Symbolic and Cerebrovascular Disorders

Question 1

What are symbolic disorders? Some examples?

Answer 1

Symbolic disorders are composed by three conditions, aphasia, apraxia and visual spatial deficits.
It should not be confused with a dysfunction in the larynx, pharynx, tongue, lips, as those are impaired by a lesion in the primary motor cortex, this is referred to as a paralysis.
Symbolic disorders instead occur when there is a higher cognitive dysfunction and prevents proper function in different aspects of the brain.
Other examples include agraphia (acquired disorder of writing), alexia (acquired disorder of reading).

Question 2

What is aphasia?

Answer 2

It is it is order of production and or comprehension of verbal messages. Usually due to focal lesions of the left hemisphere in people who previously acquired and use languages normally. The lesion is in the left hemisphere because it is the dominant hemisphere for 95% of people who are right handed and the 70% of left-handed individuals.
To be aphasia, it must be acquired and not congenital, you must also exclude dysfunction that might impair production or understanding of language, like hearing impairment, motor, primary articulation, paralysis and thought disturbances.

Question 3

What are the different etiology of language disturbances?

Answer 3

Developmental disorders (not a cause of aphasia) : congenital factors and learning disturbances, such as ADHD.

Psychiatric disorders (not a cause of aphasia) : cognitive and behavioral disturbances related to clinical complex situation like schizophrenia.

Neurological disorders (etiology of aphasia) :
- cerebral focal lesions, due to stroke, traumatic brain, injury, or tumors. It can be said that aphasia is a secondary or part of the manifestation associated a stroke.
- Focal lesions and progressive brain damage due to Nero degeneration, for example, primary progressive aphasia.
- Diffuse brain damage due to near degeneration. For example, Alzheimer’s disease. This is the most common form of aphasia, related to focal lesion/neurodegeneration in areas devoted to language.

Question 4

What is the Wernicke-Geschwind model?

Answer 4

The primary auditory area is able to filter and send what is thought to be linguistic information to the Wernicke’s area, which is located in the superior temporal sulcus in the temporal lobe, and it’s the area that understands and decodes the linguistic message.
Then there’s the arcuate fasciculus, which brings this information to Broca’s area, which allows to produce language; it has two different functions: the main one is to produce language, the second is comprehension of more complex grammatical material.

Finally the primary motor area is able to move the lips, tongue, pharynx in a way to produce meaningful language.

Question 5

Definition of Broca’s aphasia?

Answer 5

It is non fluent aphasia characterized by slow, incomplete and labored speech with major breakdown of grammatical output and comprehension material.
Damage to the inferior frontal gyrus, typically in the left hemisphere, which can be due to a stroke, tumour, etc. (secondary aphasia) or primary (primary progressive aphasia), which might be part of a more complex neurodegenerative syndrome.

Question 6

Definition of Wernicke’s aphasia?

Answer 6

Fluent aphasia with language characterized by meaning and comprehension loss.
Patient is able to speak, but not to understand. Language is characterized by meaning comprehension loss, so typically these patients have a fluent language which is, however, not very meaningful and they try to produce something in order to try to respond to what the interlocutor said, without fully understanding what the person actually said. In very advanced forms they don’t even understand their own produced language.

Question 7

Definition of conduction aphasia?

Answer 7

Reduced ability to repeat spoken words or phrases with preserved comprehension. There is damage to the arcuate fasciculus, so the information is not brought from wernicke to broca, therefore patients have trouble repeating.

Question 8

What are language features that must be assessed when checking for correct function.

Answer 8

• Articulation and prosody (speech stress, intonation, pitch)
• Fluency in spontaneous/conducted (doctor asking questions to see how patients responds) speech.
• Phoneme use (reading/writing/repetition)
• Use of words (semantics, lexic, syntax, naming)
• Single word and complex material comprehension
• Object knowledge (showing an object and asking for its name)

Question 9

What are articulation disturbances? What are the two types?

Answer 9

They must be tested for as the patient might speak in a pathological way due to different problems. It may not be a symbolic comprehension issue. There are two types : dysarthria and language apraxia.

Question 10

What is dysarthria?

Answer 10

It is an articulation disturbance. It is characterized by slurred speech, dysphonia, nasal voice, rhythm and tone alterations, patient always make the same mistake (consistency of disturbances).

Lesion/damage—> Bilateral PMA, SMA. It is a problem in correctly articulating the different muscles that are in charge of creating the set gestures that are associated to language.

Question 11

What is language apraxia?

Answer 11

Praxia is any complex movement that convey a symbolic meaning, e.g rock and roll hand sign.
Characterized by altered prosody, inconsistent errors, improvement with automatic language.

Lesion/damage—> left inferior frontal lobe/left insular cortex/bilateral basal ganglia/temporoparietal junction. There might me different regions affected.

Question 12

What are the possible primary progressive aphasia’s?

