Ep. 189: Red flags of treatable (spino)cerebellar ataxias

00:00:00: Welcome to EANcast, your weekly source for education

00:00:04: research and updates

00:00:05: from the European Academy

00:00:07: of Neurology.

00:00:15: Hello everybody!

00:00:16: My name is Jean-Durainz.

00:00:17: I'm a neurologist in the Queenborough local health unit And member of the EAN coordinating panel on rare neurological diseases.

00:00:25: In today's episode we will talk about red flags off treatable cerebellar ataxia.

00:00:31: Cerebellar ataxias are a large and heterogeneous group of diseases, And the common reason for neurological assessments.

00:00:38: They can have acute, subacute and chronic presentations... ...and frequently lead to significant impact on quality life.

00:00:46: Although ataxia is frequently regarded as main cause of progressive disability There's several conditions in which a prompt diagnosis or early treatment can stabilize Or even improve symptoms.

00:00:59: Due to clinical heterogeneity of cerebellary taxias, their diagnosis is often challenging and a well-organized approach is needed to reach an early diagnosis.

00:01:10: And avoid mistreatment opportunities.

00:01:13: Since this month we celebrate the rare disease day We will mainly focus on rare causes of taxia and not cover more common causes like alcohol infections or neoblastic diseases.

00:01:25: In this episode, we will discuss how to recognize the main rare causes of ataxia-enriched.

00:01:31: specific treatments are available.

00:01:33: We'll highlight common neurological and systemic red flags that should be assessed during clinical examination The relevance for timely and precise diagnostic workup And currently available treatment.

00:01:47: It is a pleasure welcome my guests today To internationally recognized experts in these fields.

00:01:53: Our first guest is Professor Paola Giunti Professor of Neurology at the UCL Queen Square Institute of Neurology in London, and Dr.

00:02:01: Lydia Saro, neurologist at Instituto Neurolojico Carlo Vesta in Milan.

00:02:06: Professor Giunti, Dr.

00:02:08: Saro welcome to the EAN cast!

00:02:10: And thank you very much for joining us today.

00:02:13: My first question is to Dr.

00:02:14: Saro.

00:02:16: One of the main groups neurologists think about when asked about treatable diseases are the immune mediated disorders.

00:02:23: Can you give us an overview on the main diagnosis not to miss?

00:02:26: Which clinical findings we, as neurologists must be aware of and how can we better guide diagnostic work up for this group of

00:02:34: diseases.

00:02:35: Thank You Joe!

00:02:37: Thank you for inviting me.

00:02:39: So autoimmune mediated alexia represent key area of interest, those causes account for approximately six percent sporadic cerebellar alexi cases in adults and as I said age of onset progression associated symptoms are the most critical factors to guide clinical approach and identify red frogs.

00:03:02: Episodic ataxial is the key element, so if in order to it appears some episodic attack an autoimmune etiology is highly likely and should be investigated immediately because he's amenable to therapy.

00:03:20: MRIs essentially for narrowing the differential antibody-mediated demyelinated disease.

00:03:27: There is a significant phenotype overlap between different antibodies and new antibody are constantly being discovered, so it's very challenging field of diagnosis.

00:03:41: The most frequent autoimmune type of ataxia is the glutamic acid decarbosilase-GAD-C-V antibody related anaxia.

00:03:50: It can present alongside with other GAD-related autoimmune signs such as stiff perso spectrum disorder Pyramidal Sign, Epilepsy and also Type I Diabetes Pernichose Anemia and the Vitiligo and Chiro Disease.

00:04:06: It is rare but it typically is diagnosed in women after they're twenty years old.

00:04:14: There are a limited number of instances where the presence of anti-God's.

00:04:18: sixty five coexist with cancer But these are limited like four to six percent cases.

00:04:26: Usually it has a subacute or chronic onset and gait ataxia is the most prominent feature.

00:04:34: Often patients report warning episodes of vertigo, diplopia, or slurred speech And high anti-gad tiders are also linked to stiff person syndrome sometimes.

