פרק 38 Chapter 38: Degenerative Diseases of the Nervous System Flashcards
כל הבאים קשורים לנטייה גנטית לחלות במחלת האלצהיימר פרט ל-
א. APoE4
ב. APP מוטציה בגן
ג. מוטציה בגן לפרסנילין
ד. תסמונת דאון
ה. מוטציה בגן לסינוקלאין
ה. מוטציה בגן לסינוקלאין
Synucleinopathies – PD, DLBD, MSA
Tauopathies: AD, FTD, PSP, CBD
Table 38-1
MUTATIONS AND MODULATING FACTORS ASSOCIATED WITH ALZHEIMER DISEASE (6)
מהו הקשר בין
APoE4
לבין השכיחות למחלת אלצהיימר
נוכחותו מעלה את הסיכון למחלה פי 3
Table 38-2
INITIAL SYMPTOMS IN PATIENTS WITH PARKINSON DISEASE
Table 38-3
MAIN GENETIC DEFECTS ASSOCIATED WITH PARKINSON DISEASE
Table 38-4
DRUGS COMMONLY USED IN THE TREATMENT OF PARKINSON DISEASE
Table 38-5
GENETIC DEFECTS ASSOCIATED WITH SPINOCEREBELLAR ATAXIAS (SCA)
Table 38-6
GENETIC DEFECTS ASSOCIATED WITH ALS
Table 38-7
CLASSIFICATION OF THE SPINAL MUSCULAR ATROPHIES (SMA)
Table 38-8
GENETIC DEFECTS ASSOCIATED WITH HEREDITARY SPASTIC PARAPLEGIA (HSP)
גבר אשכנזי, התקבל בתמונה של ירידה קוגניטיבית , הפרעה תחושתית בפיזורדיסטלי, החזרים מוגברים עםבבינסקי. איזו בדיקה תאשש את האבחנה ?
א.MRIמוח
ב.MRIעמ”שגבי מותני
ג.sural nerve biopsy
ד.VLCFA
sural nerve biopsy
adult polyglucosan body disease
מקרא לציורים:
* ירוק –כוראה
* צהוב –אטקסיה
* כחול :סימנים פירמידליים
* שוט –שמחזיקים-AD שנחבטים –AR
* משקפיים –עיוורון
* אוזניות-פגיעה בשמיעה
* גפיים בכתום-פולינירופתיה
* כובע-ורוד-שינוי התנהגות
* צירים –EPS
* ברקים כחולים –מיוקולוניות
* שן אחת –דמנציה
* שפם –גנטיקה XLINKED
* אדום –מיופתיה?
- דגנר\קטיבי – כחול טאופאטיה ,צהוב סינקלופתיה
- פסים ורודים –דרמטולוגיה
- אדום ורוד -פוליניורופתיה
בן 45 , עם הפרעה בהליכה שהתחילה לפני 5 שנים, ותכיפות ודחיפות במתן שתן שהחלה לפני 15 שנים.
בבדיקתו פאראפרזיס ספסטית. מה האבחנה הסבירה?
א. Hereditary spastic paraplegia
ב. Adult polyglucosan body disease
ג. Primary lateral sclerosis
ד. Adult GM2 gangliosidosis
adult polyglucosan body disease
More recently, Rifal and associates reviewed the findings in 25 cases of this disease—one observed by them and 24 reported previously. The dementia was relatively mild, consisting of impairment of retentive memory, dysnomia, dyscalculia, and sometimes nonfluent aphasia and deficits of “visual integration”; this was overshadowed by rigidity and spasticity of the limbs and the peripheral nerve disorder. Bladder dysfunction has been an early sign in many patients including a middle-aged woman under our care who had only diffuse white matter changes in the cerebral MRI and a moderate sensory neuropathy.
מקרא לציורים:
* ירוק –כוראה
* צהוב –אטקסיה
* כחול :סימנים פירמידליים
* שוט –שמחזיקים-AD שנחבטים –AR
* משקפיים –עיוורון
* אוזניות-פגיעה בשמיעה
* גפיים בכתום-פולינירופתיה
* כובע-ורוד-שינוי התנהגות
* צירים –EPS
* ברקים כחולים –מיוקולוניות
* שן אחת –דמנציה
* שפם –גנטיקה XLINKED
* אדום –מיופתיה?
- דגנר\קטיבי – כחול טאופאטיה ,צהוב סינקלופתיה
- פסים ורודים –דרמטולוגיה
- אדום ורוד -פוליניורופתיה
דף מידע על
hereditaey spastic paraplegia
תיאור של אב ובנו הסובלים מאטקסיה, הפרעה קשה בתנועות עיניים, סימנים פירמידליים וטונוס ריגידי, ללא ירידה קוגניטיבית.
מה האבחנה הסבירה ביותר?
1. פרה מוטציה של X שביר
2. ספינו-צרברל אטקסיה
3. פרידריך אטקסיה
spinocerebellar ataxia
כנראה מצ’אדו ג’וזף בגלל ששם אין דמנציה ויש ריגידיות.
מקרא לציורים:
* ירוק –כוראה
* צהוב –אטקסיה
* כחול :סימנים פירמידליים
* שוט –שמחזיקים-AD שנחבטים –AR
* משקפיים –עיוורון
* אוזניות-פגיעה בשמיעה
* גפיים בכתום-פולינירופתיה
* כובע-ורוד-שינוי התנהגות
* צירים –EPS
* ברקים כחולים –מיוקולוניות
* שן אחת –דמנציה
* שפם –גנטיקה XLINKED
* אדום –מיופתיה?
- דגנר\קטיבי – כחול טאופאטיה ,צהוב סינקלופתיה
- פסים ורודים –דרמטולוגיה
- אדום ורוד -פוליניורופתיה
בן50ממוצאתימניפנהבשלחוסריציבות.בבדיקתוישהיפררפלקסיהטונוסמוגברבגפייםקשייהליכהואופתלמופלגיה.ללאהפרעהקוגניטיבית.מהלאנמצאבמחלהזו?
1. ניווןcaudateדו”צ.
2. ניווןספינוצרבלריודנטייטבפתולוגיה.