Answer 12

Aphasia could be due to lesions that are in regions involved in neurodegeneration, which could be limited to the regions associated to damage. There are three possible primary progressive aphasias:

1. Nonfluent agrammatic (naPPA) (Broca’s area): the sentence becomes agrammatic because the patient doesn’t understand complex grammar anymore, so it’s nonfluent.
2. Logopedic variant (lvPPA), which is associated to problems with the repetition, so communication from Wernicke’s to Broca’s area.
3. Semantic variant (svPPA), which is in the temporal pole and typically involves the area of comprehension, so the Wernicke’s area.

Question 13

What are the different PPA associated to?

Answer 13

The nonfluent agrammatic and the semantic are part of a condition called Frontotemporal Dementia. The logopedic is typically associated to Alzheimer’s disease.
These syndromes can be isolated or part of more complex neurodegeneration, with two main conditions in which there might be more diffuse neurodegeneration:
- Frontotemporal dementia, which might have three possible clinical manifestations—>
Behavioural : so people start to change their behaviour.
Linguistic variants : nonfluent agrammatic and semantic.

• Alzheimer’s disease: to which logopedic variant is associated, and from PPA might evolve to a more diffuse neurodegenerative condition.

Question 14

What are the different PPA’s caused by? What can they lead to?

Answer 14

In all neurodegenerative conditions there are proteins that misfold and are not anymore removed by macrophages, therefore they deposit into the brain and create damage. In the nonfluent agrammatic PPA there’s deposition of tau, in the semantic variant TDP43, in the logopedic variant there is beta amyloid and tau.

There syndromes can degenerate towards motor neuron diseases such as amyotrophic lateral sclerosis or to atypical parkinsonisms where there is deposition of tau.

Question 15

What are phonemic paraphasias?

Answer 15

Commmon in non fluent PPA. Additions of letters to words, substitutions, deletions, using the word thing often, correcting themselves often.

Question 16

What is the syntax comprehension test?

Answer 16

Used to evaluate non fluent PPA and other conditions.

• Auditory canal. You show the two pictures, and you
  say “the women follow the men”, then you ask the patient to point which is the picture that means the women follow the men.
• Visual canal. You show the sentence and leave the it in
  front of the patient (“the policeman is pointed out by the woman”),

A patient with non fluent PPA would probably fail both but a patient with Alzheimer’s might fail only the first one as in the second test the sentence is written down.

Question 17

What is the pyramid palm test?

Answer 17

It is used to evaluate semantic content and object knowledge. It uses a pyramid of pictures and different types of questions can be used.
E.g, point to the inuit and ask where is the typical place where he or she goes.

Question 18

What is apraxia? What are the major forms?

Answer 18

a (without) and praxia (action).
- Inability to carry out learned, skilled motor actions (such as language production), despite preserved motor and sensory systems, coordination, comprehension and cooperation.
- It is a symbolic disorder.
The major forms are :
Ideomotor apraxia (limb and buccofacial), ideational/conceptual apraxia, limb-kinetic apraxia, constructional apraxia, task-specific apraxia’s (i.e., dressing-apraxia).

Question 19

Etiologies of apraxia?

Answer 19

• Cerebral focal lesions (e.g. stroke/tumour/traumatic brain injury of the left hemisphere). As for aphasia. This is a secondary apraxia to the presence of a focal lesion involving the apraxic region within the brain.
• Focal neurodegenerative disorders, such as posterior cortical atrophy (PCA).
• Alzheimer’s disease
• Corticobasal syndrome: it’s another focal neurodegenerative condition, which is associated with
  another underlying pathology, not Alzheimer’s disease, but frontotemporal dementia.

Question 20

What is the apraxia liepmann model?

Answer 20

• if the gesture involves the right hand : knowledge goes from the left inferior parietal lobe to the left primary motor cortex to the corticospinal tract to the right hand.
• if the gesture involves the left hand : knowledge from the left inferior parietal lobe goes to the left primary motor cortex then moves through the corpus callosum and reaches the right primary motor cortex and finally the left hand.

If a subject has a lesion in the leg parietal lobe, whatever the cause, he or she will have apraxia.

Question 21

What is ideomotor apraxia?

Answer 21

• It is the inability to correctly pantomime. The patient knows that to do but not how to due it.
• Intact knowledge of tasks (e.g. patient might be able to describe how to use a spoon, but not able to
  demonstrate the actual use) since the cortical part of the parietal lobule is not involved.
• Often patient is able to do certain gestures during the day, but he’s not able to do them when I asked.

Lesion/damage—> white matter bundles connecting frontal and parietal association areas.

Question 22

What is ideomotor limb apraxia?

Answer 22

The most frequent higher function disturbance in patients with Alzheimer’s is memory, but there are some atypical variants of the disease where there is primarily deposition in the parietal and occipital region.

A patient with this type of apraxia is characterized by the inability to perform complex gestures.
E.g. the patient is asked to mimic soup eating with a spoon, he can do it with the right hand but with the left he uses his whole hand as the spoon.

