Ep. 203: Diagnostic challenges in ALS and frontotemporal dementia

00:00:00: Welcome to EANcast, your weekly source for education research and updates from the European Academy of Neurology.

00:00:15: Hello!

00:00:16: And welcome to EENcast Weekly Neurology.

00:00:20: I'm Valentina Juzolino, neurologist clinical neurophysiologist and a PhD candidate at University of Naples Federico Secondo.

00:00:29: My research focus is on neuromuscular and neurodegenerative disorders especially on ALS.

00:00:37: This month we are exploring the fascinating and increasingly important topic of ALS and frontotemporal dementia.

00:00:47: And in today's episode, We will talk about Diagnostic challenges in ALS & Frontotemporary Dementia.

00:00:55: My guests today are Professor Elka Stefanova and Professor Mamede De Carvalho.

00:01:02: Professor Elka Stefanova is a professor of neurology and head of the Center for Memory Disorders and Dementia at the Clinical Center of Serbia, specializing in neurodegenerative diseases with focus on Alzheimer's disease and frontotemporal dementia.

00:01:21: Professor Mamede de Carvaggio is full professor or physiologist at Lisbon University and a Senior Consultant Neurologist & Clinical Neurophysiologist at Hospital de Santa Maria, Portugal.

00:01:36: Internationally recognized for his work in Amiatrophical Lateral Sclerosis, Neurofysiology and Neuromuscular Disorders.

00:01:45: Welcome both Professor Stefanova and Professor De Carvallo!

00:01:49: And thank you for joining us today.

00:01:52: Thank You For Inviting Us.

00:01:55: So let's start.

00:01:57: I want to start asking, what is the most frequent clinical presentation of ALS and what are the most frequently diagnostic pitfall in early ALS?

00:02:10: Which mimics do you find most challenging?

00:02:16: Thank you very much for this opportunity.

00:02:27: Opics are very related.

00:02:29: Indeed, the presentation... The region of onset in ALS depends on their age and even gender or sex of patients.

00:02:40: For example all patients tend to have more bulbous presentations in particular women And that represents very well that variability of phenotype depends both factors-the age and the sex But also depends on ethnicity, because bulb presentation is more frequent in western world than in Asia for example.

00:03:04: So there are differences that we have to consider.

00:03:06: but in Europe where you are about twenty five thirty percent of the patients present with a bulb onset almost always with these arteries very rare patient presenting with this phage.

00:03:18: And the first symptom in bulbor onset is classically a dysartery.

00:03:24: That progressed to dysphagia later on.

00:03:27: The most frequent presentation in ALS.

00:03:29: really, it's the spinal onset upper limbs or lower limbs.

00:03:34: Occasionally we have patients presenting with respiratory onset about three-to five percent which that sometimes is difficult because, I mean we believe the patient can have a medical condition and few patients present with an axiolonset like Neck Pulsee.

00:03:53: And it's again a difficult phenotype Because... We don't think about ALS many times when you see a patient like this.

00:04:02: The mimicking disorder that they can think of depends on phenotypes.

00:04:06: That why the link between both are so important.

00:04:09: If you have a patient with bulbul presentation, then we can think if the patients reported that started very rapidly and the neurologist sometimes they believed it could be a stroke.

00:04:23: And if there is more slower... The patient reports a slow progression of bulbul involvement.

00:04:28: Then we have to think about other neurogenerative disorders like superbulb palsy or even Parkinson's disease.

00:04:40: And so that depends very much where the disease starts and patients beginning with upper limbs weakness, if it is a young man we have to think very seriously about multi-focal motor neuropathy without conduction block in older patients.

00:04:59: of course we think about cervical myelopathy cervical myelopathy, we have pain.

00:05:06: We have sensory changes and sensory symptoms but anyway this is something that we have to think about.

00:05:13: And in lower lumbar onset if it's very distal and symmetric at the tracheous presentation then we think about neuropathy which should be studied.

00:05:24: If it's more proximal and unilateral, in the diabetic patients we can think about Plexopathy.

