unravelling hidden diseases · session on how collaboration can serve patients’ interests and...

CONGRESS ESSENTIALS

4th Congress of the European Academy of Neurology (EAN)

NeurogeneticsUnravelling hidden diseases

Lisbon, Portugal, June 16-19, 2018

4th Congress of the European Academy of Neurology (EAN)

NeurogeneticsUnravelling hidden diseases

Lisbon, Portugal, June 16-19, 2018

CONGRESS ESSENTIALS

This congress report was sponsored by Pfizer. The publisher retains final editorial control of thecontent. The opinions expressed in this publication arenot necessarily those of the publisher or Pfizer.

Printed and published by John Wiley & SonsThe Atrium, Southern Gate, ChichesterWest Sussex PO19 8SQ, UK

© John Wiley & Sons 2018

Medical writer in attendance: Thomas O’Boyle

Date of preparation August 2018

PR. 1813

Introduction

Set against the impressive backdrop of the 25th April sus-pension bridge, the Centro de Congressos de Lisboaplayed host to the 2018 congress of the European Academyof Neurology on June 16-19. The conference was attendedby some 6700 delegates, mostly from Europe. With theoverarching theme of neurogenetics, the conference wasrich in clinical, scientific, and educational content. Progressin all fields of neurology was presented and participantswere updated on recent developments. The conferenceoffered ample opportunity for networking and a posterpresentation covering a number of different areas in thefield of neurology.

An interesting novelty was the use of the conferenceapp, which enabled delegates to actively participate in theinteractive sessions and vote.

3

4th Congress of the European Academy of Neurology (EAN) CONGRESS ESSENTIALSNeurogenetics. Unravelling hidden diseases

Chronic headache disorders are extremelydisabling.

Proper treatment of headache starts with a correctdiagnosis and multimodal treatment plan toimprove function and well-being.

Political action can improve the lives ofneuropathic pain patients.

Research into brain disorders must be betterpositioned on the strategic research agenda, andthe prevention/management of brain disordersmust be prioritized in policy making.

Existing criteria for headache attributed to TIA aretoo insensitive.

By identifying and understanding biologicaldifferences in the various classes, progression ofmigraine can be minimized and management ofmigraine and its comorbidities optimized.

A chronic headache attack extends beyond thesevere pain phase, as defined in the ICHD-3 criteria.

Physicians can go beyond the guidelines to treatmigraine; unconventional approaches are valid.

Diagnosis of headache disorders should be basedon a proper clinical history and can includeneuroimaging. The ICHD-3 classification may ormay not be useful.

The history plays a key role in the diagnosis ofneuropathy.

Key Points

The entrance to the congress centre.

Update on chronic headache disorders

Much attention was given to the field of headache, withseveral sessions on classification and management. Chronicheadache disorders were addressed in a hands-on interactivesession based on case studies and questions that the par-ticipants resolved using the interactive conference app.Julio Pascual (University Hospital Marqués de Valdecilla,Santander, Spain) presented basic statistics on the extentto which chronic migraine reduces quality of life and dis-cussed the criteria for migraine of the InternationalHeadache Society. The subjective nature of many criteriafor classifying migraine makes it difficult to achieve auniform definition that can be applied across the board,from clinical practice to research. Consequently, diagnosescan vary.

Also widely covered was the topic of medicationoveruse headache (MOH), a challenging and costly conditionaffecting more than 50% of people with chronic migraine.Rigmor Jensen (Danish Headache Center, Copenhagen,Denmark) showed how MOH was treatable and preventableand highlighted the role of detoxification, which whilenot curing MOH completely, considerably reduces thenumber of attacks. After presenting her algorithm fortreatment (patient education, abrupt withdrawal, follow-up, reassessment, and relapse prevention), Rigmor Jensenconcluded that overuse is the cause of chronic headacheand not the consequence. Removing the trigger throughdetoxification is always the first step.

Treatment of migraine was magisterially addressed inthe Moritz Romberg Lecture by Jes Oleson (Professor ofNeurology, Copenhagen, Denmark), who discussed mi-graine mechanisms and new drug targets. According tothe WHO-GBD Study, migraine is the second mostdisabling disease, affecting patients during their mostproductive years. Research into the genetics of migrainehas revealed heritability in 30%-50% of patients who

experience migraine with aura and an associ-ation between genetic status and re-

sponse to drugs, which is betterin acute treatment than in pro-phylaxis. After summarizingthe history of migraine treat-

ment over the last 20 years –provocation models, nitric oxide

model, cortical spreading depressionmodel, CGRP model – Professor Oleson discussed

monoclonal antibodies, some of which are now marketedin the USA. The session concluded with emphasis on the

role of imaging, genetics, and provocation studies in thedevelopment of CGRP agonists.

How political action can improve the livesof neuropathic pain patients. How to builda successful health policy campaign

In an interesting short presentation, the European PainFederation addressed the issue of how political action canimprove the lives of patients with neuropathic pain. Dr.Bart Morlion, President of the EFIC, delivered an instructivesession on how collaboration can serve patients’ interestsand presented the notion of an ideal situation in which re-search unveiled the mysteries of the brain and pain basedon comparable data, flexible work arrangements wereavailable for neuropathic pain patients, and education onpain management and prevention was available.