Question 23

What is ideomotor buccofacial apraxia?

Answer 23

• Impairment of skilled movements involving the face, mouth, tongue, larynx, and pharynx (e.g., blowing a kiss). However, if you ask subject to illustrate the steps that should be performed in order to have the gesture, the patient can describe the steps.
• Automatic movements of the same muscles are often preserved.
• Frequently coexists with limb ideomotor apraxia.
• Test: the patient is required to blow out a match, protrude tongue, drink through a straw.

Lesion/Damage: left frontal (perysilvian) and white matter; and basal ganglia.

Question 24

What is ideational apraxia?

Answer 24

• Inability to correctly sequence a series of acts in performance of complex, multistep task that leads to
  a goal (inability to conceptualize a task). The subject is not only unable to perform the gesture, but at the same time, he/she is not able to describe the series of actions that should be performed to achieve the goal.
• Test: the patient is required to pantomime making a sandwich or preparing a letter to mail.

Lesion/Damage: Left parietal region.

Question 25

What is conceptual apraxia?

Answer 25

• Loss of mechanical knowledge in the tool use for altering the environment and reaching a goal.
• Test: Tool selection - How to pound a nail into wood? H If subject has lost meaning of how to correctly use the tool, the
  patient is not able to answer correctly to the question.

Lesion/Damage: Usually left caudal parietal lobe/temporoparietal junction.

Question 26

What is limb kinetic apraxia?

Answer 26

• Inability to make precise, independent but coordinated simultaneous finger and hand movements, resulting in inaccurate or clumsy movements.
• Examples of tasks requiring the motor performance: buttoning or coin rotation.

Question 27

What is constructional apraxia? Common errors?

Answer 27

• It is the inability to copy visually presented information. For example, the patient is asked to copy a drawn cube. The cube is in 3D, often patients will recognize the three-dimensionality but not able to copy it.
• if the patient has only apraxia he or she will notice that their copy is not the same. Therefore they may also have awareness problems such as in frontotemporal dementia.

Lesion/Damage: posterior parietal, temporo-parietal, frontal.

Common errors : simplified or smaller drawings, errors in positioning, spatial disorganization such as rotation errors.

Question 28

What are the “where” and “what” pathways?

Answer 28

Where: identification of objects in the space.

• Dorsal lateral occipitoparietal stream.
  1. Neglect syndrome
  2. Balint syndrome (simultanagnosia, optic ataxia, gaze apraxia)

What: identification of objects and faces.

• Ventral medial occipitotemporal stream.
  1. General visual agnosia
  2. Prosopoagnosia: inability to recognize faces.
  3. Achromatopsia.

Question 29

What is a stroke?

Answer 29

A stroke is a cerebrovascular disorder mainly concerning elderly people. It may be either due to blockage so ischemic or due to rupture so hemorrhagic. It is very sudden and there is the loss of one or more neurological functions in seconds, such as vision, movement, speech.

80% of strokes are ischemic, 20% hemorrhagic and the latter can be intraparenchymal (15%) or in the subarachnoid space (5%).

Question 30

What is a transient ischemic attack?

Answer 30

Transient ischemic attack is an ischemic stroke, a condition that causes sudden block in the blood supply of the brain that again causes a sudden loss of a neurological function (i.e., movement, vision, comprehension, sensation etc.) caused by transient blockage of an artery, with clinical recovery within 24hr and no permanent residual damage. Despite being transient, it is a red flag for future development of hemorrhagic or ischemic stroke. If you die in 6h it is less than 24h and it is not a TIA but a stroke (also if you die after 24h).

Question 31

Epidemiology of stroke?

Answer 31

It is the second most common cause of death worldwide after CAD, the first cause for physical disability in developed countries, the second cause of cognitive impairment after Alzheimer’s.
17 million new cases worldwide per year and about 50 million cases total.
In Italy the 1 month mortality for ischemic stroke is 15-20% and for hemorrhagic it is 40-50%. At 1 year 35% show severe disability, 10-15% are institutionalized.

Question 32

Risk factors of stroke?

Answer 32

Most risk factors for stroke are modifiable, around 80% of stroke are preventable.

For hemorrhagic stroke there are :
- stroke specific risk factors—> aneurysms, arteriovenous malformations, hypertension, smoking, drug use and recent ischemic stroke.
- general bleeding risk factors—> anticoagulants or anti platelet medication, impaired liver/kidney function.

For ischemic stroke :

Non modifiable—> age, sex, genetic predisposition, previous TIA, previous stroke, prior MI.
Modifiable—> hypertension, atrial fibrillation, diabetes mellitus, lipid changes, obstructive sleep apnea, homocysteine, obesity, smoking.

Question 33

Age and sex in ischemic stroke?

Answer 33

Stroke risk doubles every decade after the age of 55, and it shows a slightly higher prevalence in males (M:F ratio 1.3:1).

