NEUROLOGY EAN Virtual 2021 - EDITOR'S PICK - European Medical Journal
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NEUROLOGY
Vol. 9.1 August 2021 emjreviews.com
EAN Virtual 2021
EDITOR’S PICK INTERVIEWS
A Successful Treatment of Chronic Interviews with Sergio Baranzini,
Migraine with Hyperbaric Kristian Steen Frederiksen, and
Oxygen Therapy Riccardo Soffietti
Contents
+ EDITORIAL BOARD 4
+ WELCOME 7
+ FOREWORD 9
+ CONGRESS REVIEW
Review of the European Academy of Neurology (EAN) Virtual 2021, 13
19th–22nd June 2021
+ CONGRESS FEATURE
Rhythmicity in Primary Headache Disorders 21
Evgenia Koutsouki
+ SYMPOSIUM REVIEWS
Motor Fluctuation Management in Parkinson’s Disease: Now and 24
What Next?
+ ABSTRACT REVIEWS
Classifying and Characterising Multiple Sclerosis Disease Phenotypes 34
with Functional Connectivity and Machine Learning
Rocca et al.
Clinical Relevance of Multiparametric MRI Assessment of Cerebellar 37
Damage in Multiple Sclerosis
Bonacchi et al.
Human Spinal Cord-like Organoids to Model C9orf72 Amyotrophic 39
Lateral Sclerosis and Test New Therapies In Vitro
Costamagna et al.
Relevance of Neurite Orientation and Dispersion Density Imaging to 41
Characterise Microstructural Abnormalities of Multiple Sclerosis Cortex
and Cortical Lesions In Vivo: A 3T Study
Preziosa et al.
Magnetic Resonance T2-relaxation Time as an Indirect Measure of Brain 44
Water Content and Disease Activity in Neuromyelitis Optica Spectrum
Disorders
Cacciaguerra et al.
2 NEUROLOGY • August 2021 EMJ
Long-term Safety Outcomes with Inebilizumab Treatment in 45
Neuromyelitis Optica Spectrum Disorder: The N-MOmentum Trial
Cree et al.
Resting State Functional Connectivity Changes of the Pons in Patients 49
with Migraine: A Cross-Sectional and Longitudinal Study
Messina et al.
The Effects of Great Occipital Nerve Block Over Photophobia in 51
Patients with Migraine
Membrilla et al.
+ CONGRESS INTERVIEW
Riccardo Soffietti 54
+ INTERVIEWS
Sergio Baranzini 56
Kristian Steen Frederiksen 58
+ ARTICLES
Editor’s Pick: A Successful Treatment of Chronic Migraine with 61
Hyperbaric Oxygen Therapy
Shafee et al.
A Case Report: Internal Carotid Artery Dissection Presenting as 66
Hoarseness Secondary to Vocal Cord Palsy
Ng Kee Kwong et al.
Turner Syndrome and Craniosynostosis: An Unusual Combination 72
Becerra et al.
A Case of Subacute Combined Degeneration as a Manifestation of 77
Pernicious Anaemia
Arriaga Rocha et al.
Successful Management of Parsonage–Turner Syndrome with Steroids 81
in the Post-Acute Weakness Phase: A Case Report
Butt et al.
Creative Commons Attribution-Non Commercial 4.0 August 2021 • NEUROLOGY 3
Editorial Board
Editor-in-Chief
Prof Lászlo Vécsei University of Szeged, Hungary
Editorial Board
Dr Natan M. Bornstein Shaare-Zedek Medical Center, Israel
Dr Nitin Butala Baptist Health, Florida, USA
Prof Giancarlo Comi Scientific Institute San Raffaele, Italy
Prof Alberto Dubrovsky Favaloro University, Argentina
Prof Antonio Federico University of Siena, Italy
Dr Marco Feligioni European Brain Research Institute ‘Rita Levi-Montalcini’
Foundation, Italy
Prof Nils Erik Gilhus University of Bergen, Norway
Prof Dr Hans-Peter Hartung University of Düsseldorf, Germany
Prof Amos D. Korczyn Tel-Aviv University, Israel
Dr Rita Krishnamurthi Auckland University of Technology New Zealand
Dr Giuseppe Lanza University of Catania, Italy
Dr Inna Lutsenko I.K. Akhunbaev Kyrgyz State Medical Academy,
Kyrgyzstan
Prof Heinz Reichmann University of Dresden, Germany
Prof Dr Stefan Schwab University of Erlangen-Nuremberg, Germany
Prof Ranko Raicevic Military Medical Academy, Serbia
VIEW IN FULL
4 NEUROLOGY • August 2021 EMJ
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EMJ Neurology 9.1
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6 NEUROLOGY • August 2021 EMJ
Welcome
Dear Readers, recent advances in this sector, such as
Becerra et al. investigating Turner syndrome
Welcome to the latest issue of EMJ Neurology, an and Craniosynostosis, and an intriguing
online journal that outlines the latest important report by Arriaga Rocha et al. demonstrating
progress in this field. With the European subacute combined degeneration as a
Academy of Neurology (EAN) hosting its 7th manifestation of pernicious anaemia.