EFIC represents over 600,000 patients from 37 organi-zations in the EU and further afield (Russia, Israel) andsome 20,000 HCPs from several specialties (clinicians,neurologists, physiotherapists, and anaesthetists). One ofthe Federation’s key messages is the need for collaborationbetween various entities in order to make for a morepowerful organization that can address policy makersdirectly. The presence of the patient is paramount, anddoctors should not speak about patients without a patientrepresentative. An initiative in this direction should be inplace by the end of 2019. In addition, every effort shouldbe made to try to recruit patients who can play an activerole in the organization.

While some success has been achieved at Europeanlevel, it is now time to act at national level. Initiatives arealready under way in Portugal, France, and the Netherlands.The primary objective of current actions is to bring stake-holders together, not only patients and physicians, butalso payers and policymakers.

EFIC is carrying out advocacy work on ICD 11 (betaversion now online). Chronic pain is now recognizedthrough a code for neurological disease and for chronicpain. EFIC can contribute to future success by deliveringsolid data on chronic pain. Over 300 organizations endorsethe initiative. However, teamwork is essential if the interestsof neuropathic pain patients and the professionals whotreat them are to be advanced.

In a second presentation from the European PainFederation, the Executive Director, Sam Kynman, discussedhow to build a successful health policy campaign. Thethree basic pillars of any initiative are education (politicians,

4


“Genetics can play a

key role in assessment

of headache and

response to treatment

”

clinicians, public), research (pain mechanisms), and advocacy(change policies and government actions).

Patient visibility is problematic because it is subjectiveto a certain extent. The EFIC considers pain a biopsychosocialphenomenon that is very challenging for health professionalsand has a huge impact on patient quality of life. Furtherdifficulties in recognizing pain are the fact that paincentres do exist, although there are not nearly enough.Very often pain management is an afterthought of otherclinicians treating the patient’s primary condition (e.g.cancer, diabetes). Furthermore, it is important to addresspain early before it becomes chronic.

The objective of the campaign is to make pain matterthrough a series of strategies: quantification (hard data

should be provided to politicians to ensurethat the issue is taken seriously [1 in 5

people suffer from a painful conditionin the EU]); explanation (exactly whatpain is so that it can be appropriatelyaddressed in the current political land-

scape; funding (quantify for financeministry, annual cost in a country); emo-

tional aspects (how pain affects patients, family,and carers). Politicians, who are often subject to time con-straints, must receive clear written recommendations.

The approach adopted by the EFIC is to play to thestrength of the partner (e.g. clinicians [knowledge],patients [familiar with pain], industry). The relationshipwith politicians to date has been good: some have beeninvolved with the organization’s initiatives for 7-8 yearsand are now part of the campaign. The campaign modelwants pain centres to prioritize multimodal treatmentand to ensure that pain is no longer an afterthought.Measurement of pain should be promoted (e.g. PROMSconsensus and ICD-11 code) and efforts should be madeto appeal to other ministries where pain has an impact.The issue of chronification is particularly interesting inthat it can direct politicians’ toward thinking of pain as along-term problem. Finally, the campaign is already suc-cessful at the European level. However, this does not ruleout targeting centres of power at national level andbuilding movements in other countries.

Some of the ideas put forward by the EFIC wereechoed in the talks looking at the Value of Treatmentproject, specifically for stroke and restless leg syndrome.In the case of stroke, patient care pathway analysis hasled to the creation of integrated stroke units, althoughmuch has still to be done. Despite logistic and financialchallenges, the benefits of such an analysis are extensive

in terms of cost, death, and disability. As for restless legsyndrome, treatment gaps continue to existand many needs are unmet. Awarenessof the syndrome and professionalknowledge are poor, and currentmedications are subject to adverseeffects if administered incorrectly.In conclusion, research on braindisorders must be better positionedon the strategic research agenda, and theprevention/management of brain disorders must be prior-itized in policy making.

Headache and pain

In an interesting oral session dedicated to the generalarea of headache and pain, authors presented theirrecent findings.

Field testing the diagnostic criteria for headacheattributed to transient ischaemic attacks

Dr. Lebedeva (Urals State Medical University, Yekaterinburg,Russian Federation), presented the results of a study tofield test the diagnostic criteria for headache attributed totransient ischaemic attacks (TIA). This was the first timesuch a study had been undertaken, and the aim was topropose new diagnostic criteria if the current criteriaproved inappropriate.

The study population comprised 120 patients withTIA and focal brain or retinal ischaemia with resolutionof symptoms without the presence of new infarction onMRI with DWI scans (112) or CT (8). The control groupcomprised 192 patients admitted to the same hospitalwith gastrointestinal ulcer, lumbago, or lumbar spineosteochondrosis.

Headache was attributed to TIA according to ICHD-3.Comparison with controls revealed differences for headachewithout changes in characteristics (p=0.4), headache withchanges in characteristics (p=0.0001), and a new type ofheadache (initial onset in week before or within 24 hoursafter onset of TIA) (p=0.0001). TIA patients had headachemore often than controls at the time of the TIA.

