cover image European Journal of Neurology

European Journal of Neurology

2021 - Volume 28
Issue 7 | July 2021
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Article first published online:
10 Jun 2021 | DOI: 10.1111/ene.14346

GUIDELINES

Background and purpose

Careful counseling through the diagnostic process and adequate postdiagnostic support in patients with mild cognitive impairment (MCI) is important. Previous studies have indicated heterogeneity in practice and the need for guidance for clinicians.

Methods

A joint European Academy of Neurology/European Alzheimer’s Disease Consortium panel of dementia specialists was appointed. Through online meetings and emails, positions were developed regarding disclosing a syndrome diagnosis of MCI, pre‐ and postbiomarker sampling counseling, and postdiagnostic support.

Results

Prior to diagnostic evaluation, motives and wishes of the patient should be sought. Diagnostic disclosure should be carried out by a dementia specialist taking the ethical principles of “the right to know” versus “the wish not to know” into account. Disclosure should be accompanied by written information and a follow‐up plan. It should be made clear that MCI is not dementia. Prebiomarker counseling should always be carried out if biomarker sampling is considered and postbiomarker counseling if sampling is carried out. A dementia specialist knowledgeable about biomarkers should inform about pros and cons, including alternatives, to enable an autonomous and informed decision. Postbiomarker counseling will depend in part on the results of biomarkers. Follow‐up should be considered for all patients with MCI and include brain‐healthy advice and possibly treatment for specific underlying causes. Advice on advance directives may be relevant.

Conclusions

Guidance to clinicians on various aspects of the diagnostic process in patients with MCI is presented here as position statements. Further studies are needed to enable more evidence‐based and standardized recommendations in the future.

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Authors:
Kristian Steen Frederiksen, T. Rune Nielsen, Bengt Winblad, Reinhold Schmidt, Milica G. Kramberger, Roy W. Jones, Jakub Hort, Timo Grimmer, Jean Georges, Lutz Frölich, Sebastiaan Engelborghs, Bruno Dubois and Gunhild Waldemar
Article first published online:
23 Dec 2020 | DOI: 10.1111/ene.14668

LETTER TO THE EDITOR

Co‐occurrence of idiopathic normal‐pressure hydrocephalus‐like magnetic resonance imaging features in progressive supranuclear palsy

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Authors:
Halil Onder
Article first published online:
01 Feb 2021 | DOI: 10.1111/ene.14738

ORIGINAL ARTICLE

Background and purpose

Foveal changes were reported in aquaporin‐4 antibody (AQP4‐Ab) seropositive neuromyelitis optica spectrum disorder (NMOSD) patients; however, it is unclear whether they are independent of optic neuritis (ON), stem from subclinical ON or crossover from ON in fellow eyes. Fovea morphometry and a statistical classification approach were used to investigate if foveal changes in NMOSD are independent of ON and progressive.

Methods

This was a retrospective longitudinal study of 27 AQP4‐IgG + NMOSD patients (49 eyes; 15 ON eyes and 34 eyes without a history of ON [NON eyes]), follow‐up median (first and third quartile) 2.32 (1.33–3.28), and 38 healthy controls (HCs) (76 eyes), follow‐up median (first and third quartile) 1.95 (1.83–2.54). The peripapillary retinal nerve fibre layer thickness and the volume of combined ganglion cell and inner plexiform layer as measures of neuroaxonal damage from ON were determined by optical coherence tomography. Nineteen foveal morphometry parameters were extracted from macular optical coherence tomography volume scans. Data were analysed using orthogonal partial least squares discriminant analysis and linear mixed effects models.

Results

At baseline, foveal shape was significantly altered in ON eyes and NON eyes compared to HCs. Discriminatory analysis showed 81% accuracy distinguishing ON vs. HCs and 68% accuracy in NON vs. HCs. NON eyes were distinguished from HCs by foveal shape parameters indicating widening. Orthogonal partial least squares discriminant analysis discriminated ON vs. NON with 76% accuracy. In a follow‐up of 2.4 (20.85) years, no significant time‐dependent foveal changes were found.

Conclusion

The parafoveal area is altered in AQP4‐Ab seropositive NMOSD patients suggesting independent neuroaxonal damage from subclinical ON. Longer follow‐ups are needed to confirm the stability of the parafoveal structure over time.

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Authors:
Adriana Roca‐Fernández, Frederike Cosima Oertel, Tianrong Yeo, Seyedamirhosein Motamedi, Fay Probert, Matthew J. Craner, Jaume Sastre‐Garriga, Hanna G. Zimmermann, Susanna Asseyer, Joseph Kuchling, Judith Bellmann‐Strobl, Klemens Ruprecht, Maria Isabel Leite, Friedemann Paul, Alexander Ulrich Brandt and Jacqueline Palace
Article first published online:
23 Mar 2021 | DOI: 10.1111/ene.14766

ORIGINAL ARTICLE

Background and objective

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease. Although genetic factors are involved in its pathogenesis, limited evidence is available in this area. The aim of the present study was to identify the major genetic factors contributing to NMOSD in Chinese patients with aquaporin 4 (AQP4)‐IgG seropositivity.

Methods

Whole‐exome sequencing (WES) was performed on 228 Chinese NMOSD patients seropositive for AQP4‐IgG and 1400 healthy controls in Guangzhou, South China. () sequencing was also utilized. Genotype model and haplotype, gene burden, and enrichment analyses were conducted.

Results

A significant region of the composition is on chromosome 6, and great variation was observed in and . sequencing confirmed that the most significant allele was ( < 0.01, odds ratio [OR] 3.73). The genotype model analysis revealed that was significantly associated with NMOSD in the additive effect model and dominant effect model ( < 0.05). The proportion of haplotype “” was significantly greater in the NMOSD patients than the controls, at 8.42% and 1.23%, respectively ( < 0.001, OR 7.39). The gene burden analysis demonstrated that loss‐of‐function mutations in were more common in the NMOSD patients (11.84%) than the controls (5.71%;  < 0.001, OR 2.22). The variant was significantly more common in NMOSD, and the rate of the T allele was 0.605 in patients and 0.345 in the controls ( < 0.01, OR 2.92). The enrichment analysis indicated that most of the genetic factors were mainly correlated with nervous and immune processes.

Conclusions

is highly correlated with NMOSD. and ‐ play important roles in disease susceptibility.

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Authors:
Xiaonan Zhong, Chen Chen, Xiaobo Sun, Jingqi Wang, Rui Li, Yanyu Chang, Ping Fan, Yuge Wang, Yunting Wu, Lisheng Peng, Zhengqi Lu and Wei Qiu
Article first published online:
22 Feb 2021 | DOI: 10.1111/ene.14771

ORIGINAL ARTICLE

Background and purpose

Many drugs can worsen myasthenia symptoms. The clinician usually relies on cautionary lists compiled according to case reports. We intended to provide a quantitative basis for a risk comparison within the groups of antiepileptic, antidepressant, neuroleptic, and sedative drugs.

Methods

We extracted adverse drug reaction (ADR) counts (total and myasthenia related) for drugs from these groups and calculated the reporting odds ratio (ROR) within the drug groups from the World Health Organization pharmacovigilance database. For a given drug, the ROR was increased above 1 if the proportion of myasthenia‐related ADRs for this drug was larger than the same proportion for the rest of drugs in that same group. If the 95% confidence interval of ROR was >1, this was taken as a signal for a higher risk of the given drug as compared to the average of the respective group.

Results

Gabapentin, sertraline, citalopram, lithium, and amisulpride had a signal for the ROR to be increased above 1 within their respective groups. Bupropion, desvenlafaxine, duloxetine, escitalopram, and paroxetine had ROR values <1. For all other drugs, 1 was within the ROR confidence interval.

Conclusions

For gabapentin and lithium, the analysis of RORs confirmed case reports and cautionary lists. For a number of antidepressant drugs associated with a higher‐than‐average risk, no case reports exist substantiating our results. For these drugs, special attention should be paid to this risk. The remarkable difference between citalopram and escitalopram could prompt experimental work to confirm differential influence of the two preparations on neuromuscular transmission.

