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Νοητικές και Εκφυλιστικές Νευρολογικές διαταραχές

Ο όρος «μείζονα νοητική διαταραχή» ή αλλιώς «άνοια» όπως πιο συχνά αποκαλείται αποτελεί ένα σύνδρομο δηλαδή τον συνδυασμό από συμπτώματα και κλινικά σημεία της νοητικής κατάστασης αλλά και της συμπεριφοράς του ατόμου, τα οποία έχουν αρχίσει να έχουν αρνητική επίπτωση στις δραστηριότητες καθημερινότητας, για τις επιτέλεση των οποίων είναι απαραίτητη η βοήθεια από κάποιο συνοδό μέλος. Είναι ένας όρος που έχει δημιουργηθεί για να κάνει πιο εύκολη την περιγραφή της κλινικής εικόνας του ασθενή, στην επικοινωνία των ιατρών. Τα άτομα που πάσχουν από άνοια μπορεί να παρουσιάζουν ποικίλα συμπτώματα (κλινικός φαινότυπος). Ανεξάρτητα από την κλινική εικόνα ο μηχανισμός της διαταραχής αυτής μπορεί να οφείλεται σε ένα ή περισσότερα αίτια, με την εκφύλιση και τις αγγειακές βλάβες του εγκεφάλου είναι τα πιο συχνά. Δεν είναι σπάνιο, μερικές μορφές άνοιας να συνοδεύονται ή να έπονται κάποιων άλλων συμπτωμάτων που είναι το αποτέλεσμα άλλων διαταραχών όπως διαταραχών ύπνου ή επιληψία.

Η «ήπια νοητική διαταραχή» (Mild cognitive impairment – MCI) ή η «ελάσσονα νοητική διαταραχή» είναι ένα κλινικό σύνδρομο που περιγράφει ήπιες αλλαγές στην νόηση και την συμπεριφορά του ατόμου, οι οποίες παρόλο που γίνονται αισθητές από το ίδιο το άτομο, δεν είναι τόσο σοβαρές ώστε να ζητηθεί βοήθεια από κάποιο συνοδό μέλος για την διεκπεραίωση των δραστηριοτήτων της καθημερινότητας. Όπως ο όρος «άνοια» έτσι και ο όρος “MCI” είναι απλά ένας κώδικας επικοινωνίας που γνωστοποιεί μία νοητική κατάσταση χωρίς πολλές λεπτομέρειες, μεταξύ των ιατρών. Τα άτομα που πάσχουν από MCI μπορεί να έχουν ποικίλα συμπτώματα (κλινικός φαινότυπος) και η κάθε κλινική εικόνα με την σειρά της να οφείλεται σε περισσότερα από ένα αίτια τα οποία μπορεί να είναι εκφυλιστικά νοσήματα του εγκεφάλου, αγγειακές βλάβες του εγκεφάλου, μεταβολικές διαταραχές, επιληψία ή διαταραχές στον ύπνο. Αξίζει να σημειωθεί ότι διαταραχές στον ύπνο μπορεί να προηγούνται πολλών ετών της έναρξης των νοητικών συμπτωμάτων, το οποίο σημαίνει ότι η έγκαιρη ανίχνευση και αντιμετώπιση των υπνικών αυτών διαταραχών μπορεί να καθυστερήσει την έλευση των νοητικών διαταραχών. Τα συμπτώματα που περιγράφουν τον κλινικό φαινότυπο στην MCI οργανώνονται στα ακόλουθα πεδία: μνήμη, ομιλία, εκτελεστικές λειτουργίες, οπτικοχωρική-κατασκευαστική ικανότητα, και συμπεριφορά. Ανάλογα με το αίτιο, τα συμπτώματα στην MCI, μπορεί να επιδεινωθούν όπως συμβαίνει στις εκφυλιστικές διαταραχές ή να παραμείνουν στάσιμα όπως συμβαίνει στις αγγειακές βλάβες ή ακόμη και να υποχωρήσουν όταν το αίτιο που υποκρύπτεται είναι αναστρέψιμο.