3. הרחבתtrinucleotideexpantion
4. מצאיםהיפראינטנסייםבצרבלוםב-MRI
לא נראה ניוון של הקאודייט…
מצ’אדו ג’וזף
מקרא לציורים:
* ירוק –כוראה
* צהוב –אטקסיה
* כחול :סימנים פירמידליים
* שוט –שמחזיקים-AD שנחבטים –AR
* משקפיים –עיוורון
* אוזניות-פגיעה בשמיעה
* גפיים בכתום-פולינירופתיה
* כובע-ורוד-שינוי התנהגות
* צירים –EPS
* ברקים כחולים –מיוקולוניות
* שן אחת –דמנציה
* שפם –גנטיקה XLINKED
* אדום –מיופתיה?
- דגנר\קטיבי – כחול טאופאטיה ,צהוב סינקלופתיה
- פסים ורודים –דרמטולוגיה
- אדום ורוד -פוליניורופתיה
בת 40 עם סימנים פירמידליים דו”צ, האבחנה המבדלת כוללת את כל הבאים חוץ מ:
1. hexosaminidase A deficiency
2. mutation in the paraplegin gene
3. bulbospinal atrophy syndrome (Kennedy)
4. Primary lateral sclerosis
5. behr syndrome (with associated optic atrophy)
Kennedy syndrome is X linked.
-
Kennedy – distal muscular atrophy with prominent bulbar signs.
X- linked (some AD)
Proximal shoulder and hip muscles involved first – weakness and atrophy.
Dysarthria and dysphagia, facial fasiculations, tendon relfexes depressed. Sensory neuropathy
2/3 have gynecomastia. Oligospermia and diabetes. CPK elevated a lot
CAG expansion - androgen receptor – motor neurons.- LMN
Neuronal inclusions of long polyglutamine sequences. -
Hereditary Spastic Paraplegia:
AD inheritance. Can appear at any age.
Commonly before age 35 and protracted course or late onset – with sensory loss, urinary symtpoms and action tremor.
Gradual spastic weakness of legs. Hyper active reflexes. Pseudocontractures of calf muscles – toe walk.
Arms may be involved.
The common uncomplicated autosomal dominant form of disease has been linked to mutations in many proteins,
the most common being (proteins in parentheses) SPAST (spas tin) and ALTl (atlastin); and the common recessive
varieties, are in SPG7 (paraplegin); and X-linked in LlCAM and PLPl (proteolipid protein). The common spastin variety, associated with a mutation on chromosome 2p, results in great variability of clinical presentation within and among families
התייחסות למסיחים:
תשובה 1- TAY SACHS
תשובה 2- Heredetary spastic paraplegia
תשובה 3- ע”מ 1139 , X – LINKED
תשובה -4 UMN
תשובה 5 ע”מ 1145- Hereditary Spastic Paraplegia with Optic Atrophy
*SBMA (מחלת קנדי)- ההסתמנות היא של חולשה בולברית וסימני LMN שגורמים אטרופיה, דלדול שרירים, חולשה וירידה בהחזרים. דומה יחסית ל MND. לכן כמובן שאין סימנים פירמידליים.
כמו כן המחלה X LINKED ולכן לא מתאים לנשים (מאופיינת בגניקומסטיה ואוליגוספרמיה, סוכרת).
*פאראפלגין – HSP7, נוירופתיה, מיופתיה, אטרופיה אופטית.
סיכום מידע חשוב על אלצהיימר
- הסיבה בשכיחה ביותר לדמנציה
- נשים יותר מגברים
- רוב המקרים ספורדיים
- APOE 4 מגביר סיכון למחלה הספוראדית
- מינימנטל
1. WORKING MEMEORY – מיקום,לזכור 3 מילים – היפוקמפלי
2. VISUSPATIAL –איזורים אחוריים
3. MOCA-יותר תפקודיים אקזקוטיביים
4. DIGIT SPAN –קדימה זה קשב ,אחורה –זיכרון עבודה - אלצהיימר- מוח אטרופי ,חדרים גדולים מרכזי והיקפי (מרכזי זה חדרים)
- היסטולוגי – SENILE PLAUQE – עמילויד בטא 42
בתוך התאים נוירופיברילרי טנגלז
הצטברות עמילויד –גם במקומות מחוץ למוח –כלי הדם - App
- אפשר למדוד עמילויד בעמ”ש ,אפשר לבדוק בSPECT
- SPECT –נקשר לשתי סוגי העמילויד
- ,בLP העמילויד יהיה נמוך לפני שהספקט יראה
- ירידה במטבוליזם בפט פריאטלי וטמפוראלי
- עד 240 פיקוגראם ,מעל 400 מעיד על מחלה TAU ,לא ספיציפי
- Apoe 2 מגן
- DOWN עמילויד 42 בטא –יש גם באלצהיימר
מי מהבאים יגיב הכי טוב לדופא?
1. מחלת PSP
2. מחלת MSA
3. פרקינסון אידיופתי
פרקינסון אידיופתי
מה מאפיין הגנטיקה של מחלת פרקינסון כביטוי לפגם בגן DARDARIN
של החלבון
LRRK2
- לא תוארו מקרים ספורדיים של המוטציה
- החלבון שהוא תוצר הגן נמצא בנוירונים בלבד
- אין מצב של נשא אסימפטומטי
- הגן הוא דומיננטי בעל חדירות חלקית
- רוב החולים נשאים גם של מחלת גושה
הגן הוא דומיננטי בעל חדירות חלקית.
זה נכון שיש לו קשר לגושה אבל ממש לא רוב החולים נשאים גם של מחלת גושה…
-
LRRK2 PARK 8
implicated in both genetic and sporadic forms of the disease, particularly among those of Ashkenazic Jewish or North African origin. The LRRK2 protein (dardarin)
It has been estimated that mutations in the gene are responsible for 1 percent of sporadic cases and are found in 5 to 8 percent of individuals with a first-degree relative who has the disease.
The gene acts as a dominant trait but penetrance of the
defect increases with age, being 85 percent at 70 years.
Therefore, there may not be a family history.
noted the absence of tremor
Related to gaucher disease -
PARKIN:
identified by an extreme sensitivity to L-dopa, maintaining an almost complete suppression of symptoms over decades with only small doses of medication.
they have a low threshold for dyskinesias induced by L-dopa.