Due to women greater longevity, over an entire lifetime, about 16% of women vs. 8% of men will die of stroke. For the same reason, women show higher rates of disability and post stroke dementia. In women, early menopause has been associated with increased stroke risk, since it often accompanies other risk factors like hypertension, dyslipidemia, cerebrovascular and cardiovascular disorders. On the contrary, the age/gender risk is inverted for subarachnoid hemorrhage, which is more frequent in middle-aged women (M:F ration 0.87).

Question 34

Heritability in stroke?

Answer 34

Some rare mono genetic and more common polygenic multifactorial conditions can predispose to stroke.

Single gene disorders with ischemic stroke as principal manifestation—> CADASIL, CARASIL, MELAS, HERNS and moya moya.

Single gene disorders with ischemic stroke as a recognized feature—> sickle cell disease, faby disease, EDS type 4, Marian’s syndrome, neurofibromatosis type I.

Question 35

What is the ABCD2 score?

Answer 35

It is a clinical prediction tool for developing stroke optimized to predict the 2 day stroke risk.
It stand for age (>60) , BP (systolic > 140 mmHg or diastolic > 90 mm Hg), Clinical feature of TIA, Duration (>60 min or <60 min), Diabetes.
0-3 points hospital observation may be unnecessary unless new indication like Afib. Stroke risk 1%.
4-5 points hospital observation justified. Stroke risk 4.1%
6-7 points hospital observation worthwhile. Stroke risk 8%.

Question 36

Hypertension in stroke?

Answer 36

It is the most important modifiable risk factor. In a stroke patient younger than 65, hypertension is most likely the main character.
For individual ages between 40 and 70 and increase of 20 mm Hg in systolic BP and 10 mm Hg in diastolic BP double the chance of mortality risk due to stroke.

Question 37

Atrial fibrillation in stroke?

Answer 37

bnormal contractions of the atrium lead to a non-laminar blood flow, particularly in the left atrial appendage causing a damage to the endothelium. Tissue factor is released from the endothelium inducing hypercoagulability and formation of blood clots, which, fragmented by heart contractions, can embolize to cerebral arteries, through the anterior circulation (via the internal carotid) and the posterior circulation (via the vertebro-basilar system),

Question 38

Obstructive sleep apnea?

Answer 38

It is less frequent, often in association with obesity and increased blood pressure, has been shown to predispose to stroke. It is also an independent risk factor for ischemic stroke.
Possible mechanisms include:
• Decreased cerebral blood flow, due to the high sympathetic tone that leads to vasoconstriction.
• Hyper viscosity: from the chronic hypoxia that triggers polycythemia.
• Atherosclerosis, more common among obese patients.

OSA is frequently associated to wake-up stroke, which is a peculiar form of stroke with unknown exact time of onset, as it is generally noted by the patient on awakening due to neurological dysfunction associated with the stroke.

Question 39

What is the cerebral perfusion pressure?

Answer 39

CCP is defined as the Mean Arterial Pressure minus the Intra Cranial Pressure.
The brain need to be perfused at a certain pressure to guarantee normal function. The MAP, usually between 60 to 150 mm H, is the mean pressure that the cardiovascular cycle is able to push out at a given instant and is what perfused the whole body, even the brain. It is important to note that the ICP, between 5-15 mm Hg, is opposing the MAP and pushes out and away from the brain.
Therefore to have correct brain perfusion there must be a balance between MAP and ICP. If the ICP increases the MAP might not be high enough to counteract the increased ICP leading to brain ischemia.

Question 40

How is CCP regulated if there are changes in pressure?

Answer 40

The body can decrease or increase CSF production, vasodilate or vasoconstrict. If these compensatory mechanisms do not work the brain will not have adequate perfusion.

Question 41

The severity of cerebral damage is based on?

Answer 41

The severity of cerebral damage is related to the reduction of brain arterial flow :
• 80-60 mL/min/100g: normal.
• 60-40 mL/min/100g: changes in brain activity and metabolism such as decreased protein synthesis and selective gene expression with subclinical signs—> due to decrease in the compensatory mechanisms
• 40-20 mL/min/100g: initial cytotoxic edema, lactic acidosis with clinical signs and symptoms. (first events that can be detected clinically).
• 20-10 mL/min/100g: energy deficit, glutamate excitotoxicity.
• <10 mL/min/100g: anoxic depolarization and infarction; tissue death occurs in 3 minutes.

Question 42

What is the first event after blood flow diminishes?

Answer 42

ATP dependent ion pump fail causing neuronal depolarization and intracellular accumulation of water. Of course this in physiological condition does not occur as the ATP dependent pumps actively remove the water.
It is also the first clinically evident event, cytotoxic edema.

Question 43

What is the ischemic core and penumbra?

