Ep. 187: Red flags of treatable rare cerebral small vessels diseases

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

00:00:15: Hello and welcome to the EA Uncast, weekly neurology.

00:00:20: Hi, I'm Emanuele D'Amico and today's episode is part of our series on treatable causes of rare cerebral small vest disease or SVDS.

00:00:34: We'll explore how to recognize the clinical red flag that might point toward the rail but potentially treatable for.

00:00:42: Joining me today is Professor Anna Bersano, neurologist and she's really expert on rail and complex cerebral vascular disease.

00:00:54: Welcome Anna and it's a great pleasure to have you with us.

00:01:01: Thank you Emanuele.

00:01:03: It's really a pleasure to be here and this topic is really close to me and my expertise and also to my heart because in clinical practice recognizing these crucial signs can change the patient's eye and tear trajectory.

00:01:21: And the problem is that often clinicians don't recognize this rare form of cerebrovascular disorders.

00:01:30: Contrarily, an early detection can open the door to specific and preventive strategies.

00:01:38: Okay, let's start with the basic.

00:01:42: When we talk about cerebral small vessel disease, most clinicians immediately think about hypertension or age-related white matter change.

00:01:54: But that's not the whole story, right Anna?

00:01:59: Exactly, sporadic cerebral small vessel disease.

00:02:04: that is common in older adult is mostly caused by hypertension or the emerging disorders that is cerebral amyloid angiopathy.

00:02:15: But in some cases, mostly in young subject sometimes without the common cerebrovascular risk factor.

00:02:24: The cerebral small vessel disease may be caused by a monogenic or metabolic defect.

00:02:30: These cases are typically inherited, appear earlier in life, and importantly, sometimes they are treatable or require specific management measures.

00:02:42: And the most important example of this form are cadazils.

00:02:48: Fabri disease, carazil, all called for A-one, A-two related angiopathies.

00:02:55: Carazil is the most important irritable small vessel disease form and it's due to mutation in the notch three gene and this disease causes stroke or Tia in a large proportion of patients around eighty percent migraine with or without aura.

00:03:13: cognitive disorders, psychiatric disturbances, and also seizure.

00:03:19: Fabric disease is an X-link depressive lysosomal storage disorder caused by mutation in the GLA gene, leading to a deficiency in alpha-galactosidase enzyme.

00:03:33: and activity and accumulation of global triacyl ceramide in the vascular endothelium and the small muscle cells of different organs.

00:03:43: The disease may start with severe pain, acroparesthesia, skin lesion, hypodrosic gastrointestinal symptoms and leading to involvement of peripheral and central nervous system, kidney and heart, finally leading to organ failure.

00:04:03: Carazil is a rare autosomal recessive disorder caused by an homozygous condition, a Bialylic mutation in HTR A-one gene.

00:04:16: And it is a disease that usually present with the laconar stroke that with the onset between the twenty, forty-four years, early vascular dementia, head alopecia, and also attack of severe pain and lumbar disc herniation or severe spondylosis.

00:04:37: And it is characterized by a severe disease progression.

00:04:41: And lastly, call for A-one, A-two syndrome are autosomal dominant angiopathies due to mutation.

00:04:48: in call for A-one and two genes and coding for the chains A-one, A-two of type four collagen.

00:04:55: And it is a heterogeneous disorders conditioning fetal and perinatal or childhood demorages for encephaly seizure.

00:05:06: and also development delay, but also a cerebral small vessel disease feature, including intracerebral hemorrhages, often triggered by physical activity or trauma or antiguagulant therapy.

00:05:21: These disorders are also described cognitive symptoms and also muscle cramps and also, in some cases, are observed as cerebral aneurysm and also retinal and nephrological disorders.

00:05:39: Thanks, Anne.

00:05:40: And when you say treatable, no?

00:05:43: You mean there is something that we can do to modify that this is course, that this is trajectory?

00:05:52: Yes, there is a disease that is treatable and it is most regarded as phabrilysis.

00:06:02: where enzyme replacement therapy or chaperone therapy can prevent the disease progression, particularly heart and kidney damage, whereas it is not well known if these therapies can affect the cerebrovascular disease progression.

00:06:23: However, it is known that this therapy has to be started as soon as possible in life.