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Authors:
Peter Trillenberg, Alexander Katalinic, Klaus Junghanns and Julia Thern
Article first published online:
01 Mar 2021 | DOI: 10.1111/ene.14773

POSITION PAPER

Background and purpose

Insomnia is a common and debilitating disorder that is frequently associated with important consequences for physical health and well‐being.

Methods

An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years, discussed the current challenges in the field of insomnia and identified future priorities.

Results

The association of trajectories of insomnia with subsequent quality of life, health and mortality should be investigated in large populations. Prospective health economics studies by separating the costs driven specifically by insomnia and costs attributable to its long‐term effects are needed. Ignoring the heterogeneity of insomnia patients leads to inadequate diagnosis and inefficient treatment. Individualized interventions should be promoted. More data are needed on both the impact of sleep on overnight effects, such as emotion regulation, and the potential compensatory effort to counteract diurnal impairments. Another gap is the definition of neurocognitive deficits in insomnia patients compared to normal subjects after chronic sleep loss. There are also a number of key gaps related to insomnia treatment. Expert guidelines indicate cognitive–behavioural therapy for insomnia as first‐line treatment. They neglect, however, the reality of major healthcare providers. The role of combined therapy, cognitive–behavioural therapy for insomnia plus pharmacological treatment, should be evaluated more extensively.

Conclusion

Whilst insomnia disorder might affect large proportions of the population, there are a number of significant gaps in the epidemiological/clinical/research studies carried out to date. In particular, the identification of different insomnia phenotypes could allow more cost‐effective and efficient therapies.

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Authors:
Luigi Ferini‐Strambi, Reto Auer, Bjørn Bjorvatn, Vincenza Castronovo, Oscar Franco, Luca Gabutti, Andrea Galbiati, Goeran Hajak, Ramin Khatami, Tsuyoshi Kitajima, Doug McEvoy, Christoph Nissen, Michael Perlis, Dirk A. Pevernagie, Winfried Randerath, Dieter Riemann, Giovanni Rizzo, Eus Van Someren, Alexandros Vgontzas, Fabrizio Barazzoni and Claudio Bassetti
Article first published online:
09 Apr 2021 | DOI: 10.1111/ene.14784

SHORT COMMUNICATION

Background and purpose

Biomarkers for future adaptive deep brain stimulation still need evaluation in clinical routine. Here, we aimed to assess stimulation‐induced modulation of beta‐band activity and clinical symptoms in a Parkinson's disease patient during chronic neuronal sensing using a novel implantable pulse generator.

Methods

Subthalamic activity was recorded OFF and ON medication during a stepwise increase of stimulation amplitude. Off‐line fast fourier transfom ‐based analysis of beta‐band activity was correlated with motor performance rated from blinded videos.

Results

The stepwise increase of stimulation amplitude resulted in decreased beta oscillatory activity and improvement of bradykinesia. Mean low beta‐band (13–20 Hz) activity correlated significantly with bradykinesia (ρ = 0.662,  < 0.01).

Conclusions

Motor improvement is reflected in reduced subthalamic beta‐band activity in Parkinson's disease, supporting beta activity as a reliable biomarker. The novel PERCEPT neurostimulator enables chronic neuronal sensing in clinical routine. Our findings pave the way for a personalized precision‐medicine approach to neurostimulation.

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Authors:
Lucia K. Feldmann, Wolf‐Julian Neumann, Patricia Krause, Roxanne Lofredi, Gerd‐Helge Schneider and Andrea A. Kühn
Article first published online:
26 Mar 2021 | DOI: 10.1111/ene.14801

SHORT COMMUNICATION

Background and purpose

On the basis of occasional strong placebo responses, increased susceptibility to placebo has been proposed as a characteristic of functional neurological disorder (FND). The aim of this study was to clarify whether people with FND have a stronger placebo analgesic response than healthy controls.

Methods

A study using a classic placebo paradigm, with additional conditioning and open‐label components, was performed in 30 patients with FND, and in 30 healthy controls. Ratings of mildly to moderately painful electrotactile stimuli were compared before and after the application of a placebo “anaesthetic” cream versus a control cream, after an additional conditioning exposure, and after full disclosure (open‐label component).

Results

Pain intensity ratings at the placebo compared to the control site were similarly reduced in both groups. The conditioning exposure had no additional effect. After placebo disclosure a residual analgesic effect remained.

Conclusion

Patients with FND did not have stronger placebo responses than healthy controls. The notion of generally increased suggestibility or increased suggestibility to placebo in FND seems mistaken. Instead, occasional dramatic placebo responses may occur because functional symptoms are inherently more changeable than those due to organic disease.

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Authors:
Anne‐Catherine M. L. Huys, Brianna Beck, Patrick Haggard, Kailash P. Bhatia and Mark J. Edwards
Article first published online:
26 Mar 2021 | DOI: 10.1111/ene.14816

SHORT COMMUNICATION

Background and purpose

Monoclonal antibodies targeting CGRP or its receptor, anti‐CGRP mAbs, are proven to be effective treatments in migraine prevention. Real‐world evidence studies assessing their efficacy are scarce.

Methods

Our objective was to assess the efficacy of anti‐CGRP mAbs in our clinical cohort resistant to onabotulinumtoxinA. We prospectively analyzed ≥50% response rate in patients who initiated treatment with anti‐CGRP mAbs and who were partial or nonresponders to onabotulinumtoxinA.

Results

One hundred fifty‐five patients completed treatment with anti‐CGRP mAbs at 3 months of follow‐up. No statistically significant differences were found in ≥50% response in headache frequency in patients with prior onabotulinumtoxinA treatment partial or complete failure. Regarding dual therapy with onabotulinumtoxinA and anti‐CGRP mAbs, no statistically significant differences were found in ≥50% response in headache frequency between monotherapy or dual therapy.

Conclusions

Patients with prior treatment failure or partial efficacy to onabotulinumtoxinA respond to anti‐CGRP mAbs. After 3 months, in our cohort, dual therapy does not seem to add more benefit than anti‐CGRP mAbs in monotherapy.

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Authors:
Alicia Alpuente, Victor J. Gallardo, Edoardo Caronna, Marta Torres‐Ferrús and Patricia Pozo‐Rosich
Article first published online:
05 Apr 2021 | DOI: 10.1111/ene.14828

ORIGINAL ARTICLE

Background

In order to identify risk periods with an increased demand in technical and human resources, we tried to determine patterns and associations in the incidence of acute ischemic stroke due to embolic large vessel occlusions (eLVO) requiring mechanical thrombectomy (MT).

Methods

We conducted a time series analysis over a 9‐year period (2010–2018) based on observational data in order to detect seasonal patterns in the incidence of MT due to eLVO ( = 2628 patients). In a series of sequential negative binominal regression models, we aimed to detect further associations (e.g., temperature, atmospheric pressure, air pollution).

Results

There was a 6‐month seasonal pattern in the incidence of MT due to eLVO ( = 0.024) peaking in March and September. Colder overall temperature was associated with an increase in MT due to eLVO (average marginal effect [AME], [95% CI]: −0.15 [−0.30–0.0001];  = 0.05; per °C). A current increase in the average monthly temperature was associated with a higher incidence of MT due to eLVO (0.34 [0.11–0.56];  = 0.003). Atmospheric pressure was positively correlated with MT due to eLVO (0.38 [0.13–0.64];  = 0.003; per hectopascal [hPa]). We could detect no causal correlation between air pollutants and MT due to eLVO.

Conclusions

Our data suggest a 6‐month seasonal pattern in the incidence of MT due to eLVO peaking in spring and early autumn. This might be attributed to two different factors: (1) a current temperature rise (comparing the average monthly temperature in consecutive months) and (2) colder overall temperature. These results could help to identify risk periods requiring an adaptation in local infrastructure.

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Authors:
Philipp Bücke, Hans Henkes, Guy Arnold, Birgit Herting, Eric Jüttler, Christof Klötzsch, Alfred Lindner, Uwe Mauz, Ludwig Niehaus, Matthias Reinhard, Stefan Waibel, Thomas Horvath, Hansjörg Bäzner and Marta Aguilar Pérez
Article first published online:
05 May 2021 | DOI: 10.1111/ene.14832

ORIGINAL ARTICLE

Background and purpose

Alzheimer's disease (AD) is considered a clinical and biological continuum identified via cerebrospinal fluid (CSF) or imaging biomarkers. Chronic hypoperfusion is held as one of the main features of Alzheimer's disease, as part of the processes causing neuronal degeneration. The mechanism responsible for such condition is still debated, although recently a direct connection with amyloid peptides has been shown. Here the aim was to investigate whether measures of hypoperfusion change along the AD continuum.