As for the time of development of the headache, theauthors found that new headache can develop simultane-ously with the TIA and that it can develop with andwithout changes in characteristics. All new types of

5


“Pain management

is often an

afterthought

”

“Management of pain

should be at various

levels and involve all

stakeholders

”

headache developed within 24 hours of onset of the TIA.Many headaches lasted more than 24 hours.

Only 24% of the headaches fulfilled the criteria ofICHD-3. Therefore, the authors propose new criteriafor headache attributed to TIA, as follows: 1. Any newtype of headache occurring within 24 hours of TIAonset; 2. Any type of headache occurring within 1 hourof TIA onset. These would replace the previous criteria(headache that develops simultaneously with othersymptoms and/or clinical signs of TIA, headache resolveswithin 24 hours).

The speaker concluded that the existing criteria forheadache attributed to TIA were too insensitive (only24% of headaches fulfilled them) and proposed new highly sensitive criteria that were fulfilled by 94% ofthe headaches.

Identifying natural subgroups of migraine based on profiles of comorbidities and concomitantconditions: results of the Chronic MigraineEpidemiology and Outcomes (CaMEO) Study

Richard Lipton (Albert Einstein College of Medicine, NewYork, USA) presented the results of the CaMEO study.The objective of the study was to identify clinically mean-ingful natural subgroups of migraine based on self-reported comorbidities at a cross-section in time. Thestudy was a prospective, web-based, cross-sectional surveyincluding screening (sociodemographic data, symptomseverity, aura) and core data (disability, quality of life,anxiety, depression, headache frequency). Latent classanalysis (LCA) in persons with migraine generated 8 classes. The authors also performed an analysis of de-mographic/clinical characteristics, pain features, disability(MIDAS), and allodynia.

Respondents who fell within the LCA-derived comorbidclasses of migraine differ in various characteristics, e.g. those in the “most comorbidities” class (class 1) hadthe highest rates of allodynia and MIDAS score. In addition,the LCA-derived comorbid classes of migraine may differin underlying mechanisms. The authors concluded that byidentifying and understanding the biologic differences inthe various classes, progression of migraine can beminimized and management of migraine and its comor-bidities optimized.

When questioned on the immediate usefulness of theresults, Dr. Lipton stated that they could be used tomotivate lifestyle changes.

Cluster headache is more than the extreme painattack: a prospective diary study of 500 clusterheadache attacks

In their study, Dr. Snoer, of the Danish Headache Center,and her group undertook the task of providing a completedescription of cluster headache from beginning to end.Data were collected using questionnaires analyzing 33 chronic headache and migraine symptoms (episodicand chronic [ICHD-3]), with up to 10 attacks per patient.The authors recorded temporal development, duration,treatment, and symptoms in each phase (pre-ictal, ictal,postictal) to produce a 5-phase model of the attack.

The sample comprised a total of 57 patients (meanage, 47.2 years; 2.9 attacks per day and preventivetreatment in 70.2%) and 500 attacks (mean duration,66.3 minutes).

The authors found that a chronic headache attackextends beyond the severe pain phase, as defined in theICHD-3 criteria. Early pre-ictal symptoms indicate thatthe pathophysiological implications are supportive of acentral origin for the attacks. The authors also confirmedthat there were no differences between the sexes withrespect to photo/phonophobia and personal/family history.Similarly, there were no differences between episodicand chronic migraine.

Teaching courses

Continuing medical education was admirably providedfor at the 2018 congress, with 3- to 4-hour teachingcourses offered every afternoon.

6


Excellent attendance at major sessions.

Teaching course 1. The “difficult to treat” headachepatient

The course was divided into four parts: migraine treatmentbeyond guidelines, neuromodulation in clinical practice,unconventional treatment of cluster headache, and refractorytrigeminal neuralgia. Participants learned how to treat pa-tients not responding to treatment according to guidelines.The approach included the use of unconventional treatmentsand unapproved evidence-based treatment.

Migraine treatment beyond guidelines

Stefan Evers (Lindenbrunn Hospital, Coppenbrügge,Germany) discussed the various options available to treatthe attack, mainly with a combination of acute drugs (e.g. triptan + NSAID) in order to provide fast relief andlong-acting efficacy. Sometimes the drugs are combinedin a single tablet (e.g. Treximet single tablet [sumatriptanand naproxen sodium] in the USA). Most drugs are notapproved for children/adolescents, mainly for legal reasons.Evers’ first choice was ibuprofen 10 mg, followed bysumatriptan nasal spray, although he thought that the ap-proved dose (10 mg) was too low and recommends 20 mg. Dihydroergotamine is an approved drug for thetreatment of migraine, although its availability varies insome countries. In the case of steroids, there are no trialson efficacy in migraine, only for recurring pain.

An alternative approach involves the use of prophylacticdrugs for acute attack. Both drugs are useful in both ways(acute for prophylaxis and vice versa). Prophylaxis can bewith antihypertensive drugs (e.g. candesartan, lisinopril)and anticonvulsant drugs, although robust evidence is

only available for gabapentin, valproate, pregabalin, andtopiramate.

