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A leading UK expert has said that the development of newly-approved calcitonin gene-related peptides (CGRP) and CGRP-receptor monoclonal antibodies offer great promise in the treatment of migraine.
Dr Manjit Matharu, Lead Clinician of the Headache Group at University College London’s National Hospital for Neurology and Neurosurgery was guest lecturer at the recent Irish Institute of Clinical Neuroscience (IICN) Neurology Update meeting, which was held in the Davenport Hotel, Dublin, on 19 October.
He presented data to the meeting showing that CGRP antagonists are effective in the treatment of acute migraine.
One of these drugs, erenumab, is already available in the UK. The drug is designed to prevent migraine in those who experience frequent migraines, particularly chronic migraine (more than 15 headaches per month), and who have not benefitted from, or cannot tolerate existing treatments.
“There are three others coming along, the second one will be licensed very soon,” Dr Matharu told the Medical Independent (MI).
“They seem to be very exciting treatments. The efficacy of these agents seems to be very good. And the thing that is very promising about them is their side effect profile is excellent. They have next to nothing in the way of side effects. Part of the problems with the drugs we have right now is that the drugs have side effects. And understandably patients don’t want to take those drugs. So what we are going to have is the promise of drugs that are relatively effective and yet don’t have much in the way of side effects and that is very promising.”
Dr Matharu also spoke about CGRP small molecules, which operate in a similar manner.
“They work by the same mechanism on this same compound called CGRP, but they are not antibodies per say,” he said.
“They are traditional drugs as one would think of them normally. And their efficacy seems to be quite good, both as painkillers and preventers of migraine. Those are a little bit further behind, but I expect in the next two or three years will be coming along as well.”
However, Dr Matharu warned there is a “theoretical possibility” that patients on these agents could develop cardiovascular problems, given the likelihood that CGRP acts as a vasodilatory safeguard during cerebral and cardiac ischemia
“All the evidence seems to point against that [that the agents could pose a cardiovascular risk],” Dr Matharu stated.
“But I think the sensible thing for all of us to do will be to keep a very close eye on our patients to make sure there is nothing coming through in the open label use of these drugs that makes us worry about them.”
Dr Matharu also presented data on when to opt for occipital nerve stimulation and what outcomes to expect.
In what would be a key theme of the overall meeting, Dr Matharu said that there was increasing recognition that migraine was not one single disorder, but “multiple disorders thrown into one basket”.
This point was also made in relation to epilepsy by Consultant Neurologist in Beaumont Hospital, Dublin, Prof Norman Delanty. Prof Delanty spoke about the future of precision medicine and the role of genetic testing in refractory epilepsy.
His presentation showed how genetics may offer insights that allow better targeting of existing drug treatments and also help explain the pathophysiology of rare, refractory epilepsy.
Approximately one-quarter of transient loss of consciousness (TLoC) cases are misdiagnosed as epilepsy, the IICN Neurology Update Meeting 2018 heard.
At the meeting, Consultant Neurologist in Cork University Hospital Dr Daniel Costello delivered a presentation outlining clinical features to discriminate epilepsy from other disorders of TLoC.
Dr Costello said common semiological features across TLoC disorders are a main reason behind misdiagnoses.
He added that witness accounts of seizures are often not available, not sought or can be inaccurate.
There are also delays in access to “gold standard” tests, such as Head Tilt and video-EEG monitoring to aid diagnosis.
Speaking about epileptic seizures, Dr Costello said when they are focal in onset, the seizures usually arise from the same region of the cortex.
Seizures can be “small, medium, or large”, but are fundamentally the same, according to Dr Costello, who said the seizures are stereotyped, even when they are unusual.
“Aura, where reported, is very useful in discriminating seizures from other TLoC disorders,” he told attendees.
Aside from epilepsy, another cause of TLoC can be neurocardiogenic syncope, which is defined as reflex-mediated loss of consciousness resulting from the failure of the automatic nervous system to maintain adequate cerebral perfusion pressure.
“The subsequent cerebral hypoperfusion induces a transient loss of consciousness that is associated with myoclonic jerks and brief convulsive activity in [a number of] per cent of patients,” Dr Costello explained.
Features of cardiac syncope are that they are brief (often with no prodrome); and can be exercise-induced or startle-induced.
Dr Costello stated that cases of psychogenic non-epileptic seizures (PNES) are rarely recognised at the outset and are usually managed as epilepsy, syncope, or ‘blackout’.
The mean latency between the first event and diagnosis of PNES is four to seven years, he outlined.
Dr Costello said that disassociation was an “important overlooked feature”, with a common sequence being panic leading to disassociation leading to loss of awareness.
There are two varieties– PNES that is motionless/trance-like; and PNES with movements.
He highlighted how the movements of PNES are different to those in epileptic seizures.
“Rapid evolution to more than 10 events per day in adults is more typical of PNES than epilepsy or syncope,” Dr Costello explained.