annual congress in the midst of the COVID-19
pandemic, it was a pleasure to attend and share For this issue, Sergio Baranzini and Kristian Steen
in the fully-virtual EAN 2021. Enclosed within this Frederiksen shared with us what has motivated
eJournal are the most recent developments in them to conduct their respective research
neurology, in the form of peer-reviewed articles, works, some of their career highlights, and which
and exclusive interviews with leading specialists emerging topics to watch out for in the field in
in the field, alongside our congress review their interviews with EMJ. We also leapt at the
highlights from EAN Virtual 2021. opportunity to speak with Riccardo Soffietti,
Chair of the Education Committee for EAN, to
In this issue, readers can expect summaries of discuss his role and influence within EAN, how
the key content delivered at EAN 2021, as well as the event has adapted to virtual, the impact
abstracts written by the presenters themselves, the congress has on the community, and recent
ranging in theme from MRI assessment of significant advances in neurology.
cerebellar damage in multiple sclerosis to
connectivity changes in the pons of patients with Without the contributions from the Editorial
migraine, among other topics. Also included are Board, authors, peer-reviewers, interviewees,
feature articles sharing insights from the most and Editorial team it would not be possible to
significant congress sessions, of which there produce such high-quality content. I would like
were more than 200, contributed to by close to to express my gratitude to all of these groups as
12,000 individuals. I turn finally to you, the readers, for your loyalty,
as we continue to strive towards being the go-to
Inside EMJ Neurology are a host of innovative place for healthcare professionals. We hope you
peer-reviewed articles discussing the most enjoy this latest issue of EMJ Neurology.
Spencer Gore
Chief Executive Officer, EMG-Health
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Foreword
Dear Friends and Colleagues, In our congress review for this issue, you will
be able to catch up on the highlights and
I am delighted to welcome you to the stories from EAN 2021. You will also be able
2021 issue of EMJ Neurology, covering the to read an interview with Riccardo Soffietti,
latest updates from European Academy of Chair of the Education Committee at EAN.
Neurology (EAN) 2021, alongside a series of The issue also contains summaries of selected
key articles focussing on current topics in abstracts presented at EAN 2021, alongside
neurology. coverage of a fascinating congress session
on chrononeurology.
EAN 2021, taking place virtually, covered
a plethora of topics presented by the top For my Editor’s Pick in this year’s issue, I have
leaders in the field, with a plenary session selected an article by Shafee et al. where
focusing on precision neurology. Covering the authors describe treating a patient who
different aspects of neurology, the congress presented with migraine with hyperbaric
once again brought together the neurology oxygen. This case report highlights hyperbaric
community across Europe in a highly oxygen treatment as a potential treatment
engaging programme. With COVID-19 having path for analgesic-resistant migraine.
an ongoing effect on both organisational I would like to take this opportunity to thank
aspects and neurology practice, the message everyone who has participated in bringing this
ringing clearly from the congress was that issue together, and I hope that it makes an
the neurology community in Europe has built enjoyable and engaging read. I look forward
a strong resilience for approaching clinical to seeing you in person for next year’s
practice at this challenging time. EAN Congress.
Prof László Vécsei
University of Szeged, Szeged, Hungary
Creative Commons Attribution-Non Commercial 4.0 August 2021 • NEUROLOGY 9
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Review of European Academy of Neurology
(EAN) Virtual 2021
Location: EAN 2021
Date: 19th–22nd June 2021
Citation: EMJ Neurol. 2021;9[1]:13-20. Congress Review.
V
IENNA was the virtual home of learnt that the health, social, [and] economic
the 7th Congress of the European structures are interdependent and that
Academy of Neurology (EAN), these systems must work in a dynamic and
taking place from 19th to 22nd June. In what systematic approach to solve the problem,”
is the second year in a virtual setting, Bassetti outlined when discussing the
Claudio Bassetti, President of the EAN, lessons learnt from the COVID-19 pandemic.
welcomed the attendees by highlighting
It was exciting to hear about the activities
the vision of the EAN to be the voice of
of the EAN, especially the EAN Science
neurology in Europe, with its mission to
School, which is devoted to bridging the
reduce the burden of neurological and
gap between basic science and clinical
brain diseases. Bassetti highlighted the
medicine. The first School, taking place
impact of neurological conditions as the
in March 2021, focused on a number of
third most common cause of death and
topics including immune neurological
disability in Europe.
disorders, stroke, and epilepsy. Bassetti also
highlighted the neuro-COVID-19 research
In his introductory remarks on COVID-19,
initiative comprising a group of people
Bassetti highlighted the high variability
from 34 sites collecting data to shed light
in the levels of care and vaccination in
on manifestations and complications of
countries around the world, and emphasised
COVID-19. It is worth mentioning that the
the importance of collaboration among
EAN has published an impressive set of
partners and the importance of encouraging
data since it started: 107 guidelines, with
resilience and making care people-centric.
7 very new guidelines and 22 more in
Bassetti also highlighted the importance
the pipeline.
of digitalisation and data sharing as key
elements in fighting COVID-19. “We have"This is only the beginning of finding treatments for
Alzheimer’s Disease"
This year’s EAN virtual platform introduced a live numerous achievements, Deuschl is the founding
TV channel, live interactive sessions, networking president of the EAN, author of over 700 original
areas, translation in Spanish and Russian, and publications, and among the top 1% of scientists
many sessions around the clock with partners worldwide. Bassetti hailed Deuschl as a pioneer
outside Europe, e.g., the Academies of Neurology in diagnostic and pathophysiological studies on
of Brazil and India. This year’s plenary session tremor, who changed the way we look at deep
covered the overarching theme of precision brain stimulation in Parkinson’s disease. Phillip
neurology, and the President's Symposium Scheltens, Professor of Cognitive Neurology
covered the future of sleep medicine. With almost and Director of Alzheimer Centre, VU University
12,000 attendees taking part and a high number Medical Centre Amsterdam, the Netherlands,
of presented abstracts, the congress offered a was the second recipient, in recognition of his
plethora of highly engaging sessions. In this issue work on dementia and Alzheimer’s disease and
of EMJ Neurology we have covered a session particularly for his work on early biomarkers of
on chrononeurology and rhythmicity in primary Alzheimer’s disease. Upon acceptance of his
headache disorders. award and reflecting on the evolution of the
field from barely being an area of neurology to
The viewers of the opening ceremony also had the first approved treatment for Alzheimer’s
the pleasure of watching the opening lecture, disease, Scheltens expressed his belief that “This
given by Jürgen Knoblich, Director of the Institute is only the beginning of finding treatments for
of Molecular Biotechnology, Vienna, Austria, who Alzheimer’s disease.”