Methods

Seventy patients with mild AD were recruited and stratified according to their CSF biomarker profile—as indicated by the National Institute on Aging and Alzheimer’s Association research framework—into patients with either isolated amyloid pathology (A+T−) or full‐blown AD (A+T+), and further layered according to apolipoprotein E genotype. After evaluation of vascular risk factors, a transcranial Doppler was performed on each patient, to evaluate mean flow velocity and pulsatility index in the middle cerebral artery, and to calculate the breath‐holding index. Patients were compared to a cohort of 17 healthy controls.

Results

The breath‐holding index was reduced in the AD continuum and was inversely correlated to CSF amyloid β42 levels. Such correlation was stronger in the A+T+ than in the A+T− group, and unexpectedly reached statistical significance only in the E3 and not in the E4 genotype carriers.

Conclusions

These results suggest a tight and effective relationship between amyloid β42, vascular hypoperfusion, cerebrovascular reactivity and epsilon genotype.

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Authors:
Marina Diomedi, Alessandro Rocco, Chiara Giuseppina Bonomi, Alfredo Paolo Mascolo, Vincenzo De Lucia, Federico Marrama, Fabrizio Sallustio, Giacomo Koch and Alessandro Martorana
Article first published online:
23 Apr 2021 | DOI: 10.1111/ene.14834

ORIGINAL ARTICLE

Background and purpose

In previous studies in patients with traumatic brain injury and ischemic stroke, the size of decompressive craniectomy (DC) was reported to be paramount with regard to patient outcomes. We aimed to identify the impact of DC size on treatment results in individuals with aneurysmal subarachnoid hemorrhage (SAH).

Methods

The extent of DC in 232 patients with SAH who underwent bifrontal or hemicraniectomy between January 2003 and December 2015 was analyzed using semi‐automated surface measurements. The study endpoints were course of intracranial pressure (ICP) treatment after DC, occurrence of cerebral infarcts, in‐hospital mortality, and unfavorable outcome at 6 months (defined as modified Rankin scale score >3). The associations of DC size with the study endpoints were adjusted for DC timing, patient age, clinical and radiographic severity of SAH, aneurysm location, and treatment modality.

Results

The mean DC surface area was 100.9 (±45.8) cm. In multivariate analysis, a large DC (>105 cm) was independently associated with a lower risk of cerebral infarcts (adjusted odds ratio [aOR] 0.30, 95% confidence interval [CI] 0.16–0.56), in‐hospital mortality (aOR 0.28, 95% CI 0.14–0.56) and unfavorable outcome (aOR 0.51, 95% CI 0.27–0.98). Moreover, SAH patients with a small DC size (<75 cm) were more likely to require prolonged (>3 days, aOR 3.60, 95% CI 1.37–9.42) and enhanced (aOR 2.31, 95% CI 1.12–4.74) postoperative ICP treatment.

Conclusion

This is the first study showing the impact of DC size on postoperative ICP control and patient outcome in the context of SAH; specifically, a large craniectomy flap (>105 cm) might lead to better outcomes in SAH patients requiring decompressive surgery.

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Authors:
Ramazan Jabbarli, Shi‐Qing He, Marvin Darkwah Oppong, Annika Herten, Mehdi Chihi, Daniela Pierscianek, Philipp Dammann, Ulrich Sure and Karsten H. Wrede
Article first published online:
03 May 2021 | DOI: 10.1111/ene.14835

LETTERS TO THE EDITOR

Hunting for the genetic basis of Susac syndrome

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Authors:
Clemence David, Thomas Papo, Ibrahima Ba, Emmanuelle Ollivier, Catherine Boileau, Philippe Dieudé, Boris Keren, Caroline Kannengiesser and Karim Sacre
Article first published online:
07 Apr 2021 | DOI: 10.1111/ene.14836

LETTERS TO THE EDITOR

Chinese famine and ischemic stroke: The need to control for age differences and improve famine severity measurement

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Authors:
Chihua Li, Zhenwei Zhou and Chenfei Ye
Article first published online:
12 Apr 2021 | DOI: 10.1111/ene.14838

REVIEW ARTICLE

Background and purpose

The coexistence of peripheral neuropathy (PN) and restless legs syndrome (RLS) or Willis–Ekbom disease is relatively frequent, but its prevalence has shown a high variability across studies. In addition, several reports have shown data suggesting the presence of PN in patients with idiopathic RLS.

Methods

A search was undertaken using the PubMed, Embase and Web of Science Databases, from 1966 to 6 December 2020, crossing the search term ‘restless legs syndrome’ with ‘neuropathy’, ‘polyneuropathy’ (PNP) and ‘peripheral neuropathy’, and the references of interest for this topic were identified; a meta‐analysis was performed, according to PRISMA guidelines, and a calculation of pooled prevalences, where appropriate, was made using standard methods.

Results

Restless legs syndrome has been reported in 5.2%–53.7% of patients with PN (average 21.5%; 95% confidence interval 18.6%–24.5%), and PN has been reported in 0%–87.5% of patients with RLS (average 41.8%; 95% confidence interval 39.9%–43.6%), both being significantly more frequent than in controls. The heterogeneity across studies could be due to differences in the diagnostic criteria used for both RLS and PN. RLS is a frequent clinical complaint in patients with PN of different aetiologies, mainly diabetic PN, uraemic PNP, familial amyloid PNP, Charcot–Marie–Tooth disease and chronic dysimmune inflammatory PNP. Recent neurophysiological findings suggest the presence of small sensory fibre loss in patients diagnosed with idiopathic RLS, but it remains to be determined whether RLS associated with small sensory fibre loss and idiopathic RLS are different clinical entities.

Conclusions

Future studies including clinical and neurophysiological assessment and skin biopsy involving a large series of patients with PN and RLS are needed for a better understanding of the association between these two entities.

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Authors:
Félix Javier Jiménez‐Jiménez, Hortensia Alonso‐Navarro, Elena García‐Martín and José A.G. Agúndez
Article first published online:
21 Apr 2021 | DOI: 10.1111/ene.14840

SHORT COMMUNICATION

Background and purpose

In recent years, the use of coiling has gained increased popularity for the treatment of intracranial aneurysms, and stroke physicians are confronted with rare pathologies associated with this relatively new and evolving treatment method, such as embolization of pieces of the polymeric filaments from the coils and a subsequent inflammatory response. In particular, white matter enhancing lesions are a rare complication after aneurysm endovascular therapy (EVT), suggesting a foreign body reaction to shedding of hydrophilic coating from the endovascular devices into the blood stream. The description of such a case aims to raise the clinicians' awareness of the symptomatic delayed and recurring inflammatory changes that may occur after endovascular aneurysmal treatment with the use of coiling devices.

Case description

A 64‐year‐old woman underwent coiling of a ruptured right posterior communicating artery aneurysm. She was asymptomatic after EVT. One year later, she presented with headache, acoustic hallucinations, paresthesias and left arm weakness. Brain magnetic resonance imaging (MRI) revealed multiple enhancing white matter lesions in the right hemisphere. She was treated with pulse intravenous methylprednisolone, followed by oral prednisolone; all clinical symptoms resolved and imaging findings improved substantially. Two years after tapering the steroids, follow‐up symptoms recurred and repeat brain MRI revealed new enhancing white matter lesions.

Discussion and conclusions

There is an increasing number of similar reports of enhancing white matter lesions after coiling of intracranial aneurysms, with the incidence estimated to be between 0.5% and 2.3% in different cohort studies. Close monitoring for the appearance of new neurologic symptoms that could suggest delayed brain reactivity should be recommended.

