cover image European Journal of Neurology

European Journal of Neurology

2023 - Volume 30
Issue 10 | October 2023
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ISSUE INFORMATION

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Article first published online:
07 Sep 2023 | DOI: 10.1111/ene.15401

ORIGINAL ARTICLE

Background and purpose

We analyzed the association of neuropsychological outcomes after epilepsy surgery with the intracranial electrode type (stereo electroencephalography [SEEG] and subdural electrodes [SDE]), and electrical stimulation mapping (ESM) of speech/language.

Methods

Drug‐resistant epilepsy patients who underwent comprehensive neuropsychological evaluation before and 1 year after epilepsy surgery were included. SEEG and SDE subgroups were matched by age, handedness, operated hemisphere, and seizure freedom. Postsurgical neuropsychological outcomes (adjusted for presurgical scores) and reliable change indices were analyzed as functions of electrode type and ESM.

Results

Ninety‐nine patients aged 6–29 years were included with similar surgical resection/ablation volumes in the SEEG and SDE subgroups. Most of the neuropsychological outcomes were comparable between SEEG and SDE subgroups; however, Working Memory and Processing Speed were significantly improved in the SEEG subgroup. Undergoing language ESM was associated with significant improvements in Spelling, Letter–Word Identification, Vocabulary, Verbal Comprehension, Verbal Learning, and Story Memory scores, but a decline in Calculation scores.

Conclusions

Intracranial evaluations with SEEG and SDE are comparable in terms of long‐term postsurgical neuropsychological outcomes. Our data suggest that SEEG may be associated with improvements in working memory and processing speed, representing cognitive domains served by spatially distributed networks. Our study also supports wider use of language ESM before epilepsy surgery, preferably using other language tasks in addition to visual naming. Rather than the type of electrode, postsurgical neuropsychological outcomes are driven by whether language ESM was performed or not, with beneficial effects of language mapping.

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Authors:
Ravindra Arya, Clayton Frink, Christina Kargol, Anna W. Byars, David Huddleston, Donna B. Diedenhofer, Gewalin Aungaroon, Brian Ervin, Paul S. Horn, S. K. Z. Ihnen, Jeffrey R. Tenney, Kelly Kremer, Susan Fong, Nan Lin, Wei Liu, Todd M. Arthur, Jesse Skoch, James L. Leach, Francesco T. Mangano, Tracy A. Glauser, Hansel M. Greiner and Katherine D. Holland
Article first published online:
28 Jun 2023 | DOI: 10.1111/ene.15929

ORIGINAL ARTICLE

Background and purpose

The endocannabinoid system (ECS) has been found altered in patients with multiple sclerosis (MS). However, whether the ECS alteration is present in the early stage of MS remains unknown. First, we aimed to compare the ECS profile between newly diagnosed MS patients and healthy controls (HCs). Next, we explored the association of the ECS, biomarkers of inflammation, and clinical parameters in newly diagnosed MS patients.

Methods

Whole blood gene expression of ECS components and levels of endocannabinoids in plasma were measured by real‐time quantitative polymerase chain reaction and ultra‐high‐pressure liquid chromatography–mass spectrometry, respectively, in 66 untreated MS patients and 46 HCs.

Results

No differences were found in the gene expression or plasma levels of the selected ECS components between newly diagnosed MS patients and HCs. Interferon‐γ, encoded by the gene correlated positively ( = 0.60) with the expression of G protein‐coupled receptor 55 (), and interleukin1β () correlated negatively ( = −0.50) with cannabinoid receptor 2 () in HCs.

Conclusions

We found no alteration in the peripheral ECS between untreated patients with MS and HC. Furthermore, our results indicate that the ECS has a minor overall involvement in the early stage of MS on inflammatory markers and clinical parameters when compared with HCs.

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Authors:
Stefan Gustavsen, Anna Olsson, Annette B. Oturai, Kristian Linnet, Ragnar Thomsen, Brian S. Rasmussen, Christian F. Jørgensen, Annika R. Langkilde, Per S. Sorensen, Finn Sellebjerg and Helle B. Søndergaard
Article first published online:
07 Jul 2023 | DOI: 10.1111/ene.15930

POSITION PAPER

Abstract

Simultaneously acquiring broad clinical knowledge and scientific expertise is a major challenge for young clinical scientists. Female researchers may face additional hurdles in their career, for example, due to unconscious bias. We aimed to address clinical, research, and gender‐related challenges among young female clinical neuroscientists. We implemented a peer‐led networking group dedicated to increasing clinical and scientific knowledge, improve soft skills, and encourage exchange between fellow residents. In monthly meetings, two participants hold short presentations on a clinical topic or scientific method, followed by a discussion and feedback to the presenter. Afterwards, participants network and discuss challenges they face in their daily experience. Nine neurology residents at a Swiss University Hospital with ≤3 years of training participated in the Connecting Women in Neurosciences project from August 2020 to June 2021. In a qualitative evaluation, participants reported they felt empowered by these meetings and profited from their new network. We identified several challenges in combining clinical and research activities, some of which participants perceived to be gender‐related. In addition to women‐only meetings, we will promote events addressing all interested researchers. Peer‐to‐peer networking is an easy and low‐budget intervention to encourage female residents to engage in research activities, profit from each other's expertise, and promote interdisciplinary teamwork. It can provide a protected environment to discuss and overcome in particular gender‐related challenges. We encourage young colleagues to regularly engage in structured networking activities with their local peers.

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Authors:
Martina B. Goeldlin, Elena S. Wenz, Chantal Kottler, Urs Fischer, Claudio L. A. Bassetti, Selma Aybek and Mirjam R. Heldner
Article first published online:
05 Jul 2023 | DOI: 10.1111/ene.15932

ORIGINAL ARTICLE

Background

Neuroinflammation in the cerebral cortex of patients who died with liver cirrhosis and neuroinflammation, and neuronal death in the cerebellum of patients who died with steatohepatitis or cirrhosis, were reported. Hippocampal neuroinflammation could contribute to cognitive decline in patients with liver disease, but this has yet to be studied. The study aims were to assess if hippocampus from patients who died with steatohepatitis or cirrhosis showed: (i) glial activation, (ii) altered cytokine content, (iii) immune cell infiltration, (iv) neuronal apoptosis and (v) neuronal loss.

Methods

Post‐mortem hippocampus was obtained from 6 controls, 19 patients with steatohepatitis (SH) and 4 patients with liver cirrhosis. SH patients were divided into SH1 ( = 9), SH2 ( = 6) and SH3 ( = 4) groups depending on disease severity. Glial activation, IL‐1β and TNFα content, CD4 lymphocyte and monocyte infiltration, neuronal apoptosis and neuronal loss were analyzed by immunohistochemistry.

Results

Patients who died in SH1 showed astrocyte activation, whereas those who died in SH2 also showed microglial activation, CD4 lymphocyte and monocyte infiltration, neuronal apoptosis and neuronal loss. These changes remained in patients in SH3, who also showed increased IL‐1β and TNFα. Patients who died of liver cirrhosis did not show CD4 lymphocyte infiltration, neuronal apoptosis or increase in TNFα, but still showed glial activation, increased IL‐1β and neuronal loss.

Conclusions

Patients with steatohepatitis showed glial activation, immune cell infiltration, apoptosis and neuronal loss. Glial activation and neuronal loss remained in cirrhotic patients. This may explain the irreversibility of some cognitive alterations in hepatic encephalopathy. Cognitive reserve may contribute to different grades of cognitive impairment despite similar neuronal loss.

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Authors:
Paola Leone, Yaiza M. Arenas, Tiziano Balzano, Gergana Mincheva, Mar Martinez‐Garcia, Carmina Montoliu, Marta Llansola and Vicente Felipo
Article first published online:
04 Jul 2023 | DOI: 10.1111/ene.15935

ORIGINAL ARTICLE

Background

In amyotrophic lateral sclerosis (ALS), gait abnormalities contribute to poor mobility and represent a relevant risk for falls. To date, gait studies in ALS patients have focused on the motor dimension of the disease, underestimating the cognitive aspects.

Methods

Using a wearable gait analysis device, we compared gait patterns in ambulatory ALS patients with mild cognitive impairment (ALS MCI+;  = 18), and without MCI (ALS MCI−;  = 24), and healthy subjects (HS;  = 16) under two conditions: (1) normal gait (single task) and (2) walking while counting backward (dual task). Finally, we examined if the occurrence and number of falls in the 3 months following the baseline test were related to cognition.

Results

In the single task condition, ALS patients, regardless of cognition, displayed higher gait variability than HS, especially for stance and swing time ( < 0.001). The dual task condition revealed additional differences in gait variability parameters between ALS MCI+ and ALS MCI− for cadence ( = 0.005), stance time ( = 0.04), swing time ( = 0.04) and stability index ( = 0.02). Moreover, ALS MCI+ showed a higher occurrence ( = 0.001) and number of falls ( < 0.001) at the follow‐up. Regression analyses demonstrated that MCI condition predicted the occurrence of future falls (β = 3.649;  = 0.01) and, together with executive dysfunction, was associated with the number of falls (cognitive impairment: β = 0.63;  < 0.001; executive dysfunction: β = 0.39;  = 0.03), regardless of motor impairment at clinical examination.

Conclusion

In ALS, MCI is associated with exaggerated gait variability and predicts the occurrence and number of short‐term falls.

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Authors:
Raffaele Dubbioso, Myriam Spisto, Jeffrey M. Hausdorff, Gabriella Aceto, Valentina Virginia Iuzzolino, Gianmaria Senerchia, Stefania De Marco, Laura Marcuccio, Cinzia Femiano, Rosa Iodice, Elena Salvatore, Gabriella Santangelo, Luigi Trojano and Pasquale Moretta
Article first published online:
29 Jun 2023 | DOI: 10.1111/ene.15936

ORIGINAL ARTICLE

Background

X‐Linked Charcot–Marie–Tooth disease type 1 (CMTX1) is characterized by gender differences in clinical severity. Women are usually clinically affected later and less severely than men. However, their clinical presentation appears to be heterogenous. Our aim was to extend the phenotypic description in a large series of women with CMTX1.

Methods

We retrospectively evaluated 263 patients with CMTX1 from 11 French reference centers. Demographic, clinical, and nerve conduction data were collected. The severity was assessed by CMT Examination Score (CMTES) and Overall Neuropathy Limitations Scale (ONLS) scores. We looked for asymmetrical strength, heterogeneous motor nerve conduction velocity (MNCV), and motor conduction blocks (CB).

Results

The study included 137 women and 126 men from 151 families. Women had significantly more asymmetric motor deficits and MNCV than men. Women with an age of onset after 19 years were milder. Two groups of women were identified after 48 years of age. The first group represented 55%, with women progressing as severely as men, however, with a later onset age. The second group had mild or no symptoms. Some 39% of women had motor CB. Four women received intravenous immunoglobulin before being diagnosed with CMTX1.

Conclusions

We identified two subgroups of women with CMTX1 who were over 48 years of age. Additionally, we have demonstrated that women with CMTX can exhibit an atypical clinical presentation, which may result in misdiagnosis. Therefore, in women presenting with chronic neuropathy, the presence of clinical asymmetry, heterogeneous MNCV, and/or motor CB should raise suspicion for X‐linked CMT, particularly CMTX1, and be included in the differential diagnosis.