00:04:48: So the key diagnostic element is detecting the antibody.

00:04:52: The most significant antibody is the one that you can detect in CSF.

00:04:58: Compared to serum, those are highly specific.

00:05:02: You also find oligoclonal band in the CSF.

00:05:06: but the important thing is that titles of these antibodies need very high diagnostics.

00:05:16: In fact around two thousand units per ml.

00:05:20: Therefore, it is important to collect a peer sample of serum and CSF to get appropriate diagnosis.

00:05:28: And to rule out false positive brain imaging can be remarkable at the beginning but late in later stages atrophy cerebellum Can we detected?

00:05:39: It's very important to identify this diagnostic entity because there is a possibility of treatment not only the symptomatic treatment, but also potentially disease-modifying treatment which is essentially immunotherapy.

00:05:56: First instance intravenous immunoglobulin or retuximab or plasma Pharisees which are suggested for short term adjunct therapy for exacerbation in severe spasm and Other novel immunotherapies are in the offing, like autologous hematopedic sensual transplantation and CAR-T cell for severe refractory diseases.

00:06:25: other studies suggest to follow an escalating treatment approach, such as first line Eidos corticosteroid and then intravenous immunoglobulin or plasma pharesis.

00:06:36: And in the third-line mycophenolate or retoxemab.

00:06:40: so the prognosis.

00:06:42: usually if the treatment is started early phase there's a good response.

00:06:49: but clinical pearl.

00:06:51: we need take home that always test for anti in patients who present with ataxia, especially alongside other autoimmune conditions or stiff person syndrome.

00:07:02: Another important autoimmune cause we should discuss is the gluten ataxi.

00:07:08: In setting of chronic immune medieta enteropathy with antibodies against transglutaminase and endometrium cerebellar ataxias are most common neurological manifestations.

00:07:20: It can occur together with other symptoms such as neuropathy, brain calcification seizures and so on.

00:07:28: And it typically presents in the fifties or sixties.

00:07:32: this more prevalent in northern Europe.

00:07:36: Ninety percent of people who present with gluten ataxia

00:07:41: might

00:07:41: not have gastrointestinal symptoms even if then biopsy shows a damage.

00:07:47: The clinical presentation is a slowly progressive gait and limb ataxia, dysartia, nystagmus, associated symptoms such as peripheral neurology, neuropathy and seizures can occur.

00:08:00: And chronic malabsorption such as vitamin deficiencies in cow wars and the ataxias Diagnosis is helpful in the diagnosis, imaging because cerebellar atrophy can be seen more than half of patients.

00:08:14: But the gold standard to detect antibodies in blood and we know that elevated antigliodine and transglutamines type two are not always detected in gluten ataxia.

00:08:27: And most sensitive gluten marker is the transgluthaminase type six antibodies.

00:08:35: But the challenge is that those are not easy to assess.

00:08:40: Only a few labs can measure them, and this represents a gap which will definitely need to be bridged in coming years.

00:08:48: So given all these gluten attacks it's nowadays still controversial entity difficult to diagnose.

00:08:54: Indeed diagnosis is often confirmed statistically if symptoms stabilize or improve on strict gluten-free diets.

00:09:03: Gluten free diet and vitamin supplementation are indeed the first line treatment, they can be cobbled with confirmation that of the elimination of antibodies in blood.

00:09:17: But we need to keep in mind if cerebellar atrophy has already started then damage is not reversible.

00:09:26: And because the nervous system is slowly compared to the gut, clinicians are advised to wait at least twelve months before labelling a gluten-free diet in effecting and maybe moving through immunosuppression even more aggressive way of treating patients.

00:09:45: Then after gluten ataxia, I can say that another third important entity is the perineoplastic cerebellar ataxi which are relatively rare disorders but yet one of the most frequent perineplastic syndromes and very common immune mediatataxia.

00:10:05: Features a rapidly progressive cerebellary syndrome and it leads to dysfunction in few months.