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Authors:
Eleni Bakola, Aristeidis H. Katsanos, Lina Palaiodimou, Aikaterini Theodorou, Maria‐Ioanna Stefanou, Maria Chondrogianni, Elisabeth Andreadou, Marianna Papadopoulou, Vasileios Konstantakos, Konstantinos Voumvourakis, Stefanos Lachanis and Georgios Tsivgoulis
Article first published online:
07 Apr 2021 | DOI: 10.1111/ene.14844

LETTERS TO THE EDITOR

Reply to the comments about our article “Headache at onset of first‐ever ischemic stroke: Clinical characteristics and predictors”

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Authors:
Elena R. Lebedeva and Jes Olesen
Article first published online:
14 May 2021 | DOI: 10.1111/ene.14846

CASE REPORT

Background and purpose

Creutzfeldt–Jakob disease (CJD) is a rare form of rapidly progressive neurodegenerative disorder. Seizures are uncommon in the early stage of CJD, increasing diagnostic difficulty.

Methods

An autopsy‐proven case of CJD presenting initially as an epilepsia partialis continua is reported, in which the initial workup was unremarkable. Retrospectively, the presence of nystagmus, which proved to be non‐epileptic, pointed to a cerebellar lesion before a diagnosis of clinically probable CJD was made.

Results

A 70‐year‐old man presented with a 3‐week history of intermittent rhythmic jerking tremors in his left limbs, interfering with his gait. Examination showed left body clonic movements. Electroencephalography revealed an ictal right centroparietal pattern of focal status epilepticus. Video‐oculography revealed right‐beating nystagmus (mean slow phase velocity [SPV] 3.4º/s) in the dark and left‐beating nystagmus (SPV 2.6º/s) in the light, left‐beating nystagmus after head shaking (SPV 4º/s) and during mastoid vibration (SPV 11º/s) and mildly hypoactive horizontal head impulses. Search for occult malignancy, serologies, cerebrospinal fluid analyses, anti‐onconeural antigen, auto‐immune panel and brain magnetic resonance imaging were unrevealing. Rapid neurological decline was observed. Three weeks later, cerebrospinal fluid was positive for 14.3.3 protein, electroencephalography showed generalized periodic sharp wave complexes and brain magnetic resonance imaging revealed diffusion restriction and T2/fluid‐attenuated inversion recovery hyperintensities in the cerebellum, basal ganglia, thalamus and cortex. He died 1 month later. Neuropathological study confirmed the diagnosis of CJD.

Conclusion

This case highlights that CJD should be considered in the differential diagnosis of new onset epilepsia partialis continua and that neuro‐ophthalmological examination can be helpful in pointing to early asymmetric cerebellar involvement.

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Authors:
Inês Antunes Cunha, Inês Gomes, Helena Gens, Susana Guimarães, Ana Inês Martins and Conceição Bento
Article first published online:
10 Jun 2021 | DOI: 10.1111/ene.14847

LETTERS TO THE EDITOR

Undergraduate neurology training in the inpatient and outpatient setting: How do they differ?

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Authors:
Prateek Kumar Panda and Indar Kumar Sharawat
Article first published online:
12 Apr 2021 | DOI: 10.1111/ene.14848

ORIGINAL ARTICLE

Background

Amyotrophic lateral sclerosis (ALS) is associated with a range of clinical phenotypes and shows progressive degeneration of upper and/or lower motor neurons, and phosphorylated 43 kDa TAR DNA‐binding protein (pTDP‐43) inclusions in motor and non‐motor pathways. Parkinsonian features have been reported in up to 30% of ALS patients, and Lewy bodies, normally associated with Lewy body disease (LBD), have been reported in a small number of ALS cases, with unknown clinical relevance. This study investigates the prevalence of clinically relevant LBD in a prospectively studied ALS cohort to determine whether concomitant pathology contributes to the clinical heterogeneity.

Methods

All ALS cases held by the New South Wales Brain Bank ( = 97) were screened for coexisting LBD consistent with clinical disease (Braak ≥ stage IV). Relevant clinical and genetic associations were determined.

Results

Six cases had coexisting LBD Braak ≥ stage IV pathology. The age at symptom onset (69 ± 7 years) and disease duration (4 ± 3 years) in ALS cases with coexisting LBD did not differ from ALS cases. Three patients had lower limb onset and two patients had bulbar onset. Two patients developed the clinical features of Parkinson's disease, with one receiving a dual diagnosis. All cases had no known relevant family history or genetic abnormalities.

Conclusion

The prevalence of clinically relevant LBD pathology in ALS is higher than in the general population, and has implications for clinical and neuropathological diagnoses and the identification of biomarkers.

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Authors:
Shelley L. Forrest, Jordan Hanxi Kim, Clair De Sousa, Rosie Cheong, Daniel R. Crockford, Donna Sheedy, Julia Stevens, Toni McCrossin, Rachel H. Tan, Heather McCann, Claire E. Shepherd, Dominic B. Rowe, Matthew C. Kiernan, Glenda M. Halliday and Jillian J. Kril
Article first published online:
16 Apr 2021 | DOI: 10.1111/ene.14849

ORIGINAL ARTICLE

Background and purpose

Measurement of the cross‐sectional area (CSA) of peripheral nerves using ultrasound is useful in the evaluation of focal lesions such as entrapment syndromes and inflammatory polyneuropathies. We performed a systematic review and meta‐analysis of published CSA reference values for lower extremity nerves.

Methods

We included available‐to‐date nerve ultrasound studies on healthy adults and provide meta‐analysis for CSA of the following nerves: fibular nerve at fibular head, popliteal fossa; tibial nerve at popliteal fossa, malleolus; and sural nerve at the level of the two heads of gastrocnemius muscle. We report regression and correlation analyses for age, gender distribution, height, weight, and geographic continent.

Results

We included 16 studies with 1001 healthy volunteers (mean age = 47.9 years) and 4023 examined nerve sites. Calculated mean pooled CSA of fibular nerve at fibular head was 8.4 mm (95% confidence interval [CI] = 6.8–9.9 mm,  = 1166), at popliteal fossa was 7.9 mm (95% CI = 6.6–9.2 mm,  = 995), of tibial nerve at popliteal fossa was 25.9 mm (95% CI = 17.5–34.4 mm,  = 771), at malleolus was 10.0 mm (95% CI = 7.7–12.4 mm,  = 779), and of sural nerve was 2.4 mm (95% CI = 1.7–3.1 mm,  = 312). Substantial heterogeneity across studies ( > 50%) was found only for tibial nerve at popliteal fossa. Subgroup analysis revealed a lower CSA of tibial nerve at popliteal fossa and sural nerve in studies conducted in Europe than in North America and New Zealand.

Conclusions

We provide the first meta‐analysis on CSA reference values for the lower extremities with no or low heterogeneity of reported CSA values in all nerve sites except tibial nerve at popliteal fossa. Our data facilitate the goal of an international standardized evaluation protocol.

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Authors:
Anna Lena Fisse, Aristeidis H. Katsanos, Ralf Gold, Christos Krogias and Kalliopi Pitarokoili
Article first published online:
07 May 2021 | DOI: 10.1111/ene.14850

REVIEW ARTICLE

Background and purpose

Bradykinesia is one of the cardinal motor symptoms of Parkinson's disease. However, clinical and experimental studies indicate that bradykinesia may also be observed in various neurological diseases not primarily characterized by parkinsonism. These conditions include hyperkinetic movement disorders, such as dystonia, chorea, and essential tremor. Bradykinesia may also be observed in patients with neurological conditions that are not seen as "movement disorders," including those characterized by the involvement of the cerebellum and corticospinal system, dementia, multiple sclerosis, and psychiatric disorders.

Methods

We reviewed clinical reports and experimental studies on bradykinesia in non‐parkinsonian conditions and discussed the major findings.

Results

Bradykinesia is a common motor abnormality in non‐parkinsonian conditions. From a pathophysiological standpoint, bradykinesia in neurological conditions not primarily characterized by parkinsonism may be explained by brain network dysfunction.

Conclusion

In addition to the pathophysiological implications, the present paper highlights important terminological issues and the need for a new, more accurate, and more widely used definition of bradykinesia in the context of movement disorders and other neurological conditions.

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Authors:
Giulia Paparella, Alfonso Fasano, Mark Hallett, Alfredo Berardelli and Matteo Bologna
Article first published online:
18 May 2021 | DOI: 10.1111/ene.14851

ORIGINAL ARTICLE

Background

There has been increasing attention focused on the epidemiology of rare diseases (RDs) in recent years. Rare neurological diseases (RNDs) constitute a significant proportion of RDs; however, relevant research is still lacking.

