R. P. Murphy, R. A. Walsh and S. M. Murphy
Article first published online:
18 Sep 2019 | DOI: 10.1111/ene.14075

Review Article

Abstract

Parkinson disease (PD) is the most common neurodegenerative movement disorder. In Europe, prevalence and incidence rates for PD are estimated at approximately 108–257/100 000 and 11–19/100 000 per year, respectively. Risk factors include age, male gender and some environmental factors. The aetiology of the disease in most patients is unknown, but different genetic causes have been identified. Although familial forms of PD account for only 5%–15% of cases, studies on these families provided interesting insight on the genetics and the pathogenesis of the disease allowing the identification of genes implicated in its pathogenesis and offering critical insights into the mechanisms of disease. The cardinal motor symptoms of PD are tremor, rigidity, bradykinesia/akinesia and postural instability, but the clinical picture includes other motor and non‐motor symptoms. Its diagnosis is principally clinical, although specific investigations can help the differential diagnosis from other forms of parkinsonism. Pathologically, PD is characterized by the loss of dopaminergic neurons in the pars compacta of the substantia nigra and by accumulation of misfolded α‐synuclein, which is found in intra‐cytoplasmic inclusions called Lewy bodies. Currently available treatments offer good control of motor symptoms but do not modify the evolution of the disease. This article is intended to provide a comprehensive, general and practical review of PD for the general neurologist.

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Authors:
R. Balestrino and A.H.V. Schapira
Article first published online:
27 Nov 2019 | DOI: 10.1111/ene.14108

Editorial

A new editorial team for the

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Authors:
Didier Leys
Article first published online:
22 Nov 2019 | DOI: 10.1111/ene.14123