introduced the concept of cerebral organoids
and how development of the human brain can be Plans are already in place for the 8th EAN
modelled in 3D cell cultures, giving an insight into Congress in 2022, which will again take place
potential future practices of neurology. in Vienna. The plans for next year’s Presidential
Symposium have already been made, with
Like every other year, the opening ceremony speakers from Sweden, Austria, the UK, and USA
was not complete without the honorary already having been confirmed. The key theme of
membership awards. Günther Deuschl, Professor next year’s congress will be translating evidence
of Neurology, Christian-Albrechts University into practice, with a plenary symposium on
Kiel, Germany, was the first recipient; among his improving lives and reducing disease burden. ■
EAN 2021 REVIEWED
14 NEUROLOGY • August 2021 EMJHeadache Highlights "In terms of monoclonal
from EAN 2021 antibody therapy, Goadsby
summarised the 5-year data
Presentations for erenumab."
ON DAY 4 of this year’s EAN 2021, Peter Goadsby, In terms of monoclonal antibody therapy, Goadsby
Professor of Neurology, King’s College London, summarised the 5-year data for erenumab.
UK, summarised highlights from the headache Three hundred and eighty-three patients initially
presentations, with a focus on the variety of new treated in a placebo-controlled trial were entered
preventative and acute migraine therapies. into an open-label extension phase. At 5 years,
there were 214 patients who had completed the
Goadsby drew the audience’s attention to a study. In total, 71% of patients reported a ≥50%
randomised, double-blind, placebo-controlled reduction in mean monthly migraine days, 47%
study designed to assess the efficacy and of patients reported a ≥75% reduction, and
consistency of lasmiditan over four migraine 36% of patients reported a ≥100% reduction.
attacks. Patients were randomised to one of Eptinezumab, a calcitonin gene-related peptide
three treatment groups: lasmiditan 200 mg, monoclonal antibody, has also been shown to
lasmiditan 100 mg, or a control group that effectively prevent migraines. Patients were
received placebo for three attacks and lasmiditan randomly assigned to receive either eptinezumab
50 mg for either the third or fourth attack. The (n=238; 100 mg administered intravenously) or
incidence of treatment-related adverse events placebo (n=242) for treatment of an acute attack.
was highest during the first attack. The most At 2 hours after infusion, headache pain freedom
common adverse events included dizziness, was achieved by 23.5% of patients receiving
paresthesia, and fatigue, which were typically eptinezumab and 12.0% of patients given the
mild or moderate in severity. In addition, both of placebo (p=0.0009). Furthermore, the absence
the primary endpoints (pain freedom at 2 hours of most bothersome symptoms was achieved by
[first attack] and pain freedom at 2 hours in at 55.0% of eptinezumab-treated individuals and
least two of three migraine attacks) were met 35.8% of placebo patients (p=0.0001).
for lasmiditan. Similarly, all gated secondary
endpoints, such as pain relief, disability freedom, In conclusion, Goadsby emphasised that this
and sustained pain freedom, were met. Overall, was an exciting time to be a headache specialist
these results indicate the efficacy of lasmiditan. because of the recent advances in safe and
effective migraine treatment. ■
Creative Commons Attribution-Non Commercial 4.0 August 2021 • NEUROLOGY 15Migraine in Pregnancy care throughout pregnancy in migraine-affected
individuals; in the same way as would take place
at High Risk of in those affected by diabetes, epilepsy, or high-
blood pressure. In addition to this, “Migraine
Complications sufferers were also found to have a greater
risk of developing depression during their
pregnancy and after giving birth,” explained Levi,
CONCERNING the development of obstetric recommending a focus for any upcoming long-
and post-partum complications, research in term initiatives. “As a result, they should also
Israel led by Nirit Lev, shared at EAN 2021, has be offered a neurological consultation during
found that pregnant women who experience pregnancy and adequate follow-up support after
migraines are at increased health risk. giving birth.” Future studies should build on these
Affecting mostly individuals of reproductive important conclusions, and also incorporate
age, and one of the most prevalent disabling observation of the hormonal changes related
neurological disorders worldwide, the study to menstruation, menopause, and childbirth
aimed to evaluate the characteristics of this exhibiting effects to worsen migraine activity. ■
relationship and identify medical needs to
direct action.
Between 2014 and 2020, the study analysed the
pregnancies of 145,102 females, investigating
mode of delivery, medical and obstetric
complications, and the use of medication
throughout. Within this population, 12,222
experienced migraine, of which 1,576 were
migraine with aura. Findings included increased
risk scores for pregnant migraine patients
relating to gestational diagnosis of diabetes,
hyperlipidaemia, and blood clot. Higher rates
of epidural anaesthesia were also noted during
the labour of females with migraine; however,
this category was not particularly at risk of
assisted delivery.
Lev commented: “Our study confirms that women
who suffer from migraine are at a greater risk of
a host of medical and obstetric complications.