Methods

A list of ICD‐10 codes corresponding to RNDs was compiled using adaptations from the Orphanet Classification of Rare Diseases, and classified into rare epilepsy, movement‐related, neurocutaneous, neuroimmune, neurometabolic and neurodegenerative, neuromuscular and other RNDs. Using the Clinical Data Analysis and Reporting System, which holds public hospital healthcare records of Hong Kong anonymously, we calculated the prevalence and healthcare utilization of RND patients between 2014 and 2018. The list of RNDs was also used to review relevant pharmacological trials within the International Clinical Trials Registry Platform between 2009 and 2018.

Results

The prevalence of RNDs in Hong Kong is 3.6 in 1,000 individuals. Patients with RNDs had frequent emergency department, outpatient and inpatient healthcare utilization. The average annual cost per patient is estimated at HKD 182,075 (€ 19,688). Different categories of RNDs showed different patterns of healthcare utilization. Moreover, there were only 677 RND‐related pharmacological trials during the study period, and no trial was found for 78% of RNDs.

Conclusions

This is one of the first population studies on the prevalence and healthcare utilization patterns of RNDs, with comprehensive reviews of RND‐related pharmacological research. It shows high healthcare utilization rates among patients with RNDs, as well as a wide research gap in many RNDs. We call for better attention and tailored healthcare for these patients.

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Authors:
Annie Ting Gee Chiu, Jingjing Li, Richard Shek Kwan Chang, Claudia Ching Yan Chung, Wilfred Hing Sang Wong, Patrick Ip and Sophelia Hoi Shan Chan
Article first published online:
20 Apr 2021 | DOI: 10.1111/ene.14852

SHORT COMMUNICATION

Objective

Intravenous immunoglobulin (IVIg) consists of pooled donor immunoglobulins (IgG), possibly including anti‐ (sl) antibodies. Apparent IVIg‐related sl seroconversion could lead to incorrect diagnosis of Lyme borreliosis. This cohort study was designed to determine how often IVIg treatment leads to apparent sl seroconversion and whether antibodies disappear post‐treatment.

Methods

Sera from chronic inflammatory demyelinating polyneuropathy (CIDP) and myositis patients were analyzed, drawn pre‐treatment and 6–12 weeks after the start of IVIg. In patients with apparent seroconversion, follow‐up samples after treatment withdrawal were analyzed, if available. Patients treated with corticosteroids were included as controls. A two‐tier protocol was used for serological testing consisting of the C6 Lyme ELISA (Oxford Immunotec) and confirmation by immunoglobulin M (IgM) and immunoglobulin G (IgG) immunoblot (Mikrogen).

Results

We included 61 patients: 51 patients were treated with IVIg and 10 with dexamethasone. Of the patients treated with IVIg, 42 had CIDP (82%) and were treated with Nanogam (Sanquin Plasma Products). Nine patients had myositis (18%) and were treated with Privigen (CSL Behring). Anti‐sl IgG seroprevalence pre‐treatment was 3% (2/61). Apparent seroconversion during IVIg treatment occurred in 39% (20/51) of patients, all treated with Nanogam. Post‐treatment seroreversion occurred in 92% (12/13) of patients with available follow‐up samples; in 78% (7/9) seroreversion was observed within 3 months.

Conclusions

Transient presence of anti‐sl IgG antibodies after IVIg is regularly observed. This effect appears to be dependent on the IVIg brand, probably reflecting variation in sl exposure of plasma donors. Lyme borreliosis serological testing during, and weeks to months after, IVIg is therefore of limited utility.

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Authors:
Ilse M. Lucke, Amber Vrijlandt, Johan Lim, Anneke J. van der Kooi, Ivo N. van Schaik, Hans L. Zaaijer, Joppe W. Hovius and Filip Eftimov
Article first published online:
05 May 2021 | DOI: 10.1111/ene.14853

ORIGINAL ARTICLE

Background and purpose

Although functional recovery is most pronounced in the first 6 months after stroke, improvement is possible also in the late phase. The value of plasma neurofilament light chain (NfL), a biomarker of axonal injury and secondary neurodegeneration, was explored for the prediction of functional improvement in the late phase after stroke.

Methods

Baseline plasma NfL levels were measured in 115 participants of a trial on the efficacy of multimodal rehabilitation in the late phase after stroke. The association between NfL levels, impairment in balance, gait and cognitive domains, and improvement 3 and 9 months later was determined.

Results

Plasma NfL levels were associated with the degree of impairment in all three domains. Individuals with meaningful improvement in balance and gait capacity had higher plasma NfL levels compared with non‐improvers ( = 0.001 and  = 0.018, respectively). Higher NfL levels were associated with improvement in balance (odds ratio [OR] 2.34, 95% confidence interval [CI] 1.35–4.27,  = 0.004) and gait (OR 2.27, 95% CI 1.25–4.32,  = 0.009). Elevated plasma NfL levels showed a positive predictive value for cognitive improvement, and this effect was specific for the intervention targeting the cognitive domain. The association of NfL levels with cognitive improvement withstood correction for baseline impairment, age and total years of schooling (OR 7.54, 95% CI 1.52–45.66,  = 0.018).

Conclusions

In addition to its established role as a biomarker in the acute phase, elevated circulating NfL levels may predict functional improvement in the late phase after stroke. Our results should prompt further studies into the use of plasma NfL as a biomarker in the late phase after stroke.

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Authors:
Anna Stokowska, Lina Bunketorp Käll, Christian Blomstrand, Joel Simrén, Michael Nilsson, Henrik Zetterberg, Kaj Blennow, Milos Pekny and Marcela Pekna
Article first published online:
04 May 2021 | DOI: 10.1111/ene.14854

LETTERS TO THE EDITOR

Poststroke depression and soluble suppression of tumorigenicity 2

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Authors:
Meidi Peng, Yachi Gong and Hongtao Huang
Article first published online:
13 Apr 2021 | DOI: 10.1111/ene.14856

SHORT COMMUNICATION

Background

5‐Fluorouracil (5‐FU) and its oral prodrug capecitabine have been rarely but consistently associated with acute central nervous system toxicity, including transient leukoencephalopathies involving the splenium of the corpus callosum.

Methods

We performed a retrospective search in the French Pharmacovigilance database (FPDB) (January 1985−July 2020) for adult patients affected by solid cancers who developed acute toxic leukoencephalopathies with splenial lesions following treatment with 5‐FU or capecitabine. A comprehensive review of the literature helped to circumstantiate our findings.

Results

Our research in the FPDB identified six patients who, within 3 days from their first cycle of 5‐FU or capecitabine, developed acute neurological symptoms, including gait ataxia ( = 4), dysarthria ( = 3), dysmetria ( = 2), headache ( = 2), and confusion ( = 2). Brain magnetic resonance imaging (MRI) showed T2/FLAIR (fluid‐attenuated inversion recovery) hyperintensities in the corpus callosum, with diffusion restriction and no contrast enhancement, generally accompanied by additional alterations in the bilateral supratentorial white matter ( = 5). All patients discontinued the agent supposedly responsible for the toxicity and experienced full recovery after a median of 8.5 days from symptom onset. Control MRI showed a progressive normalization of acute MRI abnormalities. Literature review identified 26 cases with similar clinical and paraclinical characteristics. A single patient from the literature resumed 5‐FU at a lower dose, with no recurrent toxicity.

Conclusions

5‐FU and capecitabine might be responsible for acute leukoencephalopathies with transient splenial lesions that are generally reversible upon drug discontinuation. Resuming the agent responsible for toxicity might be feasible in selected cases, after having excluded dihydropyrimidine dehydrogenase deficiency, if expected benefits outweigh the risks.