H άνοια Alzheimer (AD) αναφέρεται στα 4 κύρια κλινικά σύνδρομα, τα οποία ιστορικά χαρακτηρίζονται από κοινά ανατομικά στοιχεία-βλάβες στο εγκέφαλο κάτω από την ομπρέλα της νόσου Alzheimer. Πρέπει όμως να σημειωθεί ότι υπάρχει η Άνοια τύπου Alzheimer που αναφέρεται στα συμπτώματα που περιγράφουν την κλινική αυτή οντότητα, αλλά και στη Νόσο Alzheimer στην οποία υπάρχουν συγκεκριμένες ανατομικές βλάβες. Είναι λογικό να υπάρχει σύγχυση στο άκουσμα «άνοια Alzheimer». O κοινός παρονομαστής των 4 αυτών κλινικών συνδρόμων, της νόσου Alzheimer, προέκυψε από παθολογοανατομικές παρατηρήσεις στις αρχές του 20ου αιώνα, με εναποθέσεις συγκεκριμένων πρωτεϊνών στον εγκέφαλο, του β-αμυλοειδούς και της πρωτεΐνης tau. H εναπόθεση των πρωτεϊνών αυτών σε συγκεκριμένες περιοχές του εγκεφάλου, δημιουργεί ανώμαλα πολυμερή τα οποία έχουν αρνητική επίπτωση στην λειτουργία του εγκεφάλου. Η επερχόμενη αυτή πρωτεϊνοπάθεια (κυρίως για την πρωτεΐνη tau) ανάλογα με την περιοχή εναπόθεσης είναι υπεύθυνη για την δημιουργία διαφορετικών κλινικών φαινοτύπων – συνδρόμων. Με την πάροδο του χρόνου και ολοένα και καλύτερη γνώση της νευροεκφύλισης, γίνεται κατανοητό ότι η πρωτεϊνοπάθεια στην νόσο Alzheimer αλλά και σε άλλα νευροεκφυλιστικά νοσήματα, είναι ένα μόνο μέρος της εικόνας, η οποία πλαισιώνεται και από άλλες διαταραχές όπως αυτοάνοσες, αγγειακές, μεταβολικές, και γενετικές που συμβάλλουν σε διαφορετικό βαθμό η καθεμία, σε λειτουργικό ή ανατομικό επίπεδο στον εγκέφαλο προκαλώντας συμπτώματα. Διαταραχές ύπνου αναδεικνύονται στους περισσότερους ασθενείς με AD με ένα φάσμα συμπτωμάτων από την υπνική άνοια και την αυπνία μέχρι τις διαταραχές στον κύκλο ύπνου-εγρήγορσης. Ο εγκέφαλος μπορεί να μπει σε μία «ζώνη λυκόφωτος» στην οποία από την μία δεν επιτυγχάνεται πλήρης εγρήγορση, από την άλλη ούτε πλήρης και βαθύς ύπνος, με αποτέλεσμα να υπάρχει δυσλειτουργία στις νοητικές διεργασίες κατά την διάρκεια της ημέρας που το άτομο είναι ξύπνιο, αλλά με ταυτόχρονη επιτάχυνση της πρωτεϊνοπάθειας στον εγκέφαλο.