As such, we recommend that these
women should be classed as ‘high-risk’
pregnancies and should therefore
"Our study
be treated according to a high- confirms that
risk protocol,” drawing these women who suffer from
conclusions based on their migraine are at a greater
data, which highlight a 6.9% risk of a host of medical
increased risk of admittance
to ‘high-risk’ departments in
and obstetric complications.
those with migraine, and 8.7% As such, we recommend
in those with both migraine that these women should
and aura. be classed as ‘high-risk’
The main action point this pregnancies and should
study hopes to convey, and therefore be treated
provoke future action upon, is a according to a high-
provision of special monitoring and risk protocol."
16 NEUROLOGY • August 2021 EMJTreating Fatigue and Other
Conditions in Multiple Sclerosis
FATIGUE is one of the most common yet In another study, a team assessed work
understudied symptoms in multiple sclerosis productivity and activity impairment (WPAI) in
(MS). Christian Enzinger from the EAN Organising patients with relapsing–remitting MS treated with
Committee shared the presentations and studies ocrelizumab. WPAI scores were recorded, and
he found most inspiring relating to fatigue and the results showed that there was a significant
other conditions in MS at EAN 2021. improvement in WPAI, which was maintained
over 2 years. There was also a positive correlation
A new paper aimed to measure the impacts of between this change in scores and the reduction
fatigue in patients with MS using a novel disease- of the physical and psychological impact of MS.
specific scale called FSIQ-RMS. The study is
still in progress, but initial findings show that The speaker briefly described a handful of
fatigue is one of the most reported symptoms other MS studies where objective measures
that cause impactful disruption on a day-to- of upper limb function and clinically isolated
day basis in patients with MS. Thus far, the syndrome were suggestive of MS. Finally, he
results demonstrate that FSIQ-RMS helps with examined genetic differences in MS. One study
improving understanding and management of included MRI results that showed brain volume
fatigue. Enzinger expressed his enthusiasm for differences in BDNF Val66Met polymorphism
the promising results and believes this is an area carriers compared to wild-type individuals.
that needs further research. These structural differences were significantly
associated with function and performance.
Another paper showed a unique approach in
efforts to improve fatigue using bright light Enzinger concluded that there are many
therapy (BLT) in a randomised controlled trial. interesting studies in MS and young neurologists
BLT has been known to improve fatigue in share in an important and distinctive approach to
other conditions such as depression. BLT is a treating symptoms associated with MS. He noted
fascinating alternative to medication as benefits that some of these studies had a small sample
include affordability and little to no side effects. size but overall provided a great foundation for
The results showed that BLT had a placebo effect the future of treating fatigue and corresponding
and improved the cognitive aspect of fatigue. symptoms of MS. ■
"Initial
findings
show that fatigue
is one of the most
reported symptoms
that cause impactful
disruption on a day-
to-day basis in
patients with
MS."
Creative Commons Attribution-Non Commercial 4.0 August 2021 • NEUROLOGY 17"Specific cognitive deficits in
The Road So Far spatial memory, orientation,
in Various and navigation were
discussed as early signs of
Neurodegenerative preclinical AD, and could
Diseases be used in the future as
pre-emptive biomarkers for
APPRAISING the latest updates in neurological disorders."
neurodegenerative diseases, Elisabeth Stӧgmann
provided insight at EAN 2021 for current practice Plasma biomarkers under investigation by Femke
and the direction in which neurological treatment Bouwman were presented, including plasma
is travelling. amyloid, serum p-Tau, neurofilament light,
Stӧgmann described U.S. Food and Drug and glial fibrillary acidic protein. p-Tau181, and
Administration (FDA) approval of a drug for particularly p-Tau217, were clearly elevated in AD,
Alzheimer’s disease (AD) a “seismic event for highlighting their potential as prognostic markers.
our field,” praising the potential for a treatment Plasma biomarkers presented good accuracy;
of this nature whilst recognising that approval although not as strong as CSF, obtaining blood
is still required from the European Medicines samples is more patient-friendly and practical.
Agency (EMA). The past decade was described Future studies may guide plasma biomarker
as a critical period in advancing diagnosis of use for patient selection for therapies and could
dementia and more specifically AD, during which prove helpful for general population screening
findings from genetic studies have suggested and offering a personalised medicine approach.
optimum treatment is administered before the Recent developments in genetic testing have
onset of symptoms. Going forwards, reading into involved a shift from single-gene testing to
subtle changes in cognition is recommended as a a panel method; this requires careful patient
focal point. consultation and a long waiting period before
Specific cognitive deficits in spatial memory, receiving results. There is much work to be done
orientation, and navigation were discussed as in this area; when delivering results, the discovery
early signs of preclinical AD, and could be used of other genetic predispositions and mutations,
in the future as pre-emptive biomarkers for aside from only AD, must be explained to
neurological disorders. Real progress has been the patient. There is limited ability to assess
made in this field over the last 5 years, such as expansion genes at present, and there is regular
in Henrik Zetterberg’s study of the diagnostic discovery of variants with unknown significance
accuracy of fluid biomarkers; highlighting that cannot yet be explained.
the highest AD intensities can be reflected Bringing the discussion to a close, and answering
by faster decline in cerebrospinal fluid (CSF) the question: ‘Why diagnose familial forms of
dynamics. Neurofilament light CSF seems to dementia?’ Stӧgmann described participation
be a better marker for neurodegeneration; in well-designed clinical trials as having the
with increased presence across a host of opportunity to provide support, information,
diseases, it could be a helpful marker in and treatment to patients. This will promote
monitoring progression, particularly for understanding of neurodegenerative diseases
patients with mild cognitive impairment. and guide future research, helping to shape
Both of these tie into the Amyloid/Tau/ initiatives such as preimplantation of genetic
Neurodegeneration (ATN) classification system, diagnosis for family planning and other
briefly mentioned as an unbiased classification longitudinal generation-based therapies. ■
scheme for AD biomarkers.