00:06:31: For the other cerebrovascular disease, the rare cerebrovascular disease, we have not a specific therapy, but it is well known that they require a specific management and controlling risk factor and, for instance, avoiding trauma or anticoagulants can influence disease progression.

00:06:50: Therefore, the key message is recognition leads to intervention.

00:06:56: So let's dig into those clinical red flags.

00:07:01: What future should highlight the clinician that patients more or less disease might not be the usual age-related type?

00:07:15: The first one is the age of onset when the white matter changes or stroke appear before fifty.

00:07:24: This is already a suspicious.

00:07:27: Next, another important feature is the familial history.

00:07:31: that is not only for stroke but also for the other disease manifestation as migraine, cognitive decline, or for instance psychiatric disorders across generations.

00:07:43: We have also to consider other neurological symptoms other than cerebrovascular disease manifestations, because sometimes stroke is not the most important manifestation, but also systemic clues.

00:07:57: Things that happen outside the brain, for instance, a renal failure, heart disorders, or a skin... lesion as angiokeratoma in phabrid disease, alopecia or spine disease for carazil or hepatic cardiac or of tomological involvement for call for A-one angiopathy.

00:08:19: And the last things we have to consider that sometimes in these disorders there is a lack or poor presence of the common cerebrovascular risk factor.

00:08:32: That's very interesting and so the brain isn't the only organ, the only structure giving us hints.

00:08:44: The skin, the eyes and even bones can tell us something, right?

00:08:52: Yes, and you have to think of this disease as a multi-system.

00:08:58: Signals.

00:08:59: in Fabri disease, for instance, you may see convertexilata, that is an ophthalmological disorder, and also this pain, distal pain as acroparesthesia, or also cardiac involvement.

00:09:16: And if we connect the dots early, we can often identify the disease and treat before the brain is affected severely.

00:09:27: Okay, so let's move to neuroimaging MRI or VAS.

00:09:33: know that is one of the most powerful tool in identifying cerebral vascular disease and also the small vessel disease.

00:09:43: but what kind of imaging finding imaging future should raise suspicion of a monogenic or metabolic condition?

00:09:58: MRA patterns are very telling in these disorders, despite they are not so specific.

00:10:08: In Cadazil, you typically can see white matter hyper-intensities, mostly in the anterior temporal poles and external capsules, and it is quite characteristic.

00:10:22: And in carazelle, you can see diffuse white matter lesion and also deforming spondylosis at spine MRI.

00:10:34: And also u-fibers are spared, whereas it is not clear if external capsules and also temporal lobes are involved.

00:10:46: In fabrid disease, there is often a pulvinal sign.

00:10:50: that is an hyperintensity of pulvinar, but it is not clear if it is so specific, and a dolicarctasic basilar artery.

00:11:03: And lastly in call for A-I, A-II angiopathies.

00:11:09: you can find microblitz in unusual location and also in brainstem and cerebellum, previous ICH and also porencephalic cysts.

00:11:23: Great, so pattern recognition is essential.

00:11:28: It's like reading a visual fingerprint on MRI, right?

00:11:36: Yes, but we have always to consider that the radiological signs have to be combined with the clinical and biochemical data.

00:11:47: Since, as we told before, they are sometimes not so specific and they can support the suspicion, but sometimes they are not so distinguishable from the sporadic cerebral small vessel disease.

00:12:04: So, I'm going to the diagnostic work out.

00:12:08: Suppose a clinician suspects a rare cerebral small vessel disease.

00:12:15: What's the best diagnostic flowchart, the best diagnostic strategy?

00:12:24: I should recommend a stepwise approach.

00:12:27: For instance, the first one is the clinical suspicion.

00:12:31: So we need a deep an amnestic and neurological and also systemic examination.

00:12:39: And we have to consider in this collection of data the red flag we discussed.

00:12:44: So the clinical history should include RISFACCOR collection and also familial history, not only for stroke, but also for other neurological and systemic features.

00:12:55: Secondly, we have to do basic biochemical screening to exclude other risk factors, but also to make the dosage of lysosomal enzymes, if needed.

00:13:07: And the imaging pattern analysis is fundamental, the use of MRI at CLAS.

00:13:13: to guide which genes to test.