00:10:13: It is characterized either by an acute or subacute onset, dizziness vomiting rapidly progressing over weeks to months into severe pancerebellar syndrome and sixty-to seventy percent of cases appear before the cancer diagnosis.

00:10:30: Common associated malignancies are small lung cancer breast gynecological gastric cancer.

00:10:39: Typically, in intracellular antigen autoimmunity antibodies are biomarkers but the cytotoxics T-cells believe to be primary cause of destruction of the purkinje cell in cerebellar cortex.

00:10:57: The most frequent antibodies intracellular that is linked to ataxia are the anti-yo usually associated with breast and gynecological cancer, associated to Hodgkin disease, NTU with the small cell and cancer.

00:11:15: And there is also this novel not yet available in majority of lab antibody which is Armour Tree Antibody Which can give a syndrome that's very close mimic MSA type C. It has limited perineoplastic link and it should be mentioned because he can give like the same MRI biomarker of MSAC, so the hot cross bound sign.

00:11:42: In general for perineoplastics rebelarotaxia diagnosis is achieved by detecting the antibody in blood or in CSF.

00:11:52: The CSF might show also inflammatory markers and MRI is often normal at the beginning of the disease, but then rapidly diffuse atrophy comes in.

00:12:05: So the goal, primary treatment is identifying and treating the underlying tumor And after that second most important thing to start immunotherapy classically starting with steroids or immunoglobulin intravenously or plasma exchange or cyclophosphamide.

00:12:26: Roughly, seventy-five to eighty percent of patients become non-ambulatory and the prognosis is not so good anyway.

00:12:35: for neural surface antigen autoimmunity antibodies interact directly with the surface.

00:12:41: then we can mention For example, anti-mglure one antibodies or NTEG lone five disease which is a condition that breaches the gap between autoimmunity and neurodegeneration because it is characterized by antibody interaction and inflammation.

00:13:02: And leads to tauopathy usually linked also prominent snoring up near choking in patients.

00:13:10: Other red flags we can include are, for example if ataxia is preceded by severe diarrhea you should test for antibody antidepics and so there's a great clinical overlap.

00:13:24: but this is I mean a glimpse into the perineoplastic cerebellar ataxi.

00:13:30: This is spectrum.

00:13:33: Thank You Dr.

00:13:33: Sarbonne.

00:13:35: Your answer was very insightful and highlights that we should carefully assess the type of onset and disease progression, And also be mindful about evolution in this field where new antibodies are discovered frequently.

00:13:49: Another important group of diseases were an early treatment is particularly relevant.

00:13:54: Are metabolic disorders which can be acquired or genetic.

00:13:58: In this group there are often other neurological or systemic features that can be helpful red flags to achieve a prompt diagnosis.

00:14:06: Professor Giunti, what are the different phenotypes we find in these groups of acquired metabolic disorders?

00:14:13: Thank you Joao!

00:14:14: Yeah I would say that the metabolic conditions that lead to ataxia complex and multi-systemic, as you mentioned.

00:14:26: So we have not only neurological symptoms but also exonurological symptoms.

00:14:32: I would start as well in dividing the subject in acquires or secondary and primary cause this metabolic conditions.

00:14:44: so for the secondary course is i would start with timing deficiency vitamin D one deficiency And this can occur in infantile age, called berryberry and typically from a mother with malnutrition and vitamin B-one deficiency herself.

00:15:05: Especially occurs during lactation.

00:15:07: what are the presentation of the infant?

00:15:10: What are the symptoms that we need to look at?

00:15:13: so it's typically is a pseudo meningitis symptom with seizures you said quite rightly, extra neurological symptoms of cardiac involvement in addition to atonia.

00:15:28: In the young and adult, so we talk about more dry berry berry or wet berry berry And the dried berry berry is more chronic and it's a peripheral neuropathy.

00:15:39: So who would expect a sensory attacks here with weakness reflexia?

00:15:47: wet berry berry that is more gallium ayopathy with fetus and edema, and a Soshin berry berry which is fulminant fall.

00:15:57: But what are the causes?