Answer 43

The ischemic core (central part where there is a significant decrease of CPP) is surrounded by an area of less severe ischemia (where there is an initial reduction in CPP) which has not undergone necrosis (ischemic penumbra)—> hypoperfused but not ischemic and this represents the therapeutic window because if it is reperfused in a short amount of time, tissue can be restored.
That’s why stroke is a time dependent condition. (it should be done in less than 15-30 min).

Question 44

What are Perfusion Weighted and Diffusion Weighted Imaging techniques and when are they used?

Answer 44

DWI—> detects areas of restricted water diffusion which typically indicate acute ischemic injury.
PWI—> evaluates blood perfusion to the brain tissue, it is used to identify areas with reduced perfusion.

Question 45

What affects the size of the ischemic penumbra?

Answer 45

The time from the ischemic insult and the efficiency of collateral blood flow.
The cerebral collateral circulation is provided by different systems :

• Circle of Willis : placed at the basis of the skull, connects left and right carotid and basilar arterial system. If we have a block in one of these vessels, blood supply is ensured by collaterals.
• Cortico-pia anastomoses : between the terminal branches of the internal carotid artery and the vertebro-basilar system.
• Extra cranic collaterals (ex: ophthalmic artery and caroticotympanic artery): between internal (brain) and external carotid arteries (face).

Question 46

What are the main etiology’s of strokes?

Answer 46

• Large-artery atherosclerosis (20%).
• Cardioembolism (20%).
• Small-vessel occlusion or lacunar stroke (25%).
• Stroke of other determined etiology (rare) (non-atherosclerotic vasculopathy, coagulopathy).
• Stroke of undetermined etiology / cryptogenic (rare).

Question 47

Artherosclerosis of large vessels? Which are most common locations of plaques?

Answer 47

Stable plaques—> characterized by a compact clot, internal walls integrity is preserved, they have a small risk of rupture and erosion. Stroke is caused by the progressive accumulation of material that leads to vessel occlusion. If the stenosis is >70%, it is critical, and we need to intervene.

Vulnerable plaques—> characterized by a non-homogenous clot. Stroke is caused by thrombus rupture and erosion with subsequent embolus release.

The most common locations in which we can find atherosclerotic plaques, in order of frequency, are:
1. CCA bifurcation and origin of ICA
2. Carotid siphon
3. MCA stem
4. ACA stem

Question 48

Occlusion of the small vessels?

Answer 48

Also called lacunar strokes. It is the most common phenomenon, caused by small cerebral lesions, 0.2 to 15 mm3. The two main places are :

• Perforating branches of the middle cerebral artery (lenticulostriate arteries). They supply the thalami, the internal capsule and basal ganglia and when occluded contralateral hemiparesis may arise.
• Perforating branches of the basilar artery. They supply the brainstem and when occluded bilateral hemiparesis may arise (refer to alternating syndromes, i.e.: Wallenberg’s syndrome, Weber syndrome…)

These small vessels occlusions are associated with with chronic hypertension, diabetes and intramural deposition of lipids called lipohyalinosis.
The types of conditions are microatheroma in proximal part of arteries, lipohyalinosis of very small vessels, and upstream vessel artheroma which may occlude an artery or generate microemboli.

Question 49

Cardioembolism?

Answer 49

Also common cause of stroke. The main sources of emboli are :
• Left atrial appendage
• Mitral valve (Thrombus, Vegetations, Prosthesis)
• Left ventricle thrombus (after MI)
• Aortic valve (Thrombus, Vegetations, Prosthesis)

General high risk situations include Afib, recent anterior MI, mechanical valve, rheumatic mitral stenosis and endocarditis.

Question 50

What is arterial dissection? What is its role in strokes?

Answer 50

Characterized by an abrupt formation of a tear along the inside wall of an artery, forming a small pouch called False Lumen. You have damage to the vessel wall allowing the blood to enter the false lumen, if the pouch enlarges it could occlude the real lumen leading to ischemia downstream.
Arterial dissection is a frequent cause of ischemic stroke in people <50 years old. The blood that accumulates inside the false lumen can generate blood clots or block blood flow leading to ischemia and stroke.
It may be sub intimal dissection which leads to increased vessel size and a pseudo aneurysm or sub adventitial which leads to rupture and hemorrhage.
Arterial dissection is most common in the ICA and it accounts for 20-25% of all strokes in patients younger than 50. Always keep in mind if you have a stroke in people less than 50 years old you should consider arterial dissection.

Question 51

Classification and risk factors of arterial dissection?

Answer 51

• Spontaneous / Traumatic: typically it’s traumatic, you have a trauma to the neck, and you get the tear opening inside the wall of the ICA (from a car accident), but it could also be spontaneous (due to genetic variability).
• Symptomatic / Asymptomatic: it’s typically symptomatic, sometimes when it’s small and in the initial phase it could be asymptomatic.
• Single / Multiple: most of the time it’s a single dissection, in some cases of large traumas you can get multiple dissections which could even be bilateral.
• Intracranial / Extracranial: it can occur inside the skull or outside the skull.