18 NEUROLOGY • August 2021 EMJCOVID-19 Leads to Significant Cognitive
Disturbances and Behavioural Problems
COVID-19 took the world by surprise in late At the 2-month (sub-acute) phase, >50% of
2019 as countries all over the globe entered patients showed cognitive disturbances. One
strict lockdowns and curfews to prevent the of the biggest of these issues, seen in 16% of
spread of the virus. Since then, researchers patients, was executive dysfunction including
continue to better understand how COVID-19 problem-solving, planning, and attention. Other
works and new symptoms continue to come to disturbances affected spatial awareness and
light. Surprisingly, it is not only the respiratory memory. A large percentage had a combination
system that is severely affected by this of these cognitive impairments. The study
contagious disease; recent studies shared at EAN also showed that >30% of patients had mental
2021 show that the brain is also severely affected health issues including PTSD and depression.
in both physiological and psychological ways, Surprisingly, low performance in the memory
including post-traumatic stress disorder, memory test was linked to higher levels of white matter
issues, and brain stem damage. changes in the brain, while low performance in
information processing was related to higher
A new study by Massimo Filippi, Scientific severity of respiratory symptoms.
Institute and University Vita-Salute San Raffaele,
Milan, Italy, explored the cognitive disturbances Further down the line at the 10-month
and psychopathological symptoms in a cohort follow-up, the results showed a decrease in
of patients with COVID-19 at different phases: cognitive disturbances from 53% to 36%.
2 months and 10 months. The researchers However, there was very little change in
recruited 49 patients aged between 40 and 75 PTSD and depression in patients who had
years; these individuals had to meet set criteria in these symptoms at the sub-acute phase. The
order to be included such as hospital admission latest research confirms that COVID-19 leads
with confirmed diagnosis of COVID-19, objective to significant cognitive disturbances and
cognitive disturbances, and MRI consent. Filippi behavioural problems. Larger sample sizes and
and their team examined white matter and grey longer duration of follow-up could help answer
matter MRI changes in patients and performed how long-term these neurological impairments
correlations between neurological scores and from COVID-19 might be. ■
brain features to obtain the results in this study.
"At the 2-month (sub-acute) phase, >50% of patients
showed cognitive disturbances."
Creative Commons Attribution-Non Commercial 4.0 August 2021 • NEUROLOGY 19The Mozart Effect in Epilepsy
ACOUSTIC qualities-based analysis of A meta-analysis of 12 publications also showed
stereoelectroencephalography (SEEG) and the the reduction of epileptiform discharges (ED) in
benefits of Mozart's music in patients diagnosed 84% of patients who were listening to the Mozart
with epilepsy was one of the highlights of composition. However, this methodology is
EAN 2021, presented by Ivan Rektor, Masaryk controversial and further research is required to
University, Brno, Czech Republic, on 19th apply to clinical practice.
June 2021.
Rektor then discussed his study carried out on 18
The Mozart effect is the influence of Mozart's patients diagnosed with epilepsy with implanted
Sonata for two pianos in D major K. 448 on SEEG to observe ED. The aim of the research
brain activity in the process of spatial learning. was to compare the impact of listening to Mozart
Rektor started the presentation by sharing and Haydn Symphonie No. 94, by observing the
previous research that stated that Mozart’s spikes in ED to reveal differences leading to the
sonata enhanced spatio-temporal reasoning effects on epileptiform activity.
by activating areas in the brain that were task-
relevant. Rektor played Mozart’s sonata in the Results showed that listening to Haydn's music
background during the session and emphasised reduced EDs only in the female participants but
the repetition in melody played an important increased in the male participants. Furthermore,
role in brain activity when listened to by the effect on the ED depended on the acoustic
patients diagnosed with epilepsy. Dastgheib characteristics (rhythm, dynamics, and timbre) of
et al. proposed that long-term listening could the compositions. The males were more sensitive
produce new pathways in the brain, which may to dissonance and high-frequency content, whilst
alter patterns exhibited by an epileptic brain and the female participants were sensitive to the
release different neurotransmitters like dopamine energy of the composition. In conclusion, the
in the brain. SEEG recordings revealed overall suppressed
ED following exposure to classical music. An
anti-epileptic effect was observed after listening
"...long-term listening could to Mozart’s sonata; however, the suppression of
produce new pathways in ED is different in males versus females due to
acoustic characteristics of the compositions. ■
the brain, which may alter
patterns exhibited by an
epileptic brain"
20 NEUROLOGY • August 2021 EMJRhythmicity in Primary
Headache Disorders
Evgenia Koutsouki
Editor
Citation: EMJ Neurol. 2021;9[1]:21-23.
A
MONG the many engaging sessions in this year’s European Academy of Neurology
(EAN) Virtual 2021 was the session on chrononeurology discussing rhythmicity in
neurological disorders. In a presentation given by Christoph Schankin, Bern University
Hospital, Switzerland, the main topic addressed was rhythmicity in headache disorders.