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Authors:
Luce Barbat du Closel, Nathalie Bonello‐Palot, Yann Péréon, Andoni Echaniz‐Laguna, Jean Philippe Camdessanche, Aleksandra Nadaj‐Pakleza, Jean‐Baptiste Chanson, Simon Frachet, Laurent Magy, Julien Cassereau, Pascal Cintas, Ariane Choumert, Perrine Devic, Sarah Leonard Louis, Robinson Gravier Dumonceau, Emilien Delmont, Emmanuelle Salort‐Campana, Françoise Bouhour, Philippe Latour, Tanya Stojkovic and Shahram Attarian
Article first published online:
05 Jul 2023 | DOI: 10.1111/ene.15937

LETTER TO THE EDITOR

Comment on: Risk of myocardial infarction in Parkinson's disease: A systematic review and meta‐analysis

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Authors:
Jintao Liu, Tianlu Wang and Xia Li
Article first published online:
19 Jul 2023 | DOI: 10.1111/ene.15938

ORIGINAL ARTICLE

Background and purpose

Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising neuro‐axonal damage and astrocytic activation biomarkers. Susac syndrome (SS) is an increasingly recognized neurological condition and biomarkers that can help assess and monitor disease evolution are highly needed for the adequate management of these patients. sNfL and sGFAP levels were evaluated in patients with SS and their clinical relevance in the relapse and remission phase of the disease was assessed.

Methods

As part of a multicentre study that enrolled patients diagnosed with SS from six international centres, sNfL and sGFAP levels were assessed in 22 SS patients (nine during a relapse and 13 in remission) and 59 age‐ and sex‐matched healthy controls using SimoaTM assay Neurology 2‐Plex B Kit.

Results

Serum NfL levels were higher than those of healthy controls ( < 0.001) in SS patients and in both subgroups of patients in relapse and in remission ( < 0.001 for both), with significantly higher levels in relapse than in remission ( = 0.008). sNfL levels showed a negative correlation with time from the last relapse ( = −0.663;  = 0.001). sGFAP levels were slightly higher in the whole group of patients than in healthy controls ( = 0.046) and were more pronounced in relapse than in remission ( = 0.013).

Conclusion

In SS patients, both sNFL and sGFAP levels increased compared with healthy controls. Both biomarkers had higher levels during clinical relapse and much lower levels in remission. sNFL was shown to be time sensitive to clinical changes and can be useful to monitor neuro‐axonal damage in SS.

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Authors:
Domenico Plantone, Eleonora Sabatelli, Sara Locci, Mariano Marrodan, Sini M. Laakso, Farrah J. Mateen, Amalia Feresiadou, Tom Buelens, Assunta Bianco, Marcela P. Fiol, Jorge Correale, Pentti Tienari, Paolo Calabresi, Nicola De Stefano and Raffaele Iorio
Article first published online:
29 Jun 2023 | DOI: 10.1111/ene.15939

ORIGINAL ARTICLE

Background and purpose

People with multiple sclerosis (pwMS) report reduced quality of life (QoL). Engagement with healthy lifestyle behaviours, including consuming a healthy diet, regular physical activity, and adequate vitamin D exposure, is associated with higher QoL. We aim to assess whether individual lifestyle behaviours are more beneficial to QoL than others, and whether there are additive benefits to QoL by engaging in multiple healthy behaviours concurrently.

Methods

Data from pwMS who completed an online survey at baseline, and at 2.5‐, 5‐ and 7.5‐year follow‐up, were analysed. Behaviours assessed were consumption of a no‐meat/dairy‐plus‐omega‐3 supplementation diet, meditation practice, physical activity, non‐smoking, and vitamin D exposure. Mental QoL (mQoL) and physical QoL (pQoL) were assessed by the Multiple Sclerosis Quality of Life (MSQOL‐54) questionaire. Linear regression analyses were performed to assess associations of individual behaviours at baseline and follow‐up time points with QoL, as well as between number of behaviours and QoL.

Results

At baseline, healthy diet and regular physical activity were associated with higher mQoL (5.3/100 and 4.0/100) and higher pQoL (7.8/100 and 6.7/100). Prospectively, diet was positively associated with mQoL, and physical activity with both mQoL and pQoL. At baseline, engagement with ≥3 behaviours was positively associated with mQoL and pQoL, with additive positive associations for each additional behaviour. Prospectively, engagement with ≥3 behaviours was positively associated with mQoL and pQoL, with strongest associations observed with engagement with five behaviours.

Conclusion

Consumption of a healthy diet, and regular physical activity, are both potential interventions to improve QoL. Engagement with multiple lifestyle behaviours may provide additional benefits and should be encouraged and supported for multiple sclerosis management.

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Authors:
Alexander Fidao, George Jelinek, Steve Simpson‐Yap, Sandra Neate and Nupur Nag
Article first published online:
09 Jul 2023 | DOI: 10.1111/ene.15940

ORIGINAL ARTICLE

Background and purpose

Spinal cord lesions are observed in 40% of all central nervous system lesions in intravascular large B‐cell lymphoma (IVLBCL). However, because IVLBCL is a very rare disease, its clinical features are not well defined, which may delay appropriate diagnosis and treatment, whilst the acute to subacute course of brain lesions in patients with IVLBCL is well established. Therefore, this study aimed to clarify the clinical features of spinal cord lesions in patients with IVLBCL.

Methods

The medical records of patients with IVLBCL admitted to our hospital between 2010 and 2020 were searched. The inclusion criteria were preceding neurological symptoms without non‐neurological symptoms and pathologically confirmed IVLBCL in various organs. Clinical features of spinal cord involvement in patients with IVLBCL were assessed and distinguished from those of brain involvement.

Results

Sixteen consecutive patients with IVLBCL were divided into two groups: six patients with spinal involvement (spinal cord type) and 10 patients with brain involvement (brain type). In the spinal cord type, four patients had chronic progression and two had subacute progression. Acute progression (0% vs. 80.0%) and sudden onset (0% vs. 50.0%) occurred significantly less frequently in the spinal cord than in the brain. All spinal cord lesions involved the conus medullaris.

Conclusions

Spinal cord involvement in IVLBCL has a predominantly chronic progressive course that is exclusive to brain involvement. Conus medullaris lesions are suggestive of IVLBCL and are useful for early and accurate diagnosis and treatment.

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Authors:
Sho Kitahara, Masato Kanazawa, Manabu Natsumeda, Aki Sato, Masanori Ishikawa, Kenju Hara, Hiroyuki Tabe, Kunihiko Makino, Kouichirou Okamoto, Nobuya Fujita, Akiyoshi Kakita, Yukihiko Fuji and Osamu Onodera
Article first published online:
04 Jul 2023 | DOI: 10.1111/ene.15941

ORIGINAL ARTICLE

Background and purpose

Little is known about risk factors for developing neurological immunological adverse events (neuro‐irAEs) from immune checkpoint inhibitors (ICIs). We report the incidence, predictors for development, impact on mortality of neuro‐irAEs, and impact of ICIs on pre‐existing neurological conditions in a large clinical cohort.

Methods

Patients who received ICIs between January 2011 and December 2018 were identified from a tertiary cancer center registry. Descriptive statistics were used to summarize patient, cancer, and treatment data. Odds ratios from univariable and multivariable logistic regression models were calculated to identify potential predictors for developing a neuro‐irAE. Impact of neuro‐irAEs on overall survival was estimated by Kaplan–Meier and Cox proportional hazard models.

Results

Overall frequency of neurological irAEs was 2.3%. Peripheral nervous system complications were most frequent (53.6%). Melanoma, younger age, prior chemotherapy, prior resection, CTLA‐4 ICIs exposure, and combination PD‐1 and CTLA‐4 ICIs exposure had significantly higher odds for developing a neuro‐irAE ( < 0.05) in univariate but not multivariate models. Those with a neuro‐irAE were less likely to die at 3 years compared to those without a neuro‐irAE (69% vs. 55%,  = 0.004) in univariate but not multivariate model. Flare of pre‐existing neurological condition after exposure to ICIs was present (15.4%, 2 of 13 patients) but manageable. One patient was rechallenged with ICIs without recurrent flare.

Conclusions

Neuro‐irAEs are not associated with increase in overall mortality. Potential predictors for the development of neuro‐irAEs are younger age, melanoma, prior chemotherapy and resection, CTLA‐4, or combination ICIs exposure.

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Authors:
Chen Yan, Merry Huang, Carol Swetlik, Karlo Toljan, Ahmad Z. Mahadeen, James Bena, Amy Kunchok, Pauline Funchain and Marisa McGinley
Article first published online:
02 Jul 2023 | DOI: 10.1111/ene.15942

ORIGINAL ARTICLE

Background and purpose

The lack of reliable early biomarkers still causes substantial diagnostic delays in amyotrophic lateral sclerosis (ALS). The aim was to assess the diagnostic accuracy of a novel electrophysiological protocol in patients with suspected motor neuron disease (MND).

Methods

Consecutive patients with suspected MND were prospectively recruited at our tertiary referral centre for MND in Utrecht, The Netherlands. Procedures were performed in accordance with the Standards for Reporting of Diagnostic Accuracy. In addition to the standard diagnostic workup, an electrophysiological protocol of compound muscle action potential (CMAP) scans and nerve excitability tests was performed on patients' thenar muscles. The combined diagnostic yield of nerve excitability and CMAP scan based motor unit number estimation was compared to the Awaji and Gold Coast criteria and their added value was determined.

Results

In all, 153 ALS or progressive muscular atrophy patients, 63 disease controls and 43 healthy controls were included. Our electrophysiological protocol had high diagnostic accuracy (area under the curve [AUC] 0.85, 95% confidence interval [95% CI] 0.80–0.90), even in muscles with undetectable axon loss (AUC 0.78, 95% CI 0.70–0.85) and in bulbar‐onset patients (AUC 0.85, 95% CI 0.73–0.95). Twenty‐four of 33 (73%) ALS patients who could not be diagnosed during the same visit were correctly identified, as well as 8/13 (62%) ALS patients not meeting the Gold Coast criteria and 49/59 (83%) ALS patients not meeting the Awaji criteria during this first visit.

Conclusions

Our practical and non‐invasive electrophysiological protocol may improve early diagnosis in clinically challenging patients with suspected ALS. Routine incorporation may boost early diagnosis, enhance patient selection and generate baseline measures for clinical trials.

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Authors:
D. J. L. Stikvoort García, B.T.H.M. Sleutjes, L. J. van Schelven, H. S. Goedee and L. H. van den Berg
Article first published online:
05 Jul 2023 | DOI: 10.1111/ene.15954

ORIGINAL ARTICLE

Background and purpose

This study was undertaken to determine the association of hospital‐diagnosed morbidity and recent surgery with risk of subsequent Guillain–Barré syndrome (GBS) development.

Methods

We conducted a nationwide population‐based case–control study of all patients with first‐time hospital‐diagnosed GBS in Denmark between 2004 and 2016 and 10 age‐, sex‐, and index date‐matched population controls per case. Hospital‐diagnosed morbidities included in the Charlson Comorbidity Index were assessed as GBS risk factors up to 10 years prior to the GBS index date. Incident major surgery was assessed within 5 months prior.

Results

In the 13‐year study period, there were 1086 incident GBS cases, whom we compared with 10,747 matched controls. Any pre‐existing hospital‐diagnosed morbidity was observed in 27.5% of GBS cases and 20.0% of matched controls, yielding an overall matched odds ratio (OR) of 1.6 (95% confidence interval [CI] = 1.4–1.9). The strongest associations were found for leukemia, lymphoma, diabetes, liver disease, myocardial infarction, congestive heart failure, and cerebrovascular disease, with 1.6‐ to 4.6‐fold increased risks of subsequent GBS. GBS risk was strongest for morbidities newly diagnosed during the past 5 months (OR = 4.1, 95% CI = 3.0–5.6). Surgical procedures within 5 months prior were observed in 10.6% of cases and 5.1% of controls, resulting in a GBS OR of 2.2 (95% CI = 1.8–2.7). Risk of developing GBS was highest during the first month following surgery (OR = 3.7, 95% CI = 2.6–5.2).