An excellent response of tremor, postural changes, and bradykinesia to anticholinergic drugs.
a remarkable restorative benefit from sleep, which creates a diurnal pattern of symptoms.
there may be a wide variety of additional features: hyperreflexia, cervical, foot, or other focal dystonias, sometimes induced by exercise; and, less often, autonomic dysfunction, peripheral neuropathy, and psychiatric symptoms.
מה מאפיין מחלת פרקינסון עם מוטציה בגן
Parkin 2
- ברובם ימצאו גופיפי לואי
- תגובה טובה לטיפול אנטכולינרגי
- תגובה ירודה לטיפול בלבודופה
- שינה מחמירה סימפתומים
- סף גבוה לדיסקינזיות מלבודופה
תגובה טובה לטיפול אנטיכולינרגי
-
PARKIN:
identified by an extreme sensitivity to L-dopa, maintaining an almost complete suppression of symptoms over decades with only small doses of medication.
they have a low threshold for dyskinesias induced by L-dopa.
An excellent response of tremor, postural changes, and bradykinesia to anticholinergic drugs.
a remarkable restorative benefit from sleep, which creates a diurnal pattern of symptoms.
there may be a wide variety of additional features: hyperreflexia, cervical, foot, or other focal dystonias, sometimes induced by exercise; and, less often, autonomic dysfunction, peripheral neuropathy, and psychiatric symptoms. -
LRRK2 PARK 8
implicated in both genetic and sporadic forms of the disease, particularly among those of Ashkenazic Jewish or North African origin. The LRRK2 protein (dardarin)
It has been estimated that mutations in the gene are responsible for 1 percent of sporadic cases and are found in 5 to 8 percent of individuals with a first-degree relative who has the disease.
The gene acts as a dominant trait but penetrance of the
defect increases with age, being 85 percent at 70 years.
Therefore, there may not be a family history.
noted the absence of tremor
Related to gaucher disease
Parkin
-
PARKIN:
identified by an extreme sensitivity to L-dopa, maintaining an almost complete suppression of symptoms over decades with only small doses of medication.
they have a low threshold for dyskinesias induced by L-dopa.
An excellent response of tremor, postural changes, and bradykinesia to anticholinergic drugs.
a remarkable restorative benefit from sleep, which creates a diurnal pattern of symptoms.
there may be a wide variety of additional features: hyperreflexia, cervical, foot, or other focal dystonias, sometimes induced by exercise; and, less often, autonomic dysfunction, peripheral neuropathy, and psychiatric symptoms. -
LRRK2 PARK 8
implicated in both genetic and sporadic forms of the disease, particularly among those of Ashkenazic Jewish or North African origin. The LRRK2 protein (dardarin)
It has been estimated that mutations in the gene are responsible for 1 percent of sporadic cases and are found in 5 to 8 percent of individuals with a first-degree relative who has the disease.
The gene acts as a dominant trait but penetrance of the
defect increases with age, being 85 percent at 70 years.
Therefore, there may not be a family history.
noted the absence of tremor
Related to gaucher disease
תגובה טובה ללבודופה
-
PARKIN:
identified by an extreme sensitivity to L-dopa, maintaining an almost complete suppression of symptoms over decades with only small doses of medication.
they have a low threshold for dyskinesias induced by L-dopa.
An excellent response of tremor, postural changes, and bradykinesia to anticholinergic drugs.
a remarkable restorative benefit from sleep, which creates a diurnal pattern of symptoms.
there may be a wide variety of additional features: hyperreflexia, cervical, foot, or other focal dystonias, sometimes induced by exercise; and, less often, autonomic dysfunction, peripheral neuropathy, and psychiatric symptoms. -
LRRK2 PARK 8
implicated in both genetic and sporadic forms of the disease, particularly among those of Ashkenazic Jewish or North African origin. The LRRK2 protein (dardarin)
It has been estimated that mutations in the gene are responsible for 1 percent of sporadic cases and are found in 5 to 8 percent of individuals with a first-degree relative who has the disease.
The gene acts as a dominant trait but penetrance of the
defect increases with age, being 85 percent at 70 years.
Therefore, there may not be a family history.
noted the absence of tremor
Related to gaucher disease
מה מהבאים מאפיין פרקינסון אידיופטי?
1. הפרעה אוטונומית מוקדמת
2. דמנציה מוקדמת
3. תגובה לא טובה לדופמין
4. אסימטריה בתחילת המחלה
אסימטריה בתחילת המחלה
מה אין בפתולוגיה של פרקינסון?
1. שקיעת סינוקלאין בסובסטנציה ניגרה
2. שקיעת סינוקלאין בגנגליונים סימפטטיים
3. ירידה בפעילות של תירוזין הידרוקסילאז
4. שקיעה של סינוקאלין בפריאקוודוקטל גריי
אין שקיעה של סינוקלאין בפריאקוודוקטל גריי
איזה אינזים אינו משתתף בתהליך סינתזת או פירוק דופמין?
1. monoamine oxidase B
2. Thyrosine hydroxylase
3. Catechol-O- methyl transferase
4. Beta secretase
5. Dopa decarboxylase
Beta secretase- part of amyloid in Alzheimer disease
Metabolic pathway of dopamine synthesis and clearance. Dopamine is synthesized from phenylalanine or tyrosine via sequential reactions catalyzed mainly by PH, TH, and DOPA decarboxylase. It can also be synthesized from tyramine in a minor pathway by CYP2D6. Dopamine is effectively degraded into the main inactive metabolites DOPAC and HVA via a series of reactions mediated predominantly by the enzymes MAO, COMT, ALDH, and ADH
Thyrosine hydroxylase
הוא האנזים קובע הקצב בסינתזה של איזה מבין הנוירוטרנסמיטורים הבאים?