  • Άνοια Alzheimer όψιμης έναρξης (Late age onset Alzheimer Dementia – LOAD) – Αμνησιακό κυρίως έλλειμμα: Είναι η πιο συχνός τύπος άνοιας Alzheimer (AD), πλήττοντας ηλικίες μεγαλύτερες των 65 ετών. Χαρακτηρίζεται από τις διαταραχές μνήμης που είναι το κύριο αλλά και το πρωτοεμφανιζόμενο σύμπτωμα. Η ανίχνευση των πρώτων συμπτωμάτων γίνεται από τα συνοδά μέλη των ασθενών, που αναφέρουν ότι υπάρχει δυσκολία στο να θυμάται ο ασθενής ραντεβού, πρόσφατες συζητήσεις, ενώ έχουν την ικανότητα να θυμούνται με λεπτομέρειες παρελθόντα γεγονότα. Παρόλο που στην πλειονότητα των ασθενών που έχουν νόσο Alzheimer, οι περιοχές του εγκεφάλου που επηρεάζονται είναι οι Ιππόκαμποι στους οποίους γίνεται η εγχάραξη της μνήμης, πολύ συχνά στους περισσότερους ανθρώπους υπάρχουν και άλλες διαταραχές που προκαλούν εγκεφαλική βλάβη όπως η αρτηριακή υπέρταση, δυσλιπιδιαμία και σακχαρώδη διαβήτη. Πρέπει να σημειωθεί ότι πολλά άτομα που εμφανίζουν κλινικό φαινότυπο άνοιας Alzheimer με έναρξη άνω των 80ετών, δεν έχουν στην πραγματικότητα νόσο Alzheimer, αλλά μία άλλη νοσολογική οντότητα που ονομάζεται LATE (Limbic-predominant Age related TDP-43 encephalopathy) που ενώ μοιράζεται τα ίδια κλινικά συμπτώματα με την AD, έχει άλλο παθογενετικό μηχανισμό που οφείλεται στην εναπόθεση της πρωτεΐνης TDP-43. Οι ανωτέρω επισημάνσεις κάνουν αναγκαία την προσέγγιση και την παρακολούθηση των ασθενών αυτών από εξειδικευμένη διεπιστημονική ομάδα ιατρών - ψυχολόγων.
  • Οπίσθια Φλοιϊκή Ατροφία (Posterior Cortical Atrophy – PCA) – Οπτικοχωρικό κυρίως έλλειμμα: Η μορφή αυτή, περιγράφηκε για πρώτη φορά από τον Frank Benson, είναι λιγότερο συχνή από την LOAD και πλήττει άτομα πιο νεαρής ηλικίας. Το κύριο χαρακτηριστικό είναι η δυσκολία στην αναγνώριση πολύπλοκων-σύνθετων σχημάτων, όπως το πρόσωπο, στην σωστή αντίληψη αποστάσεων και του εύρους της κίνησης (πχ κατά την διάρκεια παρκαρίσματος) χωρίς ωστόσο να υπάρχει δυσκολία στην αντίληψη των χρωμάτων και των στατικών σχημάτων. Στην περίπτωση αυτή ο εγκέφαλος δεν μπορεί να συγχρονίσει και να συνδυάσει τα οπτικά ερεθίσματα σε μία προβολή
    τρισδιάστατης κίνησης. Η PCA οφείλει το όνομα της στις οπίσθιες περιοχές του εγκεφάλου που πλήττονται και που είναι υπεύθυνες για την οπτική αντίληψη. Σε πολλούς ασθενείς η διάγνωση γίνεται καθυστερημένα, διότι οι ασθενείς θεωρούν ότι η δυσκολία αυτή είναι το αποτέλεσμα κακής όρασης, από την στιγμή που δεν υπάρχει άλλο νοητικό έλλειμμα, όπως η μνήμη. Ένα άλλο χαρακτηριστικό είναι το καταθλιπτικό συναίσθημα το οποίο αποδίδεται σε κοινωνικά αίτια και όχι σε δυσλειτουργία του εγκεφάλου. Η ανατομικές βλάβες στην PCA είναι όμοιες με εκείνες της νόσου Alzheimer.
  • Λογοπενική Πρωτοπαθής Προϊούσα Αφασία (Logopenic Primary Progressive Aphasia - lvPPA) – Έλλειμμα κυρίως στην Ομιλία: H προϊούσα αφασία (PPA) αναφέρεται σε τρία κλινικά σύνδρομα, στα οποία το πρώτο και το κυριότερο έλλειμμα που αναφέρεται είναι η προοδευτική δυσκολία στην ομιλία: (α) Λογοπενική, (β) μη-ρέουσα/αγραμματική, (γ) σημασιολογική. Ο πρώτος υποτύπος ανήκει στο φάσμα του συνδρόμου της άνοιας Alzheimer, ενώ ο 2ος και ο 3ος υποτύπος ανήκουν στο φάσμα της Μετωποκροταφικής άνοιας. Τα άτομα με lvPPA έχουν κυρίως δυσκολία στην ανεύρεση λέξεων, το οποίο υποδεικνύει διαταραχή στο αριστερή οπίσθια κροταφική περιοχή. Παρουσιάζουν μεγάλες παύσεις κατά την διάρκεια της ομιλίας, προσπαθώντας να βρουν την κατάλληλη λέξη, παρόλο που γνωρίζουν την έννοια της λέξης με αποτέλεσμα να έχουν περιφραστικό λόγο προκειμένου να γίνουν σαφείς. Είναι επίσης συχνό να θυμούνται λιγότερες πληροφορίες, κατά την συζήτηση, διότι τους είναι πολύ δύσκολο να καταλάβουν «με την πρώτη» αυτό που ακούν. Η επικοινωνία χρησιμοποιώντας με σύντομες και ευθείς προτάσεις έχει καλύτερα αποτελέσματα. Σε ένα μικρό ποσοστό των ασθενών αυτών υπάρχει ιστορικό Δυσλεξίας, ενώ στο μεγαλύτερο ποσοστό οι βλάβες είναι εκείνες της νόσου Alzheimer.
  • Άνοια Alzheimer Πρώιμης Έναρξης (Early age of onset Alzheimer’s Disease) – Δυσεκτελεστικό κυρίως έλλειμμα: Η EOAD είναι μία λιγότερο συχνός υπότυπος άνοιας, στην οποία η έναρξη των συμπτωμάτων γίνεται σε ηλικία μικρότερη των 65 ετών. Σε σχέση με την LOAD (Άνοια Alzheimer Όψιμης έναρξης), το κύριο σύμπτωμα μπορεί να μην είναι οι διαταραχές στην μνήμη, αλλά οι διαταραχές στην οργάνωση και τον προγραμματισμό που είναι χαρακτηριστικά των εκτελεστικών λειτουργιών. Επιπλεόν σε σχέση με τις άλλους τύπους της νόσου Alzheimer, η ατροφία στην εγκεφάλο δεν είναι τόσο εμφανής, και συχνά κρίνεται απαραίτητη η αναζήτηση συγκεκριμέων βιοδεικτών νευροεκφύλισης για την επιβεβαίωση της ως νόσο Alzheimer. Ασθενείς με EOAD πολύ συχνά χαρακτηρίζονται λανθασμένα ως ασθενής που έχουν άλλες νευροφκυλιστικές διαταραχές, όπως η Μετωποκροταφική άνοια, αναδεικνύοντας με τον τρόπο αυτό την αξία στην ύπαρξη και την τήρηση ειδικού πρωτοκόλου διάγνωσης.

Το σύνδρομο FT-NCD είναι περισσότερο γνωστό ως Μετωποκροταφική Άνοια (FTD) και αναφέρεται σε τρία διαφορετικά κλινικά σύνδρομα στα οποία κοινό χαρακτηριστικό είναι η εκφύλιση των μετωπιαίων και των πρόσθιων κροταφικών περιοχών του εγκεφάλου. Αυτή η μορφή εκφύλισης ονομάζεται Μετωποκροταφική λοβώδης εκφύλιση (FTLD) και χαρακτηρίζεται κλινικά από την εμφάνιση συμπτωμάτων που έχουν να κάνουν πρόβλημα με την κοινωνική συμπεριφορά (bvFTD), την ομιλία (nfvPPA και svPPA). Επιπλέον η πρωτεϊνοπάθεια που σχετίζεται με την FTD είναι διαφορετική από εκείνη που βλέπουμε στην νόσο Alzheimer, με την παρουσία συγκεκριμένων κλινικών συνδρόμων να σχετίζονται συχνά με συγκεκριμένες πρωτεϊνοπάθειες, στις οποίες δεν είναι σπάνιο να υπάρχει υποκείμενο γενετικό υπόβαθρο. Ο Παρκινσονισμός ο οποίος κλινικά καθορίζεται
από το συνδυασμό βραδύτητας στην κίνηση (Βραδυκινησία), μυϊκή υπερτονία, τρόμο ή αστάθεια στάσης και βάδισης, είναι πολύ συχνός στο σύνδρομο FTD ίδια όταν η υποκείμενη παθολογία είναι η πρωτεϊνοπάθεια tau (tauopathy). Οι διαταραχές στον ύπνο είναι επίσης συχνές στο σύνδρομα μετωπιαίας εκφύλισης. Τρεις στου τέσσερις ασθενείς αναφέρουν αυπνία ή υπνική άπνοια.