00:15:59: in adults?

00:16:00: It's a malnutrition as I said and mainly it's alcohol use disorders but also gastroenterological cause like persistent vomiting and heterogenic causes of bariatric surgery anorexia netosa, and also in the Asian population they're happy to use Polish rice as a staple food.

00:16:24: So what are the red blood?

00:16:26: What is the presentation?

00:16:27: so that presentation?

00:16:29: typically it's quite cute statuses adept at nickel one In which you have the etaxia and oftalmopleager and confusion.

00:16:43: The key clinical features are delusion, hallucination, gaital lymphatoxias with nystagmus and oftalmoplegia.

00:16:52: But other feature can occur like hypotension, hypothermia and coma.

00:16:57: What are the diagnostic elements that we look for?

00:17:02: So elevated lactate and thyroid rate And low blood tyramine viral phosphate and transocylatase, and then thyroid function.

00:17:15: but also some very important red flag comes with an MRI.

00:17:22: And the MRI T-toe flare showed a hyperintensity in the thalamus typically in the amyloary bodies and peri aqueductal region of the neck.

00:17:34: So we need to bear in mind that this is an emergency treatment.

00:17:38: We do not have to wait for the lab test.

00:17:41: if we suspect the NIC and get timing immediately ventral, it's suspected at that time needs to be administered before the glucose.

00:17:52: so IV therapy followed up by oral maintenance.

00:17:57: I will move on another vitamin deficiency.

00:18:01: this is a vitamin B-II deficiency.

00:18:03: again this can occur in young patients and also other patients.

00:18:10: We know that we have aging, it's predisposed to the vitamin B-twelve.

00:18:16: so what are the causes in general?

00:18:19: And we need to look for pernicious anemia looking at anti intrinsic factors antibodies a vegan strict vegetarian diet without supplementation heterogenic causes like bariatric surgery, gastrectomy and also other condition-like Crohn disease.

00:18:42: But very importantly we need to suspect with a chronic association of two drugs that are quite common administrative for the conditions.

00:18:52: they have been quite common metformin and proton pump inhibitors.

00:18:57: The other thing there is an emerging as well cause, especially in teenagers and young adults is the cause of nitrous oxide exposure.

00:19:11: So it's a laughing gas.

00:19:12: so it's important to that one.

00:19:15: we have a teenage young adult.

00:19:17: you need to really spend a little bit of time and understand their recreational drugs they're taking because an inactivation of vitamin B-II.

00:19:31: What is the presentation?

00:19:33: Well, that's the red flag.

00:19:34: so this is a sensoritaxia with peripheral neuropathy and myelopathy.

00:19:40: So it's really important to deduce combination changes and the blood test showed low vitamine B-twelfth, but can be normal.

00:19:52: So we need to as well request that they emit melonic acid a normal cysteine and food blood count in looking for macrocytosis antibodies anti intrinsic factors.

00:20:05: And again MRI is helpful especially MRI's spinal cord indicating apostero colon T two hyperintensities.

00:20:17: So the treatment is a replacement and depending on the severity, obviously it's oral or parental.

00:20:24: And this is something that we need to evaluate depending when they answer their progression.

00:20:34: We move onto vitamin E deficiency.

00:20:38: This is typically in childhood and young adults for premature babies.

00:20:45: Again, malabsorption is one of the corporate baleary disease and reduction in lipid absorption like we have in Abitaliproprenemia but also chronic cholestasis and pancreatic issues cystic fibrosis and then Crohn's disease clinical chromatouristics, spinoserebellary taxis and sensorine neuropathy.

00:21:13: And we have as well the retinal degeneration and cardiomyopathy.

00:21:18: moving on to genetic causes so primary cause of vitamin deficiency I will start certainly with Vitamin E. This is a recessive inheritance and this could be caused by, as I said before, beta-lipoprotonemia due to the gene mutation in the genes MTTP that lead to fat malabsorption.

00:21:43: secondary deficiency of vitamins A D E K. And then there's also primary cause, really a primary cause.