1. dopamine
2. serotonin
3. acetyl choline
4. glutamate
5. calcitonin
thyrosine hydroxylase is the rate limiting step in Dopamine synthesis
Metabolic pathway of dopamine synthesis and clearance. Dopamine is synthesized from phenylalanine or tyrosine via sequential reactions catalyzed mainly by PH, TH, and DOPA decarboxylase. It can also be synthesized from tyramine in a minor pathway by CYP2D6. Dopamine is effectively degraded into the main inactive metabolites DOPAC and HVA via a series of reactions mediated predominantly by the enzymes MAO, COMT, ALDH, and ADH
מטופל הסובל מספר שנים ממחלת הפרקינסון, תחת טיפול תרופתיף מתלונן על ישנוניות ולעיתים “התקפים” של שינה במהלך היום. איזו תרופה מהבאות גורמת לתופעה זו?
1. Amantadine
2. Ropinerole
3. Entacapone
4. Biperidene
5. Rasagiline
Dopamine agonists- Ropinerole and Pramipexole
side effects- orthostatic hypotension, excessive and abrupt sleepiness, confusion, hallucinations.
——-
שאר התרופות
* L-DOPA- carbidopa-L-Dopa. side effects: Nausea, dyskinesias, hallucinations, confusion.
* glutamate agonist- Amantadine. side effects: leg swelling, congestive heart failure, prostatic outlet obstruction, confusion, hallucinations, insomnia
* anticholinergics- benztropine and trihexyphenidyl, biperidene. side effects: atropinic effects: dry mouth, urinary outlet obstruction, confusion and psychosis.
* COMT inhibitors- Entacapone. side effects: Urine discoloration, diarrhea, increased dyskinesias
* MAO inhibitors- rasagiline and selegiline. side effects: hypertensive crisis with tyramine-rich foods and sympathomimetics.
מה הסיבה לתת אגוניסט דופמין לחולה פרקינסון צעיר?
יש פחות דיסקינזיות
Dopamine agonists- Ropinerole and Pramipexole
side effects- orthostatic hypotension, excessive and abrupt sleepiness, confusion, hallucinations.
——-
שאר התרופות
* L-DOPA- carbidopa-L-Dopa. side effects: Nausea, dyskinesias, hallucinations, confusion.
* glutamate agonist- Amantadine. side effects: leg swelling, congestive heart failure, prostatic outlet obstruction, confusion, hallucinations, insomnia
* anticholinergics- benztropine and trihexyphenidyl, biperidene. side effects: atropinic effects: dry mouth, urinary outlet obstruction, confusion and psychosis.
* COMT inhibitors- Entacapone. side effects: Urine discoloration, diarrhea, increased dyskinesias
* MAO inhibitors- rasagiline and selegiline. side effects: hypertensive crisis with tyramine-rich foods and sympathomimetics.
מה לא תופעת לוואי של אגוניסטים דופמינרגים?
א. ישנוניות
ב. אורתוסטטיזם
ג. אצירת שתן
ד. בלבול
אצירת שתן אינה תופעת לוואי של אגונסיטים דופמינרגים אלא של אנטיכולינרגים.
Dopamine agonists- Ropinerole and Pramipexole
side effects- orthostatic hypotension, excessive and abrupt sleepiness, confusion, hallucinations.
——-
שאר התרופות
* L-DOPA- carbidopa-L-Dopa. side effects: Nausea, dyskinesias, hallucinations, confusion.
* glutamate agonist- Amantadine. side effects: leg swelling, congestive heart failure, prostatic outlet obstruction, confusion, hallucinations, insomnia
* anticholinergics- benztropine and trihexyphenidyl, biperidene. side effects: atropinic effects: dry mouth, urinary outlet obstruction, confusion and psychosis.
* COMT inhibitors- Entacapone. side effects: Urine discoloration, diarrhea, increased dyskinesias
* MAO inhibitors- rasagiline and selegiline. side effects: hypertensive crisis with tyramine-rich foods and sympathomimetics..
מטופלת הסובלת מפרקינסון ומטופלת בטיפול תרופתי התקבלה עקב הרעלה של אחת התרופות עם ביטוי של עור יבש עצירות ובלבול.
מי היא קבוצת התרופות האשמה?
אנטי כולינרגים.
anticholinergics- benztropine and trihexyphenidyl, biperidene. side effects: atropinic effects: dry mouth, urinary outlet obstruction, confusion and psychosis.
-
Dopamine agonists- Ropinerole and Pramipexole
side effects- orthostatic hypotension, excessive and abrupt sleepiness, confusion, hallucinations.
שאר התרופות - L-DOPA- carbidopa-L-Dopa. side effects: Nausea, dyskinesias, hallucinations, confusion.
- glutamate agonist- Amantadine. side effects: leg swelling, congestive heart failure, prostatic outlet obstruction, confusion, hallucinations, insomnia
- COMT inhibitors- Entacapone. side effects: Urine discoloration, diarrhea, increased dyskinesias
- MAO inhibitors- rasagiline and selegiline. side effects: hypertensive crisis with tyramine-rich foods and sympathomimetics.
איזו תרופה לא טובה כמונותרפיה לפרקינסון?
1. אנטקפון
2. לבודופה
3. סלגלין
אנטקפון- מאריכה את ההשפעה של לבודופה, לא ניתנת לבד.
איזה מהתרופות האנטי פרקינסוניות הבאות גורמת לאורטוסטטיזם ברמה החמורה ביותר?
1. COMT inhibitor
2. MAO B inhibitor
3. Dopamine agonist
4. Amantadine
Dopamine agonist
Even small doses of dopaminergic drugs, when first introduced, may induce orthostatic hypotension, but most patients are tolerant of them. They may also produce abrupt and unpredictable sleepiness, and patients should be warned of this possibility in relation to driving.
In some individuals, particularly the elderly, dopamine agonists may produce hallucinosis or confusion;
Dopamine agonists- Ropinerole and Pramipexole
side effects- orthostatic hypotension, excessive and abrupt sleepiness, confusion, hallucinations.
——-
שאר התרופות
* L-DOPA- carbidopa-L-Dopa. side effects: Nausea, dyskinesias, orthostatic hypotension, hallucinations, confusion.
* glutamate agonist- Amantadine. side effects: leg swelling, congestive heart failure, prostatic outlet obstruction, confusion, hallucinations, insomnia
* anticholinergics- benztropine and trihexyphenidyl, biperidene. side effects: atropinic effects: dry mouth, urinary outlet obstruction, confusion and psychosis.