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Authors:
Valentine Perrain, Kevin Bihan, Flavie Bompaire, Caroline Houillier, Fanny Jomier, Delphine Leclercq, Sandrine Combret, Julien Mahé, Damien Ricard, Giulia Berzero and Dimitri Psimaras
Article first published online:
19 Apr 2021 | DOI: 10.1111/ene.14857

LETTERS TO THE EDITOR

Undergraduate neurology teaching: Comparison of an inpatient versus outpatient clinical setting

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Authors:
Isabel Pavão Martins, Ana Catarina Fonseca and José M. Ferro
Article first published online:
20 Apr 2021 | DOI: 10.1111/ene.14858

ORIGINAL ARTICLE

Background and purpose

Patients with secondary progressive multiple sclerosis (SP MS) and clinical and/or radiological activity could be the more likely to benefit from disease‐modifying treatments. To evaluate the proportions each year after progression onset, patients with SP MS onset between 2002 and 2012 from a population‐based multiple sclerosis registry in northeastern France were studied.

Methods

Progression onset was first identified by the neurologist's diagnosis (N cohort), and then by using an automated data‐driven definition (D cohort). In a given year after onset of progression, clinical activity was defined as at least one relapse, and radiological activity as at least one new T2 and/or gadolinium‐enhancing lesion. A multivariate mixed logistic regression was used to assess factors associated with activity during the year.

Results

In the N cohort, amongst 833 patients with SP MS with a median follow‐up of 8 years, 10.0%–14.8% had at least one relapse in a year during the first 5 years of progression. Including both clinical and radiological activity increased these proportions to 11.9%–23.7%, with the proportion having a magnetic resonance imaging scan in the year ranging from 29.8% to 40.5%. The first year of progression, a young age and a high relapse rate during the 5 years before progression were associated with activity in a given year. The D cohort results confirmed these findings.

Conclusions

A substantial proportion of patients with SP MS present disease activity. Further studies should evaluate the impact of disease‐modifying treatments on the disease course of these patients.

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Authors:
Guillaume Mathey, Thomas Ancel, Teresa Garot, Marc Soudant, Sophie Pittion‐Vouyovitch, Francis Guillemin, Marc Debouverie and Jonathan Epstein
Article first published online:
18 May 2021 | DOI: 10.1111/ene.14861

ORIGINAL ARTICLE

Background and purpose

Measurement of the cross‐sectional area (CSA) of cervical nerve roots using ultrasound is useful in the evaluation of inflammatory polyneuropathies, and measurement of CSA of the vagal nerve might give information about involvement of the autonomic nervous system. We performed a systematic review and meta‐analysis of published CSA reference values for cervical nerve roots and vagal nerve.

Methods

We included available‐to‐date nerve ultrasound studies on healthy adults and provide meta‐analysis for CSA of the following nerves: cervical nerve roots C5, C6, and C7 as well as vagal nerve in the carotid sheath at the carotid bifurcation level. We report regression and correlation analyses for age, gender, height, weight, and geographic continent.

Results

We included 11 studies with 885 healthy volunteers (mean age = 42.7 years) and 3149 examined nerve sites. Calculated mean pooled CSA of C5 root was 5.6 mm (95% confidence interval [CI] = 4.6–6.7 mm,  = 911), of C6 root was 8.8 mm (95% CI = 7.4–10.3 mm,  = 909), of C7 root was 9.5 mm (95% CI = 8.0–10.9 mm,  = 909), and of vagal nerve was 2.2 mm (95% CI = 1.5–2.9 mm,  = 420). No heterogeneity was found across studies for any site. Subgroup analysis revealed no significant effects of age, gender, height, weight, and geographic continent on CSA for any of these nerve sites.

Conclusions

We provide the first meta‐analysis on CSA reference values for the cervical nerve roots and the vagal nerve, with no heterogeneity of reported CSA values at all nerve sites. Our data facilitate the goal of an international standardized evaluation protocol.

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Authors:
Anna Lena Fisse, Aristeidis H. Katsanos, Ralf Gold, Kalliopi Pitarokoili and Christos Krogias
Article first published online:
02 May 2021 | DOI: 10.1111/ene.14862

ORIGINAL ARTICLE

Background and objectives

Facioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient‐reported Rasch‐built interval scale on activity and participation for FSHD.

Methods

A pre‐phase FSHD‐Rasch‐built overall disability scale (pre‐FSHD‐RODS; consisting of 159 activity/participation items), based on the World Health Organization international classification of disease‐related functional consequences was completed by 762 FSHD patients (Netherlands:  = 171; UK:  = 287; United States:  = 221; France:  = 52; Australia:  = 32). A proportion of the patient cohort completed it twice ( = 230; interval 2–4 weeks; reliability studies). The pre‐FSHD‐RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the motor function measure.

Results

The pre‐FSHD‐RODS did not meet the Rasch model expectations. Based on determinants such as misfit statistics and misfit residuals, differential item functioning, and local dependency, we systematically removed items until a final 38‐inquiry (originating from 32 items; six items split) FSHD‐RODS was constructed achieving Rasch model expectations. Adequate test‐retest reliability and (cross‐cultural and external) validity scores were obtained.

Conclusions

The FSHD‐RODS is a disease‐specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good item/person reliability and validity scores. The use of this scale is recommended in the near future, to determine the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD.

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Authors:
Karlien Mul, Tatiana Hamadeh, Corinne G. C. Horlings, Rabi Tawil, Jeffrey M. Statland, Sabrina Sacconi, Alastair J. Corbett, Nicol C. Voermans, Catharina G. Faber, Baziel G. M. van Engelen and Ingemar S. J. Merkies
Article first published online:
02 May 2021 | DOI: 10.1111/ene.14863

REVIEW ARTICLE

Abstract

Many clinicians lack experience in managing trigeminal autonomic cephalalgias (TACs) in pregnancy and lactation. In addition to cluster headache, TACs include hemicrania continua, paroxysmal hemicrania, and short‐lasting unilateral neuralgiform headache with conjunctival injection and tearing/autonomic symptoms (SUNCT/SUNA). Treating these rare, severe headache conditions often requires off‐label drugs that have uncertain teratogenic potential. In the last few years, several new treatment options and safety documentation have emerged, but clinical guidelines are lacking. This narrative review aimed to provide an updated clinical guide and good clinical practice recommendations for the management of these debilitating headache disorders in pregnancy and lactation.

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Authors:
Marte‐Helene Bjørk, Espen Saxhaug Kristoffersen, Erling Tronvik and Hedvig Marie Egeland Nordeng
Article first published online:
18 May 2021 | DOI: 10.1111/ene.14864

EDITORIAL

Outcomes after large decompressive craniectomy in patients with subarachnoid haemorrhages

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Authors:
Barbara Casolla
Article first published online:
27 Apr 2021 | DOI: 10.1111/ene.14865

ORIGINAL ARTICLE

Background and purpose

People with multiple sclerosis (PwMS) often report walking limitations even when the gold standard Expanded Disability Status Scale (EDSS) indicates normal walking endurance/autonomy. The present multicenter study on early‐stage PwMS aims at analyzing which aspects are associated with patient‐reported walking limitations measured with the 12‐item Multiple Sclerosis Walking Scale (MSWS‐12).

Methods

Eighty‐two PwMS (EDSS ≤ 2.5) were assessed using the Fullerton Advanced Balance Scale—short (FAB‐s), the Fatigue Severity Scale (FSS) and the 6‐min Walk Test (6MWT), the latter administered also to 21 healthy subjects. Participants performed the 6MWT wearing three inertial sensors on ankles and trunk. Instrumented metrics describing gait velocity (stride length and frequency) and quality (regularity, symmetry, instability) were computed from sensor data. Fatigue (FSS), balance (FAB‐s), walking endurance (6MWT) and instrumented metrics were entered in a multiple regression model with MSWS‐12 as dependent variable.

Results

Gait symmetry, gait instability, fatigue and balance were significantly associated with self‐rated walking ability, whilst walking endurance and velocity were not. Fatigue, balance, gait symmetry and instability were more impaired in participants reporting mild‐to‐moderate (MS, 25 ≤ MSWS‐12 < 75) compared to those reporting none‐to‐minimal (MS, 0 ≤ MSWS‐12 ≤ 25) perceived walking limitations. Compared to healthy subjects, gait symmetry and stability were reduced in MS and MS, even in those participants with EDSS ≤ 1.5.

Conclusion

Instrumentally assessed gait quality aspects (symmetry and instability) are associated with patient‐reported walking ability in early‐stage PwMS and seem sensitive biomarkers to detect subtle impairments even in the earliest stages of the disease (EDSS ≤ 1.5). Future studies should assess their ability to follow walking change due to MS progression or pharmacological/rehabilitation interventions.