00:05:31: Although PlexOPathy is in general associated with very intense pain And generally in lower limb onset root lesions are something that you have to think about and explore with imaging.

00:05:44: In patients with upper and lower limb onsets of course myopathy particularly if their weakness is more proxima Myopathy is something that we have to think about.

00:05:55: And so the Minicine disorder, I think depends very much on phenotype and we cannot dissociate both.

00:06:03: That's my point.

00:06:05: Thanks!

00:06:06: This shows how clinical heterogeneity is really interesting... ...and really tricky for differential diagnosis.

00:06:16: So staying in this topic of clinical practice When can we confidently apply the Gold Coast criteria?

00:06:25: And how do they compare with earlier criteria like L.S.

00:06:29: Corial and Rashi?

00:06:33: Thank you very much!

00:06:34: About the criteria for disease diagnosis is a very important point, I mean... The Gold Coast Criteria is a simple set of conditions that includes patients with progressive muscle the atrophy, in other words patients with pure lower motor neuron involvement.

00:06:52: So by default it's impossible not to be a golden-coast.

00:06:58: criteria is more sensitive than Awajie and then elsewhere.

00:07:02: criteria just because are including patient that were excluded before... That one point!

00:07:08: Another point here is very simple we don't have categories yet.

00:07:12: So the problem with L-scoreal and Wajji, which was more sensitive than the L-scoreal but again following them categories is that what's difficult for the neurologists to understand the categories.

00:07:28: And interrater agreement.

00:07:29: there are very good paper problems about this.

00:07:32: Interrater agreements regarding the categories were poor

00:07:35: I

00:07:36: mean, because of that.

00:07:38: Because it was difficult for them, the neurologists and neurophysiologists to keep in mind complexities of the categories.

00:07:45: So this is much simpler.

00:07:47: The patient has ALS or has not ALS And that depends on involvement with two regions With lower motor neuron involvement On clinical ground Or supported by electromyography.

00:08:01: Or a patient presents one region with upper and lower motor Neural involvement at least the minimum.

00:08:08: And so they are very simple, there is no paper really studying the integrated agreement with the Gold Coast criteria but for

00:08:17: sure

00:08:19: it's higher than when using an old squirrel or a watcher.

00:08:24: So really increased sensitivity by default including group of patients that were excluded and based on literature you have There is no lower specificity, so there's not risk of saying the patient has ALS or having ALS.

00:08:41: So specificity is still high because we have to exclude other conditions that I had mentioned before by imaging and other methods for diagnosis, laboratory evaluation for example.

00:08:54: And you need stress the importance of neurophysiology and supporting diagnosis in ALS, in this criteria... In the previous criteria that we have mentioned before.

00:09:08: And how does neurophysiology help resolve diagnostic uncertainty?

00:09:15: Neurophysiology is very essential for diagnosing.

00:09:19: We had the privilege of having a way to measure the generation of neurons directly the lower motor neurons in spinal cord that we don't have in Parkinson's disease or Alzheimer's disease, in front of temporal dimension because... We cannot put a needle there to evaluate generation after neurons.

00:09:37: We had that privilege at ALS and for diagnosing ALS you need to find that the disease is not focal it widespread And do know that with neurophysiology can find changes in muscles which are very well preserved clinically.

00:09:54: That this point And we have to find that muscle, it seems completely normal clinically.

00:10:00: they are not really normal.

00:10:01: They're normal on neurophysiology in EMG and these are the advantages.

00:10:07: of course We can trace that with neurophyiology is We have to screw other conditions, we have to screwed myopathy.

00:10:16: We had to screw conduction blocks when that is reasonable and

00:10:20: etc.,

00:10:21: but... ...we can find very early changes in muscles That you cannot really replace by using ultrasound for example finding fisculations in early effected muscles, which is really the first change to muscle.

00:10:36: We can use ultrasound for that.

00:10:38: but with ultrasound we cannot really analyze the morphology of the fisculation potentials and their stability or instability.

00:10:51: And very important is the end plate.