  • Συμπεριφορική μορφή Μετωποκροταφικής Άνοιας (bvFTD): Τα κλινικά χαρακτηριστικά του κλινικού συνδρόμου bvFTD είναι οι διαταραχές στην συμπεριφορά του ατόμου που εκδηλώνονται αρκετά νωρίς στην ηλικία περίπου των 50 ετών. Τα άτομα αυτά χαρακτηρίζονται με άρση κοινωνικής αναστολής, έλλειμμα ενσυναίσθησης, εμμονές, ειδικές διατροφικές συνήθειες, απάθεια ή και πολύ μεγάλη δυσκολία στο να οργανώσουν και να διεκπεραιώσουν σύνθετες δραστηριότητες. Η κοινωνικά μη αποδεκτή συμπεριφορά μπορεί να χαρακτηρίζεται από βωμολοχίες, εξωστρέφεια με έντονο φλερτ, όπου η έλλειψη ενσυναίσθησης και η εγωκεντρισμός, προκαλεί μεγάλη συναισθηματική φόρτιση και οδύνη στα συγγενικά τους μέλη καθώς έχουν την αίσθηση ότι ο ασθενής έχει γίνει απόμακρος, διαφορετικός και δεν τους νοιάζεται πλέον. Λόγω αυτών τον αλλαγών στην συμπεριφορά, που προηγούνται της εμφάνισης των νοητικών συμπτωμάτων που δυσκολεύουν
  • Non-fluent/Agrammatic Primary Progressive Aphasia (nfvPPA): The term Primary Progressive Aphasia (PPA) refers to three syndromes where people’s first and predominant difficulties involve a gradually progressive deficit in language, and they are further subdivided into three subtypes: logopenic, non-fluent/agrammatic, and semantic. Logopenic variant is one of the Alzheimer’s dementia syndromes, whereas the other two are Frontotemporal Dementia Syndromes.  People with nfvPPA have a predominant deficit in speech or language planning and organization, which is the result of impaired left frontal lobe function.  This is perceived as either a difficulty (a) in precisely organizing the motor sequences of effective speech, or (b) in properly applying grammar when speaking.  As a result, symptoms may include stuttering speech, poor articulation, or omission of words in a sentence. Some people may become mute even if other cognitive functions, such as memory, are relatively intact.  It is also not uncommon for people with nfvPPA to overlap with other neurodegenerative diseases, such as PSPS (Progressive Supranuclear Palsy Syndrome) or bvFTD, depending on the underlying proteinopathy that caused the symptoms in the first place.  As in most FTD, the most common proteinopathies relate to abnormal clustering of tau or TDP-43 proteins.
  • Semantic Variant Primary Progressive Aphasia (svPPA): The term Primary Progressive Aphasia (PPA) refers to three syndromes where people’s first and predominant difficulties involve a gradually progressive deficit in language, and they are further subdivided into three subtypes: logopenic, non-fluent/agrammatic, and semantic. Logopenic variant is one of the Alzheimer’s dementia syndromes, whereas the latter two are Frontotemporal Dementia Syndromes. The characteristic feature of svPPA is that people lose their ability to understand the meaning of words, as a result of left anterior temporal lobe dysfunction. As a result, people are unable to follow a conversation, but also reveal a disorganized thought process, because language is one of the cornerstones of analytical thinking. In contrast, patients with svPPA often develop a visual artistic interest as they lose their language abilities, and many paint elaborate colorful paintings, or mold clay in unique ways. As the disease progresses to involve the right anterior temporal lobe, many people lose their ability to understand others’ emotions and often become more rigid in their thinking, showing perseverating and hoarding behaviors. Eating habits can be quite distinct, where people may eat only one type or color of food. For people whose brain is first affected at the right anterior temporal lobe, a key area of behavior, these abnormal social behaviors will precede the language deficits. The underlying cause of anterior temporal lobe neurodegeneration is almost exclusively a TDP-43 proteinopathy. Some studies suggest that it is more likely for people with svPPA, or their direct relatives, to have a history of autoimmune disease or cancer, suggesting that certain therapies implemented in those conditions may help in svPPA, however, clinical trials are lacking due to their rare presentation and delayed diagnosis.