Conclusions

In this large nationwide study, individuals with hospital‐diagnosed morbidity and recent surgery had a considerably increased risk of GBS.

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Authors:
Lotte S. Levison, Reimar W. Thomsen and Henning Andersen
Article first published online:
05 Jul 2023 | DOI: 10.1111/ene.15955

GUIDELINES

Background and Purpose

Cluster headache is a relatively rare, disabling primary headache disorder with a major impact on patients' quality of life. This work presents evidence‐based recommendations for the treatment of cluster headache derived from a systematic review of the literature and consensus among a panel of experts.

Methods

The databases PubMed (Medline), Science Citation Index, and Cochrane Library were screened for studies on the efficacy of interventions (last access July 2022). The findings in these studies were evaluated according to the recommendations of the European Academy of Neurology, and the level of evidence was established using GRADE (Grading of Recommendations Assessment, Development, and Evaluation).

Recommendations

For the acute treatment of cluster headache attacks, there is a strong recommendation for oxygen (100%) with a flow of at least 12 L/min over 15 min and 6 mg subcutaneous sumatriptan. Prophylaxis of cluster headache attacks with verapamil at a daily dose of at least 240 mg (maximum dose depends on efficacy and tolerability) is recommended. Corticosteroids are efficacious in cluster headache. To reach an effect, the use of at least 100 mg prednisone (or equivalent corticosteroid) given orally or at up to 500 mg iv per day over 5 days is recommended. Lithium, topiramate, and galcanezumab (only for episodic cluster headache) are recommended as alternative treatments. Noninvasive vagus nerve stimulation is efficacious in episodic but not chronic cluster headache. Greater occipital nerve block is recommended, but electrical stimulation of the greater occipital nerve is not recommended due to the side effect profile.

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Authors:
Arne May, Stefan Evers, Peter J. Goadsby, Massimo Leone, Gian Camillo Manzoni, Julio Pascual, Vanessa Carvalho, Michele Romoli, Katina Aleksovska, Patricia Pozo‐Rosich and Rigmor H. Jensen
Article first published online:
28 Jul 2023 | DOI: 10.1111/ene.15956

ORIGINAL ARTICLE

Background and purpose

COVID‐19 is associated with multiple neurological manifestations. The clinical presentation, trajectory, and treatment response for three cases of myoclonus during COVID‐19 infection, with no previous neurological disease, are decsribed.

Metods

Analysis of cerebrospinal fluid from the cases using indirect immunohistochemistry.

Results

Antibodies against rodent brain tissue, and similarities in staining patterns were observed, indicating the presence of antineuronal immunoglobulin G autoantibodies targeting astrocytes in the hippocampus.

Conclusion

Our results demontrate cerebrospinal fluid antineuronal antibodies indicating an an autoimmune involvment in the pathogenesis in COVID‐19 associated myoclonus.

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Authors:
Isa Lindqvist, Janet L. Cunningham, Jan Mulder, Amalia Feresiadou, Elham Rostami, Johan Virhammar and Eva Kumlien
Article first published online:
13 Jul 2023 | DOI: 10.1111/ene.15958

ORIGINAL ARTICLE

Background

The homeostatic chemokines CCL19 and CCL21 are involved in carotid plaque vulnerability and post‐ischemic neuroinflammatory responses. This study aimed to examine the prognostic values of CCL19 and CCL21 in ischemic stroke.

Methods

Plasma CCL19 and CCL21 were measured in 4483 ischemic stroke patients from two independent cohorts of CATIS (China Antihypertensive Trial in Acute Ischemic Stroke) and IIPAIS (Infectious Factors, Inflammatory Markers, and Prognosis of Acute Ischemic Stroke), and participants were followed up at 3 months after stroke. The primary outcome was the composite outcome of death or major disability. The associations of CCL19 and CCL21 levels with the primary outcome were examined.

Results

In CATIS, multivariable‐adjusted odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 compared with the lowest quartiles were 2.06 and 2.62, respectively. In IIPAIS, odds ratios of the primary outcome in the highest quartiles of CCL19 and CCL21 were 2.81 and 2.78 compared with the lowest quartiles, respectively. In the pooled analysis of the two cohorts, odds ratios of the primary outcome associated with the highest quartiles of CCL19 and CCL21 were 2.24 and 2.66, respectively. Similar findings were observed in the analysis with major disability, death, and the composite outcome of death or cardiovascular events as the secondary study outcomes. Adding CCL19 and CCL21 to conventional risk factors significantly improved risk reclassification and discrimination for adverse outcomes.

Conclusions

Both CCL19 and CCL21 levels were independently associated with adverse outcomes within 3 months after ischemic stroke and should be further investigated for risk stratification and potential therapeutic targets of ischemic stroke.

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Authors:
Bizhong Che, Chongke Zhong, Jigang Du, Mengyuan Miao, Mengyao Shi, Yanbo Peng, Pinni Yang, Daoxia Guo, Jing Chen, Aili Wang, Tan Xu, Yonghong Zhang and Jiang He
Article first published online:
10 Jul 2023 | DOI: 10.1111/ene.15959

LETTER TO THE EDITOR

Inflammatory profile in mitochondrial diseases: A cohort study

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Authors:
Guido Primiano, Domenico Plantone, Geny Piro, Carmine Carbone, Andrea Sabino, Cristina Sancricca, Michela Di Nottia, Rosalba Carrozzo and Serenella Servidei
Article first published online:
16 Jul 2023 | DOI: 10.1111/ene.15962

ORIGINAL ARTICLE

Background

Cerebrovascular disease (CVD) is a major contributor to epilepsy; however, patients with epilepsy also have a significantly increased risk of stroke. The way in which epilepsy contributes to the increased risk of stroke is still uncertain and is ill‐characterized in neuropathological studies. A neuropathological characterization of cerebral small vessel disease (cSVD) in patients with chronic epilepsy was performed.

Methods

Thirty‐three patients with refractory epilepsy and hippocampal sclerosis (HS) submitted to epilepsy surgery from a reference center were selected between 2010 and 2020 and compared with 19 autopsy controls. Five randomly selected arterioles from each patient were analyzed using a previously validated scale for cSVD. The presence of CVD disease imaging markers in pre‐surgical brain magnetic resonance imaging (MRI) was studied.

Results

There were no differences in age (43.8 vs. 41.6 years;  = 0.547) or gender distribution (female gender 60.6% vs. male gender 52.6%;  = 0.575) between groups. Most CVD findings in brain MRI were mild. Patients had a mean time between the epilepsy onset and surgery of 26 ± 14.7 years and were medicated with a median number of three antiseizure medication (ASMs) [IQR 2–3]. Patients had higher median scores in arteriolosclerosis (3 vs. 1;  < 0.0001), microhemorrhages (4 vs. 1;  < 0.0001) and total score value (12 vs. 8.9;  = 0.031) in comparison with controls. No correlation was found between age, number of years until surgery, number of ASMs or cumulative defined daily dosage of ASM.

Conclusion

The present study provides evidence supporting the increased burden of cSVD in the neuropathological samples of patients with chronic epilepsy.

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Authors:
Pedro Coelho, João Madureira, Ana Franco, Ana Rita Peralta, Carla Bentes, Alexandre Rainha Campos, Jasper Anink, Eleonora Aronica, Rafael Roque and José Pimentel
Article first published online:
16 Jul 2023 | DOI: 10.1111/ene.15963

ORIGINAL ARTICLE

Background and purpose

Relying on a single biomarker for early diagnosis of Parkinson disease (PD) may not yield accurate results. We aimed to assess the combined diagnostic value of multiple biomarkers, including plasma CCL2, plasma CXCL12, and plasma neuronal exosomal α‐synuclein (α‐syn) for early stage PD diagnosis and their predictive value in PD progression.

Methods

This study included both cross‐sectional and longitudinal designs. The CCL2, CXCL12, and neuronal exosomal α‐syn levels were analyzed in 50 healthy controls (HCs) and 50 early stage PD patients. Then, a prospective follow‐up of 30 early stage PD patients was performed.

Results

In early stage PD, we observed a significant increase in CCL2, CXCL12, and plasma neuronal exosomal α‐syn compared to HCs ( < 0.05). Utilizing a combined diagnostic approach of CCL2, CXCL12, and α‐syn significantly improved the area under the curve (AUC = 0.89,  < 0.001). Spearman correlation analysis revealed that CCL2 levels were correlated with PD clinical stage and autonomic symptoms ( < 0.05). CXCL12 levels were associated with nonmotor symptoms ( < 0.05). Plasma neuronal exosomal α‐syn levels were connected to the clinical stage, motor symptoms, and nonmotor symptoms in early stage PD ( < 0.01). In the longitudinal cohort, the Cox regression analysis showed that high CCL2 levels were associated with motor progression after a mean follow‐up of 24 months.

Conclusions

Our study suggested that the combined measurement of plasma CCL2, CXCL12, and neuronal exosomal α‐syn can improve early stage PD diagnosis, and CCL2 may serve as a prognostic marker for PD progression.

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Authors:
Yang Jiao, Xue Zhu, Xinyi Zhou, Yuanyuan Li, Liche Zhou, Aonan Zhao, Ningdi Luo, Mengyue Niu and Jun Liu
Article first published online:
16 Jul 2023 | DOI: 10.1111/ene.15964

ORIGINAL ARTICLE

Background and purpose

This study was undertaken to assess the most sensitive combination of tests to detect peripersonal unilateral neglect (UN) after stroke.

Methods

The present study is a secondary analysis of a previously reported multicentric study of 203 individuals with right hemisphere damage (RHD), mainly subacute stroke, 11 weeks postonset on average, and 307 healthy controls. A battery of seven tests, providing 19 age‐ and education‐adjusted ‐scores, were given: the bells test, line bisection, figure copying, clock drawing, overlapping figures test, and reading and writing. Statistical analyses used a logistic regression and a receiver operating characteristic (ROC) curve after adjustment on demographic variables.

Results

A combination of four ‐scores based on the following three tests provided good discrimination of patients with RHD from matched healthy controls: the starting point and the difference between the number of omissions on left and right sides from the bells test, rightward deviation in bisection of long lines (20 cm), and left‐sided omissions in a reading task. The area under the ROC curve was 0.865 (95% confidence interval = 0.83–0.901), with sensitivity = 0.68, specificity = 0.95, accuracy = 0.85, positive predictive value = 0.90, and negative predictive value = 0.82.

Conclusions

The most sensitive and parsimonious combination of tests to detect UN after stroke relies on four scores from three simple tests (bells test, line bisection, and reading). Future study is warranted to assess its ability to account for the functional difficulties of UN in daily life in the patient's actual environment.

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Authors:
Philippe Azouvi, Marc Rousseaux, Paolo Bartolomeo, Dominic Pérennou, Pascale Pradat‐Diehl, Laurent Wiart, Gilles Rode, Olivier Godefroy, C. Samuel, A. Louis‐Dreyfus, T. Bernati, J.‐M. Beis, S. Chokron, M. Leclercq, F. Marchal, Y. Martin, G. de Montety, S. Olivier, C. Prairial and E. Sieroff
Article first published online:
21 Jul 2023 | DOI: 10.1111/ene.15965

SHORT COMMUNICATION

Background and purpose

Until the outbreak reported during the COVID‐19 pandemic, functional tics were considered to be a relatively rare clinical phenotype, as opposed to other functional movement disorders such as functional tremor and dystonia. To better characterize this phenotype, we compared the demographic and clinical characteristics of patients who developed functional tics during the pandemic and those of patients with other functional movement disorders.