Individual risk factors include arteritis, Marfans syndrome, ehlers Danlos syndrome, hypertension, A1A.
Environmental risk factors include smoking, trauma, infections and oral contraceptives.

Question 52

Hypercoagulability in stroke?

Answer 52

If you have increased coagulability tendencies, there is a higher chance of forming clots inside vessels which could lead to stroke.
Hypercoagulability can be due to :

Hereditary causes—> antithrombin III deficiency, protein S and C deficiency, hyperhomocysteinemia.
Acquired—> paraneoplastic syndromes, myeloproliferative syndromes, antiphospholipid antibodies, heparin induced thrombocytopenia and thrombosis syndrome.

Question 53

Vasculitides in stroke?

Answer 53

Vasculitides can cause clot formation and stenosis of blood vessels possibly leading to ischemic stroke.
GCA, takayasu, SLE, GPA are some examples.
Other secondary Vasculitides that affects the brain include drug abuse specifically cocaine, TB infections, celiac disease, chrons.

Question 54

What is CADASIL?

Answer 54

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy. It’s an autosomal dominant condition with a mutation of NOTCH3 gene on chromosome 19, it’s a monogenic cause of damage and stroke events. It especially affects the white matter, you get a very diffused and distributed tissue damage (you may confuse it with multiple sclerosis).

Things to remember :
Where are the lesions—> mainly in temporal pole, bilaterally, external capsule also bilaterally, and the orbitofrontal region which is almost never affected by MS therefore it is a good DDX.
Are the lesions symmetric—> in CASADIL they are.

Patients typically are affected by migraines with auras, they tend to have mostly lacunar strokes or trans ischemic insults in young age, they can be affected by subcortical dementia, mood alteration and death usually occurs between 40 and 60 years of age.

Question 55

Cortical vs subcortical dementia?

Answer 55

Cortical brain areas are devoted to cognitive functions like language and speaking. Damage to these areas can cause cognitive problems and lead to cortical dementia.

Subcortical areas are activated while doing a cortical task for example while speaking you are looking at peoples faces. Damage tp there areas will lead to slower processing speed of these areas, although main cognitive function is maintained.

Question 56

What is CARASIL?

Answer 56

Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, an autosomal recessive condition with a mutation of HTRA1 gene on chromosome 10, CARASIL has the same manifestation of CADASIL with the addition of alopecia and spondylosis deformans, it has a slower progression than CADASIL so death occurs later.

Question 57

What is 1-MELAS?

Answer 57

It is a metabolic disorder. Mitochondrial myopathy-Encephalopathy-Lactic Acidosis and Stroke like episodes, it is a maternally inherited mitochondrial DNA A-to-G transition at nucleotide 3243, it is characterized by, stroke like episodes before the age of 40, encephalopathy characterized by epileptic seizures and dementia, damage to muscles causing diffuse myopathy, lactic acidosis, deafness, and in biopsy you find ragged-red muscle fibers, which are clumps of diseased mitochondria accumulating in the periphery of muscle fibers making disrupting their linear borders, they appear as “Ragged Red Fibers” when the muscle is stained with modified Gomori trichrome stain.

You should think of this disease when you have a young patient with strokes and muscle involvement.

Question 58

What is 2- Homocystinuria?

Answer 58

An autosomal recessive mutation causing a deficit in the cystathionine beta synthase system (CBS), which is an enzyme that uses vitamin B6 to metabolise homocysteine. It is characterized by, childhood onset, stroke events, eye abnormalities (ectopia lentis in 85% of cases) with severe myopia, skeletal deformations (kyphosis-scoliosis) and osteoporosis, intellectual deficits and psychiatric illnesses, and almost 25% of patients die from thromboembolism before the age of 30.

Question 59

What is Fabry disease?

Answer 59

It is a lysosomal storage disease, an X-linked alpha galactosidase A deficiency affecting lysosomal function leading to cell damage, it’s a brain disease that also affects mainly 2 other organs: the heart and the kidneys.
Fabry disease is characterized by : peripheral neuropathy causing burning pain, kidney failure, cardiac conduction tissue involvement (may need pacemaker implantation), it may involve the intima and media of small arterioles increasing the risk of stroke, could involve the eye causing Cornea Verticillata or Angiokeratoma (highly specific). Life expectancy of affected males is 60 years.

Question 60

Classification and main signs of hemorrhagic stroke?

Answer 60

They can be intracerebral/intraparenchymal hemorrhages or subarachnoid hemorrhages.
CT is the first thing you do in the emergency room when you suspect a stroke, there are 3 main indirect signs:
1) a big ischemia with edema.
2) if the ischemia is big enough it might flatten the cortical gyri or change the ventricles shape.
3) you get a big clot typically in the middle cerebral artery, which is denser than the blood, so it shows as white spots at CT.

Question 61

Intracerebral/intraparenchymal hemmorhage? Locations? Risk factors?