00:13:16: After we have to do the genetic testing, we can perform a specific gene or otherwise perform a next generation sequencing panel that can include a panel of genes involved.

00:13:29: in Cervarous Wall Messer disease.

00:13:32: And if the variant is uncertain, we can use functional studies, family segregation, or in some cases a SCADASIL scheme biopsy to confirm the relevance and the pathogenity of the mutation.

00:13:46: So, thanks.

00:13:49: A really great roadmap.

00:13:51: And I imagine early testing that can prevent the year of diagnostic delay.

00:14:02: Yes, sure.

00:14:04: In fact, many of these patients wandered through the health care system for years with a diagnosis of creptogenic stroke or unspecified leucoencephalopathy.

00:14:18: Whereas a simple enzyme assay or a genetic panel could give them a name and avoid unusual investigation and when possible make possible a treatment for this patient.

00:14:35: Okay,

00:14:35: thanks.

00:14:37: So let's move and focus on treatment.

00:14:41: Which, you know, expertise around small vessel disease, can we actually treat and well manage today?

00:14:50: The most important one is Fabri disease.

00:14:53: For this disease is available the enzyme replacement therapy, that is Al-Ghazi days Alpha or Beta, and also the oral chaperone therapy, that is Migalastat.

00:15:08: And this therapy is... have been demonstrated to reduce the accumulation of global triosidic ceramide and therefore reduce the stroke risk.

00:15:24: but it is whether we clearly know that the therapy is affecting the heart and the kidney.

00:15:33: in the environment, it is less clear.

00:15:36: if this therapy can really impact the cerebrous bulbous disease progression.

00:15:44: So thanks that it's really encouraging and it's a reminder that healthy detection can truly change lives and quality of lives of our patients.

00:16:02: Yes, we recommend to patients to go to specialists, in fact even in a non-carable form like Kadazil, to know that It can cause, helps to avoid unnecessary procedures, help in guiding familial counseling, and focus also on lifestyle modification.

00:16:28: In fact, it has been demonstrated, for instance, for cadazil, that hypertension and smoke influence the disease progression.

00:16:38: And we have also to consider that there are specific indications also for the treatment of the other synth disease and for therapies that should be avoided.

00:16:52: for instance, specific European efforts as an EEN guideline on monogenic disorders, management, and also some fact sheets as do-and-don'ts documents from the European Reference Network for Rare Disorders that may guide clinicians but also patients in managing this disease.

00:17:15: So, going to the summary and... the take-home messages.

00:17:21: and so before we wrap up, could you summarize the key take-home messages of this presentation?

00:17:32: Of course, we have to think rare and treatable or manageable when you see early or a typical Cerebrovascular disease, especially at young age without risk factor, but it is not mandatory and with a familial history.

00:17:49: always look for other neurological and systemic features, they are often the biggest clue, and go to MRI pattern recognitions, helps narrow the diagnosis, and don't hesitate to perform biochemical and genetic testing.

00:18:08: Early diagnosines means better outcomes and sometimes even reversals of symptoms.

00:18:15: I completely agree, perfectly said, Anna, and really thank you.

00:18:20: for sharing your expertise and obviously to all our listeners.

00:18:26: And just an advice, all of us, we have to remember that small vessel can carry big diagnostic messages.

00:18:35: Thank you, Emmanuel.

00:18:36: It was really a pleasure to discuss this topic.

00:18:40: Thank you, Anne.

00:18:41: Again, thank you.

00:18:43: all for joining our cast.

00:18:46: Weekly Neurology and please all of you can visit our EN campus for more resources on rare cerebral vascular disease.

00:18:58: And until the next time and the next podcast, stay curious, stay vigilant and obviously keep learning.

00:19:13: This has been EANcast Weekly Neurology.

00:19:16: Thank you for listening.

00:19:17: Be sure to follow us on Apple Podcasts, Spotify or your preferred podcatcher for weekly updates from the European Academy of Neurology.

00:19:25: You can also listen to this and all of our previous episodes on the EAN campus to gain points and become an EAN expert in any of our twenty-nine neurological specialties.

00:19:35: Simply become an EAN individual member to gain access.

00:19:39: For more information, visit ean.org slash membership.

00:19:43: That's EAN.

00:19:47: Thanks for listening!