Methods

Data from 110 patients were collected at the same neuropsychiatry centre: 66 consecutive patients who developed functional tics without other functional motor symptoms or neurodevelopmental tics and 44 patients with a mix of functional dystonia, tremor, gait, and myoclonus.

Results

Both groups were characterized by female sex preponderance (70%–80%) and (sub)acute onset of functional symptoms (~80%). However, patients with functional tics had a significantly earlier age at onset of functional symptoms (21 vs. 39 years). Exposure to relevant social media content was reported by almost half of the patients with functional tics, but by none of the patients with other functional movement disorders. Comorbidity profiles were similar, with relatively high rates of anxiety/affective symptoms and other functional neurological symptoms (nonepileptic attacks).

Conclusions

Patients who developed functional tics during the pandemic represent a phenotypic variant of the wider group of patients with functional movement disorders, associated with younger age at onset and influenced by pandemic‐related factors, including increased exposure to specific social media content. Diagnostic protocols and treatment interventions should be tailored to address the specific features of this newly defined phenotype.

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Authors:
Andrea E. Cavanna, Giulia Purpura, Anna Riva, Renata Nacinovich and Stefano Seri
Article first published online:
13 Jul 2023 | DOI: 10.1111/ene.15967

ORIGINAL ARTICLE

Background and purpose

Several risk factors of symptomatic intracerebral hemorrhage (SICH) following intravenous thrombolysis for acute ischaemic stroke have been established. However, potential predictors of good functional outcome post‐SICH have been less studied.

Methods

Patient data registered in the Safe Implementation of Treatment in Stroke—International Stroke Thrombolysis Register (SITS‐ISTR) from 2005 to 2021 were used. Acute ischaemic stroke patients who developed post intravenous thrombolysis SICH according to the SITS Monitoring Study definition were analyzed to identify predictors of functional outcomes.

Results

A total of 1679 patients with reported SICH were included, out of which only 2.8% achieved good functional outcome (modified Rankin Scale scores of 0–2), whilst 80.9% died at 3 months. Higher baseline National Institutes of Health Stroke Scale (NIHSS) score and 24‐h ΔNIHSS score were independently associated with a lower likelihood of achieving both good and excellent functional outcomes at 3 months. Baseline NIHSS and hematoma location (presence of both SICHs, defined as remote and local SICH concurrently;  = 478) were predictors of early mortality within 24 h. Independent predictors of 3‐month mortality were age, baseline NIHSS, 24‐h ΔNIHSS, admission serum glucose values and hematoma location (both SICHs). Age, baseline NIHSS score, 24‐h ΔNIHSS, hyperlipidemia, prior stroke/transient ischaemic attack, antiplatelet treatment, diastolic blood pressure at admission, glucose values on admission and SICH location (both SICHs) were associated with reduced disability at 3 months (≥1‐point reduction across all modified Rankin Scale scores). Patients with remote SICH ( = 219) and local SICH ( = 964) had comparable clinical outcomes, both before and after propensity score matching.

Conclusions

Symptomatic intracerebral hemorrhage presents an alarmingly high prevalence of adverse clinical outcomes, with no difference in clinical outcomes between remote and local SICH.

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Authors:
Georgios Tsivgoulis, Lina Palaiodimou, Maria‐Ioanna Stefanou, Aikaterini Theodorou, Janika Kõrv, Ana Paiva Nunes, Paolo Candelaresi, Elisa Dall'Ora, Payam Sariaslani, Leandro Provinciali, Adriana B. Conforto, Alan Alves de Lima Cidrao, Theodore Karapanayiotides and Niaz Ahmed
Article first published online:
14 Jul 2023 | DOI: 10.1111/ene.15968

REVIEW ARTICLE

Background

Most episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non‐paroxysmal features. EA is often caused by pathogenic variants in the , , and genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype–phenotype correlation of the different genetic EA forms.

Methods

We performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website ().

Results

Information on 717 patients (: 491, : 125, : 90, and : 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype–phenotype correlation aside from a few key ‘red flags’.

Conclusion

Given this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances.

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Authors:
Diana Angelika Olszewska, Aakash Shetty, Rajasumi Rajalingam, Jon Rodriguez‐Antiguedad, Moath Hamed, Jana Huang, Marianthi Breza, Ashar Rasheed, Natascha Bahr, Harutyan Madoev, Ana Westenberger, Joanne Trinh, Katja Lohmann, Christine Klein, Connie Marras and Olga Waln
Article first published online:
17 Jul 2023 | DOI: 10.1111/ene.15969

ORIGINAL ARTICLE

Background and purpose

Transthyretin familial amyloid polyneuropathy (TTR‐FAP) is a rare genetic disease with autosomal‐dominant inheritance. In this study, we aimed to quantify fatty infiltration (fat fraction [FF]) and magnetization transfer ratio (MTR) in individual muscles of patients with symptomatic and asymptomatic TTR‐FAP using magnetic resonance imaging. Secondarily, we aimed to assess correlations with clinical and electrophysiological variables.

Methods

A total of 39 patients with a confirmed mutation in the TTR gene (25 symptomatic and 14 asymptomatic) and 14 healthy volunteers were included. A total of 16 muscles were manually delineated in the nondominant lower limb from T1‐weighted anatomical images. The corresponding masks were propagated on the MTR and FF maps. Detailed neurological and electrophysiological examinations were conducted in each group.

Results

The MTR was decreased (42.6 AU;  = 0.001) and FF was elevated (14%;  = 0.003) in the lower limbs of the symptomatic group, with preferential posterior and lateral involvement. In the asymptomatic group, elevated FF was quantified in the gastrocnemius lateralis muscle (11%;  = 0.021). FF was significantly correlated with disease duration ( = 0.49,  = 0.015), neuropathy impairment score for the lower limb ( = 0.42,  = 0.041), Overall Neuropathy Limitations Scale score ( = 0.49,  = 0.013), polyneuropathy disability score ( = 0.57,  = 0.03) and the sum of compound muscle action potential ( = 0.52,  = 0.009). MTR was strongly correlated to FF ( = 0.78,  < 0.0001), and a few muscles with an FF within the normal range had a reduced MTR.

Conclusion

These observations suggest that FF and MTR could be interesting biomarkers in TTR‐FAP. In asymptomatic patients, FF in the gastrocnemius lateralis muscle could be a good indicator of the transition from an asymptomatic to a symptomatic form of the disease. MTR could be an early biomarker of muscle alterations.

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Authors:
Clémence Durelle, Emilien Delmont, Constance Michel, Amira Trabelsi, Marc‐Adrien Hostin, Augustin Ogier, David Bendahan and Shahram Attarian
Article first published online:
23 Jul 2023 | DOI: 10.1111/ene.15970

SHORT COMMUNICATION

Background and purpose

Different algorithms aiming to identify individuals at risk of Parkinson disease (PD) have been proposed. Comparative studies of these scores and their recent updates in the general elder population are needed.

Methods

We have previously applied the “basic” PREDICT‐PD algorithm, designed for remote screening, and the original and updated Movement Disorder Society (MDS) criteria for prodromal PD to the longitudinal population‐based Bruneck study cohort. We have now additionally employed the “enhanced” PREDICT‐PD algorithm (which includes motor assessment, olfaction, probable rapid eye movement sleep behaviour disorder status, pesticide exposure, and diabetes as additional factors). Risk scores were calculated based on comprehensive baseline assessments (2005) in 574 subjects aged 55–94 years (290 females), and cases of incident PD were identified at 5‐year ( = 11) and 10‐year follow‐up ( = 9). We analysed the association of the different log‐transformed risk scores with incident PD at follow‐up (calculated per 1‐SD unit change).

Results

The enhanced PREDICT‐PD algorithm was associated with incident PD over 10‐years of follow‐up, yielding higher odds for incident PD (odds ratio [OR] = 4.61, 95% confidence interval [CI] = 2.68–7.93,  < 0.001) compared with the basic PREDICT‐PD score (OR = 2.38, 95% CI = 1.49–3.79,  < 0.001). The updated MDS prodromal criteria yielded a numerically higher OR of 7.13 (95% CI = 3.49–14.54,  < 0.001) in comparison with the original criteria as well as the enhanced PREDICT‐PD algorithm, with overlapping 95% CIs.

Conclusions

The enhanced PREDICT‐PD algorithm was significantly associated with incident PD. The consistent performance of both the enhanced PREDICT‐PD algorithm and the updated MDS prodromal criteria compared to their original versions supports their use in PD risk screening.

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Authors:
Kathrin Marini, Klaus Seppi, Stefan Kiechl, Heike Stockner, Peter Willeit, Johann Willeit, Atbin Djamshidian, Gregorio Rungger, Werner Poewe and Philipp Mahlknecht
Article first published online:
16 Jul 2023 | DOI: 10.1111/ene.15971

ORIGINAL ARTICLE

Background and purpose

Dystonia is a heterogeneous movement disorder, and it remains unclear whether neurodegeneration is involved. Neurofilament light chain (NfL) is a biosignature of neurodegeneration. We aimed to investigate whether plasma NfL levels were elevated and associated with disease severity in patients with dystonia.

Method

We enrolled 231 unrelated dystonia patients (isolated dystonia  = 203; combined dystonia  = 28) and 54 healthy controls from movement disorder clinics. Clinical severity was evaluated using the Fahn Marsden Dystonia Rating Scale, the Unified Dystonia Rating Scale, and the Global Dystonia Rating Scale. Blood NfL levels were measured by single‐molecule array.

Results

Plasma NfL levels were significantly higher in those with generalized dystonia compared to those with focal dystonia (20.1 ± 8.8 vs. 11.7 ± 7.2 pg/mL;  = 0.01) or controls ( < 0.01), while the level was comparable between the focal dystonia group and controls ( = 0.08). Furthermore, the dystonia combined with parkinsonism group had higher NfL levels than the isolated dystonia group (17.4 ± 6.2 vs. 13.5 ± 7.5 pg/mL;  = 0.04). Notably, whole‐exome sequencing was performed in 79 patients and two patients were identified as having likely pathogenic variants: one had a heterozygous c.122G>A (p.R41H) variant in (DYT6) and the other carried a c.1825G>A (p.D609N) substitution in (DYT12). No significant correlation was found between plasma NfL levels and dystonia rating scores.

Conclusion

Plasma NfL levels are elevated in patients with generalized dystonia and dystonia combined with parkinsonism, suggesting that neurodegeneration is involved in the disease process of this subgroup of patients.

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Authors:
Meng‐Chen Wu, Yung‐Yee Chang, Min‐Yu Lan, Ying‐Fa Chen, Chun‐Hwei Tai, Szu‐Ju Chen and Chin‐Hsien Lin
Article first published online:
16 Jul 2023 | DOI: 10.1111/ene.15972

ORIGINAL ARTICLE

Background and purpose

Haploinsufficiency of TANK‐binding kinase 1 () loss‐of‐function (LoF) variants has been shown to be pathogenic in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the genetic spectrum of and clinical features of ALS patients with variants remain largely unknown in Asians.

Methods

Genetic analysis was performed on 2011 Chinese ALS patients. Software was used to predict the deleteriousness of missense variants in . In addition, PubMed, Embase and Web of Science were searched for related literature.

Results

Twenty‐six variants were identified in 33 of 2011 ALS patients, including six novel LoF variants (0.3%) and 20 rare missense variants, 12 of which were predicted to be deleterious (0.6%). In addition to variants, 11 patients had other ALS‐related gene variants. Forty‐two previous studies found that the frequency of variants was 1.81% in ALS/FTD patients. The frequency of LoF variants in ALS was 0.5% (Asians 0.4%; Caucasian 0.6%) and that of missense variants was 0.8% (Asians 1.0%; Caucasian 0.8%). ALS patients with LoF variants affecting the kinase domain had a significantly younger age of onset than patients carrying LoF variants affecting the coiled coil domains CCD1 and CCD2. FTD has a frequency of 10% in Caucasian ALS patients with LoF variants, which was not found in our cohort.