“Regaining consciousness on ground where you collapsed is more typical of syncope than epilepsy or PNES.”
However, he admitted in many cases it is impossible to be certain of a PNES diagnosis.
Overall, Prof Costello concluded by saying that clinical history is “far more important” than investigations in cases of TLoC and that it was not advisable to assign a diagnosis when uncertain.
He added that physicians should be aware of a dual diagnosis of epilepsy and non-epileptic seizures in the same patients, and that close assessment of movements was very useful in diagnosing the latter.
“It is helpful to think of non-epileptic seizures as dissociative phenomena,” he stated.
“And it is helpful to differentiate between unprovoked and provoked seizures.”
Consultant Neurologist in Tallaght University Hospital, Dublin, Dr Richard Walsh provided a comprehensive description of differential diagnoses of tremor to the IICN Neurology Update Meeting 2018.
Dr Walsh stated how the condition is characterised most simply as “rest” or “action” tremor.
Action tremor can be either postural or kinetic, with “intention” tremor being a feature of some action tremors that worsen as a target is approached.
Dr Walsh listed some of the questions he asks when presented with a patient with tremor such as: The length of time the tremor has been present; whether it is a rest or action tremor or both; whether there is symmetry and whether other body parts are affected.
He told delegates it is useful to ask the patient whether the tremor is a “curiousity, a concern or a disability”.
Distinguishing features of Parkinsonian tremor include asymmetrical limb movement, with tremor in the chin or head less common.
“The thumb tends to be flexed in the rest position,” he stated, “and some patients can exert control.”
He also noted the “alternating pattern of agonist-antagonistic muscle activation” and that “nigostriatal dopamine depletion correlates well with rigidity and bradykinesia”, but does not “correlate with striatal dopamine depletion”.
Dr Walsh pointed out that tremor is not a feature in approximately one-third of Parkinson’s patients.
Dr Walsh also spoke about tremor that is resistant to treatment by levodopa, the aromatic amino acid which is a common medication for Parkinson’s disease. He stated that while there is an incomplete benefit in as many as 30 per cent of cases, a complete lack of response is rare.
Levopoda-resistant tremor should always raise questions about diagnosis, according to Dr Walsh, adding that the most common cause for a lack of response is insufficient dosing.
Moving on, Dr Walsh stated that “essential tremor” is the most common movement disorder syndrome, but was a clinical syndrome rather than a disease entity.
In these cases, isolated head tremor is rare, if existing at all, he explained.
There is a misdiagnosis in between 30 to 50 per cent of cases of essential tremor, but Dr Walsh said that alcohol response is a useful diagnosis clue.
Meanwhile, “dystonic tremor” is seen in dystonic body parts or is associated with dystonia in the absence of posturing.
The tremor is instigated typically with action, is “jerky”, and may have a “nul point”.
“Like dystonia, the pathophysiology is largely unknown,” according to Dr Walsh.
Unfortunately there is no evidence of benefit of any drug therapy for these patients, though deep brain stimulation may be an option.
Dr Walsh also mentioned how consensus is emerging that SWEDD tremor is a term only to be applied as a descriptive term for an imaging finding.
“This is a term that may only reflect diagnostic inaccuracy and limited accuracy of DaTscans in early Parkinson’s disease,” he stated.
Dr Walsh said that “red flags” for “functional tremor” are: Sudden onset; variability of phenomenology; distractibility; and entrainment.
Another talk at the meeting focused on the common diagnostic problem in clinical practice of patient with white matter disorders identified on MRI.
Dr Debs Bhattacharya, Consultant Neuroradiologist from the Belfast HSC Trust outlined his own approach to demyelinating disorders.
Dr Bhattacharya highlighted the dangers of relying solely on pattern recognition without thinking about the pathophysiology of demyelination itself.
According to Consultant Neurologist in Beaumont Hospital, Dublin, and Clinical Professor of Neurology at Trinity College Dublin, Prof Orla Hardiman, motor neurone disease (MND) is a spectrum disorder and not a single disease entity. Prof Hardiman made the observation during her talk at the Neurology Update meeting in the Davenport Hotel Dublin on 19 October, organised by the recent Irish Institute of Clinical Neuroscience (IICN). Prof Hardiman said that multiple subcohorts exist within differing pathogenic processes and disease trajectories.
“Multimodal interrogation of patient cohorts is required to define subcategories and understand disease progression,” according to Prof Hardiman.
Cognitive impairment and behavioural change
Prof Hardiman said the cognitive impairment was a common, but often under-recognised feature of MND. She stated that cognitive decline progresses with the disease but is often difficult to detect. “Cognitive status is linked with the rate of motor decline and risk of attrition,” according to the professor. It is linked with the rate and pattern of cognitive decline.
Behavioural change also occurs in people with MND. Examples include: Violation of personal spaces; lack of judgement; ignoring social etiquette; and swearing. The most prominent behavioural symptom reported in MND is apathy, defined as the loss of motivation, initiative or interest.