Answer 61

They can be supratentorial (80%) or infratentorial (20%), infratentorial brain is smaller than the supratentorial (for that you have more frequent hemorrhages in the supratentorial brain).

In the supratentorial you can have typical intraparenchymal hemorrhages (located in the basal ganglia and thalamus) or atypical intraparenchymal hemorrhages (which are subcortical or lobar).
In the infratentorial they can be in the cerebellum or the pons.

Primary risk factors—> hypertension and cerebral amyloidosis.
Secondary risk factors—> aneurysms, arteriovenous malformations, anticoagulant or anti platelet therapy, tumors, alcohol or drug abuse, caogulopathy.

In people <40 the main etiology is vascular malformations.
In patients 40-70 years old the main etiology is hypertension.
In old patients > 70 the main etiology is hypertension and cerebral amyloidosis; it leads to typical hemorrhages and deposition of amyloid in the vessel wall making it more vulnerable to rupture.

Question 62

ICH risk factors in detail?

Answer 62

Hypertension —> increases risk 2 to 6 fold. If hypertension therapy discontinued risk if ICH doubles. Pathogenesis is the same as lacunar ischemic stroke : deposition of intramural fibrin and lipids, formation of microaneurysms.

Cerebral amyloid antipathy —> typical of elderly people, characterized by beta amyloid deposition in tunica media and adventitia of brain vessels which leads to sub cortical hemorrhages, typically multifocal.

Vascular malformations —> cerebral vascular malformations are congenital and mostly cause atypical hemorrhages. The most common categories : developmental venous anomalies (60% of CVM), cavernous malformation (10%), arteriovenous malformation which is the most symptomatic (15%) and telangiectasia (15%).

Aneurysms —> typically cause subarachnoid hemorrhage but 30-40% cause ICH. Can be saccular, fusiform or pseudo. Most common location is near the anterior communicating artery followed by the middle cerebral artery, posterior communicating artery, ICA, basilar artery tip.

Tumors —> 5% of all ICH are caused by tumor bleeds. Primary tumors such as GBM, anaplastic astrocytoma tend to bleed more than secondary tumors like melanoma, lung, kidney.

Venous thrombosis —> can lead to ischemic strokes but also hemorrhages by rupture of small subcortical vessel. Risk factors include pregnancy, oral contraceptives, smoking, female gender, tumors.

Question 63

Clinical features of ICH?

Answer 63

Clinical presentation of ICH is composed of 2 elements.

• General symptoms related to increased intracranial pressure. Anything growing inside the skull (like hemorrhages and tumors) increases the pressure in it, examples of symptoms : headache, nausea, projectile vomiting, confusion, drowsiness. They are mostly abrupt but can gradually evolve over minutes, hours, days.
• Focal neurological deficits reflecting specific locations of hematoma. Lobar regions causes headache localized to ICH site, motor/sensory/visual field deficit, aphasia, neglect. Deep region causes motor/sensory/visual field deficit, cerebellar causes nausea, vomiting, ataxia and coma. Brainstem leading to tetraplegia and coma.

Question 64

Subarachnoid hemorrhage etiology/risk factors, symptoms?

Answer 64

Etiology/risk factors include : aneurysm in 85% of cases, non aneurysmal hemorrhages 15% caused by cerebral vasculitides, tumors, dural arteriovenous fistula, dural sinus thrombosis.
Of course hypertension is a comorbidity.

Symptoms : sudden onset of severe thunderclap headache often describes as the worst of my life. Nausea and projectile vomiting due to increased pressure in the brainstem. Loss of consciousness. Seizures are frequent. Meningismus after a few hours. Sentinel leaks, small leaks, in the previous weeks causing headaches. Prodromal focal symptoms depending on location can cause compression of CN like oculomotor anf cause double vision.

Question 65

Main differences between ICH and SAH?

Answer 65

ICH —> mostly abrupt symptoms but gradual progression, alteration of consciousness is gradual, most common in older males, seizures are rare except for lobar ICH, usually no warning symptoms, no meningismus.
SAH —> abrupt onset of sudden severe headache, may present brief loss of consciou.sness, F>M, seizures occur in 10 to 30% of cases, sentinel leaks in 50% of patients, meningismus after a few hours

Question 66

Treatment flowchart?

Answer 66

In a patient with acute presentation of symptoms or signs that can be possibly attributed to involvement of large vessels in the brain, CT scan is ALWAYS mandatory before any therapeutic decision is made.

Symptoms appear >24 h before evaluation : too late for pharmacological and non pharmacological treatment. Manage symptoms

Question 67

Treatment for stroke? Treatment flowchart?

Answer 67

Pharmacological treatment of stroke regards only the ischemic stroke, hemorrhagic stroke must be excluded because treating it would be detrimental. In a patient with acute presentation of symptoms or signs that can be possibly attributed to involvement of large vessels in the brain, CT scan is ALWAYS mandatory before any therapeutic decision is made.