Conclusion

Our study expanded the genotypic spectrum of ALS patients with variants and found that the clinical manifestations of carriers are diverse.

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Authors:
Bi Zhao, Qirui Jiang, Junyu Lin, Qianqian Wei, Chunyu Li, Yanbing Hou, Bei Cao, Lingyu Zhang, Ruwei Ou, Kuncheng Liu, Tianmi Yang, Yi Xiao and Huifang Shang
Article first published online:
18 Jul 2023 | DOI: 10.1111/ene.15973

ORIGINAL ARTICLE

Background and purpose

Transcranial direct current stimulation (tDCS) has been shown to improve signs of consciousness in a subset of patients with disorders of consciousness (DoC). However, no multicentre study confirmed its efficacy when applied during rehabilitation. In this randomized controlled double‐blind study, the effects of tDCS whilst patients were in rehabilitation were tested at the group level and according to their diagnosis and aetiology to better target DoC patients who might repond to tDCS.

Methods

Patients received 2 mA tDCS or sham applied over the left prefrontal cortex for 4 weeks. Behavioural assessments were performed weekly and up to 3 months’ follow‐up. Analyses were conducted at the group and subgroup levels based on the diagnosis (minimally conscious state [MCS] and unresponsive wakefulness syndrome) and the aetiology (traumatic or non‐traumatic). Interim analyses were planned to continue or stop the trial.

Results

The trial was stopped for futility when 62 patients from 10 centres were enrolled (44 ± 14 years, 37 ± 24.5 weeks post‐injury, 18 women, 32 MCS, 39 non‐traumatic). Whilst, at the group level, no treatment effect was found, the subgroup analyses at 3 months’ follow‐up revealed a significant improvement for patients in MCS and with traumatic aetiology.

Conclusions

Transcranial direct current stimulation during rehabilitation does not seem to enhance patients' recovery. However, diagnosis and aetiology appear to be important factors leading to a response to the treatment. These findings bring novel insights into possible cortical plasticity changes in DoC patients given these differential results according to the subgroups of patients.

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Authors:
Aurore Thibaut, Felipe Fregni, Anna Estraneo, Salvatore Fiorenza, Enrique Noe, Roberto Llorens, Joan Ferri, Rita Formisano, Giovanni Morone, Andreas Bender, Martin Rosenfelder, Gianfranco Lamberti, Ekaterina Kodratyeva, Sergey Kondratyev, Liudmila Legostaeva, Natalia Suponeva, Carmen Krewer, Friedemann Müller, Nadia Dardenne, Haroun Jedidi, Steven Laureys, Olivia Gosseries, Nicolas Lejeune and Géraldine Martens
Article first published online:
28 Jul 2023 | DOI: 10.1111/ene.15974

SHORT COMMUNICATION

Background

Pathogenic variants in the GAP activity towards RAGs 1 (GATOR1) complex genes (, , ) cause focal epilepsy through hyperactivation of the mechanistic target of rapamycin pathway. We report our experience using everolimus in patients with refractory GATOR1‐related epilepsy.

Methods

We performed an open‐label observational study of everolimus for drug‐resistant epilepsy caused by variants in and . Everolimus was titrated to a target serum concentration (5–15 ng/mL). The primary outcome measure was change in mean monthly seizure frequency compared with baseline.

Results

Five patients were treated with everolimus. All had highly active (median baseline seizure frequency, 18/month) and refractory focal epilepsy (failed 5–16 prior anti‐seizure medications). Four had variants (three loss‐of‐function, one missense) and one had a splice‐site variant. All patients with loss‐of‐function variants had significantly reduced seizures (74.3%–86.1%), although one stopped everolimus after 12 months due to psychiatric symptoms. Everolimus was less effective in the patient with a missense variant (43.9% seizure frequency reduction). The patient with ‐related epilepsy had seizure worsening. The most common adverse event was stomatitis.

Conclusions

Our study provides the first human data on the potential benefit of everolimus precision therapy for epilepsy caused by loss‐of‐function variants Further studies are needed to support our findings.

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Authors:
Patrick B. Moloney, Hugh Kearney, Katherine A. Benson, Daniel J. Costello, Gianpiero L. Cavalleri, Kathleen M. Gorman, Bryan J. Lynch and Norman Delanty
Article first published online:
07 Aug 2023 | DOI: 10.1111/ene.15975

ORIGINAL ARTICLE

Background and purpose

Previous studies in neurological emergency rooms (nERs) have reported many non‐acute, self‐presenting patients, patients with delayed presentation of stroke, and frequent visits of persons with seizures (PWS). The aim of this study was to evaluate trends during the last decade, with special focus on PWS.

Methods

We retrospectively analyzed patients who presented to our specialized nER during the course of 5 months in 2017 and 2019, and included information on admission/referral, hospitalization, discharge diagnosis, and diagnostic tests/treatment in the nER.

Results

A total of 2791 patients (46.6% male, mean age 57 ± 21 years) were included. The most common diagnoses were cerebrovascular events (26.3%), headache (14.1%), and seizures (10.5%). Most patients presented with symptoms lasting >48 h (41.3%). The PWS group included the largest proportion of patients presenting within 4.5 h of symptom onset (171/293, 58.4%), whereas only 37.1% of stroke patients presented within this time frame (273/735). Self‐presentation was the most common admission pathway (31.1%), followed by emergency service referral (30.4%, including the majority of PWS: 197/293, 67.2%). Despite known diagnosis of epilepsy in 49.2%, PWS more often underwent accessory diagnostic testing including cerebral imaging, compared to the overall cohort (accessory diagnostics 93.9% vs. 85.4%; cerebral imaging 70.1% vs. 64.1%). Electroencephalography in the nER was only performed in 20/111 patients (18.0%) with a first seizure. Nearly half of the patients (46.7%) were discharged home after nER work‐up, including most self‐presenters (632/869, 72.7%) and headache patients (377/393, 88.3%), as well as 37.2% (109/293) of PWS.

Conclusion

After 10 years, nER overuse remains a problem. Stroke patients still do not present early enough, whereas PWS, even those with known epilepsy, often seek acute and extensive assessment, indicating gaps in pre‐hospital management and possible over‐assessment.

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Authors:
Tamara M. Welte, Sebastian Ernst, Jenny Stritzelberger, Stephanie Gollwitzer, Johannes D. Lang, Caroline Reindl, Maximilian I. Sprügel, David Olmes, Stefan Schwab, Christian Blinzler and Hajo M. Hamer
Article first published online:
21 Jul 2023 | DOI: 10.1111/ene.15976

ORIGINAL ARTICLE

Background and purpose

Patients with idiopathic trigeminal neuralgia (TN) with absent arterial contact or venous contact only and classic TN with morphological changes of the trigeminal nerve secondary to venous compression are not routinely recommended microvascular decompression at our institution. In patients with these anatomical subtypes of TN, limited data exists describing the outcomes of percutaneous glycerol rhizolysis (PGR) of the trigeminal ganglion (TG).

Methods

We performed a retrospective single‐center cohort study and analyzed outcomes and complications after PGR of the TG. Clinical outcome after PGR of the TG was assessed via the Barrow Neurological Institute (BNI) Pain Scale.

Results

Forty‐five patients underwent a total of 66 PGRs of the TG. At short‐term follow‐up, 58 procedures (87.9%) resulted in a BNI score of I (i.e., freedom from pain without medication). At a median follow‐up of 3.07 years, 18 procedures (27.3%) resulted in a BNI score of I, 12 procedures (18.1%) resulted in BNI score of IIIa, and 36 procedures (54.5%) resulted in a BNI score of IIIb‐V. The median length of freedom from pain without medication was 1.5 years. Eighteen procedures (27.3%) caused hypesthesia and two (3.0%) caused paresthesias. There were no serious complications.

Conclusion

In patients with these anatomical subtypes of TN there was a high rate of short‐term pain relief for the first 1–2 years and thereafter a large proportion of patients experienced pain relapse. In this patient group, PGR of the TG represents a safe procedure that is efficacious in the short term.

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Authors:
Raviteja Bethamcharla, Hussam Abou‐Al‐Shaar, Stine Maarbjerg, Yue‐Fang Chang, Caroline N. Gacka and Raymond F. Sekula
Article first published online:
18 Jul 2023 | DOI: 10.1111/ene.15977

ORIGINAL ARTICLE

Background and purpose

Our aim was to examine the correlation between biomarkers of neuronal and glial cell damage and severity of disease in patients with tick‐borne encephalitis.

Methods

One hundred and fifteen patients with tick‐borne encephalitis diagnosed in Lithuania and Sweden were prospectively included, and cerebrospinal fluid (CSF) and serum samples were obtained shortly after hospitalization. Using pre‐defined criteria, cases were classified as mild, moderate or severe tick‐borne encephalitis. Additionally, the presence of spinal nerve paralysis (myelitis) and/or cranial nerve affection were noted. Concentrations of the brain cell biomarkers glial fibrillary acidic protein (GFAP), YKL‐40, S100B, neurogranin, neurofilament light (NfL) and tau were analysed in CSF and, in addition, NfL, GFAP and S100B levels were measured in serum. The Jonckheere‐Terpstra test was used for group comparisons of continuous variables and Spearman's partial correlation test was used to adjust for age.

Results

Cerebrospinal fluid and serum concentrations of GFAP and NfL correlated with disease severity, independent of age, and with the presence of nerve paralysis. The markers neurogranin, YKL‐40, tau and S100B in CSF and S100B in serum were detected, but their concentrations did not correlate with disease severity.

Conclusions

Neuronal cell damage and astroglial cell activation with increased NfL and GFAP in CSF and serum were associated with a more severe disease, independent of age. Increased GFAP and NfL concentrations in CSF and NfL in serum were also indicative of spinal and/or cranial nerve damage. NfL and GFAP are promising prognostic biomarkers in tick‐borne encephalitis, and future studies should focus on determining the association between these biomarkers and long‐term sequelae.

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Authors:
Malin Veje, Vytautas Griška, Jolita Pakalnienė, Auksė Mickienė, Daniel Bremell, Henrik Zetterberg, Kaj Blennow, Lars Lindquist and Marie Studahl
Article first published online:
23 Jul 2023 | DOI: 10.1111/ene.15978

ORIGINAL ARTICLE

Background and purpose

Meningiomas are the most common primary tumours of the central nervous system. This study aimed to provide comprehensive nationwide estimates on the incidence, prevalence and prognostic impact of meningioma diagnosis in the Netherlands.

Methods

Adult patients diagnosed with meningioma in 2000–2019 were selected from the Dutch Brain Tumour Registry (DBTR), part of the Netherlands Cancer Registry (NCR). Time trends in age‐adjusted incidence and prevalence rates were evaluated using the estimated annual percentage change (EAPC). Relative survival rates were calculated using the Pohar Perme estimator. Case completeness of the DBTR/NCR was estimated through record linkage with one of the Dutch neuro‐oncology centres.

Results

From a total of 23,454 cases of meningioma, 11,306 (48.2%) were histologically confirmed and 12,148 (51.8%) were radiological diagnoses. Over time, the incidence of diagnosis increased from 46.9 per 1,000,000 inhabitants (European Standardized Rate [ESR]) to 107.3 (EAPC 4.7%,  < 0.01), with an increase in the incidence of radiological diagnoses from 14.0 to 70.2 per 1,000,000 ESR (EAPC 9.1%,  < 0.01). The prevalence of meningioma was estimated at 1012/1,000,000 on 1 January 2020, with almost 17,800 individuals having had a diagnosis of meningioma. Relative survival rate at 10 years for grade 1 meningiomas was 91.0% (95% confidence interval [CI] 89.4%–92.3%), 71.3% (95% CI 66.8%–75.2%) for grade 2 meningiomas and 36.4% (95% CI 27.3%–45.6%) for grade 3 meningiomas. Local case completeness was estimated at 97.6% for histologically confirmed meningiomas and 84.5% for radiological diagnoses.