00:10:53: The very early change in the endplate function, so you see unstable motor units and that unstable motor unit are just not earlier but they're very sacial to confirm that muscle is affected.

00:11:07: That's something we can really obtain by using needle ebg signs of ongoing denervation, a dynamic process of denervation.

00:11:20: Finding fiduciation sharp waves with needles is very important to show that it's not chronic condition something going on and this again for the diagnosis of ALS.

00:11:32: so really in neurophysiology we can see suffering After lower motor neurons, we can see the dynamic of the disease.

00:11:41: We can see changes in a muscle that they seem very normal clinically.

00:11:45: and all that information is essential for supporting diagnosis And also for excluding other conditions That can mimic ALS.

00:11:56: Thanks This is an important point especially In daily clinical practice.

00:12:04: Turning to FTD for Professor Stefanova.

00:12:09: What are the most common early signs of frontotemporal dementia that are misinterpreted in clinical practice?

00:12:19: Let's start with short introduction on demographic and clinical characteristics.

00:12:37: cause of early onset dementia after Alzheimer's disease.

00:12:41: The estimated prevalence is around twenty cases per one hundred thousand people in general population with twenty percentage of young onset, the Mesh.

00:12:56: The typical onset is between forty five and sixty-five years of age which means course.

00:13:09: Females and males are affected roughly equally, about forty percent of patients have a positive family history with twenty percentage of patient without dosomal dominant inheritance pattern.

00:13:29: there three core clinical syndromes or front temporal dementia spectrum.

00:13:36: one is the behavior variant which is the most prevalent in this spectrum, with personality and behavioral changes like disinhibition, apathy loss of empathy compulsive behaviors changes in eating habits poor judgment an executive dysfunction.

00:14:02: The second one is primary progressive aphasia either as non-fluent agrammatic variant with affordable speech or fluent semantic variant, with loss of word meaning and lost object knowledge.

00:14:23: The third one is overlapping syndrome between frontotemporal dementia and motor syndromes.

00:14:33: Usually behavioral variants with amyotrophic lateral sclerosis, corticobasal syndrome or progressive supranuclear palsy.

00:14:46: You are right when you mention that FTD is likely under diagnosis especially early in the course of this disease.

00:14:56: it's very difficult to differentiate between psychiatric disorders and patient with front temporal dementia.

00:15:07: It usually misdiagnoses with bipolar disorder, depression and personality disorders or atypical Alzheimer's disorders.

00:15:20: FTD should be suspected in a middle-aged patient with progressive behavioural or language changes especially when memory is relatively preserved.

00:15:32: early orientation is spared during the course of this disease.

00:15:43: This brings us to another important challenge, how do you distinguish between a behavioral frontotemporal dementia and primary psychiatric disorders?

00:15:56: As a neurologist I must admit that differentiation is one of the biggest real-world diagnostic challenges, especially in early course of the frontotemporal dementia.

00:16:19: Behavioral variant can closely resemble depression bipolar disorder schizophrenia spectrum illness obsessive compulsive disorders or personality disorders.

00:16:36: therefore As a neurologist, we usually use several distinguishing features in favor of behavioral variant or frontotemporal damage.

00:16:50: The first one is progressive deterioration.

00:16:53: Psychiatric disorders often fluctuate and usually in behavior variants have gradual but relentless progression accumulating functional impairment during the course of disease, worsening social and occupational dysfunction over time.

00:17:19: The message is that serial history or

00:17:23: serial

00:17:24: visit often more valuable than a single visit in clinic.

00:17:35: might be loss of social cognition and empathy.

00:17:40: The subjects with frontotemporal dementia presents emotional coldness, reduce concerns for others even the very close relatives.

00:17:52: socially inappropriate comments violation of interpersonal boundaries.

00:18:00: This pattern is less typical in primary mood disorders.

00:18:04: The third one is lack of insight.

00:18:08: The patient with frontotemporal dementia usually deny behavioral changes, minimize their symptoms and they have a lack of awareness of the consequences of this behavior.

00:18:26: Patient with depression in contrast often report distress

00:18:31: And

00:18:34: this is the most important differential diagnosis feature.