CHRONOBIOLOGY AND RHYTHMICITY The SCN is a region in the hypothalamus that
is calibrated by light via pituitary adenylate
IN THE HUMAN BODY
cyclase activating polypeptide (PACAP). Food,
In his introductory remarks, Schankin explained temperature, exercise, and circadian hormones,
the concept of chronobiology, which studies such as steroids and melatonin, are other
biological periodic phenomena that occur in calibrators of the SCN.
cycles, giving rhythm to processes. Examples of
such cycles that are adapted by environmental RHYTHMICITY IN MIGRAINES
stimuli include the circadian rhythm, which is a
24-hour-long circle, and similarly, circaseptan When it comes to migraines, Schankin continued,
cycles, which are cultural and based on the there is clear evidence of a circadian rhythmicity,
7-day week, which includes weekends and work shown in that most migraine attacks start at noon
days. Another type of rhythm is the natural or 1 pm. Further to this, a 2007 study on those
phenomenon of the moon phase lasting 28 days, affected by migraine distinguishing between
which is important for the hormonal cycle in
early risers and late risers showed that early risers
females, and finally the circannual rhythm, which
experience their migraine attacks earlier in the
refers to the year, the seasons, the length of the
day, whereas, typically, late risers experience their
daytime, and temperatures.
migraine attacks later in the day. Interestingly,
Schankin explained that the circadian rhythm is there is also evidence of circaseptan rhythmicity
present at a single-cell level and has a number in migraines, as fewer migraines occur on Sundays
of transcriptional products, among which are than any other day. Finally, there is evidence of
the CLOCK protein, Period 1 and 2, and Casein monthly migraine rhythmicity in females who are
Kinase 1, which influence each other. The body not on oral contraceptives, as it has been shown
organs formed by cells act as a single circadian that they often experience their migraines on the
unit or peripheral clock, each of which runs first or second day of their menstrual period.
independently and is synchronised by a central
pacemaker, the suprachiasmatic nucleus (SCN).
Creative Commons Attribution-Non Commercial 4.0 August 2021 • NEUROLOGY 21MIGRAINE TRIGGERS determine the oscillation period, a 2018 study
found that the most prevalent oscillation period
was the 24-hour period, followed by the 12-hour
When discussing the underlying causes for
and 4.8-hour periods. Comparison of patients with
this rhythmicity, Schankin emphasised the
episodic or chronic cluster headaches showed
importance of the premonitory (early) phase
that these three periods were only present in
of the migraine attack, which can start hours
patients with episodic cluster headaches, whereas
to days before the main headache phase. The
the patients with chronic cluster headaches
hypothalamus, cortical, and subcortical areas
had a more diverse chrono-distribution of their
are key areas implicated in this phase, as are
headaches. In interpreting these results, Schankin
neurotransmitters and neuropeptides such as
explained that the group with chronic cluster
noradrenaline, orexins, and dopamine. Discussing
headaches had a more disturbed chronobiology.
a study in which migraine attacks were triggered
In addition to this, cluster headaches appear to
in patients using nitroglycerine infusions, and
have a clear circannual rhythmicity. It is believed
scanning the brain during the premonitory
that cluster headaches occur in bouts when
phase, Schankin explained that hypothalamic
there are extremes in day length (summer and
activation was observed. According to Schankin,
winter solstice). Other kinds of rhythmicities
one working theory is that the hypothalamus
are observed in groups of patients who never
suppresses trigeminal cervical complex activity
get their cluster headaches in summer, or other
and any information that comes from the
patients who get their headaches on the winter
meninges is suppressed by this hypothalamic
or summer equinox.
activity and not perceived as head pain. During
a migraine attack, it is believed that there is a
dysfunction in this hypothalamic suppressive UNDERLYING CAUSES OF
activity and, as a result, patients perceive RHYTHMICITY
signals from the meninges as head pain. Similar
mechanisms are involved in response to sound, Studies have looked into whether the causes
light, and gastrointestinal function. for this rhythmicity could be genetic. Studies
looking at the CLOCK gene and its variants
Although little is known about the involvement of
found an association between some variants and
neurotransmitters, Schankin presented an animal
the incidence of cluster headaches. Orexins are
study that has shown differential involvement of
another factor that has been studied; reduced
orexins A and B in the trigeminal transmission
levels of orexin A were found in cerebrospinal
mechanism.
fluid in cluster headaches. The orexin receptor
It is not well-known which molecules might be has also been studied. A study from Italy and
involved in the migraine attack mechanism at another from Germany found strong correlations
a cellular level; however, Schankin highlighted between a mutation in the receptor and cluster
casein kinase as an important player. People that headaches; however, other studies have not
carry a mutated form of this protein experience shown such a correlation. Schankin commented
an early sleep phase syndrome and this is co- that the receptor might play an important role,
segregated with migraine with aura. An animal however, the geographical area as well as the
study by Brennan in 2013 found that there was genetic background of the patient might also
a lower threshold for triggering migraine attacks play a part. Finally, studies have shown that
in animals that carry this mutation compared to the PACAP gene variant is more prevalent in
wild-type animals. individuals that suffer from cluster headaches
compared to controls.
RHYTHMICITY IN CLUSTER HEADACHES
THE ROLE OF SLEEP AND THE
The rhythmicity of cluster headache has been HYPOTHALAMUS
extensively studied and it has now been shown
that the majority of cluster headaches happen When it comes to studying the link between
at night (1 or 2 am). When performing statistical headache rhythmicity and sleep, Schankin
analyses of the chrono-distribution of attacks to explained that there seems to be a higher
22 NEUROLOGY • August 2021 EMJ"chronobiology…
studies biological
periodic phenomena
that occur in cycles,
giving rhythm to
processes."
likelihood of having a cluster headache during TREATMENT OPTIONS AND
rapid eye movement (REM) sleep, with 30%
CONCLUDING REMARKS
of cluster headaches occurring at this period
compared to 17% during non-REM sleep.