Conclusion

With a near‐complete registry, meningioma prevalence was estimated at over 1000 per 1,000,000 inhabitants.

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Authors:
Vincent K. Y. Ho, Monique M. Anten, Anniek Garst, Eelke M. Bos, Tom J. Snijders, Daniëlle B. P. Eekers and Tatjana Seute
Article first published online:
21 Jul 2023 | DOI: 10.1111/ene.15979

ORIGINAL ARTICLE

Background and purpose

Modifiable lifestyle factors, including diet, have been implicated in multiple sclerosis (MS) progression, but prospective evidence is limited. The aim of this study was to examine prospective relationships between quality of diet and subsequent disability over 7.5 years in an international cohort of people living with MS (pwMS).

Methods

Data from 602 participants in the HOLISM (Health Outcomes and Lifestyle In a Sample of people with Multiple sclerosis) study were analysed. Quality of diet was assessed using the modified Diet Habits Questionnaire (DHQ). Disability was assessed using the Patient‐determined MS Severity Score (P‐MSSS). Characteristics of disability were assessed by log‐binomial, log‐multinomial and linear regression, adjusted for demographic and clinical covariates, as appropriate.

Results

Higher baseline total DHQ scores (>80–89, >89%) were associated with lower risks of increased P‐MSSS at 7.5 years (adjusted risk ratio [aRR] 0.46, 95% confidence interval [CI] 0.23, 0.91 and aRR 0.48, 95% CI 0.26, 0.89, respectively), and with less P‐MSSS accrual (aβ = −0.38, 95% CI −0.78, 0.01 and aβ = −0.44, 95% CI −0.81, −0.06). Of the DHQ domains, fat subscore was most strongly associated with subsequent disability. Participants with reducing baseline‐to‐2.5‐ years total DHQ scores had greater risk of increased P‐MSSS at 7.5 years (aRR 2.77, 95% CI 1.18, 6.53) and higher P‐MSSS accrual (aβ = 0.30, 95% CI 0.01, 0.60). Participants reporting baseline meat and dairy consumption had greater risk of increased P‐MSSS at 7.5 years (aRR 2.06, 95% CI 1.23, 3.45 and aRR 2.02, 95% CI 1.25, 3.25) and higher P‐MSSS accrual (aβ = 0.28, 95% CI 0.02, 0.54 and aβ = 0.43, 95% CI 0.16, 0.69, respectively). However, reported meat consumption was confounded by quality of diet. Changes in meat or dairy consumption from baseline were inconsistently associated with subsequent disability.

Conclusions

We show for the first time robust long‐term associations between quality of diet and subsequent disability progression in pwMS. Subject to replication, dietary modification may represent a point of intervention for reducing disability in pwMS.

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Authors:
Steve Simpson‐Yap, Sandra L. Neate, Nupur Nag, Yasmine C. Probst, Maggie Yu, George A. Jelinek and Jeanette C. Reece
Article first published online:
20 Jul 2023 | DOI: 10.1111/ene.15980

ORIGINAL ARTICLE

Background and purpose

Idiopathic normal pressure hydrocephalus (iNPH) is a potentially treatable disorder, but prognostic tests or biomarkers are lacking. The aim was to study the predictive power of clinical, neuroimaging and lumbar infusion test parameters (resistance to outflow , cardiac‐related pulse amplitude PA and the PA to intracranial pressure ICP ratio).

Methods

In all, 127 patients diagnosed with iNPH who had a lumbar infusion test, a subsequent ventriculo‐peritoneal shunt operation and at least 2 months of postoperative follow‐up were retrospectively included. Preoperative magnetic resonance images were visually scored for NPH features using the iNPH Radscale. Preoperative and postoperative assessment was performed using cognitive testing, as well as gait and incontinence scales.

Results

At follow‐up (7.4 months, range 2–20 months), an overall positive response was seen in 82% of the patients. Gait was more severely impaired at baseline in responders compared to non‐responders. The iNPH Radscale score was borderline significantly higher in responders compared with non‐responders, whereas no significant differences in infusion test parameters were seen between responders and non‐responders. Infusion test parameters performed modestly with high positive (75%–92%) but low negative (17%–23%) predictive values. Although not significant, PA and PA/ICP seemed to perform better than , and the odds ratio for shunt response seemed to increase in patients with higher PA/ICP, especially in patients with lower iNPH Radscale scores.

Conclusion

Although only indicative, lumbar infusion test results increased the likelihood of a positive shunt outcome. Pulse amplitude measures showed promising results that should be further explored in prospective studies.

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Authors:
Steen Gregers Hasselbalch, Jonathan Frederik Carlsen, Mohamed Moussa Alaouie, Tina Nørgaard Munch, Anders Vedel Holst, Sarah Taudorf, Christina Rørvig‐Løppentien, Marianne Juhler and Gunhild Waldemar
Article first published online:
20 Jul 2023 | DOI: 10.1111/ene.15981

CASE REPORT

Background and purpose

Defects in the mitochondrial respiratory chain (MRC) can lead to combined MRC dysfunctions (COXPDs) with heterogenous genotypes and clinical features. We report a patient carrying heterozygous variants in the gene who presented with clinical features compatible with COXPD4 and radiological findings mimicking multiple sclerosis (MS).

Methods

A 37‐year‐old French Canadian woman was investigated for recent onset of gait and balance problems. Her previous medical history included recurrent episodes of hyperventilation associated with lactic acidosis during infections, asymptomatic Wolff–Parkinson–White syndrome, and nonprogressive sensorineural deafness.

Results

Neurological examinations revealed fine bilateral nystagmus, facial weakness, hypertonia, hyperreflexia, dysdiadochokinesia, dysmetria, and ataxic gait. Brain magnetic resonance imaging (MRI) showed multifocal white matter abnormalities in cerebral white matter as well as cerebellar hemispheres, brainstem, and middle cerebellar peduncles, some of which mimicked MS. Analysis of native‐state oxidative phosphorylation showed a combined decrease in CI/CII, CIV/CII, and CVI/CII. Exome sequencing detected two heterozygous gene variants. Little clinical progression was noted over a 5‐year follow‐up. Brain MRI remained unchanged.

Conclusions

Our report broadens the phenotypic and radiological spectrum of ‐related disorders by adding milder, later onset forms to the previously known early onset, severe presentations. The presence of multifocal white matter abnormalities can be misinterpreted as due to acquired demyelinating diseases, and thus ‐related disorders should be added to the list of mitochondrial MS mimickers.

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Authors:
Shihan Chen, Grant A. Mitchell, Jean‐Francois Soucy, Julie Gauthier, Bernard Brais and Roberta La Piana
Article first published online:
19 Jul 2023 | DOI: 10.1111/ene.15982

REVIEW ARTICLE

Background

Differentiating neuromyelitis optica spectrum disorder (NMOSD) from its mimics is crucial to avoid misdiagnosis, especially in the absence of aquaporin‐4‐IgG. While multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein‐IgG associated disease (MOGAD) represent major and well‐defined differential diagnoses, non‐demyelinating NMOSD mimics remain poorly characterized.

Methods

We conducted a systematic review on PubMed/MEDLINE to identify reports of patients with non‐demyelinating disorders that mimicked or were misdiagnosed as NMOSD. Three novel cases seen at the authors' institutions were also included. The characteristics of NMOSD mimics were analyzed and red flags associated with misdiagnosis identified.

Results

A total of 68 patients were included; 35 (52%) were female. Median age at symptoms onset was 44 (range, 1–78) years. Fifty‐six (82%) patients did not fulfil the 2015 NMOSD diagnostic criteria. The clinical syndromes misinterpreted for NMOSD were myelopathy (41%), myelopathy + optic neuropathy (41%), optic neuropathy (6%), or other (12%). Alternative etiologies included genetic/metabolic disorders, neoplasms, infections, vascular disorders, spondylosis, and other immune‐mediated disorders. Common red flags associated with misdiagnosis were lack of cerebrospinal fluid (CSF) pleocytosis (57%), lack of response to immunotherapy (55%), progressive disease course (54%), and lack of magnetic resonance imaging gadolinium enhancement (31%). Aquaporin‐4‐IgG positivity was detected in five patients by enzyme‐linked immunosorbent assay ( = 2), cell‐based assay ( = 2: serum, 1; CSF, 1), and non‐specified assay ( = 1).

Conclusions

The spectrum of NMOSD mimics is broad. Misdiagnosis frequently results from incorrect application of diagnostic criteria, in patients with multiple identifiable red flags. False aquaporin‐4‐IgG positivity, generally from nonspecific testing assays, may rarely contribute to misdiagnosis.

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Authors:
Pietro Zara, Alessandro Dinoto, Sara Carta, Valentina Floris, Davide Turilli, Adrian Budhram, Sergio Ferrari, Stefania Milia, Paolo Solla, Sara Mariotto, Eoin P. Flanagan, A. Sebastian Lopez Chiriboga and Elia Sechi
Article first published online:
19 Jul 2023 | DOI: 10.1111/ene.15983

COMMENTARY

Toward a serum biomarker of disease activity in Susac syndrome

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Authors:
Todd A. Hardy
Article first published online:
24 Jul 2023 | DOI: 10.1111/ene.15984

ORIGINAL ARTICLE

Background and purpose

The development of high‐resolution magnetic resonance imaging (HR‐MRI) has enabled submillimeter‐level evaluation of intracranial artery plaque and luminal thrombus. We sought to investigate the value of HR‐MRI in assessing the pathogenesis of acute intracranial artery thrombus.

Methods

We examined the presence of intracranial thrombus on three‐dimensional T1‐weighted HR‐MRI in acute ischemic stroke patients with intracranial artery occlusion on magnetic resonance angiography. We defined two thrombus‐related HR‐MRI features (peri‐thrombus plaque and distal residual flow beyond the thrombus) and analyzed their association with potential embolic sources.

Results

Luminal thrombus and a shrunken artery without luminal thrombus were detected in 162 (96.4%) and six (3.6%) of 168 patients with intracranial artery occlusion, respectively. Among 111 patients with culprit major artery thrombus, peri‐thrombus plaques were observed in 46.8% and distal residual flow beyond the thrombus in 64.0%. Patients with peri‐thrombus plaque had a higher prevalence of diabetes (44.2% vs. 25.4%;  = 0.037), a lower prevalence of potential sources of cardioembolism (0% vs. 16.9%;  = 0.002), and a nonsignificantly lower prevalence of potential embolic sources from extracranial arteries (9.6% vs. 20.3%;  = 0.186) than those without. Patients with distal residual flow beyond the thrombus had a lower prevalence of potential sources of cardioembolism (1.4% vs. 22.5%;  < 0.001) and smaller infarct volumes (5.0 [1.4–12.7] mL vs. 16.6 [2.4–94.6] mL;  = 0.012) than those without.

Conclusions

Our study showed that HR‐MRI helps clarify the pathogenesis of acute intracranial artery thrombus. The presence of peri‐thrombus plaque and distal residual flow beyond the thrombus favor the stroke mechanism of atherosclerosis rather than cardioembolism.