• symptoms appear more than 24 h before evaluation —> too late for both pharmacological and non pharmacological treatment. Treatment is trying to manage symptoms and prevent a secondary stroke.
• symptoms appear more than 4.5h but less than 24h before evaluation —> If large artery is involve patient should undergo thrombectomy as not eligible for thrombolysis.
• symptoms appear less than 4.5h before evaluation —> thrombolysis should be done if patient is eligible while understanding if stroke is due to large vessel occlusion so to perform in case thrombectomy.

Question 68

What is thrombolysis? Risks?

Answer 68

It is the main treatment for ischemic stroke and it consists of an injection of thrombolysis drug to dissolve clots and re-establish blood flow.
The main drug used is Alteplase which is a recombinant tissue plasminogen activator. This drug converts plasminogen into plasmin which dissolves fibrin clots.

Standard dose is 90mg —> 10% bolus over 1 min and the rest over 1 hour.

Eligibility —> diagnosi of ischemic stroke, age over 18 and symptoms onset less than 4.5 h from evaluation.

Main risks include sudden neurological deterioration, decline in level of consciousness, nausea, vomiting or headache. Systemic bleeding may occur and is usually mild.
Angioedema is a rare complication which occurs as Alteplase trigger production of bradykinin which mediates vasodilation.

Question 69

Absolute contraindications for thrombolysis?

Answer 69

The major risk we want to exclude is transformation of ischemic stroke to hemorrhagic. We should exclude all patients who have :

• CT revealing acute intracranial hemorrhage.
• Subject who has a preziosi ischemic stroke within 3 months.
• Subject with severe head trauma within 3 months.
• Since thrombosis is a systemic pharmacological treatment pay attention to tumors in brain or other organs such as GI tract.
• Severe coagulopathy.

Question 70

Additional recommendations for thrombolysis?

Answer 70

1. Early improvement : Alteplase treatment is reasonable in patients with moderate to severe ischemic stroke even if they demonstrate early improvement but remain moderately impaired.
2. Seizure at onset : a seizure could mimic an ischemic stroke but an ischemic stroke can be associated with a seizure at onset. A seizure could be part of clinical picture of ischemic stroke at onset and it is not a contraindication, but understand whether clinical manifestations are just
   part of the clinical manifestation of the seizure or part of the stroke.
3. Blood glucose: treatment with Alteplase in patients presenting with glucose < 50 or > 400 is possible, but try first to normalize glucose levels and understand if clinical manifestations are related only to glucose level or if part of the stroke
4. coagulopathy : patient having a coagulopathy can be treated with Alteplase if having history of warfarin use.

Question 71

Timeline and outcome in thrombolysis? Management?

Answer 71

When looking at outcome time is of the essence. Each 15 min reduction in our approach in a patient with ischemic stroke there are significant better odds of the patient being discharged and decreased chance of death and hemorrhagic transformation.

We should aim to start IV Alteplase within 60 min from patient arrival.

Patient should be monitored closely as risk for hemorrhagic transformation is high, especially in the first hour. Anticoagulant and anti platelet treatment should not be administered for at least 24h and placement of intra arterial catheter, bladder catheter and nasogastric tubes should be avoided for at least 24h.
CT scan should be performed after 24h from therapy start.

Question 72

What is thrombectomy?

Answer 72

Patients who are not eligible for thrombolysis can be treated with mechanical thrombectomy.
To perform it an angiography should demonstrate the occlusion of a large artery.

Risks include appearance of new ischemic strokes during or after procedure as part of the thrombus can go further and block smaller vessels.

Question 73

Secondary prevention for stroke?

Answer 73

Risk factors that can be treated include hypertension, DM, smoking, dyslipidemia and physical inactivity. Stroke causes that can be modified are Afib and carotid artery stenosis.

Pharmacological treatment for prevention include aspirin and clopidrogel which are anti platelet drugs.

Anti platelet drugs should be used all the time except in 4 specific condition where they are not sufficient and anticoagulant therapy is needed. The 4 conditions are : non valvular Afib, cerebral venous thrombosis, anti phospholipid syndrome and extra cranial artery dissection.

Anticoagulants are preferred over antiplatelets in the listed conditions because the clots are not primarily caused by platelet aggregation, but by mechanisms involving fibrin deposition or autoantibodies, which require anticoagulation for effective prevention and management.

Question 74

What is carotid endarteriectomy?

Answer 74

Carotid Endarterectomy (CEA) is a surgical procedure used to remove atherosclerotic plaque from the carotid artery to prevent recurrent ischemic strokes. Indications for CEA are primarily based on the degree of carotid artery stenosis and clinical symptoms.

Always recommending in patients with TIA or ischemic stroke within past 6 months and ipsilateral severe CAS.

Patients with moderate CAS, CEA is recommended based on specific factors such as age, sex, comorbidities.