Petasites hybridus is an interesting option in legalterms. The agent is not approved in some countries (e.g. Germany), although it can be used if bought elsewhere(e.g. in the UK). Magnesium 1000 mg iv has been shownto be efficacious in acute migraine with but not withoutaura [1,2,3]. Coenzyme Q10 and riboflavin are also usefulas prophylactic agents [4,5].

Interestingly, combinations of prophylactic drugs havenot proven successful.

The many non-drug treatment options include lymphaticdrainage, interventional treatment (the only evidence avail-able in chronic migraine is for onabotulinumtoxin), andpatent foramen ovale closure (results from trials arepromising [6]). Other options include anticoagulation [7],mindfulness-based stress reduction (meditation) [8], andCGRP antibodies. Evers concluded with an interestinganecdote about Sant’Eustorgio church in Milan. It is saidthat if those who suffer from bad headaches tap theirhead against the marble ark in church, then they will befree from pain for a year!

Neuromodulation in clinical practice

Jan Hoffmann (University Medical Center Hamburg-Eppendorf, Germany) provided a series of interestingoptions for the treatment of migraine. Noninvasive vagalnerve stimulation has been shown to be good based onevidence from open label studies, although this did nothold up in randomized controlled trials. The ACT2 study[9] showed nVNS to be effective in the acute treatment ofepisodic but not chronic cluster headache. New, promisingdata on the mode of action have been reported byAckerman et al [10].

Sphenopalatine ganglion stimulation reduces the intensity(acute treatment) and frequency (preventive treatment) ofcluster headache. One study showed remission in a subgroupof patients, who were also able to reduce or stop prophylaxis [11]. Good results have been reported forexternal trigeminal nerve stimulation, although these arefrom open-label trials [12]. Occipital nerve stimulation is aproblematic therapeutic approach because of infection andcable breakage, and no evidence is available from RCTs.

Single-pulse and repetitive-pulse transcranial magneticstimulation have been shown to reduce frequency andimprove severity by >50% in over three-quarters ofpatients [13].

7


Poster presentation area.

Unconventional treatment of cluster headache

Peter Goadsby, of Kings College London, looked at someof the more unconventional approaches to treatment.Defining the word “unconventional” as “not recommendedby EFNS guidelines at Level A (effective)”, he also addressedcontroversy over the definition of the term “chronic”,since not everyone agrees on what it means (now consideredto be 3 months, whereas before it was 1 month).

Evidence is generally from RCTs. Professor Goadsbydiscussed the special case of melatonin, which is more ad-junctive than primary, although it is difficult to prescribe insome countries (e.g. UK). Other currently used options aretopiramate and gabapentin, although evidence is fromopen-label trials. Some RCT data are available for valproate,and there is modest evidence for botulinum toxin. Currentpossibilities also include dihydroergotamine, other tetracyclicergolines, and hallucinogenics (psilocybin, 2-bromo-LSD,5-MeO-DALT).

Echoing Hoffmann’s recommendations, Goadsby pro-vided data on Gammacore nVNS [9,14], showing that thisapproach was superior to sham therapy for the treatmentof episodic but not cluster headache. Octreotide subcuta-neous has proven effective and safe for the treatment ofcluster headache [15]; pasireotide has also been assessedfor treatment of cluster headache [NCT02619617]. Trialsare currently under way with CGRP monoclonal antibody[NCT02397373, episodic; NCT02438826, chronic].

Goadsby’s recommended options for acute treatmentwere oxygen 100% 15 L/m, sumatriptan 6 mg sc, zolmitrip-tan 5 mg NS, sumatriptan 20 mg NS, and GammacorenVNS. The recommendations for preventive treatmentwere verapamil, greater occipital nerve injection, corticos-teroids, melatonin, topiramate, Gammacore nNVS, andsphenopalatine ganglion stimulation.

Refractory trigeminal neuralgia

Giorgio Cruccu, Sapienza University, Rome, discussed theterminology and the most recent classification of trigeminalneuralgia (TN) and the AAN/EFNS guidelines on management [16] and provided a flow chart for the clas-sification of TN as classic, idiopathic, and secondary. Themost recent classification of the International HeadacheSociety is soon to be reflected in the forthcomingInternational Classification of Diseases (ICD 11).

The consensus (neurophysiologic, neuroimaging, and histology) is that the primary mechanism in classic and

secondary TN is focal demyelination of primary afferentsnear the entry of the trigeminal root into the pons. A sec-ondary mechanism – and one which is more debatable – isthat damaged primary afferents at the site of injury becomea source of ectopic generation of impulses.

The ideal standard treatment for TN is voltage-gated,frequency-dependent sodium channel blockers, and theireffect is well documented in recordings. Cruccu prefersoxcarbazepine because it is better tolerated and recommendssurgery if there is no pain relief despite reaching adequatedoses. Surgery is considered to be very effective, and itmight be interesting to discuss this option with the patientfrom the outset.