00:21:53: that is ataxia with vitamin E deficiency A VED.

00:21:58: That it's due to the genetic mutation in the TTPG.

00:22:03: What are the neurological features of these conditions?

00:22:08: They are the spinal cerebellum ataxi as I said before with peripheral neuropathy and then as well cerebellar involvement with typical nystagmus, but also we have the retinal degeneration.

00:22:27: So there is a retinitis pigment also.

00:22:29: so it's very important to have as well... Very much in all this condition proper assessment on the eyes and the retina.

00:22:40: So like changes may occur for example in TTPA But also in Abidalipropyrotaining.

00:22:48: So in addition, nowadays we have quite a high number of patients that had fine head tremor with the titubation and with the nono.

00:22:58: This can be a clue but it could also be absent.

00:23:01: And there are other things as well like the presence of cardiomyopathy.

00:23:05: so very important to have as well the cardiological assessment.

00:23:10: What is the diagnosis?

00:23:12: The diagnosis is low vitamin E, so they're low lipid-adjusted vitamin E. But also in the FPC when we ask for a blood test, acanthocytosis and this really important because it can lead as well to the diagnosis of Abida lipoprotein.

00:23:30: For treatment you have high dose of Vitamin E from eight hundred two thousand five hundred milligrams but is important that this needs to be adjusted for the patient's need, so it needs to been monitored.

00:23:47: Moving on another genetic cause of rare genetic causes of cerebellar ataxia or spinal cerebral ataxial we're talking about nemenpic type C. This is an autosomal recessive conditions and is a lysosomals storage disorder used mainly to NPC-I and NPC true.

00:24:09: This is most common in childhood, rarely in young adults and even more rarely in adulthood.

00:24:18: The clinical pictures are the vertical supranocular gaze palsy that it's kind of a hallmarking adolescent and young adult and the saccadic pulse.

00:24:30: There cerebellia ataxia, but what as well is characteristic.

00:24:36: It's a cognitive involvement that occurs.

00:24:39: so this leads depending on the age either in learning disability or cognitive decline and prominent psychiatric symptoms.

00:24:48: one thing said it really important especially for children of young adults.

00:24:54: there is presence of hepatosplenomegaly.

00:24:57: don't be shy to do any medical examination because that could be really revealing and can give you a clue.

00:25:05: There is one thing as well, it's important to note.

00:25:08: very rarely has been reported peripheral neuropathy so this would be a distinguished factor for example in other spinal cerebellar ataxias.

00:25:17: So the other symptoms of dystonia and cataplexis.

00:25:22: what is the diagnosis?

00:25:25: Is NPC do genetics bile acid, oxysterol.

00:25:31: And on the MRI usually is of limited support and help for the diagnosis of nematopicotype C because this show only mild cerebellar atrophic.

00:25:45: What is the treatment?

00:25:46: The treatment we have migrostate that has been recognized with EMA and image array it.

00:25:55: citule leucine that has been approved by EMA but not by MHRA.

00:26:00: and then arymochromo, it's been approved to be prescribed in association with Negrostat.

00:26:10: So moving on the Glute I deficiency is a very rare genetic disorder.

00:26:18: this is an autosomal dominant due to SLC-AI mutation in this gene, dysfunction is the glucose transport type one and unable to transport a glucose across.

00:26:32: The brain barrier that onset can be an infancy too late.

00:26:37: adults and children usually more prominent.

00:26:41: the presence of seizures and paroxysmal iron head movement with developmental delay and cognitive issue whereas in order we have a paroxysmal motor.

00:26:54: On disorders like ataxia, dystonia or mild Korea my clonus and this can be associated as well.

00:27:02: There are words.

00:27:04: obviously triggered of these episodes is when the patient is fast.

00:27:10: but how do we diagnose?

00:27:12: When the blood test received that the glucose is normal.

00:27:16: But on the CSF We have hypoglycorechia with low CSF and serum glucose aeration.

00:27:28: And the MRI, unfortunately brain is not contributory because it can be normal.