In PSPS people tend to have difficulties in moving their eyes vertically or maintain their balance. As a result, they often have unexpected falls and report a difficulty reading through lines in a book. Cognitive-behavioral symptoms are practically always present, especially with difficulties in speech fluency, motivation, and planning. Sleep problems are almost invariably present, with insomnia interfering significantly with people’s lives. The most typical characteristic of PSPS is parkinsonism with muscle stiffness and slowness in movement, explaining people often being misdiagnosed having Parkinson disease. In contrast, however, to Parkinson disease where the underlying pathology is due to abnormal synuclein protein deposition, PSPS almost always have an abnormal underlying tau proteinopathy.

CBS is one of the most variable dementia syndromes, where people have difficulties in perceiving the position of their limbs in space or in controlling their movements accurately. In some people, the so-called alien limb phenomenon is present, where limbs seem to move as if they have a mind of their own. For example, hands may compete with each other when buttoning shirts. In other instances, people may not realize being touched if they don’t look at that part of the body, a phenomenon called neglect. Symptoms of parkinsonism are present in most people, becoming stiff and having difficulty in moving, further delaying accurate diagnosis. CBS takes its name from the cortical and basal ganglia of the brain being affected in the disease process, but the cause of the syndrome ranges from a tauopathy in more than half of people, to Alzheimer’s disease in a third of people.

SA-NCD refers to three syndromes with overlapping clinical symptoms, namely Lewy Body Dementia (LBD), Parkinson Disease Dementia (PDD), and Multiple System Atrophy (MSA), that usually affect people over age 50 and share α-synuclein proteinopathy as the common underlying pathology. This pathology is distributed differently across the brain and body between the three syndromes, leading to the three overlapping, but different, phenotypes. Even though people with any of the three have some level of parkinsonism symptoms, the predominant symptoms early in the disease process are different between them. Specifically, people with LBD mostly have cognitive-behavioral symptoms, people with MSA have pronounced autonomic deficits, whereas people with PDD predominantly have parkinsonism motor symptoms upon which other symptoms may follow. That said, all of the above symptoms tend to be present at different frequencies between the three as α-synuclein pathology spreads across the nervous system, explaining why physicians give a diagnosis of synucleinopathy rather than of an individual syndrome. Sleep disorders are very common and pronounced in synucleinopathies, with people being sleepy or going in and out of sleep frequently within the day, having sleep apnea, and almost four out of five having the telling symptom of REM-behavior disorder (RBD), which may present several years before parkinsonism occurs. For older people with SA-NCD, it is not uncommon for additional brain pathologies to be present, such as Alzheimer’s disease or vascular brain disease, contributing to symptom severity.

  • Lewy Body Dementia (LBD): The cognitive-behavioral symptoms of LBD are usually affecting executive functions of planning, organizing, multitasking, and thinking fast, as well as visuospatial functions of constructing complex objects or perceiving things. It is not uncommon for people to mention visual hallucinations, often misperceiving things in poorly lit environments and in settings where they get sleepy. Similarly, they may report a sense of shadows at the edge of their vision as if someone is following them, which disappear when they turn to look. A fluctuating level of alertness within several minutes makes all the above symptoms even more pronounced and can help in making a diagnosis. Autonomic symptoms of constipation, dizziness upon standing suddenly, and erectile dysfunction are also common, but may not be troubling to many patients. Similarly, parkinsonism invariably presents in all people as symptoms progress, but may not be pronounced from the very beginning.
  • Multiple System Atrophy (MSA): In MSA, autonomic symptoms are often severe and have patients seek medical help. People tend to faint frequently due to orthostatic hypotension or slow heart rate, and erectile dysfunction is commonly present even years before other symptoms. Motor symptoms are invariably present and distinguish two MSA phenotypes depending if they are predominantly parkinsonian (MSA-P), with stiff slow movements, or cerebellar (MSA-C), with poor coordination of goal-directed movements and imbalance. Fluctuating levels of alertness and cognitive symptoms of slow processing speed are also present but not often the ones that trigger the first visit to the physician’s office. When noticed, cognitive difficulties affect executive function of planning and organization of thinking, whereas memory is relatively spared. A concerning symptom to caregivers is the loud noise during sleep called stridor, highlighting sleep disordered breathing and the need for sleep study testing and treatment.
  • Parkinson’s Disease Dementia (PDD): In PDD, people are mainly affected by motor symptoms of bradykinesia (slowness in movement), rigidity (muscle stiffness), imbalance and resting tremor that are usually worse on one side of the body. Not all symptoms need to be present, although bradykinesia and stiffness are almost always present. Most people have a decreased facial expression, termed masked facies, that is often interpreted as depression when combined with bradykinesia, even though patients may not complain of depression. The accompanying symptoms of REM-behavior disorder (RBD), constipation, erectile dysfunction and decreased ability to smell are usually present, with RBD presenting several years before motor symptoms. As in other synucleinopathies, cognitive features affect executive function of organizing and planning with decreased processing speed, but are milder than in other synucleinopathies, and the fluctuations in level of alertness are not as pronounced.