Patients generally respond well to oxcarbazepine andcarbamazepine, and finding a nonresponder could be in-dicative of misdiagnosis. In the case of refractory diseaseand patients who cannot take oxcarbazepine and carba-mazepine because of contraindications and adverse effects,the AAN/EFNS recommends lamotrigine, baclofen, andpimozide (as monotherapy or add-on). Refractory patientsare often referred for surgery or botulinum toxin.

Evidence on the efficacy of botulinum toxin is increasing.Pain relief lasts for several months, with the main adverseeffect being transient weakness of the facial muscles in theinjected area.

The take-home message of the session was that oxcar-bazepine should be tried as the first option, with everyeffort made to manage adverse effects. Botulinum toxin canbe applied, and surgery is very effective. Physicians shouldconsider early referral depending on the patient’s attitude.

Teaching course 2. Tips and tricks in diagnosingheadache disorders

This very well attended session covered 3 areas: taking aproper headache diagnosis, introduction to the IHS classi-fication, and neuroimaging in headache. The aim of thecourse was to teach participants to diagnose headachedisorders according to the IHS classification and to applyimaging and other investigations.

Taking a proper clinical history

Rigmor Jensen, of the Danish Headache Center, stressedhow little attention is given to headache during medicaltraining, both for students and GPs, who are an importanttarget for collaboration in their role as “gate-keepers” to

8


referral. In addition, despite the availability of severaldrugs, so much can be done for the patient before drugsare necessary. Every effort should be made to identify thepatient before their condition becomes chronic and reducethe burden. Advances are being made in genetics, althoughstudies have not yet proved fruitful.

The ideal situation for the physician would be theability to predict migraine. In this sense, management ofmigraine is lagging behind other areas of neurology.Emphasis should be placed on the study of risk factors topredict progression from episodic to chronic migraine.

A detailed clinical history based on simplequestions and the headache diary is an

essential component of diagnosis.The physician should try to build

as accurate a picture as possibleof the individual patient’sheadache risk. For their part, pa-

tients should know their own mi-graine status. Also important is the

study of the prodrome so that theheadache can be tackled in the early phase,

thus enabling early treatment and prediction.

Introduction to the IHS classification

Gisela Terwindt, of Leiden University Medical Center, theNetherlands, provided a detailed analysis of the ICHD-3classification, showing how it was useful and how it wasnot. The detailed nature of this systematic classificationcan help physicians to tailor treatment; however, it is nota treatment guide. The terminology used in the classificationis not always clear, for example, “chronic” may meansomething slightly different depending on context: in thecase of chronic cluster headache, it means without remissionperiods, whereas in the case of chronic migraine, it refersto very frequent migraine attacks.

The case of chronic migraine in particular was examinedin depth, with the speaker stating that patients withchronic migraine and medication overuse headache shouldbe given both diagnoses. The classification is subject tocriticism, for example, the number of days per monthwith headache (15 days) is an arbitrary number, with nostrict basis. Dr. Terwindt was unable to provide solutionsand confirmed that physicians prefer to be conservativewhen thinking about changing the classification.

In conclusion, the classification is an ongoing job thatwill never be finished because there are so many options.

Neuroimaging in headache: why, when, how?

Gioacchino Tedeschi (University of Campania “LuigiVanvitelli”, Italy) based his session on a series of cases,with details on the type of imaging that should be usedor not used in specific types of headache. His mainmessage was that neuroimaging is not always necessaryin headache, but may require further scanning of(intra)cranial vasculature, the pituitary gland, and thecavernous sinus.

MRI is indicated for some rare conditions (e.g. cough, headache, nummular headache), andboth MRI and MRA are indicated in primary exerciseheadache, primary headache associated with sexualactivity, primary thunderclap headache, and primarystabbing headache. MRI can also be used to assess asudden change in the features of a stable headachepattern. CT and CT angiography can replace MRI andMRA in an emergency setting.

Teaching course 3. How to approach a patient withneuropathy: from symptoms to diagnosis.

This session was divided into 4 separate areas.

Sensory motor neuropathy

After providing a general approach to nerve anatomyneurophysiology and general principles of diagnosis ofneuropathy, Michael Lunn (National Hospital for Neurologyand Neurosurgery, London, UK) set out a schema comprisingtoxicity, medical aspects, genetic features, and idiopathicconditions. In an interesting approach to diagnosis, theimportance of the clinical history was stressed: by thetime the history is taken, the clinician should be close toa diagnosis. Moreover, professionals should trust theirknowledge and instinct. Many diagnoses are idiopathicand diagnoses of exclusion. As a general rule of thumb,we should remember that uncommon presentations ofcommon things are always more common than commonpresentations of uncommon things.

The diagnostic pathway (algorithm) for neuropathy isbased on clinical patterns, history, and antecedents. Drugs,alcohol, and diet should also be taken into account. Thisshould be complemented by a family history and geneticwork-up (selected Sanger sequencing and next-generationsequencing) to determine whether the disease is hereditary

9


“More emphasis

should be placed on

the study of risk

factors for prediction

of migraine

”

or acquired. While additional testing is important, itshould be remembered that not all positive tests make adiagnosis and that this is often based on specific features.