00:27:34: The treatment is a ketogenic diet Another condition that is also rare That's is the serobrotendinous scantomatosis and this due to mutation in the C-one P-II, seven A one gene and again this is can occur in early onset or rarely in adult onset.

00:27:59: The key features chronic childhood diarrhea juvenile cataract And when you're juveniles it's very early.

00:28:09: Achilles tendon St Thomas but St Thomas cannot occur as well In other part of the body and for some routes.

00:28:17: So the neurological characteristic is this progressive attack with spasticity, then cognitive decline.

00:28:26: The blood test showed elevated cholesterol And then genetic tests will as well confirm clinical suspicion.

00:28:37: Treatment is with a cannodeoxycholic acid Moving on as well, another rare disease is Fabri disease and this is an X-link lysosomal disorder with really a truly multisystemic condition mutation in the GLAG.

00:28:56: And it features hereteritis by sensory ataxia with neuropathic pain, angiocardomas and hypohydrosis With gastrointestinal symptoms renal cardiac And we have a cerebral vascular involvement that can then lead to when severe and stroke.

00:29:18: What is as well, when present it's helpful in the diagnosis is tix corneal verticillata or opaque cornea.

00:29:29: The diagnosis is done by a blood test showed low alpha-galoxidase A, and obviously the genetic test as well to confirm that clinical suspicions.

00:29:42: The treatment is an enzyme replacement therapies And also there are possibilities of treat these disorders.

00:29:50: with megalostate We move on on a Wilson disease and Wilson disease is due to a mutation in ATP.

00:30:01: The neurological disorders is very complex, the onset can be early onset for majority but also late onset.

00:30:10: And it encompasses dystonia, Parkinsonism, tremor and ataxias.

00:30:16: so its quite challenging as a diagnosis But also quite relevant psychiatric symptoms.

00:30:24: They are liver dysfunction and cystic kidney, and also endocrine system.

00:30:30: So the test is revealed.

00:30:34: loceruptus mean but can be normal.

00:30:36: then it's very relevant to have a twenty-four hour urinary copper that reveal high copper.

00:30:45: another clue can be with the ophthalmological examination of sleep lamp in the presence of case flasher rings due to copper deposition in the detriment membrane, but in this case its division is not affected.

00:31:03: Again for as a good hallmark of MRI brain we have signal changes and there's the so-called phase giant panda an abnormal change in the midbrain with increased T two signals In treatment administration or deep asynomine, pre-antin zinc and copper restricted diet.

00:31:28: Moving on now, CoQtan is a gene that's all involved in CoQTan pathway.

00:31:37: so CoQtans two, eight A B nine, PDS was one and PDSS too.

00:31:44: the red flag is an early onset of late onset with more regressive than early onset less aggressive and sometimes the late onset seems to be a result of MSA type C. So, their diagnosis is blood tests in muscles or in blood test in muscle on blood with low CoQ-Tan And genetic test was involved in that pathway.

00:32:09: The treatment is CoQ TAN supplementation.

00:32:13: We have secondary CoQTAN deficiency.

00:32:17: it's presence as well in the EO-I and EO II, there seems to be interfering with pathway of this CoQ-Tan.

00:32:29: And the ENO I and SCAR-TAN as well is being linked with CoQ TAN deficiency.

00:32:36: The diagnosis has said that muscles level of CoQ Tan or blood cells with level of coq-tan genetic testing should... then support the clinical suspicious.

00:32:50: The treatment is a high dose of Cochitin, moving on under other multisystemic condition.

00:33:00: this is a perixosovomote disorder and we're talking about redsome disease And it's due to the PHYH gene mutations.

00:33:12: that leads to accumulation or phytonic acid Presentation is a sensory toxic with retinitis pigment, ptosis and neuropathy.

00:33:23: With the diagnosis have the plasma phytanic acid and treatment.

00:33:32: it's a phytanic acid free diet And sometimes plasmapheresis.

00:33:39: Thank you Joao!