* COMT inhibitors- Entacapone. side effects: Urine discoloration, diarrhea, increased dyskinesias
* MAO inhibitors- rasagiline and selegiline. side effects: hypertensive crisis with tyramine-rich foods and sympathomimetics.
מוריד תופעות לוואי
GI
By combining L-dopa with a decarboxylase inhibitor (carbidopa or benserazide), which is unable to penetrate the central nervous system (CNS), decarboxylation of L-dopa to dopamine is greatly diminished in
peripheral tissues. This permits a greater proportion of L-dopa to reach nigral neurons and, at the same time, reduces the peripheral side effects of L-dopa and dopamine (nausea, hypotension, confusion).
בצקות פריפריות
The antiviral agent amantadine (100 mg bid) has mild or moderate benefit for tremor, hypokinesia, and postural symptoms. In some patients, it reduces Ldopa– induced dyskinesias (see further on). Its mechanism of action is unknown but antagonism of NMDA or release of stored dopamine has been proposed. It should be noted that amantadine commonly causes leg swelling, may worsen congestive heart failure, and can have an adverse
effect on glaucoma, as well as exaggerate the cognitive changes associated with anticholinergic medications.
בן 55 , אובחן כסובל ממחלת פרקינסון ומתחיל טיפול ב-
ropinirole .
איזה סוג של הפרעה עלול להופיע כתוצאה מהטיפול?
א. REM sleep behavior disorder
ב. Insomnia
ג. Sleep walking
ד. Sleep attacks
Sleep attacks
Dopamine agonists- Ropinerole and Pramipexole
side effects- orthostatic hypotension, excessive and abrupt sleepiness, confusion, hallucinations.
——-
שאר התרופות
* L-DOPA- carbidopa-L-Dopa. side effects: Nausea, dyskinesias, hallucinations, confusion.
* glutamate agonist- Amantadine. side effects: leg swelling, congestive heart failure, prostatic outlet obstruction, confusion, hallucinations, insomnia
* anticholinergics- benztropine and trihexyphenidyl, biperidene. side effects: atropinic effects: dry mouth, urinary outlet obstruction, confusion and psychosis.
* COMT inhibitors- Entacapone. side effects: Urine discoloration, diarrhea, increased dyskinesias
* MAO inhibitors- rasagiline and selegiline. side effects: hypertensive crisis with tyramine-rich foods and sympathomimetics..
מטופלת עם ירידה קוגנטיבית, הפרעה בהתנהגות ותנועות לא רצוניות עם היסטוריה משפחתית של הורה שחלה בגיל מבוגר יותר, מה בהדמיה?
1. ראש קאודייט - אטרופיה
2. פלידום- שקיעה של סידן
3. צרבלום- היפוגנזה
אטרופיה של ראש הקאודייט אופייני להנטינגטון
This disease, distinguished by the triad of dominant inheritance, choreoathetosis, and dementia
-
huntingtin gene (also termed HTT) and localized to the short arm of chromosome 4.
excessively long repeat of the trinucleotide CAG within the gene,
the length (number) of which determines not only the presence of the disease, but also the age of onset, longer repeat lengths being associated with an earlier appearance of signs
At the Huntington gene locus there are normally 11 to 34 (median: 19)
Individuals with 35 to 39 triplets may eventually manifest the disease but it tends to be late in onset and mild in degree
Those with more than 42 repeats almost invariably acquire the signs of disease if they live long enough.
there is a general relationship between the number of CAG repeats and the age of onset of symptoms. It has been found that it is the longer sequence on either of the 2 alleles that determines the age of onset, the size of the expansion of the normal allele exerting no influence (Lee et al, 2012). Earlier onset in successive generations (anticipation) is well described in the early writings on the subject and is now known to be attributable to increasing lengths of the CAG repeat sequence. - The rare alternative mutation, termed HDL2 (Huntington disease-like-2), is associated with CATCG repeat expansion of the juntophilin-3 gene, but it is so infrequent that few clinicians will encounter it.
- Gross atrophy bilaterally of the head of the caudate nucleus and putamen is the characteristic abnormality, usually accompanied by a moderate degree of gyral atrophy in the frontal and temporal regions.
.
מה מאפיין את מחלת הנטינגטון?
- רמות חזרות של הטרינוקלאוטיד האופייני בין 25-32 אבחנתי בד”כ
- דמנציה קורטיקלית
- Anticipation
- הופעה מוקדמת מנבאת בד”כ פרוגנוזה טובה יותר
- בMRI מוח פגיעה בLenticular nucleus ד”צ
קיים
anticipation
אטרופיה של ראש הקאודייט אופייני להנטינגטון
This disease, distinguished by the triad of dominant inheritance, choreoathetosis, and dementia
-
huntingtin gene (also termed HTT) and localized to the short arm of chromosome 4.
excessively long repeat of the trinucleotide CAG within the gene,
the length (number) of which determines not only the presence of the disease, but also the age of onset, longer repeat lengths being associated with an earlier appearance of signs
At the Huntington gene locus there are normally 11 to 34 (median: 19)
Individuals with 35 to 39 triplets may eventually manifest the disease but it tends to be late in onset and mild in degree
Those with more than 42 repeats almost invariably acquire the signs of disease if they live long enough.
there is a general relationship between the number of CAG repeats and the age of onset of symptoms. It has been found that it is the longer sequence on either of the 2 alleles that determines the age of onset, the size of the expansion of the normal allele exerting no influence (Lee et al, 2012). Earlier onset in successive generations (anticipation) is well described in the early writings on the subject and is now known to be attributable to increasing lengths of the CAG repeat sequence. - The rare alternative mutation, termed HDL2 (Huntington disease-like-2), is associated with CATCG repeat expansion of the juntophilin-3 gene, but it is so infrequent that few clinicians will encounter it.
- Gross atrophy bilaterally of the head of the caudate nucleus and putamen is the characteristic abnormality, usually accompanied by a moderate degree of gyral atrophy in the frontal and temporal regions.
.
אמפליפיקציה של
CAG
מה אופייני למחלת הנטינגטון בילדים לעומת המחלה במבוגרים?