VaD refers to cognitive impairment whose cause is an underlying vascular injury such as an ischemic stroke or intracerebral hemorrhage. Symptoms are highly variable depending on the location and extent of the vascular injury, with executive, language, and visuospatial symptoms presenting more frequently, but also learning and memory, as well as behavioral symptoms interfering with daily life. People may become unable to attend or process information fast, plan or make effective decisions and prevent mistakes, speak or understand what they are told, perceive visual or other stimuli, recall information effectively, or remain motivated or even empathize. Motor symptoms are also present and usually recognized by others before cognitive symptoms. Symptoms may present suddenly right after a large stroke or a stroke affecting a critical brain area, or gradually as a result of extensive vascular injury to the small brain vessels. The specific cause of the stroke can range from clots forming in atherosclerotic large vessels feeding the brain or in the heart of people with atrial fibrillation, which in turn travel to the brain and cause ischemia, to direct injury of brain vessels leading to local ischemia or bleeding. Vascular risk factors that can be modified and prevent future strokes are hypertension, hyperlipidemia, diabetes, smoking and sleep apnea, whereas regular moderate exercise and a Mediterranean diet further help vascular integrity.

Sleep and Circadian Rhythm Disorders​

Chronic Insomnia Disorder is present in about one in seven to one in ten adults with symptoms of difficulty initiating sleep, maintaining sleep or waking up earlier than desired despite adequate opportunity for sleep. International criteria require that these symptoms interfere with daily life and must be present for more than three times a week for more than three months. This way, brief episodes of insomnia most people naturally experience across the lifespan are not misdiagnosed as chronic insomnia. In children, symptoms can also relate to either resistance to sleeping or needing rituals to sleep. In adults, it is associated with other medical conditions, including cognitive impairment, cardiovascular and metabolic disorders, chronic pain and depression. In such conditions, detailed evaluation with neuropsychological and laboratory tests may clarify an underlying cause to the insomnia and direct a combined treatment that improves quality of life. First line treatment for almost all people is Cognitive Behavioral Therapy for Insomnia (CBTi), whereas medications are considered for a period of time for certain people.

ISS refers to inadequate sleep amount for a period of 3 months and is often misinterpreted as insomnia by patients due to the common feature of not falling asleep when desired. However, in contrast to insomnia syndromes where people have the opportunity to sleep, people with ISS are usually not given the opportunity to sleep or do not pursue sleep and, if sleep is pursued, they tend to fall asleep within minutes. ISS is usually accompanied by excessive daytime somnolence, a sense of fatigue, and inability to focus and perform tasks effectively in the daytime, which are the main symptoms people visit their clinician for. People with ISS are at increased risk of neurological (e.g., dementia, stroke), cardiovascular (e.g., heart attack, hypertension), and metabolic-endocrine (hypothyroidism, diabetes, hyperlipidemia) problems. ISS is driven by social causes that lead to sleep deprivation, such as extended work hours or being a caregiver to others. The detrimental effects of ISS worsen as sleep deprivation accumulates over time, whereas weekend catch-up sleep, although helpful, is not sufficient to fully replenish the body’s lost rest. As a syndrome caused by social factors, treatment is achieved by changes in social habits, which also avoids unnecessary use of medications or coffee that people tend to take to remain awake.

Sleep apnea is the most commonly diagnosed syndrome of sleep disordered breathing (SDB) and refers to shallower breathing or breathing arrests during sleep that lead to either a decrease in the body’s oxygen or awakenings from sleep. About a third of adult men and post-menopausal women, and 9% of pre-menopausal women have sleep apnea. It is classified generally into Obstructive Sleep Apnea (OSA) and Central Sleep Apnea (CSA), depending on whether the disordered breathing is caused by narrowing or collapsing of the upper airway (OSA), or by a decreased or non-existent respiratory effort (CSA). The main risk factors for OSA are male sex, narrow upper airway anatomy, and age. CSA is observed in people with certain neurological or cardiac diseases (e.g., heart failure), although brief central apnea events are normally observed in people the first seconds of entering sleep and in pre-kindergarten children during REM sleep. The vast majority of people with sleep apnea have or are at risk of cardiac (e.g., arrhythmias), metabolic (e.g., hyperlipidemia, diabetes), neurological (e.g., stroke, dementia) and psychiatric (e.g., depression and anxiety) disorders. Of the cognitive deficits associated with sleep apnea, vigilance is the most affected, but improves with treatment of sleep apnea as deep sleep is achieved.

SDB also explains why many people use the bathroom in the middle of the night (nocturia) even though they don’t have prostate or cardiac problems, because certain hormones that regulate urine production are poorly regulated due to decreased oxygen. It is not uncommon for men to receive surgical prostate procedures for nocturia, even though the cause to their symptoms is sleep apnea. In children that remain asleep throughout the night, SDB can present as enuresis into later childhood. Children with sleep apnea may also not seem sleepy in the daytime, and are often given a diagnosis of Attention Deficit Hyperactivity Disorder that is treated with stimulants, which could otherwise improve by treating the underlying sleep apnea.

The view that only obese older men who are sleepy in the daytime and snore loudly have SDB is incorrect, and instead even young thin women and children have SDB. Very thin younger people with SDB may not have the typical sleep apnea described above, and instead have the, often undiagnosed, syndrome Upper Airway Resistance Syndrome (UARS). People with UARS take progressively more effortful breaths during sleep because their body tries to push air through the bottleneck caused by a long and thin upper airway, which in turn leads to brief arousals. Sleep becomes fragmented and unrefreshing, leading to trouble focusing in the daytime, but not necessarily causing daytime somnolence.