00:33:41: Thank You Professor Giunti for organizing so well this dance topic.

00:33:46: Indeed, careful past medical history assessment brain imaging and use of biochemical studies not namely metabolite assessments or enzymatic activity assays can be really helpful for this group of diseases.

00:34:00: Also related to the topic.

00:34:01: I would like to invite listeners look at a recent EANcast episode on the topic of treatable mitochondrial disorders – A Group Of Diseases Who Can Often Present With Cerebellar Attaches.

00:34:12: And now we move to an often overlooked topic when talking about treatable ataxias, the other genetic causes.

00:34:20: We all focus on diseases with specific treatments although they are mainly symptomatic and not proven to be disease-modifying.

00:34:28: Friedreich Ataxia is a prime example of recent therapeutic advancements.

00:34:33: Dr.

00:34:33: Sarah why isn't early diagnosis of Friedreich's ataxia particularly important this time?

00:34:40: Thank you, Zohan for asking.

00:34:42: Fidraic ataxia is indeed one of the most common hereditary ataxi... ...the most common recessive ataxias and since in year two thousand twenty-four AMA approved a therapy which was called omaveloxalone with disease modifying potential.

00:34:59: This is why we need to recognize Friedrichotaxia.

00:35:03: Usually it begins in adolescence, though can range from two over seven years the start of this disease.

00:35:13: GAA expansion in the Prataxin gene coding for a protein... which is a mitochondrial protein essential for iron sulfur cluster biogenesis and also has antioxidant regulatory functions.

00:35:32: So, a deficiency in frataxine as it happens in predicatexia leads to a mitochondria-iron accumulation causing oxidative stress and cellular injury.

00:35:46: And these primarily affect tissues with high energy demands such as the brain, heart and pancreas.

00:35:54: So this is where new first approved therapy fits since homoveloxalone has a mechanism of action that's primary antioxidant.

00:36:05: in fact it activates the NLF-II which an antioxidant agent and also inhibits other pro-inflammatory factors.

00:36:18: We need to recognize free dry cataxia, and the clinical red flags are progressive loss of coordination a significant impairment of proprioception and ribratory scents, loss of deep tendon reflexes, dysarthria, dysphagin, visual loss and hearing loss.

00:36:36: in later stages was often coupled by a systemic involvement which can be first hypertrophic cardiomyopathy, which is present also in about eighty-five percent of patients and also scoliosis food deformities pescabus.

00:36:57: Diabetes occurs in thirty percent of the patient's and MRI connects help in terms that it shows atrophy of the spinal cord and medulla while cerebellum is often spared in early stages.

00:37:15: Electromyography tests reveal axonal sensory neuropathy, Before it's on the loxolone.

00:37:33: It has been approved in February, two thousand twenty three by FDA and then EMA approved it in February.

00:37:40: two thousand Twenty four for patients with Friedreich at AXIA which are older than sixteen years.

00:37:48: a trial targeted to prove safety and efficacy in younger patient is ongoing And the original trial that made the drug approval possible was the Moxie Trial, in which patients were scored with modified frederica taxia rate score.

00:38:08: Which is called MFARS and the results proved that treatment led to a minus-two point four difference in MFAR score compared to placebo over forty eight weeks.

00:38:21: And also, long term extension data suggests benefits is preserved overtime.

00:38:28: inting that drug may be slowing underlying disease progression rather than just masking symptoms.

00:38:36: so The dosing is one hundred and fifty milligrams once daily on empty stomach.

00:38:44: The common side effects are elevated liver enzymes that we need to test, so ALT, AST, bilirubin monthly for the first three months And also other common side effects are edaic nausea and diarrhea, but still is a well-tolerated drug.

00:39:02: So the clinical perillier with Friedreich assasia is that homovaloxalone was present as historic milestone for treatment of such ataxia.

00:39:13: Its value lies in potential to change long term trajectory of disease.

00:39:17: therefore Friedreich's diagnosis not too miss.

00:39:22: Thank you Dr.