א. פרכוסים
ב. קוגניציה שמורה
ג. כוריאה
ד. מהלך מחלה איטי
פרכוסים
The first signs of the disease may appear in childhood, before puberty (even younger than the age of 4 years), and several series of such early-onset cases have been described (Farrer and Conneally; van Dijk et al). Mental deterioration at this early age is more often accompanied by cerebellar ataxia, behavior problems, seizures, bradykinesia, rigidity, and dystonia than by chorea
.
מידע על רטיניטיס פיגמנטוזה
Retinitis pigmentosa
This remarkable retinal abiotrophy, usually begins in childhood and adolescence. Unlike the optic atrophy of Leber, which affects only the third neuron of the visual neuronal chain, retinitis pigmentosa affects all the retinal layers, both the neuroepithelium and pigment epithelium.
* The incidence of this disorder is 2 or 3 times greater in males than in females. Inheritance is more often autosomal recessive than dominant. Mutations in approximately 60 genes have been associated with the disorder but the most commonly affected in autosomal dominant cases is RHO.
* The first symptom is usually an impairment of twilight vision (nyctalopia). Under dim light, the visual fields tend to constrict; but slowly, as the disease progresses, there is permanent visual impairment in all degrees of illumination. The perimacular zones tend to be the first and most severely involved, giving rise to partial or complete ring scotomata. Peripheral loss sets in later. Usually both eyes are affected simultaneously, but cases are on record where one eye was affected first and more severely.
* Ophthalmoscopic examination shows the characteristic triad of pigmentary deposits that assume the configuration of bone corpuscles, attenuated vessels, and pallor of the optic discs. The pigment is caused by clumping of epithelial cells that migrate from the pigment layer to the superficial parts of the retina as the rod cells degenerate. The pigmentary change spares only the fovea, so that eventually the world is perceived by the patient as though he were looking through narrow tubes.
RP is associated with:
* Friedrich and other spinocerebellar ataxias
* Laurence Moon Syndrome
* Refsum Disease (polyneuropathy and deafness)
* Colour blindness
* Deaf mutism
* Cockayne syndrome
* Bassen Kornzweig
* Mitochondrial – Kearnes Sayre and PEO (PEO bears a close relationship to the Kearnes-Sayre
syndrome of retinitis pigmentosa (onset before age 20 years), ataxia, heart block and other conduction defects, and elevated CSF protein; sensorineural deafness, seizures, or pyramidal signs may be added.)
Retinal degeneration:
The most frequent in youth and middle age is retinitis
pigmentosa, a hereditary disease of the outer photoreceptor layer and subjacent pigment epithelium. The retina is thin, and there are fine deposits of black pigment in the shape of bone corpuscles, more in the periphery; later the optic discs become pale. The disorder is marked by constriction of the visual fields with relative sparing of
central vision (“gun-barrel” vision), metamorphopsia
(distorted vision), delayed recovery from glare, and nyctalopia
(reduced twilight vision). associates syndromes- SCA, Friedreich ataxia, Refsum, Cockayne, Bassen-kornzweig, PEO and kearnes sayre
בחור צעיר שהחל לפתח טיקים, תנועות כוראה וירידה קוגניטיבית, מה הבדיקה לאבחנה?
1. הדמיה מוחית
2. רמת שומנים בשתן
3. משטח דם
משטח דם
Acanthocytosis with chorea
-
Neuroacanthocytosis (bassen Kornzweig - Abetalipoproteinemia) – defect in red cell lipid membrane and HARP (hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration).
a. AR inheritance (chrom 9 – mutation in gene Chorein)
b. Chorea, Dystonia, tics, vocalisations, rigidity, tongue biting
c. Cognitive impairment
d. Average onset 32
e. Atrophy and gliosis of caudate nucleus an putamen but no neuronal loss in cortex
f. acanthocytes -
Acanthocytosis that lacks lipid abnormality (classic type) is characterized by:
a. Onset in adolescence, early adult life of generalized involuntary movements (chorea, dystonia and tics) usual onset orofacial dyskinesia.
b. Mild to moderate mental deterioration
c. Decreased or absent tendon reflexes – chronic axonal neuropathy and denervation atrophy of muscles
d. Acanthocytes -
Mcleod – X linked (KX protein)
a. Gradual chorea in mid-late life
b. Degeneration of caudate and putamen
c. Myopathy with elevated CPK
d. Fewer facial tics and orofacial features
.
מקרא לציורים:
* ירוק –כוראה
* צהוב –אטקסיה
* כחול :סימנים פירמידליים
* שוט –שמחזיקים-AD שנחבטים –AR
* משקפיים –עיוורון
* אוזניות-פגיעה בשמיעה
* גפיים בכתום-פולינירופתיה
* כובע-ורוד-שינוי התנהגות
* צירים –EPS
* ברקים כחולים –מיוקולוניות
* שן אחת –דמנציה
* שפם –גנטיקה XLINKED
* אדום –מיופתיה?
- דגנר\קטיבי – כחול טאופאטיה ,צהוב סינקלופתיה
- פסים ורודים –דרמטולוגיה
- אדום ורוד -פוליניורופתיה
לא נראה ערות החזרים באקנטוציטוזיס.
Acanthocytosis with chorea
-
Neuroacanthocytosis (bassen Kornzweig - Abetalipoproteinemia) – defect in red cell lipid membrane and HARP (hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration).
a. AR inheritance (chrom 9 – mutation in gene Chorein)
b. Chorea, Dystonia, tics, vocalisations, rigidity, tongue biting
c. Cognitive impairment
d. Average onset 32
e. Atrophy and gliosis of caudate nucleus an putamen but no neuronal loss in cortex
f. acanthocytes -
Acanthocytosis that lacks lipid abnormality (classic type) is characterized by:
a. Onset in adolescence, early adult life of generalized involuntary movements (chorea, dystonia and tics) usual onset orofacial dyskinesia.
b. Mild to moderate mental deterioration
c. Decreased or absent tendon reflexes – chronic axonal neuropathy and denervation atrophy of muscles
d. Acanthocytes -
Mcleod – X linked (KX protein)
a. Gradual chorea in mid-late life
b. Degeneration of caudate and putamen
c. Myopathy with elevated CPK
d. Fewer facial tics and orofacial features
Acanthocytosis associated either with conditions of cell lipid membrane deficiency i.e. Bassen Kornzweig or without the deficiency – as in Neuroacanthocytosis.