Motor neuropathy

Eduardo Nobile-Orazio (University of Milan, Italy) pointedout the genetic heterogeneity of motor neuropathiesand stressed the importance of genetic assessment inthe work-up for lower motor neuron diseases and lowermotor neuron syndromes of possible immune-mediatedorigin: chronic inflammatory demyelinating polyneuropathyand multifocal motor neuropathy. IVIg in particular hasproven successful in multifocal motor neuropathy.

The treatment algorithm should be based on carefulclinical evaluation to distinguish a multineuropathiccondition from a merely asymmetric weakness, a reviewof nerve conduction studies to search for marked asym-metry of motor nerve impairment, and anti-GM1 IgMtesting, which, while not diagnostic, should raise doubtsabout the diagnosis. CSF may reveal unexpected abnormalities (and lead to an alternative diagnosis).Biopsy of the motor nerve may help distinguish motorneuropathy from lower motor neuron disease anddetect other causes (amyloidosis). A course of IVIgcould help to clarify the diagnosis in patients with anunclear presentation.

Sensory neuropathy

Claudia Sommer (Neurologische Klinik und Poliklinik,Würzburg, Germany) discussed various syndromes basedon case studies. Using the case of a patient with numbnessand pain in the feet, she stressed the importance of thebasic examination, neurophysiology, key questions to putto the patient, and which laboratory tests to order. Sommerexamined the issue of how to address negative results.Using chronic idiopathic axonal neuropathy as an example,the differential diagnosis should be with Charcot-Marie-Tooth disease, impaired glucose tolerance/early diabeticneuropathy, and vasculitic neuropathy. In the case of smallfiber neuropathy, diagnosis should be based on the history,clinical findings, and laboratory data (quantitative sensorydata, specialized neurophysiology, and skin biopsy). Thedifferential diagnosis should include diabetes, drug toxicity,and genetic causes. In cases of doubt, a full laboratorywork-up should be performed for polyneuropathy. Patients

should be followed up for potential involvement of largefibers. The take-home messages from the session werethat if the patient’s condition is slowly progressive andbasic laboratory data normal, then the physician shouldreassure the patient and abstain from invasive diagnostictechniques. If a diagnosis of sensory neuropathy isconfirmed, then the possibility of an autoimmune causeor malignancy should be considered.

How to approach a patient with neuropathy: fromsymptoms to diagnosis

Jean-Marc Léger (Hôpital de la Salpêtrière, Paris, France)presented a session highlighting some of the pitfalls of di-agnosis of mononeuropathy (association with polyneu-ropathy in several diseases, possible first event of mononeu-ropathy multiplex [MM], which may have axonal and de-myelinating causes). It is important to consider the causesof MM by frequency and by the pathological process. Thekey components in the work-up are establishing the typeof course (acute, subacute), clinical and electrophysiologicalfeatures, absence of signs/symptoms indicative of a systemicor infectious disease, and, in some cases, the pathologicalfeatures on skin/neuromuscular biopsy.

Symposium: Diagnosing genetic epilepsies

It is now thought that there might be a genetic basis in al-most half of all people with epilepsy.Diagnosis of genetic epilepsy may ob-viate the need for unnecessary andinvasive investigations, and the re-cent advances in gene sequencinghave made genetic testing availableat the bedside. The objective of the sym-posium was to give physicians an overview of genetictesting and to encourage them to consider it in additionto EEG and MRI.

Molecular diagnosis in genetic epilepsies: why weneed to test

Sarah Weckhuysen (University of Antwerp, Belgium) gavea very technical and complete review of genetic testingtechniques in epilepsy and in other diseases. She identified3 key questions:

10


“Genetic assessment

could prove to be

a useful adjunct to

imaging tests

”

Who should I test?

Genetic epilepsies cover a broad spectrum ranging frommonogenic disorders to complex genetic disorders. Thecomplexity of some disorders makes it difficult to explainthe problem to patients accurately. Therefore, every effortshould be made to focus on these patients.

Of note, few patients have genetic epilepsy, and it isoften not viable to test for common genetic risk factors(e.g. microdeletions) in clinical practice unless the epilepsypresents with other conditions. Monogenic epilepsies canbenefit from discoveries of new genes with better tech-nologies (copy number variant [CNV] analysis, next-gener-ation sequencing [panels, whole-exome sequencing, wholegenome sequencing]). Most of the genes discovered inthe last year were in epileptic encephalopathies (EE),leading us to change our understanding of the disease.

Through a presentation of cases of epilepsy from anadult clinic, Dr. Weckhuysen discussed the presence ofmosaicism and showed how parental mosaicism is foundin cases of children with EE. Somatic mosaicism cannot al-ways be tested with classic techniques and needs specialistapproaches.

Which test do I order?

Sanger sequencing is not commonly used today, unlikegene panels, which have a good yield, especially in specificconditions. The yield of copy number variant analysis isnot high (<10%), although it can be higher in specificgroups (patients with dysmorphic features and/or congenitalmalformations).