The first line treatment for sleep apnea is Positive Airway Pressure (PAP) therapy during sleep where ambient air is pushed into the airway through the nose (or nose and mouth in some cases). This air works like a wedge that stabilizes the airway and prevents its collapse. For people who also have problems exhaling enough CO2 during sleep or have CSA (e.g., morbid obesity, neuromuscular disorders, cardiac disease), non-invasive ventilation (NIV) machines are more effective.

Hypersomnia syndromes refer to excessive sleepiness in the daytime even though people have had adequate and fair quality sleep the previous nights. Distinct from hypersomnia is hypersomnolence, a symptom referring to sleepiness in the daytime that does not necessarily lead to sleep. There are three main hypersomnia syndromes: narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH).

NT1 is the best described hypersomnia and it is caused by decreased levels of a chemical produced at the hypothalamus of the brain called hypocretin or orexin (Hcrt/Orx). Hcrt/Orx helps people consolidate sleep periods, preventing the brain from going in and out of sleep randomly. As a result, people with NT1 report excessive daytime somnolence with sudden sleep attacks and fragmented unrefreshing sleep at night. Because sleep and wake are poorly dissociated, people have experiences as if being simultaneously in both states, such as having dream-like hallucinations around sleep periods, and sleep paralysis with inability to move for several seconds upon awakening. Almost unique to NT1 is the symptom of cataplexy, where people report sudden loss of muscle tone where their jaw drops or their knees buckle with strong emotional reactions, such as laughter. Diagnosis of NT1 is based on sleep studies both at night (overnight polysomnography [PSG]) and in the daytime (multiple sleep latency test [MSLT]) that reveal fast onset of sleep and especially REM sleep. To the extent available, Hcrt/Orx levels in the cerebrospinal fluid that is obtained through a lumbar puncture are also helpful in making a diagnosis.

NT2 is similar to NT1 with excessive sleepiness in the daytime and rapid onset of REM sleep on PSG and MSLT, but it is not accompanied by low Hcrt/Orx levels or by cataplexy symptoms. People with IH, instead, do not have rapid onset of REM sleep on PSG or MSLT even though they fall asleep within minutes during testing. They also don’t have cataplexy symptoms or low orexin levels, and their main complaint is long sleep duration throughout a 24-hour period that usually lasts 12-14 hours.

For a group of people with excessive daytime sleepiness, especially when this first presents over age 55, there is frequently co-existing cognitive impairment, which justifies a clinician’s decision to pursue multidisciplinary evaluation with neuropsychological testing and brain imaging to examine if the hypersomnolence symptoms hint to a comorbid neurocognitive disorder such as Lewy Body Dementia or Alzheimer’s dementia.

Overall, people with hypersomnia syndromes usually benefit by pharmacological therapies that consolidate sleep and wake periods, and by establishing daily habits, such as scheduling naps in the daytime and being exposed to sunlight in the morning, that decrease the chance of a sudden urge to sleep.

CRSD are syndromes where the timing of sleep throughout the day, the so-called circadian rhythm, is out of synchrony to the established societal norms. People whose natural sleep-wake cycle is much later than most, falling asleep in the early morning hours and waking up very late in the day, are typical “night owls” and have a Delayed Sleep Phase Chronotype, whereas people who are “morning larks,” going to bed early in the evening and waking up very early in the morning have an Advanced Sleep Phase Chronotype. These chronotypes have a strong genetic background, are regulated by the body’s response to sunlight and a hormone secreted in the evening called melatonin, but are only considered disorders if they interfere with people’s lives. People with Delayed Sleep Phase Disorder (DSPD) often misinterpret their delayed sleep-wake cycle as insomnia and may pursue inappropriate pharmacological or other treatments, because the symptom recognized is an inability to fall asleep at a socially expected time. It is not uncommon for people with DSPD to become sleep deprived during workdays and have catch-up sleep on weekends. Delayed Sleep Phase Chronotypes are extremely common in teenagers as their body changes, justifying later school start times and their association to better student academic performance. In contrast, Advanced Sleep Phase Chronotypes are more common in older people, possibly an indication of less sunlight passing through the eyes due to cataracts or, even, early neurodegenerative changes in sleep-wake regulating brain centers.

In older people with neurocognitive disorders due to advanced neurodegeneration it is common to observe Irregular Sleep-Wake Rhythm Disorder, during which circadian rhythms become fragmented even though total sleep time remains normal. As a result, people go in and out of sleep throughout the 24-hour cycle.

A rare but well-described CRSD is the non-24-hour CRSD, where some people who are blind or lack specific light receptors in the eye have a gradual delay of their circadian rhythm, progressing their sleep-wake times over the 24-hour cycle. Not all people who are blind will have non-24-hour CRSD, because the specific light receptors can be intact, even though visual stimuli are not perceived in the brain.

In addition to intrinsic causes leading to CRSD, there are two extrinsic mechanisms that can lead to difficulties in daily life. The first, called Shift Work Rhythm Disorder, presents in people who are forced to have a work schedule that interferes with their natural sleep times. Similar to people with DSPD, they may become sleep deprived and, because their circadian rhythms are poorly consolidated, also exhibit features of insomnia or excessive daytime somnolence depending on the time of day. The second extrinsic mechanism of CRSD is jet lag, observed in people traveling across multiple time zones by plane, where their internal circadian rhythm is misaligned to their new environment.