Neuroacanthocytosis:
Onset in adolescence of generalised involuntary movements – chorea, dytonia, tics, vocalisations, lip and tongue biting often beginning orofacial dyskinesias and spreading.
Mild to moderate mental retardation, behavioural disturbances
Absent tendon reflexes due to chronic axonal neuropathy and denervation atrophy of muscles
Acanthocytes in RBC smear.
Associated with gene for Chorein
May be AR,
X - linked (McLeod) – which has the feature of degeneration of caudate and putamen and myopathy with elevated CPK – due to gene defect in KX Protein – Kell Antigens
העדר החזרים גידים הוא אחד המרכיבים המאפיינים של המחלה.
המרכיבים הם: 1-מחלה בגיל צעיר עם מרכיבים של תנועות בלתי רצוניות (טיקים, כוריאה, דיסטוניה) 2- פיגור שכלי קל 3- העדרות החזרים גידיים ו נוירופתיה אקסונלית ודנרוציה של שרירים 4- אקנטוציטוזיס
מקרא לציורים:
* ירוק –כוראה
* צהוב –אטקסיה
* כחול :סימנים פירמידליים
* שוט –שמחזיקים-AD שנחבטים –AR
* משקפיים –עיוורון
* אוזניות-פגיעה בשמיעה
* גפיים בכתום-פולינירופתיה
* כובע-ורוד-שינוי התנהגות
* צירים –EPS
* ברקים כחולים –מיוקולוניות
* שן אחת –דמנציה
* שפם –גנטיקה XLINKED
* אדום –מיופתיה?
- דגנר\קטיבי – כחול טאופאטיה ,צהוב סינקלופתיה
- פסים ורודים –דרמטולוגיה
- אדום ורוד -פוליניורופתיה
לא נראה רעד באקנטוציטוזיס.
לא נראה ערות החזרים באקנטוציטוזיס.
Acanthocytosis with chorea
-
Neuroacanthocytosis (bassen Kornzweig - Abetalipoproteinemia) – defect in red cell lipid membrane and HARP (hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration).
a. AR inheritance (chrom 9 – mutation in gene Chorein)
b. Chorea, Dystonia, tics, vocalisations, rigidity, tongue biting
c. Cognitive impairment
d. Average onset 32
e. Atrophy and gliosis of caudate nucleus an putamen but no neuronal loss in cortex
f. acanthocytes -
Acanthocytosis that lacks lipid abnormality (classic type) is characterized by:
a. Onset in adolescence, early adult life of generalized involuntary movements (chorea, dystonia and tics) usual onset orofacial dyskinesia.
b. Mild to moderate mental deterioration
c. Decreased or absent tendon reflexes – chronic axonal neuropathy and denervation atrophy of muscles
d. Acanthocytes -
Mcleod – X linked (KX protein)
a. Gradual chorea in mid-late life
b. Degeneration of caudate and putamen
c. Myopathy with elevated CPK
d. Fewer facial tics and orofacial features
Acanthocytosis associated either with conditions of cell lipid membrane deficiency i.e. Bassen Kornzweig or without the deficiency – as in Neuroacanthocytosis.
Neuroacanthocytosis:
Onset in adolescence of generalised involuntary movements – chorea, dytonia, tics, vocalisations, lip and tongue biting often beginning orofacial dyskinesias and spreading.
Mild to moderate mental retardation, behavioural disturbances
Absent tendon reflexes due to chronic axonal neuropathy and denervation atrophy of muscles
Acanthocytes in RBC smear.
Associated with gene for Chorein
May be AR,
X - linked (McLeod) – which has the feature of degeneration of caudate and putamen and myopathy with elevated CPK – due to gene defect in KX Protein – Kell Antigens
העדר החזרים גידים הוא אחד המרכיבים המאפיינים של המחלה.
המרכיבים הם: 1-מחלה בגיל צעיר עם מרכיבים של תנועות בלתי רצוניות (טיקים, כוריאה, דיסטוניה) 2- פיגור שכלי קל 3- העדרות החזרים גידיים ו נוירופתיה אקסונלית ודנרוציה של שרירים 4- אקנטוציטוזיס
מקרא לציורים:
* ירוק –כוראה
* צהוב –אטקסיה
* כחול :סימנים פירמידליים
* שוט –שמחזיקים-AD שנחבטים –AR
* משקפיים –עיוורון
* אוזניות-פגיעה בשמיעה
* גפיים בכתום-פולינירופתיה
* כובע-ורוד-שינוי התנהגות
* צירים –EPS
* ברקים כחולים –מיוקולוניות
* שן אחת –דמנציה
* שפם –גנטיקה XLINKED
* אדום –מיופתיה?
- דגנר\קטיבי – כחול טאופאטיה ,צהוב סינקלופתיה
- פסים ורודים –דרמטולוגיה
- אדום ורוד -פוליניורופתיה
תיאור חולה קלאסי של
DLBD
איפה תהיה ירידה בקליטה ב
SPECT?
1. פריאטלי אחורי
2. פרונטלי
3. טמפורלי
4. גרעיני בסיס
גרעיני בסיס.
With regard to diagnostic testing, SPECT scans with radiolabeled dopamine transporter or dopamine receptor tracers show reductions in lenticular nuclei and caudate (striatal) activity, usually asymmetrically, compared to controls, as also seen with Parkinson’s disease but unlike Alzheimer disease. Increased avidity with FDG PET in these same structures is also an abnormal and characteristic finding in both Lewy body and Parkinson diseases. With radiolabeled dopamine ligands, PET in Lewy body disease shows reduced avidity in these regions. Therefore, these studies can be used to distinguish Lewy body (and Parkinson’s disease) from normal individuals and those with other dementias, including Alzheimer disease but are not used to distinguish the two parkinsonian disorders from each other. There has been increased interest in detecting phosphorylated alpha-synuclein in the small (presumably autonomic) nerves in the skin and it has been found that this test can distinguish Lewy body from other dementias (Donadio et al). Whether it differentiates this from Parkinson disease is not clear.