00:39:23: Salov for this timely update on the topic, although discussions regarding reimbursement of ompiloxone in different countries are still ongoing and early diagnosis is always important in these conditions.

00:39:36: Another interesting topic is use of repurposed drugs with interesting results in diseases like SCA-IIB and episodic ectaxis.

00:39:45: Professor Giotti would you like to elaborate?

00:39:49: Yeah, thank you.

00:39:50: I think this group of drugs that has been a trial and anecdotally they improve symptoms.

00:40:00: so again there are symptomatic for this condition.

00:40:05: So the first two are the episodic ataxias.

00:40:08: One is Episodic Ataxia type one with an onset in childhood or adolescence And episode characteristically grief, seconds or minutes attacks and they can have as well the features that is myokemia, neuromyotonia muscle spasm.

00:40:28: And obviously it acts as a diagnosis made genetically with identified mutations in the KCNA-I.

00:40:40: The treatment is acetazolomide or can be as well carbamazepine phenytoin.

00:40:47: And another episodic ataxia is an episodic-ataxiotype II.

00:40:51: These are onset in childhood, adolescence rarely in adulthood.

00:40:56: these are also paroxysmal episodes of ataxias that have much more prolonged and typically interictory.

00:41:03: patients has a downward nystagmus they often associated as well with migraine which can be like familial hemiplegic migraine And this has as well the characteristic to become progressive.

00:41:18: The diagnosis is genetic, it's in the mutation in the Cagna Ia and treatment is again acetazolamide.

00:41:27: there are some reports for aminopurin but also report with flunarosis.

00:41:36: Another emerging cause of disease is spinoceleveloid axiotl-IIB that have been reported, and this is a very much part of the expansion disorders because demutation is a GAA expansion like Friedrich Attaxia for example but in FGF-IV.

00:42:03: So there's typically an late onset.

00:42:06: it has rather pure cerebellar ataxia which again down with nystagmus at the Royal POR and there is a presence of episodic symptoms either before or after the onset of progressive attacks.

00:42:22: And treatment seems to be responding, this patient has four aminopivity.

00:42:29: Thank you for your answer Professor Junki!

00:42:33: To summarize key points on these episodes... Although individually rare, the causes of pitaxia we discussed do appear on our clinical practice and their timely recognition is essential.

00:42:44: Therefore every neurologist should try to incorporate a practical check-risk of warning signs into the diagnostic approach to avoid mistreatment opportunities.

00:42:55: In our premium mediated diseases We should be really alert to that type presentation particularly in acute or episodic symptoms and we should also be careful on the diagnostic workup, namely its fluid biomarkers including a variety of antibodies.

00:43:10: Dr.

00:43:10: Saro mentioned.

00:43:12: This autoimmune group is in evolving fields so look out for new emerging ones as these conditions could be treatable In the acquired metabolic disease.

00:43:22: there's a careful risk factor assessment that is critical when clinical suspicion In this group of diseases, simple blood tests and in some cases MRI imaging can provide important clues for the diagnosis.

00:43:34: Regarding the genetic metabolic disorders biochemical tests in the blood or other tissues are still very relevant to our routine clinical practice particularly settings when genetic testing is not as easily accessible.

00:43:47: Professor Junty mentioned before a detailed list of blood tests that are relevant identifying rare metabolic diseases that should be requested specially in familiar or idiopathic cerebellar ataxia.

00:44:02: The clinical picture and the other fluid, or imaging biomarkers could also be relevant to establish a diagnosis.

00:44:09: when we find a variable of unknown significance in an NGS test For other genetic causes We should always be careful on requesting the genetic tests And remember to specifically look for repeat expansion diseases like Friedrich's Ataxia who usually do not appear on standard NGS panels.

00:44:30: I would like to thank our guests for their valuable insights and for helping us organize this complex topic, also to all listeners!

00:44:38: Thank you for joining us on EANcast Weekly Neurology – we hope that episode will help neurologists be alert of the often-heavened red flags for treatable cerebellar attacks.

00:44:49: Until next time, goodbye.

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