00:18:42: The fourth feature is stereotyped or compulsive behaviors, which could start early in the course of diseases like repetitive rituals pacing very fixed routines hoarding or changes in eating habits.

00:19:05: These behaviours are highly supportive of behavioural variant when it is progressive.

00:19:13: The fifth favouring feature is neurologic or cognitive, something like executive dysfunction which present either in neuropsychological testing and everyday life with impaired verbal fluency without strategy, without planning or utilization.

00:19:40: behavior, presence of the primitive reflexes.

00:19:44: Or you can find the signs for motor neuron disease or Parkinsonism in some syndroms.

00:19:52: Memory and visual spatial abilities may be relatively preserved early on during the course.

00:20:01: and the most important issue is the collateral history or the history which was given from memory, family member care giver co-worker.

00:20:20: It's essential because patients often like inside relatives can describe personality changes longitudinally.

00:20:31: Usually they say that the person is not the same as it used to be and this a very highest yield components of assessment.

00:20:45: We can finish these introduction with red flags which suggesting behavioral variant rather than psychiatric disorder when you have consider psychiatric presentation after the age of forty-five as a key distinguishing feature for behaviour variant or frontotemporal dementia.

00:21:15: Progressive personality change, marked disinhibition or apathy, compulsive eating or outer food behavior poor response to psychiatric treatment or functional decline despite stable mood.

00:21:41: Thanks, I think you touched on a key issue there early recognition longitudinal evaluation.

00:21:57: What

00:21:58: K imaging and CSF findings support the diagnosis of frontotemporal dementia in clinical practice?

00:22:08: Unfortunately, nowadays the diagnosis or frontotemperal dementia is still clinical.

00:22:17: We do not have enough specific or enough sensitive CSFs for frontotemporal dementia, as we have got in Alzheimer's disease.

00:22:32: Neurologists in everyday clinical practice usually are looking for additional diagnostic tools like neuropsychological testing, structural MRI or FDG-PAT scanning gene mutation in C-noref-II or MAPT or progranuline.

00:23:05: MRI usually could present the asymmetrical, bilateral frontotemporal atrophy.

00:23:16: Very similarly In FDG PET scanning we are seeing hypermetabolism.

00:23:28: Thanks, that's extremely relevant.

00:23:32: And now before we close I would like to thank again Professor Stefanova and Professor De Carvalho for this extremely insightful discussion.

00:23:42: Todays conversation really highlighted how ALS and frontotemporal dementia should no longer be considered completely separate disorders but rather part of a border neurodegenerative spectrum where motor, cognitive and behavioral symptoms can overlap in complex ways.

00:24:05: Professor Stefanova reminded us that frontotemporal dementia is not a single entity but an heterogeneous clinical spectrum.

00:24:13: one of the key take-off message Is that behaviour or personality changes are often misinterpreted as psychiatric disorders.

00:24:24: Recognizing the so-called red flag is essential for an earlier and more accurate diagnosis.

00:24:31: Another very important point discussed today, it's current lack of definitive biomarkers for FTD in routine clinical practice because these neuroimaging still play a central role.

00:24:46: Professor Decarbaio also emphasized how challenging the diagnosis of ALS can be, particularly in bulbar phenotype or early and slow progressive presentation.

00:24:58: We

00:24:58: discussed our importance to combine careful clinical observation with neurophysiology not only to support the diagnosis but also to exclude important mimics.

00:25:14: Another important message from today is that diagnostic criteria are a useful tool, but they should never replace clinical judgment.

00:25:25: The gold cost criteria have improved sensitivity and may facilitate early diagnosis But uncertainty still part of real-world clinical practice.

00:25:37: So the KTECO message is probably this early recognition of cognitive, behavioural and motor symptoms together with multidisciplinary and longitudinal approach.

00:25:51: It's essential to improve diagnostic accuracy in patient care.

00:25:56: Thank you again to Professor Stefanova and Professor De Carvaggio for joining us today And thank you our listeners for tuning into EANcast Weekly Neurology.

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