Therapies for CRSD include pharmacological and non-pharmacological approaches that an expert can recommend.

Parasomnia syndromes refer to abnormal complex behaviors during sleep. Parasomnias are divided in NREM and REM sleep parasomnias, depending on the sleep stage that they occur in.

NREM parasomnias are complex behaviors during deep NREM sleep (slow-wave sleep) and are divided into confusional arousals, sleep related sex behaviors (sexsomnia), sleep walking, and sleep eating. Because they occur at a stage of sleep that the cortex is inactive, people waking up from NREM parasomnias are confused and have no recollection of their actions. Being a variation to an underlying sleep stage where NREM sleep and wakefulness are not fully dissociated, people with one NREM parasomnia may exhibit other NREM parasomnias at different times. They are usually associated with sleep deprivation, alcohol consumption or certain medications. A NREM parasomnia specific to children is night terrors, where children wake up frightened and crying inconsolably during sleep with no recollection of a bad dream. If the diagnosis of a NREM parasomnia is not clear from the history or videos provided, an overnight sleep study is required to distinguish it from other neurological disorders that can occur during sleep (e.g., seizures), or from other parasomnias that may have a different underlying cause and prognosis (e.g., RBD vs. NREM parasomnias).

REM parasomnias are complex behaviors that occur during REM sleep (dream sleep) with the main culprit being REM Behavior Disorder (RBD). RBD refers to acting out of dreams, where people move violently as if fighting off someone in 80% of cases, or perform complex movements as if playing a musical instrument or a sport. People are able to recall elements of a dream in most cases upon awakening, because RBD reflects an overlapping state between REM sleep and wakefulness. This dissociated state is caused by dysfunction of a part of the brain called the brainstem. In contrast to NREM parasomnias, however, RBD is almost always associated with an underlying brain disease, which in most cases is a synucleinopathy, such as Parkinson’s disease or Lewy Body Dementia. RBD is often the first symptom of a synucleinopathy, preceding other symptoms by an average of eight years, with some people having had RBD symptoms for up to 50 years before motor symptoms. RBD is also observed in other conditions that affect the brainstem where REM sleep and wakefulness are poorly dissociated, that affect the brainstem, such as narcolepsy type 1, spinocerebellar ataxia type 3, and certain rare immune-mediated encephalopathies (e.g., IgLON5). A sleep study with video monitoring is almost always indicated for its diagnosis, because of its clinical association to an underlying brain disease that can be managed with pharmacological or non-pharmacological therapies.

Sleep talking without any other abnormal sleep behaviors is not considered a parasomnia and can present at any stage of normal sleep in healthy people.

Neuromuscular and Motor Neuron Disorders​​

MND are a family of diseases defined by the degeneration of motor neurons that control voluntary muscle movements. There are three main MND: Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), and Progressive Muscular Atrophy (PMA). The most common MND is ALS where both upper motor neurons and lower motor neurons are affected. Degeneration of upper motor neurons alone defines PLS, whereas degeneration of lower motor neurons defines PMA. Another specific type of MND is Progressive Bulbar Palsy (PBP) where the degeneration preferentially affects motor neurons of the brainstem that control throat and facial muscles. Depending on the type and distribution of motor neurons affected in MND, there are differences in how symptoms present and progress. Almost invariably, however, motor neuron degeneration leads to people losing control of voluntary movement, becoming weak, and gradually being unable to speak clearly, even though they retain their ability to feel and think. Additional problems with disease progression include swallowing difficulties and excessive salivation, to which a parenteral feeding tube and medications improve quality of life. Furthermore, people eventually tend to suffer from respiratory failure due to weak breathing, and non-invasive ventilation has been proven to increase survival in MND. For those people where upper motor neurons are affected, such as in ALS, FT-NCD are not uncommon.​​

Epilepsy and Seizure Disorders

The term Epilepsy refers to a syndrome during which people have recurrent unprovoked seizures that arise from abnormal, hypersynchronous, and sustained brain hyperactivity. Depending on the affected hyperactive part of the brain, a person’s seizures present in different ways, such as an abnormal sensation (e.g., taste, smell, vision, or sound), movement (e.g., uncontrollable shaking or posturing), or behavior (e.g., loss of consciousness).​​​

Autoimmune Neurological Disorders

Multiple Sclerosis (MS) is a disease of the brain and spinal cord defined primarily by inflammatory damage to the sheath (myelin) of neuronal cells that is often accompanied by neurodegeneration of the neurons themselves. A key pathological process leading to MS is the mistargeted action towards myelin of the body’s immune cells that normally serve as a defense mechanism to external agents, such as viruses. Symptoms vary depending on the area of the brain and spinal cord that is affected, and can range from imbalance to double vision and numbness. Most symptoms last a few days and improve as the inflammation resolves, but recurrent attacks, called relapses, can eventually lead to permanent deficits. For this reason, pursuing early and effective disease modifying treatment protocols is often recommended to prevent long-term permanent deficits. It not uncommon for people with MS to experience relapse-like events of previously resolved symptoms if their body is under stress, such as during a fever or having a hot shower. These do not reflect a relapse of the disease and resolve when the stressful factor resolves as well.