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Authors:
Ilaria Carpinella, Elisa Gervasoni, Denise Anastasi, Rachele Di Giovanni, Andrea Tacchino, Giampaolo Brichetto, Paolo Confalonieri, Marco Rovaris, Claudio Solaro, Maurizio Ferrarin and Davide Cattaneo
Article first published online:
02 May 2021 | DOI: 10.1111/ene.14866

ORIGINAL ARTICLE

Background and purpose

Fatigue in multiple sclerosis (MS) is common and disabling; medication efficacy is still not fully proven. The aim of this study was to investigate 4‐week modifications of fatigue severity in 45 relapsing‐remitting MS patients after different symptomatic treatments, and changes in concomitant resting state (RS) functional connectivity (FC).

Methods

Patients were randomly, blindly assigned to treatment with fampridine ( = 15), amantadine ( = 15) or placebo ( = 15), and underwent clinical assessment and 3‐Tesla RS functional magnetic resonance imaging at baseline (t0) and after 4 weeks (w4) of treatment. Fifteen healthy controls (HCs) were also studied. Changes in modified fatigue impact scale (MFIS) score and network RS FC were assessed.

Results

In MS, abnormalities of network RS FC at t0 did not differ between treatment groups and correlated with fatigue severity. At w4, global scores and subscores on the MFIS decreased in all groups, with no time‐by‐treatment interaction. At w4, all patient groups had changes in RS FC in several networks, with significant time‐by‐treatment interactions in basal ganglia, sensorimotor and default‐mode networks in fampridine‐treated patients versus the other groups, and in frontoparietal network in amantadine‐treated patients. In the fampridine group, RS FC changes correlated with concurrently decreased MFIS score ( range = −0.75 to 0.74, range = 0.003–0.05).

Conclusions

Fatigue improved in all MS groups, independently of treatment. Concomitant RS FC modifications were located in sensorimotor, inferior frontal and subcortical regions for fampridine‐ and amantadine‐treated patients, and in associative sensory cortices for placebo‐treated patients.

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Authors:
Maria A. Rocca, Paola Valsasina, Bruno Colombo, Vittorio Martinelli and Massimo Filippi
Article first published online:
26 Apr 2021 | DOI: 10.1111/ene.14867

EDITORIAL

New insights into the pathophysiology of Alzeimer's disease

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Authors:
Giovanna Viticchi and Mauro Silvestrini
Article first published online:
28 Apr 2021 | DOI: 10.1111/ene.14869

ORIGINAL ARTICLE

Background and purpose

A reduction of retinal thickness and an alteration of retinal perfusion have been found in Alzheimer disease (AD). Nowadays, retinal layers and retinal perfusion can be evaluated by means of noninvasive imaging techniques, namely, optical coherence tomography (OCT) and OCT‐angiography (OCT‐A). Here, we have compared the retinal thickness and the perfusion index, measured by means of OCT and OCT‐A, in patients with mild cognitive impairment due to AD (MCI‐AD) and in age‐ and sex‐matched cognitively healthy controls.

Methods

Twenty‐four MCI‐AD patients and 13 control subjects were enrolled. MCI‐AD patients underwent lumbar puncture; all of them showed a cerebrospinal fluid (CSF) profile compatible with AD. OCT was used for evaluating retinal volumes and thicknesses, whereas with OCT‐A we measured fractal dimension (FD), vascular perfusion density (VPD), and vessel length density (VLD) of superficial capillary plexus (SCP), intermediate capillary plexus (ICP), deep capillary plexus (DCP), and choriocapillaris. The comparisons between groups were made after adjustment for age, diabetes, and hypertension.

Results

A significant reduction of SCP‐VLD ( = 0.012), ICP‐VPD ( = 0.015), ICP‐VLD ( = 0.004), DCP‐VPD ( = 0.012), and DCP‐VLD ( = 0.009) was found in MCI‐AD patients compared to controls. Conversely, FD was higher in MCI‐AD than in controls ( = 0.044). CSF Aβ42/total tau negatively correlated with FD ( = −0.51,  = 0.010).

Conclusions

OCT‐A might have a potential role in detecting new noninvasive biomarkers for early AD detection. Retinal VPD might identify amyloid angiopathy‐related chronic injury, and FD could show early vessel recruitment as a compensative mechanism at disease onset. Further studies will be needed to confirm these findings.

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Authors:
Leonardo Biscetti, Marco Lupidi, Elisa Luchetti, Paolo Eusebi, Ramkailash Gujar, Andrea Vergaro, Carlo Cagini and Lucilla Parnetti
Article first published online:
30 Apr 2021 | DOI: 10.1111/ene.14871

SHORT COMMUNICATION

Background and purpose

There has been an increasing interest in chronic active multiple sclerosis (MS) lesions as a new magnetic resonance imaging (MRI) marker of disease progression. Chronic active lesions are characterized by progressive tissue matrix damage, axonal loss and chronic inflammation. Sodium (Na) MRI provides a biochemical marker of cell integrity and tissue viability in a quantitative manner. The aim of this study was to investigate with Na MRI tissue abnormalities in chronic active lesions as indicators of tissue destruction.

Methods

To identify chronic active lesions, two 3D magnetization‐prepared rapid acquisition gradient‐echo datasets obtained 12 months apart were processed using the voxel‐guided morphometry algorithm. Cross‐sectional Na MRI was performed during the 12‐month follow‐up period. Total sodium concentration was calculated in chronic active lesions compared to shrinking, chronic stable and acute contrast‐enhancing lesions.

Results

Overall, 70 MS lesions (21 chronic active, 10 shrinking, 29 chronic stable lesions, 10 acute contrast‐enhancing lesions) in 12 patients were included. Total sodium concentration in chronic active lesions (49.57 ± 8.47 mM) was significantly higher than in shrinking (42.16 ± 3.9 mM;  = 0.03) and chronic stable lesions (39.92 ± 4.82 mM;  < 0.001). Chronic active lesions showed similar sodium values compared to acute contrast‐enhancing lesions (48.06 ± 6.65 mM;  = 0.97). No differences between shrinking and chronic stable lesions were observed ( = 0.89).

Conclusion

High sodium values in chronic active MS lesions may be an indicator of ongoing inflammation and tissue damage.

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Authors:
Philipp Eisele, Matthias Kraemer, Andreas Dabringhaus, Claudia E. Weber, Anne Ebert, Michael Platten, Lothar R. Schad and Achim Gass
Article first published online:
06 May 2021 | DOI: 10.1111/ene.14873

ORIGINAL ARTICLE

Background and purpose

Mortality is known to be markedly increased in people with dementia. However, the association between multiple chronic conditions and mortality in dementia is not well clarified. The aim of this study was to investigate the impact of somatic and psychiatric diseases on mortality in dementia compared with the general elderly population.

Methods

Using a cohort study design, nationwide registry data from 2006 to 2015 on dementia and psychiatric and somatic comorbidities defined by the Charlson Comorbidity Index (CCI) were linked. Impact of chronic conditions was assessed according to mortality rate ratios (MRRs) in all Danish residents aged ≥65 years with and without dementia.

Results

Our population comprised 1,518,917 people, of whom 114,109 people were registered with dementia. The MRRs was 2.70 (95% confidence interval 2.68, 2.72) in people with dementia after adjusting for sex, age, calendar year, and comorbidities. MRRs increased with higher CCI score, and when comparing people with a similar comorbidity load, MRRs were significantly higher for people with dementia.

Conclusions

The comorbidity load was associated with increased mortality in both people with and without dementia. Mortality in dementia remained increased, even after adjusting for psychiatric and chronic somatic comorbidities. Our findings suggest that dementia disorders alone contribute to excess mortality, which may be further increased by comorbidities.

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Authors:
Lærke Taudorf, Ane Nørgaard, Henry Brodaty, Thomas Munk Laursen and Gunhild Waldemar
Article first published online:
14 May 2021 | DOI: 10.1111/ene.14875

ORIGINAL ARTICLE

Background and purpose

The objectives of the present analysis were to assess 28‐day stroke case fatality according to the stroke aetiology and to identify associated factors.