The dilemma of what to do if genetic testing is negativewas discussed. Many of the tests have limitations, and thedisease may not necessarily be genetic in origin. In addition,the gene targeted may not be on the panel or may be onan undiscovered region of the exome. Genetic diagnosisis further complicated by the fact that, while it is easy togenerate genetic data, it is often difficult to interpretthem. This is largely accounted for by the complexity ofthe human genome. Genetic testing should be seen as agood tool in the diagnostic armamentarium, but it doesnot solve all problems, and its yield varies with technique,patient, and disease.

Knowledge of the genetics of disease is not static,but is advancing continuously, and the classification ofvariants is strict, objective, and based on specific criteria.The speaker highlighted the importance of communication,collaboration, and data sharing between all of the stake-holders (neurologist and patient, neurologist and diag-nostic lab, and between clinicians, researchers, and diagnostic labs).

Why should we test?

Despite the pitfalls, genetic diagnosis can reduce the needfor further invasive testing and even surgery. It can facilitategenetic counseling and guide treatment (precision medicine)and lead to the formation of patient organizations anddevelopment of a group identity. It can be used in olderpatients. The presentation of a case study showed a 51-year-old patient with cognitive decline and languagedifficulties. Knowledge of the genetic origin of his diseasemade it possible to change medication.

The notion of the individual patient is very important,in the sense that there is not only one specific gene in allpatients. Very often, the investigation is for one variant inone patient, or the same gene may lead to disease thatpresents differently in different patients.

New therapeutic strategies in development forgenetic epilepsies

Current medication treats seizures, not epilepsy. José MaríaSerratosa (Hospital Universitario Fundación Jiménez Díaz,Madrid, Spain) illustrated how genetics provides us withmany new opportunities. Research efforts should focuson treatments that modulate the functional effects of aspecific defect. Genetic epilepsies provide the opportunity

11


Preparing for a presentation at the conference.

for development of new therapies, and newer animalmodels (zebrafish) are making it possible to develop moretargeted therapy.

Gene therapy based on the adeno-associated viralvector, lentiviral vector, and gene-editing complex isnow being studied in several diseases. Antisense oligonu-cleotides are increasingly used, and 6 have been approvedfor treatment of different diseases. An example of howthey are being used in the real world can be seen in thecase of progressive myoclonus epilepsy (Lafora disease).However, therapy requires intrathecal administration andinduces toxicity.

Targeted therapy can be administered with antibodydrug conjugates and repurposed non-antiepileptic drugs(e.g. NMDA receptors, calcium channel blockers, sodiumchannel blockers, potassium channel blockers, rapalogs).Mutations in DEPDC5 are being studied in zebrafish andcan now be managed with memantine.

Epilepsy surgery in 2018: Has anythingchanged in recent decades?

The objectives of the session were to review current indi-cations for epilepsy surgery in children and adults, reviewthe clinical features and outcomes of common and not socommon surgically treatable epilepsy syndromes, and toreview the current approach with invasive electrodes.

Update on the concept of drug resistance. When should pediatric and adult patients be referred for epilepsy surgery?

The session tied in well with the session on the ILAE clas-sification. Once again, it was stressed that not everyoneagrees with the classifications in the ILAE and prefer touse their own system.

Edouard Hirsch (CHRU, Strasbourg, France) highlightedthe need to discuss concepts and clearly determine thegoal of epilepsy treatment. There is some difference inconcept between freedom and control: seizure controldoes not mean that the patient is seizure-free. In otherwords, we must decide whether we are improving healthor curing epilepsy. Eligibility and presurgical evaluationhave a key role in the work-up and on the decision to optfor surgery in patients with disabling seizures despite ap-propriate medication. Any decision on presurgical evaluationmust be on an individual basis. Patients must be clear on

expectations with respect to the chances of success andrisk of postsurgical deterioration.

Dr. Hirsch presented the European pilot network(Institut des epilepsies-Europe: Idée) for children andadults with refractory epilepsy in Europe. The projectaims to develop epilepsy surgery through cooperationbetween EU centres, to facilitate access to surgery, andoptimize presurgical diagnostic procedures. The statisticspresented show that resective surgery reduced seizuresin 50-90% of cases and left the patient seizure-free in50-80% of cases [18].

When asked if there was a gap in how we diagnosethe etiology of epilepsy and whether he felt there was aneed for a thorough work-up, that is, carrying out athorough work-up and not turning straight to surgery, hereplied that epilepsy control should take into account theright time for the child and the right time for the parents.In addition, treatment should be the best treatment forthe patient, not necessarily the treatment used at aspecific centre.

Common and not so common surgically remediablesymptoms

Christoph Baumgartner (Sigmund Freud University, Vienna,Austria) provided a list of 10 common diagnoses, of which6 are particularly common (hippocampal sclerosis, benigntumors, focal cortical dysplasia, glial scar, cavernoma, nolesion), and stated that there were some differencesbetween adults and children. The less common surgically

12


View of the panel at a named lecture.

remediable syndromes were a group comprising 36 con-ditions, all with very low frequencies.