When putting this evidence together, Shankin
The hypothalamus also seems to play a role explained that chronobiology plays a major
in cluster headaches as there appear to be role in primary headache syndromes and there
be functional and structural alterations in the is some evidence on the involvement of the
hypothalamic region and there are differences hypothalamus and its major mediators. With
in melatonin excretion. Melatonin levels are regard to the role of sleep, it appears to be a two-
increased in healthy patients at night, whereas way mechanism as sleep affects headaches and
with patients with cluster headaches have no vice versa.
such change in melatonin between the day and
When it comes to treating rhythmicity in
night. headaches, lithium is used for cluster and hypnic
headache prophylaxis as it is an inhibitor of
THE HYPNIC HEADACHE glycogen synthase kinase 3 β. Valproic acid is
another therapy used as it shifts timing of Period2
The hypnic headache, which occurs exclusively protein. Randomised controlled trials in this topic
during sleep and causes awakening, is a type from the 1990s have shown that melatonin is
of headache likely to be REM-sleep-related able to significantly reduce the number of cluster
as patients report it occurring during vivid headaches and a recent study by Oberman
dreams. Another possibility is that there is a confirmed that steroids were helpful in cluster
chronobiological link as they usually occur at the headache prophylaxis.
same time in the night (mostly 2–3 am) and could
With regard to orexin A and B, however, no
involve the suprachiasmatic nucleus part of the
differences have been shown between placebo
hypothalamus and reduced melatonin secretion.
and an orexin inhibitor. Similarly, a study using
However, a study by Holle in 2013 failed to find
PACAP antibody versus placebo showed no
an association with REM sleep or any differences
difference when used as migraine prophylaxis.
in melatonin secretion. What this study did show,
however, was hypothalamic involvement in the In his concluding remarks, Schankin said
hypnic headache, finding decreased grey matter that medications altering rhythmicity could be
density in the hypothalamus in patients with helpful for treatment; however, a lot of evidence
hypnic headache compared to controls. is still lacking. ■
Creative Commons Attribution-Non Commercial 4.0 August 2021 • NEUROLOGY 23Motor Fluctuation Management in Parkinson’s
Disease: Now and What Next?
This satellite symposium took place on 20th June 2021, as part of the
7th Congress of the European Academy of Neurology – Virtual 2021
Chairperson: Fabrizio Stocchi1
Speakers: Joaquim Ferreira,2 Mónica Kurtis,3 Francesca Morgante,4 Heinz Reichmann5
1. Parkinson’s Disease Research Centre and Drug Development Centre, IRCCS San
Raffaele Hospital, Milan, Italy
2. Faculty of Medicine, University of Lisbon, Portugal
3. Department of Neurology, Ruber International Hospital, Madrid, Spain
4. Department of Neurology, St George’s Hospital, London, UK
5. Department of Neurology, University of Dresden, Germany
Disclosure: Stocchi has received consultant’s honoraria from BIAL, Chiesi, GSK, IMPAX, Kyowa,
Lundbeck, TEVA, UCB, Merck, Zambon, Britannia, Neuroderm, Sunovion, Biogen,
ROCHE, Synegile, and Lusofarmaco. Ferreira has received payments for consultancy,
advisory boards, and grants from BIAL, GSK, Novartis, TEVA, Lundbeck, Solvay,
Abbott, Merck-Serono, Merz, Ipsen, Biogen, Sunovion Pharmaceuticals, Grunenthal,
Fundação MSD (Portugal), MSD, Allergen, Novartis, Medtronic, and ONO Pharma.
Kurtis has received advisory board fees from AbbVie, BIAL, and Zambon; and
honoraria from BIAL and the International Parkinson and Movement Disorder Society.
Morgante has received speaking honoraria from Abbvie, Medtronic, BIAL, and Merz;
travel grants from the International Parkinson and Movement Disorder Society;
advisory board fees from AbbVie, Boston Scientific, and Merz; consultancy fees from
Boston Scientific, Merz, and BIAL; research support from Boston Scientific, Merz, and
Global Kynetic; and royalties from Springer. Reichmann has participated in advisory
boards, given lectures, and has received research grants from BIAL, Desitin, Eisai,
Kyowa Kirin, Merz, Stadapharm, UCB Pharma, and Zambon.
Acknowledgements: This article was developed with writing and editorial support from Makara Health
Communications and funding support from BIAL.
Support: The symposium and publication of this article were funded by BIAL.
Citation: EMJ Neurol. 2021;9[1]:24-33.