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Authors:
Zong‐Mu‐Yu Zhang, Qian‐Qian Si, Hui‐Sheng Chen, Yi Yang, Meng Zhang, Shi‐Wen Wu, Yao Meng, Ming‐Li Li, Qian‐Qian Lin, David S. Liebeskind, Yi‐Ning Huang and Wei‐Hai Xu
Article first published online:
07 Aug 2023 | DOI: 10.1111/ene.15985

ORIGINAL ARTICLE

Background and purpose

In idiopathic intracranial hypertension (IIH), magnetic resonance imaging (MRI) features are promising diagnostic markers, but the impact of rater experience and the specific referral question is unknown.

Methods

From the Vienna Idiopathic Intracranial Hypertension database, patients were included with definitive IIH and routine cranial MRI performed during diagnostic work‐up. Frequencies of partial empty sella (ES), optic nerve sheath distension (ONSD), optic nerve tortuosity (ONT), posterior globe flattening (PGF) and transverse sinus stenosis (TSS) were compared in three settings: (i) real‐world rating, (ii) junior neuroradiologist without special IIH training and (iii) senior neuroradiologist with experience in IIH imaging (gold standard).

Results

Magnetic resonance imaging scans of 84 IIH patients (88% female, mean age 33.5 years) were evaluated. By gold standard, ONSD was the most frequent (64.3%) followed by TSS (60.0%), ONT (46.4%), ES (44.4%) and PGF (23.8%). Compared to the gold standard, IIH features were described significantly less frequently in routine MRI reports (ONSD 28.6%, ONT 13.1%, PGF 4.8%, TSS 42.9%,  < 0.01 respectively) except for ES (42.9%,  = 0.9). A specific referral question regarding IIH increased detection rates in routine reports, but rates remained significantly lower than by gold standard. In contrast, a rating by a neuroradiologist without special training produced significantly higher frequencies of ONSD (81.0%,  < 0.01) and ONT (60.7%,  < 0.01) but not of ES (47.6%), PGF (29.8%) and TSS (68.1%).

Conclusions

Idiopathic intracranial hypertension MRI features are underestimated in routine MRI reports and partly overcalled by less experienced neuroradiologists, driven by features less well known or methodologically difficult. Reevaluation of MRI scans by an experienced rater (and to a lesser degree a specific referral question) improves diagnostic accuracy.

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Authors:
Gabriel Bsteh, Wolfgang Marik, Stefan Macher, Victor Schmidbauer, Nik Krajnc, Philip Pruckner, Christoph Mitsch, Klaus Novak, Christian Wöber and Berthold Pemp
Article first published online:
27 Jul 2023 | DOI: 10.1111/ene.15986

ORIGINAL ARTICLE

Background and purpose

‐methyl‐‐aspartate receptor (NMDAR) and leucine‐rich glioma‐inactivated protein 1 (LGI1) encephalitis are important types of autoimmune encephalitis (AE) with significant morbidity. In this study, we used a proteomic approach in search of novel clinically relevant biomarkers in these types of encephalitides.

Methods

Swedish and Czech tertiary neuroimmunology centers collaborated in this retrospective exploratory study. Fifty‐eight cerebrospinal fluid (CSF) samples of 28 patients with AE (14 definite NMDAR, 14 with definite LGI1 encephalitis) and 30 controls were included. CSF samples were analyzed using proximity extension assay technology (Olink Target 96 Inflammation panel). For each CSF sample, 92 proteins were measured. Clinical variables were retrospectively collected, and correlations with protein levels were statistically analyzed.

Results

Patients and controls differed significantly in the following 18 biomarkers: TNFRSF9, TNFRSF12, TNFRSF14, TNFβ, TNFα, IL7, IL10, IL12B, IFNγ, CD5, CD6, CASP8, MMP1, CXCL8, CXCL10, CXCL11, IL20RA, and sirtuin 2 (SIRT2). In LGI1 encephalitis, no clinically useful association was found between biomarkers and clinical variables. In the NMDAR encephalitis group, SIRT2, TNFβ, and CD5 were significantly associated with ovarian teratoma. For SIRT2, this was true even for the first patients' CSF sample (SIRT2 without vs. with tumor, mean ± SD = 2.2 ± 0.29 vs. 2.88 ± 0.48;  = 0.007, 95% confidence interval = −1.15 to −0.22; r statistic in point‐biserial correlation (rpb) = 0.66,  = 0.011). SIRT2 was positively correlated with age (rpb = 0.39,  = 0.018) and total hospital days ( = 0.55,  = <0.001).

Conclusions

SIRT2 should be investigated as a biomarker of paraneoplastic etiology in NMDAR encephalitis.

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Authors:
Oskar Stevens‐Jones, Hana Mojzisova, Martin Elisak, Radu Constantinescu, Jitka Hanzalova, Markus Axelsson and David Krysl
Article first published online:
02 Aug 2023 | DOI: 10.1111/ene.15987

SHORT COMMUNICATION

Introduction

Progressive multifocal leukoencephalopathy is a rare but often fatal complication of some multiple sclerosis treatments. Although it has mainly been associated with natalizumab treatment, its appearance with other immunosuppressive therapies has also been reported.

Aims

The aim of this case report is to describe the development of progressive multifocal encephalopathy in a patient with relapsing–remitting multiple sclerosis treated with ocrelizumab without previous use of natalizumab.

Conclusions

A summary of the presentation and disease course is provided, presented in the context of the current literature and likely pathophysiology.

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Authors:
Marc Puig‐Casadevall, Gary Álvarez‐Bravo, Ana Quiroga Varela, René Robles‐Cedeño, Laura Sànchez Cirera, Albert Miguela, Gemma Laguillo, Xavier Montalban, Stephen L. Hauser and Lluis Ramió‐Torrentà
Article first published online:
31 Jul 2023 | DOI: 10.1111/ene.15988

SHORT COMMUNICATION

Background and purpose

It is still debated whether the COVID‐19 pandemic affected disease activity in people with autoimmune diseases, including multiple sclerosis (MS). The aim of this study, therefore, was to explore the impact of COVID‐19 in people with MS (pwMS) not receiving continuative disease‐modifying therapy (DMT) after previous treatment with autologous hematopoietic stem cell transplantation (AHSCT).

Materials and methods

We included pwMS treated with AHSCT who were in disease remission without receiving DMTs during the pandemic and who were followed up at our centre during the study period. Data on SARS‐CoV‐2 infection and vaccination were recorded, with details of adverse events and clinical‐radiological disease activity.

Results

A total of 36 pwMS (31 females; 86%) were included, of whom 23 (64%) had relapsing‐remitting (RR‐MS) and 13 had secondary progressive MS (SP‐MS). Thirty‐three pwMS (92%) received anti‐SARS‐CoV‐2 mRNA vaccines. Thirteen patients (36%) developed mild to moderate COVID‐19 a median (range) of 58 (4–224) months after AHSCT; seven (54%) of these patients were not yet vaccinated. Transient neurological symptoms after vaccination or infection were reported in 9% and 36% of the patients, respectively. The rate of new inflammatory events (relapses or asymptomatic magnetic resonance imaging [MRI] activity) after AHSCT increased from 0.006 (one asymptomatic new lesion/159 patient‐years) before the pandemic to 0.083 (five relapses plus two cases of asymptomatic MRI activity/84 patient‐years) since the pandemic start ( = 0.004).

Conclusions

People with MS with a history of highly active disease, who are untreated or receiving moderate‐efficacy DMTs might be more vulnerable to disease reactivation, possibly elicited by exogenous triggers. Careful monitoring and further investigation are warranted to ascertain whether special precautions are needed in these cases.

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Authors:
Alice Mariottini, Antonio Lotti, Chiara Innocenti, Anna Maria Repice, Chiara Nozzoli, Riccardo Boncompagni, Enrico Fainardi, Riccardo Saccardi and Luca Massacesi
Article first published online:
02 Aug 2023 | DOI: 10.1111/ene.15989

ORIGINAL ARTICLE

Background and purpose

Motor fluctuations are a significant driver of healthcare resource utilization (HCRU) in people with Parkinson's disease (pwPD). A common management strategy is to include catechol‐O‐methyltransferase (COMT) inhibition with either opicapone or entacapone in the levodopa regimen. However, to date, there has been a lack of head‐to‐head data comparing the two COMT inhibitors in real‐world settings. The aim of this study was to evaluate changes in HCRU and effect on sleep medications when opicapone was initiated as first COMT inhibitor versus entacapone.

Methods

In this retrospective cohort study, we assessed HCRU outcomes in pwPD naïve to COMT inhibition via UK electronic healthcare records (Clinical Practice Research Datalink and Hospital Episodes Statistics databases, June 2016 to December 2019). HCRU outcomes were assessed before (baseline) and after COMT inhibitor prescription at 0–6 months, 7–12 months and 13–18 months. Opicapone‐treated pwPD were algorithm‐matched (1:4) to entacapone‐treated pwPD.

Results

By 6 months, treatment with opicapone resulted in 18.5% fewer neurology outpatient visits compared to entacapone treatment; this effect was maintained until the last follow‐up (18 months). In the opicapone group, the mean levodopa equivalent daily dose decreased over the first year and then stabilized, whereas the entacapone‐treated group showed an initial decrease in the first 6 months followed by a dose increase between 7 and 18 months. Neither COMT inhibitor had a significant impact on sleep medication use.

Conclusions

This head‐to‐head study is the first to demonstrate, using ‘real‐world’ data, that initiating COMT inhibition with opicapone is likely to decrease the need for post‐treatment HCRU versus initiation of COMT inhibition with entacapone.

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Authors:
Glynn Harrison‐Jones, Xiaocong Li Marston, Francesca Morgante, K. Ray Chaudhuri, Guillermo Castilla‐Fernández and Valentina Di Foggia
Article first published online:
19 Aug 2023 | DOI: 10.1111/ene.15990

ORIGINAL ARTICLE

Background and purpose

Migraine aura, near‐death experiences (NDEs), and rapid eye movement (REM) sleep intrusions might share common mechanisms. Here, we investigated the prevalence of NDEs and REM sleep intrusions in people with migraine. We hypothesized that NDEs and REM sleep intrusions are more prevalent in migraine patients with aura than in those without.

Methods

We conducted a prospective cross‐sectional cohort study at a tertiary headache center, based on a prespecified sample size ( = 808). Migraine patients completed a series of questionnaires, including questions about demographic and headache characteristics, the 16‐item Greyson NDE scale, four questions about REM sleep intrusions, and the Depression, Anxiety, and Stress Scale 21 (DASS‐21).

Results

Of 808 migraine patients (mean age 44.4 ± 13.3 years, 87.0% women), 353 (43.7%) had a current or previous history of migraine aura. Prevalence of NDE was 2.7% and not different in patients with and without aura (2.8% vs. 2.6%;  > 0.999). REM sleep intrusions were reported by 5.4% of participants and in a similar proportion of patients with and without aura (6.3% vs. 4.9%;  = 0.43). However, participants with REM sleep intrusions had had an NDE more often than participants without REM sleep intrusions ( = 5/44, 11.4% vs.  = 17/754, 2.2%;  = 0.005). Higher DASS‐21 scores were associated with REM sleep intrusions ( < 0.001).

Conclusions

In this tertiary center cohort study, the prevalence of NDE and REM sleep intrusions was not influenced by migraine aura status. However, we identified an association between NDE and REM sleep intrusions, which corroborates the notion that they might share pathophysiological mechanisms.

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Authors:
Bianca Raffaelli, Pia Kull, Jasper Mecklenburg, Kristin S. Lange, Lucas H. Overeem, Mira P. Fitzek, Anke Siebert, Maureen Steinicke, Paul Triller, Lars Neeb, Jens P. Dreier, Uwe Reuter and Daniel Kondziella
Article first published online:
28 Jul 2023 | DOI: 10.1111/ene.15991

ORIGINAL ARTICLE

Background and purpose

The correlates of motor parkinsonism in Alzheimer's disease (AD) remain controversial. The effects of nigrostriatal dopaminergic degeneration on parkinsonism and cognition in biomarker‐validated patients with AD were evaluated.