An analysis of trends in presurgical evaluation duringthe period 1990-2013 revealed stable numbers for surgerydespite increasing presurgical volumes. Presurgical evalu-ations increased continuously over time, and an increasingnumber of evaluated patients did not eventually undergosurgery. Similarly, an analysis of trends in decisions againstsurgery during the same period revealed an increasing fre-quency of neurological explanations for rejection. As fortrends in etiological subgroups, the age at surgeryincreases/decreases according to condition.

The role of imaging techniques was also addressed.fMRI can be used to predict memory decline after surgery,and the use of a minimally invasive approach (laserinterstitial thermal therapy) led to high percentages of pa-tients free of seizures. Dr. Baumgartner spoke at somelength about imaging in various less common syndromes(focal cortical dysplasia, gray matter nodular heterotopia[radiofrequency thermocoagulation], periventricular nodularheterotopia [stereotactic laser ablation], hypothalamichamartomas [MR-guided laser ablation]).

During the question and answer session, there wassome reference to the lack of standardization of memorytests and the fact that protocols were difficult to use. Thespeaker commented that only a small percentage go tosurgery (1%) and that more comprehensive evaluationsare possible.

Epilepsy surgery in patients without obvious MRI lesions: are we overusing intracranialelectrodes?

José M Serratosa (Hospital Universitario Fundación JiménezDíaz, Madrid, Spain) explained that the substantial advancesmade in recent years mean that non-invasive presurgicalinvestigations are often sufficient to define the epileptogeniczone and plan surgery. However, invasive EEG recordingsare still required in more complex cases (e.g. surgical can-didates without visible lesions on MRI).

Dr. Serratosa provided good reasons for intracranialrecordings, but also stated that there were no prospectiveoutcome studies comparing surgery with and without in-vasive recordings. Despite the need for comparative studies,single-stage procedures have been associated with goodoutcome (>70% of patients seizure-free or almost). Invasivestudies can reassure the epileptologist/neurosurgeon andconfirm the results of previous studies.

All in all, there is no evidence of better surgicaloutcomes with a previous evaluation based on intracranialrecording (ICR). In fact, the opposite is true, i.e. ICR isconsidered risk factor for poorer outcomes. Some centresproceed directly to surgery without intracranial monitoring,and some never or rarely use ICR. The results in terms ofsurgical outcome are the same, only with less morbidity,time, and expense.

Noninvasive alternatives for the identification of epilep-togenic lesions include MRI with better software, thin-ner-slice FDG-PET, MSI+MRI, and better selection of can-didates. Furthermore, MRI post-processing can make itpossible to detect small focal cortical dysplasia in MRI-negative patients.

The speaker concluded that management of epilepsycan be made more efficient by considering more one-stage procedures. In addition, new protocols and paradigmsare necessary, and ICR continues to be necessary in caseswith questionable lesions.

When asked whether he considered treatinga patient to be removing a lesion orsomething else, Dr. Serratosa repliedthat he focuses on surgery withoutICR but commented that genetic as-sessment and other work-ups are usedif necessary. Laser ablation would bepreferable, although it is not used in Europe.

The 4th Congress of the European Academy of Neurologyprovided delegates with a wide range of activities, includingoral sessions, symposia, teaching courses, and poster pre-sentations.

13


EAN meeting and greeting area.

“Surgery continues

to play a key role

in the management

of epilepsy

”

References

1. Bigal et al. Cephalalgia. 2002;22:345-353.

2. Cete et al. Cephalalgia. 2005;25:199-204.

3. Demirkaya et al. Headache. 2001;41:171-177.

4. Sandor et al. Efficacy of coenzyme Q10 in migraine prophylaxis:

A randomized controlled trial. Neurology. 2005;64:713-715.

5. Schoenen et al. Effectiveness of high-dose riboflavin in

migraine prophylaxis. A randomized controlled trial. Neurology.

1998;50:466-470.

6. Dowson et al. Migraine Intervention With STARFlex Technology

(MIST) TrialA Prospective, Multicenter, Double-Blind, Sham-

Controlled Trial to Evaluate the Effectiveness of Patent

Foramen Ovale Closure With STARFlex Septal Repair Implant

to Resolve Refractory Migraine Headache. Circulation.

2008;117:1397-1404.

7. Fragoso. Headache. 1997;37:667-668.

8. Wells et al. Headache. 2014;54:1484-1495.

9. Goadsby et al. Non-invasive vagus nerve stimulation for the

acute treatment of episodic and chronic cluster headache: A

randomized, double-blind, sham-controlled ACT2 study.

Cephalalgia. 2018;38:959-969

10. Ackerman et al. Neurobiol Disease. 2017;102:96-104.

11. Barloese et al. J Headache Pain. 2016;17:67.

12. Chou et al. Neuromodulation. 2017;20:678-683.

13. Misra et al. J Neurol. 2013;260:2793-2801.

14. Silberstein et al. Headache. 2016;56:1317.

15. Ann Neurol. 2004;56:488-494.

16. Cruccu et al. Eur J Neurol. 2008;15:1013-1028.

17. Zakrzewska et al. Lancet Neurol. 2017;16:291-300.

18. Mitchell et al. J Centr Nerv Syst Dis. 2012;4:105-115.

14


unravelling hidden diseases · session on how collaboration can serve patients’ interests and...

Documents