Methods

All stroke events in adults aged ≥35 years between 2008 and 2017 were collected in a population‐based stroke registry in northern France.

Results

Out of a total of 2933 strokes, there were 479 (16%) haemorrhagic strokes and 2454 (84%) ischaemic strokes; the 28‐day case fatality rates were 48% and 15%, respectively. Three‐quarters of the 28‐day case fatalities occurred within 6 days of the event for haemorrhagic strokes and within 16.5 days for ischaemic strokes. After an ischaemic stroke, the case fatality rate was higher for women (18%) than for men (12%,  < 0.0001); however, this difference disappeared after adjustment for age. Cardioembolic strokes (34%) and strokes of undetermined cause (33%) were the most common ischaemic subtypes, with case fatality rates of 16% and 18%, respectively. Large artery atherosclerosis (11%) and lacunar strokes (10%) were less common, and both types had a case fatality rate of 3%. Age at the time of the event and stroke severity were both significantly associated with case fatality. For some types of stroke, a history of cardiovascular events and residence in a nursing home were associated with a poor prognosis. Medical care in a neurology ward was inversely associated with case fatality, for all stroke subtypes.

Conclusions

In northern France, post‐stroke case fatality remains high, especially for haemorrhagic stroke. Being treated in a neurology ward improved survival by around 80%.

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Authors:
Victoria Gauthier, Dominique Cottel, Philippe Amouyel, Jean Dallongeville and Aline Meirhaeghe
Article first published online:
03 May 2021 | DOI: 10.1111/ene.14876

LETTER TO THE EDITOR

Cryptogenic stroke: Much and nothing at the same time

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Authors:
Yelson Alejandro Picón‐Jaimes, Ivan David Lozada‐Martinez, Tariq Janjua and Luis Rafael Moscote‐Salazar
Article first published online:
06 May 2021 | DOI: 10.1111/ene.14880

ORIGINAL ARTICLE

Background and objective

Nerve ultrasound is a promising new tool in chronic inflammatory neuropathies. The aim of this study was to determine its prognostic value in a prospective multicenter cohort study including incident and prevalent patients with CIDP and MMN.

Methods

We enrolled 126 patients with CIDP, and 72 with MMN; 71 were treatment‐naive. Patients with chronic idiopathic axonal polyneuropathy (CIAP;  = 35) were considered as disease controls. Standardized neurological examination, questionnaires, and nerve ultrasonography were obtained at time of inclusion and 1‐year follow‐up. Nerve size development over time and correlation between nerve size and clinical outcome measures were determined using linear mixed effects models.

Results

Nerve size development over time was heterogeneous. Only in MMN was there a correlation between C5 nerve root size and deterioration of grip strength (−1.3 kPa/mm (95% confidence interval [CI] −2.3 to −0.2). No other significant correlations between nerve size and clinical outcome measures were found. In MMN, presence of nerve enlargement at inclusion predicted deterioration of grip strength, and MMN patients with enlargement confined to the brachial plexus seemed to have more favorable outcomes. No other predictive effects of sonographic nerve size were found.

Conclusions

The present study indicates that the natural course of nerve size development in CIDP and MMN is heterogeneous, and that the prognostic value of sonographic nerve enlargement is limited. It had some predictive effect in patients with MMN. Further research in specific subgroups of chronic inflammatory neuropathy is necessary to determine the usefulness of nerve ultrasonography after the diagnostic phase.

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Authors:
Johan A. Telleman, Ingrid J. T. Herraets, Hendrik Stephan Goedee, Ruben P. A. van Eijk, Camiel Verhamme, Filip Eftimov, Doris Lieba‐Samal, Jan Thies van Asseldonk, Leonard H. van den Berg, Willem Ludo van der Pol and Leo H. Visser
Article first published online:
14 May 2021 | DOI: 10.1111/ene.14885

ORIGINAL ARTICLE

Background and purpose

This study was undertaken to identify clinically meaningful comorbidity patterns and their associations with the demographic/clinical characteristics of people with multiple sclerosis (MS).

Methods

We conducted latent class analysis to identify clinically distinct comorbidity patterns in MS using the 15 most common comorbidities among 1518 Australian Multiple Sclerosis Longitudinal Study participants. The associations between demographic/clinical characteristics and comorbidity patterns were examined using log‐binomial and multinomial logistic regression.

Results

Five distinct comorbidity patterns were identified: “minimally diseased class” (30.8%), consisting of participants with no or one comorbidity; “metabolic class” (22.7%); “mental health–allergy class” (21.7%); “nonmetabolic class” (7.6%); and “severely diseased class” (7.0%), consisting of participants with higher prevalence of these comorbidities. The relative probabilities of being assigned to comorbidity classes compared to the minimally diseased class were significantly increased for participants who were older (metabolic: relative risk ratio [RRR] = 1.09, 95% confidence interval [CI] = 1.06–1.11; nonmetabolic: RRR = 1.07, 95% CI = 1.04–1.11; severely diseased: RRR = 1.04, 95% CI = 1.01–1.08), female (nonmetabolic: RRR = 5.35, 95% CI = 1.98–14.42; severely diseased: RRR = 2.21, 95% CI = 1.02–4.77), and obese (metabolic: RRR = 4.06, 95% CI = 2.45–6.72; mental health–allergy: RRR = 1.57, 95% CI = 1.00–2.46; severely diseased: RRR = 4.53, 95% CI = 2.21–9.29) and who had moderate disability (mental health–allergy: RRR = 2.32, 95% CI = 1.47–3.64; severely diseased: RRR = 2.65, 95% CI = 1.16–6.04).

Conclusions

Comorbidity patterns exist in MS. Women, people who were older, people who were obese, and people who had higher disability levels were more likely to be in classes with higher levels of comorbidity. These findings may offer opportunities for designing more personalised approaches to comorbidity prevention and treatment.

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Authors:
Lara Marie Pangan Lo, Bruce V. Taylor, Tania Winzenberg, Andrew J. Palmer, Leigh Blizzard, Mohammad Akhtar Hussain and Ingrid van der Mei
Article first published online:
20 May 2021 | DOI: 10.1111/ene.14887

ORIGINAL ARTICLE

Background and purpose

Vestibular migraine (VM) patients are ictally and interictally hypersensitive for self‐motion and visual perception. Increased cortical excitability of the vestibular system represented by lowered motion perception thresholds might play an important role in the pathophysiology of VM. We aimed to compare motion perception thresholds and the vegetative response to rotatory motion, as well as the vestibulo‐ocular reflex (VOR) during rotation in VM patients compared to healthy controls (HC).

Methods

In this cross‐sectional study, 28 female VM patients in the interictal state and 33 age‐ and gender‐matched HC were investigated sitting in a motorized rotary chair shielded regarding visual and acoustic stimuli for 20 min with slowly increasing velocity (maximum = 72°/s). The motion perception threshold was indicated by the participants by pushing a button. During and after rotation, participants rated the presence and extent of motion sickness using a sickness rating scale.

Results

We detected lower motion perception thresholds (7.54°/s vs. 23.49°/s;  < 0.001) in VM patients compared to HC but no difference at the basic VOR thresholds. Furthermore, the patients showed enhanced susceptibility to motion sickness during and after the rotation.

Conclusions

We provide evidence for decreased motion perception thresholds and pronounced susceptibility to motion sickness in VM patients in the interictal state, which could indicate alterations in higher levels of vestibular processing. Future studies should determine whether this could be the pathophysiological hallmark of VM either as a unique disease entity or in differentiation from other forms of migraine.

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Authors:
Sebastian Wurthmann, Steffen Naegel, Miriam Roesner, Michael Nsaka, Armin Scheffler, Christoph Kleinschnitz, Dagny Holle and Mark Obermann
Article first published online:
14 May 2021 | DOI: 10.1111/ene.14889

LETTERS TO THE EDITOR

Response to Chinese famine and ischemic stroke: The need to control for age differences and improve famine severity measurement

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Authors:
Boni Tao, Peng Yang, Cun Wang, Wei Du, Peixuan Shen, Ying Wu, Xiong Ding, Shuohua Chen, Shouling Wu and Yun Li
Article first published online:
20 May 2021 | DOI: 10.1111/ene.14894