“Disinhibition can manifest as loss of manners or a new onset of socially inappropriate behaviour,” she said.
“Patients can also present with a reduced awareness or insight of their deficits and symptoms.”
Genomics and linked conditions
There are 30 genes “of major effect” in MND, Prof Hardiman said. The genomic profile of the disease differs depending on the population. For example, C9orf72 accounts for 50 per cent of known “familial” motor neurone disease in Ireland. There is also a biological link between some forms of MND, psychosis and impulse dyscontrol.
“These links are most apparent in kindreds with C9orf72 expansions but are also present in non- C9orf72 kindreds,” according to Prof Hardiman. She added that there is strong epidemiological evidence for common pathogenic processes in MND and some neuropsychiatric disorders. For example, MND and schizophrenia share common susceptibility genes. In Ireland, up to 15 per cent of people with MND have another family member with MND or a frontotemporal dementia (FTD). Also, up to 30 per cent of people with MND have a family member with FTD or three first/second degree relatives with a neuropsychiatric condition.
Prof Hardiman said the development of precision medicine approaches for MND promise a breakthrough in how the disease is treated. She argued that as MND is a spectrum disorder, effective treatment is likely to be in a subgroup of patients. For this to occur, however, she said that trial design and outcome measures have to be refined.
Speaking to the Medical Independent (MI) after her talk, Prof Hardiman said future treatments will either comprise a “single-target precision medicine approach” for genetic variants, or “it will be a polypharmacy approach”.
“We know there are a number of things that happen and you could intervene in a number of different areas,” according to Prof Hardiman.
“We know that in these neuro-degenerative diseases that one of the things that happens is that proteins fold in the wrong way and they damage cells. We know that if we can intervene in the protein misfolding stage that is really important. We also know that it spreads along networks. One of the aphorisms is, ‘what wires together dies together’. And if we can understand how the networks work and if the networks are a little bit vulnerable, I think our data would suggest that some people are born with networks that don’t modulate quite as well and that makes them more prone to get neuro-degenerative diseases later in life. I think our data would support that. It is totally a conceptual hypothesis at the moment, but I have reason to believe there is some truth to it. And then if we could find some way of modulating the network or let the network modulate a little bit better we might be able to improve or slow down the progression of the disease for that reason. We also want drugs that help with the protein misfolding, or slowing down the misfolding, or making the misfolding protein less toxic or improve the bioenergetics of the individual cell as well. So I think it is going to be at a number of different levels. But I think it is really exciting.”
Prof Hardiman added that the recognition of different phenotypes of the disease was vital to develop better treatments.
“That’ll drive the development of treatments because we’ll be incorporating them into our outcomes,” according to Prof Hardiman.
“And that’s one of the reasons why our trials failed. Some of our trials failed because the drugs didn’t work. And some of our trials failed because the drugs didn’t get to where you thought they were supposed to go in. Some of our trials failed because we didn’t measure the right thing. So we recognise those three things. So we have better trial design; we are better at including people that are kind of the same; we are better identifying what we want to measure; and then we are better at actually measuring, coupled with all the work that is happening with early drug development in pharma, lots of small biotech companies and the insights that we have in terms of the cell biology as to what is going on.”
As revealed by this newspaper, Prof Hardiman was recently appointed as the new Clinical Lead for the Clinical Programme for Neurology. Prof Hardiman is still working out the details with her employer, but is expected to take up the post in December. Speaking about her priorities for the role, Prof Hardiman said that implementation of the recently developed Model of Care for neurology was vital.
“I think we need to be strategic about what we can do,” Prof Hardiman said.
“From my perspective anyway, what makes neurological care good is a multi-disciplinary approach. A lot of neurology can be outpatient based now. I think if we can build on the multi-disciplinary team approach and actually empower some of the multi-disciplinary team members, I think that will be a much more productive way of driving the service. So the Neurological Alliance conducted a survey a couple of years ago looking at the level of multi-disciplinary team support across the whole country. And there was no centre in the whole country, even in Beaumont and Cork, that has a full complement of service. That’s something I think we need to look at.”
For rare diseases, Prof Hardiman said it is important for a “single centre” approach, such is the case for MND in Beaumont Hospital.
“Then for common diseases [such as migraine] it is important that we have really good outreach into the community, and good diagnostics. And then feedback into the community with really good support to the GP in terms of management. And that can be done both electronically, and with good nurses. And then the intermediate diseases [such as multiple sclerosis] we need targeted support.”
Prof Hardiman said implementation of the Model of Care is essential to improve services for people with neurological conditions.
“The Model of Care is big and it’s aspirational and that’s the way it should be. The Model of Care is sort of the bible. We have to be strategic about what we can do, and if you take on a position like this, you should set yourself goals and targets. And they should be achievable.”
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