Meeting Summary
Motor fluctuations (MF) are still under-recognised and under-treated in patients with Parkinson’s
disease (PD). End-of-dose wearing-off is a considerable problem in the overall management of
PD and is a result of the decreased therapeutic effect of levodopa/dopa-decarboxylase inhibitors
(DDCI). It can be present in the early stages of PD and be difficult to recognise. During a routine
neurological clinical evaluation, key questions and specific rating scales for fluctuations can be helpful
to gain insights into a patient’s movements throughout their day. Wearable technology has been
developed to overcome the shortfalls of frequent home diary entries for patient ON-/OFF-times, and
can measure daytime variations of bradykinesia, tremor, dyskinesia, and freezing of gait. Telemedicine
also provides physicians with a ‘window’ into their patients' daily lives. Treatment decisions for newly-
identified MF should consider current PD treatments, which adjunctive to add first (for levodopa/
24 NEUROLOGY • August 2021 EMJDDCI monotherapy), or which adjunctive to add next (for combination therapy). Choice of adjunctive therapies include catechol-O-methyltransferase (COMT) inhibitors, such as opicapone, monoamine oxidase-B (MAO-B) inhibitors, and dopamine agonists. Opicapone 50 mg has shown efficacy as a first-line adjunctive to levodopa/DDCI in patients with end-of-dose MF (OFF-time reduction: 68.8 minutes; ON-time increase: 79.8 minutes) versus placebo (p=0.0161 and p=0.0049, respectively), with a two-fold greater reduction in OFF-time versus placebo for both low-dose and higher-dose levodopa regimens, and significant OFF-time reductions in patients receiving
Table 1: Case study of wearing-off in early Parkinson’s disease.
Patient history Patient’s description of her symptoms
59-year-old female Coinciding with the time before her next levodopa dose
4 years since PD diagnosis the patient describes:
3 years since levodopa initiation • Return of some tremor
Current levodopa regimen: • Fatigue, tiredness
• Total dose 300 mg • Movement becomes a bit slower
• Dose schedule 100 mg TID (taken at 5-hour intervals) • No mood changes during this time
Other PD medication: rasagiline 1 mg (one tablet) These symptoms occur once or twice per day; once
the patient has taken another levodopa intake, these
symptoms disappear and do not re-occur until the next
dose is due
PD: Parkinson’s disease; TID: three times daily.
to identify MF; similar questions phrased in of each fluctuation symptom or on sleep-related
different ways and the use of diagrams may also fluctuations.7
help to gain insights into a patient’s movements
It is important to note that none of these
throughout their typical day (Figure 1).
instruments provide an understanding of
Screening and rating instruments to fluctuation timings during the day and this
identify fluctuations information is needed to precisely adjust
medication doses.
There are a number of rating scales for
fluctuations, including UPDRS-IV, Part B;5 the Telemedicine during the COVID-19 era:
Non-Motor Fluctuation Assessment (NoMoFA) motor fluctuations on show
Questionnaire;6 and the WOQ-19.7 The UPDRS-
Telemedicine offers improvements to the
IV, Part B can be used to screen a patient for
quality of care8 by providing clinicians with an
time spent in the OFF-state, and has advantages opportunity to ‘step into the homes of their
in that it can be used to screen for the functional patients’ and presenting a ‘window’ into patients’
impact of fluctuations and complexity of MF.5 daily lives.9 In Mónica Kurtis’ experience,
The NoMoFA rates the severity of non-motor observing a patient on-screen is preferable to a
symptoms and whether these are worse during phone consultation. Being able to see the patient
ON- versus OFF-time; the NoMoFA is potentially in a video call can remove the ‘performance
more useful in the research setting.6 The bias’ that may occur during a routine clinic visit,
WOQ-19 is an easy-to-use questionnaire based enable a physician to see a patient when they are
on patient-reported outcomes and includes OFF (which rarely happens during a clinic visit),
items for both MF and non-MF.7 Using this tool and offers an opportunity to pinpoint the types
can save time during a clinic visit as it can be of spaces that can cause movement difficulties;
filled in by the patient in the waiting room before for example, freezing of gait is often triggered
the consultation. when passing through narrow spaces/passages
such as doorways.10 Practical tips for conducting
In the case study described, the WOQ-19
telemedicine consultations are given in Table 2.
questionnaire would be a useful tool to identify
both the patient’s motor and non-motor In the case study described (Table 1), a
symptoms, including item 1 (tremor), item 6 telemedicine consultation coinciding with the
(weakness), item 8 (slowness of movement), patient’s next levodopa dose may allow the
and item 5 (mood changes). However, the physician to observe the patient’s tremor and
WOQ-19 does not offer any insights on severity slowness of movement.
26 NEUROLOGY • August 2021 EMJAsk your patients about their movements Ask your patients about their medication
• Do you feel you have the same capacity
throughout the day? • Do you feel the effect of medication
kicking in or waning down?
• Are some moments better than others?
• Do any PD symptoms appear before
• Are mornings better than afternoons or
taking the next dose?
evenings?
• Are afternoons and evenings better
than mornings?
• What do you do if you forget a
• When does tremor/dyskinesia* come? dose?
• When does tremor/dyskinesia* go away?
• Can you show me/act out these movements?
*Explain the difference between tremor and
dyskinesia • Do you ever feel that one of
the doses doesn’t work?
Ask your patients about night-time
• Can you turn/move your bed sheets?
• How comfortable do • How do you move if you wake up to go to
you feel at night? the bathroom? Can you walk?
• Do you have difficulty • Do you ever wake up
getting into bed? feeling that you can’t
move properly? Does
stiffness wake you?
• Do you have any
painful contractions,
particularly in the
morning?
Educate your patients
• Use videos to explain dyskinesia dyskinesias dyskinesias
movements
• Explain what ON/OFF means, and that
dyskinesia (involuntary movements) may
appear at peak dose times ON
• Use a graphic to explain motor fluctuations,
which can occur in the early stages of PD
OFF OFF
• Ask your patient to use a diary to keep
track of symptoms throughout the day
• Consider using rating scales
08:00 12:00 16:00 20:00
Medication schedule
Figure 1: Key questions: identifying motor fluctuations in early Parkinson’s disease.
PD: Parkinson’s disease.
Creative Commons Attribution-Non Commercial 4.0 August 2021 • NEUROLOGY 27You can also read