Methods

This study recruited 116 patients with AD who underwent dual‐phase F‐N‐(3‐fluoropropyl)‐2β‐carbon ethoxy‐3β‐(4‐iodophenyl) nortropane positron emission tomography, F‐florbetaben positron emission tomography, 3 T brain magnetic resonance imaging, and Unified Parkinson's Disease Rating Scale (UPDRS) and neuropsychological tests. The mean cortical thickness in the frontal, temporal, parietal and occipital cortices, and the dopamine transporter (DAT) uptake in the caudate, anterior/posterior putamen and substantia nigra were quantified. The relationship between DAT uptake, mean lobar cortical thickness, UPDRS motor score and cognition was investigated using general linear models (GLMs) after controlling for age, sex, education, intracranial volume, and deep and periventricular white matter hyperintensities. A path analysis was performed for the UPDRS motor score with the same covariates.

Results

Path analysis and multivariable GLMs for UPDRS motor score showed that lower caudate DAT uptake was directly associated with a higher UPDRS motor score, whereas caudate DAT uptake confounded the association between mean frontal/parietal thickness and UPDRS motor score. Multivariable GLMs for cognitive scores showed that lower caudate DAT uptake was associated with visuospatial/executive dysfunction independent of mean frontal or parietal thickness.

Conclusions

Nigrostriatal dopaminergic dysfunction is associated with parkinsonism and visuospatial/executive dysfunction in patients with AD.

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Authors:
Sungwoo Kang, Seun Jeon, Young‐gun Lee and Byoung Seok Ye
Article first published online:
08 Aug 2023 | DOI: 10.1111/ene.15995

CASE REPORT

Background and purpose

Iatrogenic cerebral amyloid angiopathy (iCAA) is a specific type of cerebral amyloid angiopathy which is becoming increasingly diagnosed. It has been hypothesized that iCAA might arise as a late consequence of past neurosurgical interventions involving dural patch grafts. Positron emission tomography (PET) scans with amyloid tracers and the assay of beta‐amyloid levels in cerebrospinal fluid (CSF) are auxiliary criteria, however, definite diagnosis remains histopathologically determined.

Methods

Case report.

Results

We present a 48‐year‐old patient who suffered multiple lobar cerebral haemorrhages from the age of 47. The patient had undergone surgery for remolval of hemangioblastoma with lyophilized dural graft at the age of 11, in 1987. Brain MRI, amiloid PET and CSF analysis led to a diagnosis of probable iCAA.

Conclusion

It is necessary to increase the awareness of iCAA, in order to avoid overlooking the potential causal involvement of surgical procedures which took place far back in time. Moreover, the diagnostic relevance of amyloid PET and beta‐amyloid levels in CSF must be emphasised.

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Authors:
Benedetta Storti, Isabella Canavero, Maria Magdalena Gabriel, Antonella Capozza, Nicola Rifino, Mario Stanziano, Luca Tagliabue and Anna Bersano
Article first published online:
08 Aug 2023 | DOI: 10.1111/ene.15997

ORIGINAL ARTICLE

Background

Recreational use of nitrous oxide (NO) has dramatically increased in recent years, resulting in numerous cases of acute sensorimotor tetraparesis secondary to nitrous oxide‐induced neuropathy (NOn). Challenging clinical features can mimic Guillain‐Barré syndrome (GBS), the main differential diagnosis upon admission. The most sensitive biomarkers for distinguishing between these two conditions remain to be determined.

Methods

Fifty‐eight NOn patients from three referral centers were retrospectively included over a 2‐year period and compared to GBS patients hospitalized during the same timeframe (47 patients). Collected demographic, clinical, biological, and electrophysiological data were compared between the two groups.

Results

The typical NOn clinical pattern included distal sensorimotor deficit in lower limbs with absent reflexes, proprioceptive ataxia, and no cranial involvement (56.7% of our cohort). Misleading GBS‐like presentations were found in 14 NOn patients (24.1%), and 13 patients (22.4%) did not report NO use during initial interview. Only half the NOn patients presented with reduced vitamin B12 serum levels upon admission. A slightly increased cut‐off (<200 pmol/L) demonstrated 85.1% sensitivity and 84.5% specificity in distinguishing NOn from GBS. Only 6.9% of NOn patients met the criteria for primary demyelination ( < 0.01), with only one presenting conduction blocks. A diagnostic algorithm combining these two biomarkers successfully classified all GBS‐like NOn patients.

Conclusions

Vitamin B12 serum level < 200 pmol/L cut‐off and conduction blocks in initial electrophysiological study are the two most sensitive biomarkers for rapidly distinguishing NOn from GBS patients. These two parameters are particularly useful in clinically atypical NOn with GBS‐like presentation.

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Authors:
Etienne Fortanier, Edouard Berling, Adrien Zanin, Adrien Le Guillou, Joelle Micaleff, Guillaume Nicolas, Pierre Lozeron and Shahram Attarian
Article first published online:
07 Aug 2023 | DOI: 10.1111/ene.15998

ORIGINAL ARTICLE

Background and purpose

The choroid plexus (CP) clears harmful metabolites from the central nervous system as part of the glymphatic system. We investigated the association of CP volume (CPV) with baseline and longitudinal cognitive decline in patients with Parkinson disease (PD).

Methods

We retrospectively reviewed the medical records of 240 patients with newly diagnosed PD who had undergone detailed neuropsychological tests and high‐resolution T1‐weighted structural magnetic resonance imaging during the initial assessment. The CPV of each patient was automatically segmented, and the intracranial volume ratio was used in subsequent analyses. The relationship between CPV and baseline composite scores of each cognitive domain was assessed using multivariate linear regression analyses. A Cox proportional hazards model was used to compare the risk of dementia conversion with CPV.

Results

CPV negatively correlated with composite scores of the frontal/executive function domain (β = −0.375,  = 0.002) after adjusting for age, sex, years of education, and parkinsonian symptom duration. The Cox regression model revealed that a larger CPV was associated with a higher risk of dementia conversion (hazard ratio [HR] = 1.509,  = 0.038), which was no longer significant after adjusting for the composite scores of the frontal/executive function domain. A mediation analysis demonstrated that the effect of CPV on the risk of dementia conversion was completely mediated by frontal/executive function (direct effect: HR = 1.203,  = 0.396; indirect effect: HR = 1.400,  = 0.015).

Conclusions

Baseline CPV is associated with baseline frontal/executive function, which subsequently influences dementia conversion risk in patients with PD.

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Authors:
Seong Ho Jeong, Hyun‐Jae Jeong, Mun Kyung Sunwoo, Sung Soo Ahn, Seung‐Koo Lee, Phil Hyu Lee, Yun Joong Kim, Young H. Sohn, Chae Jung Park and Seok Jong Chung
Article first published online:
06 Aug 2023 | DOI: 10.1111/ene.15999

ORIGINAL ARTICLE

Background and purpose

Idiopathic Parkinson's disease (IPD) is a progressive neurodegenerative disorder that is strongly associated with age. The aim of the present study was to describe current sex‐ and age‐specific trends and regional differences in the incidence of IPD diagnosed in older people in Germany.

Methods

This study was based on nationwide outpatient claims and drug prescription data from the German Statutory Health Insurance, covering approximately 87% of the general population. We conducted a cohort study in patients aged 50 years or older with observation time of at least 4 years. To assess the robustness of nationwide annual IPD incidence trends from 2013 to 2019, three case definitions with varying levels of stringency regarding coded outpatient diagnoses and drug prescriptions were applied.

Results

In 2019, the population at risk comprised 30,575,726 persons. Using the primary and most specific case definition, annual age‐ and sex‐standardized cumulative IPD incidence decreased stepwise from 137 (2013) to 106 (2019) new cases per 100,000 persons. The decline in incidence was seen in both sexes, in all age groups and in the majority of German regions. The relative decrease (2013–2019) in the annual age‐ and sex‐standardized IPD incidence varied from 23% to 28% among case definitions.

Conclusion

Our findings indicate a nationwide decline in the age‐ and sex‐standardized incidence of IPD from 2013 to 2019 in Germany. This trend was consistent using different case definitions. Further research is needed to elucidate the factors underlying this trend.

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Authors:
Lotte Dammertz, Anette Schrag, Jens Bohlken, Joachim Heuer, Claudia Kohring, Julia Schorlemmer, Manas K. Akmatov, Jörg Bätzing and Jakob Holstiege
Article first published online:
09 Aug 2023 | DOI: 10.1111/ene.16000

CASE REPORT

Background and purpose

The recent off‐label use of botulinum neurotoxin (BoNT) for intragastric obesity treatment has led to 67 cases of systemic botulism in Türkiye, Germany, Austria and Switzerland. This case report highlights the potential risks and adverse effects associated with this treatment.

Case report

A 36‐year‐old female presented to the emergency room with shortness of breath, fatigue, difficulty in eating and holding her head, constipation and double vision after receiving intragastric BoNT injection for obesity treatment. She had bilateral orbicularis oculi weakness, facial diplegia, weak tongue, masseter, neck and extremity muscles. Electromyography showed a presynaptic type neuromuscular junction disorder. The patient was admitted to the intensive care unit and administered botulinum heptavalent equine‐derived antitoxin, but the medication had to be stopped due to a reaction. The patient was started on pyridostigmine for symptomatic treatment and was transferred to an inpatient clinic after minimal improvement. She was discharged after 7 days of follow‐up.

Conclusion

Clinicians should be cautious of the potential risks of intragastric BoNT injection for obesity treatment and consider systemic botulism as a potential adverse effect. Antitoxin treatment should be considered in clinically progressing patients despite negative botulinum toxin testing.

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Authors:
Bekir Burak Kılboz, Zekeriya Ervatan, Rıdvan Dumlu and Onur Akan
Article first published online:
07 Aug 2023 | DOI: 10.1111/ene.16005

CASE REPORT

Background

Myopathies associated with monoclonal gammopathy are relatively uncommon and underrecognized, treatable myopathies, and include sporadic late onset nemaline myopathy, light chain amyloid myopathy, and a recently described vacuolar myopathy with monoclonal gammopathy and stiffness (VAMGS). Herein, we report a new subtype of monoclonal gammopathy‐associated myopathy (MGAM) in a polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) patient.

Method

Case report.

Results

A 51‐year‐old woman presented with a 6‐month history of progressive bilateral foot drop, lower limb edema, and a 15‐lb weight loss. She denied muscle stiffness. Neurologic exam showed severe distal weakness, mild proximal weakness, and length‐dependent sensory deficits. Laboratory studies revealed biclonal gammopathy (IgG kappa and IgA lambda), thrombocytosis, and elevated vascular endothelial growth factor. Creatine kinase was normal. Electrodiagnostic studies identified mixed demyelinating and axonal polyradiculoneuropathy and a superimposed proximal myopathy. Gluteus medius biopsy demonstrated scattered fibers with glycogen‐filled vacuoles, similar to VAMGS, with additional rare myofibers containing polyglucosan bodies. She was diagnosed with POEMS syndrome and concomitant glycogen storage myopathy. Next‐generation sequencing of glycogen storage and polyglucosan body myopathy‐related genes was unrevealing. Proximal weakness resolved after autologous stem cell transplant.

Conclusions

This patient expands a spectrum of MGAM. Recognition of this condition and other subtypes of MGAM is of utmost important because they are treatable.

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Authors:
Pannathat Soontrapa, Jennifer A. Tracy, Wilson I. Gonsalves and Teerin Liewluck
Article first published online:
11 Aug 2023 | DOI: 10.1111/ene.16008