בן 70 עם ירידה קוגניטיבית, הפרעות זיכרון, הזיות ופרקינסוניזם. נלקחה ביופסיה מוחית. מה נראה?
1. Lewy bodies
2. Pick bodies
3. NF tangles
נראה גופיפי לואי-
LBD – synucleinopathy along with PD and MSA
Nf tangles – alzhiemer
Pick bodies –picks disease-FTLD.
-
LBD-
Ubiquitin and synuclein, main components of the Lewy body, by immunostaining. With this improved detection has come a better definition of the clinical syndrome and its distinctions from Alzheimer and other dementias. The disease in its typical form is marked by parkinsonian features, dementia, and a tendency to episodic delirium, especially nocturnally, and rapid eye movement (REM) sleep behavior disorder.
Diagnostic criteria requiring 2 of 3 of the following: - a parkinsonian syndrome (usually symmetric),
fluctuations in behavior and cognition
recurrent hallucinations. - REM sleep behavior disorder
-
severe neuroleptic sensitivity.
The parkinsonian features can respond favorably to L-dopa, but only for a limited time and sometimes at the expense of causing an agitated delirium or hallucinations. Others have commented on an extreme sensitivity of such patients to neuroleptic drugs, including increased confusion and greatly worsening parkinsonism or the development of the neuroleptic malignant syndrome.
Some patients also have orthostatic hypotension corresponding to cell loss and Lewy bodies in the intermediolateral cell column of the spinal cord or in the sympathetic ganglia, thereby simulating striatonigral degeneration or Shy-Drager syndrome.
—–
גופיפי פיק נוכל לראות ב: -
Behavioral variant FTLD
בגדול שינויים התנהגותיים – אפאטיות, ירידה ביוזמה, דיסאנהיבציה, פרסברציה, שיפוט לקוי, אפקט ביזארי, הפרעת אכילה ובאופן כללי שינוי כללי בהנהלות היומיומית. הפרעות פסיכיאטריות מקושרות לסוציופאטיות עם דיסאינהיבציה עם היפראוראליות, היפרפאגיות.
הדמיה מוחית תדגים אטרופיה שאינה פרופורציונאלית של האונות הפרונטליות.
חלק ממטופלים אלו יראו גם הסתמנות פרקינסונית.
ישנו גם וריאנט במעט החולים האלו שקשור גם למחלת הנוירון המוטורי. ALS
במיוחד במטופלים עם Guamanian (או western pacific).
וריאנט משפחתי קשור לדפקט בכרומוזום 17.
בחלק מהספרות פרונטו טמפורל דמנציה מיוחס רק לשקיעת טאו – לא מדוייק, כן ניתן להגיד שהוריאנט בו פרונטו טמפורל דמנציה מופיע עם פרקינסון כן מראה שקיעה ניכרת של חלבון טאו, וריאנט זה קשור לכרמוזום 17 (בו מקודד חלבון הטאו).
אכן משקעי טאו הוא דבר שנפוץ לראות הרבה מתתי הסוג של פרונטוטמפורל דמנציה, אולם משקעים אלו קיימים גם במחלות נווניות אחרות והמשקע אינו ספציפי.
(PSP, אלצהיימר).
כמו כן נראו סוגים של פרונטו טמפורל דמנציה ללא משקעי טאו או סינוקלאין אלא עם משקעי פרוגרנולין המכילים בעיקר יוביקוויטין בגופיפי הסגר המכילים גם
TDP-43 (DNA binding protein),
תוצאה של פגם בגן PGRN.
-
Primary progressive aphasias (PPA)
לעיתים אפאזיה או אפרקסיה הן הביטוי הראשוני של מחלת ניוון לוברי, ממקור פרונטלי או טמפורלי. הפרעת שפה קיימת בלפחות 2/3 מהמטופלים האלו. ישנם מספר וריאנטים בסיסיים:
1. Progressive non fluant aphasia –
תחילה המטופל מדבר לאט יותר עם קושי במציאת מילים אך מבנה השפה נשאר שלם, בהמשך הוא שוכח מילים ומשתמש בהם בצורה לא נכונה, בנוסף מפתח קושי הבנתי בדיבור ובקריאה. משפטים נהיים קצרים וטלגרפיים, לבסוף המטופל מפתח אפרקסיה ודיסארטריה ולאחר מכן משתתק.
2. Semantic aphasia-
קושי בשיום חפצים, אנשים ומילים עם פרסברציה ורבלית אולם שטף שמור. קיים קושי רב בשליפת שמות בקטגוריה מסוימת (למשל חיות). מטופלים אלו ערים לבעיה ולקושי בשליפת המילים. לבסוף המטופלים אינם מבינים את משמעות המילה פרט לקושי בשיום. פרוסופגנוזיה יכולה להופיע בעיקר עם מעורבות משמעותית של המיספרה ימנית. זכרון שמור.
3. Logopenic aphasia
מכיל את רוב האפסקטים של אפאזיה לא פלואנטית , אולם כאן הבנת משמעות המילים נשמרת.
60% אחוז מהמטופלים אינם מראים שינויים פתולוגיים, כאשר 20% עם גופיפי פיק, ו20% מאחרים שינויים דומים למחלת אלצהיימר באזור האטרופי.
נוירופיברילרי טנגלס נוכל לראות באלצהיימר.
מחלת לואי בודי
* LBD-
Ubiquitin and synuclein, main components of the Lewy body, by immunostaining. With this improved detection has come a better definition of the clinical syndrome and its distinctions from Alzheimer and other dementias. The disease in its typical form is marked by parkinsonian features, dementia, and a tendency to episodic delirium, especially nocturnally, and rapid eye movement (REM) sleep behavior disorder.
Diagnostic criteria requiring 2 of 3 of the following:
- a parkinsonian syndrome (usually symmetric),
fluctuations in behavior and cognition
recurrent hallucinations.
- REM sleep behavior disorder
- severe neuroleptic sensitivity.
The parkinsonian features can respond favorably to L-dopa, but only for a limited time and sometimes at the expense of causing an agitated delirium or hallucinations. Others have commented on an extreme sensitivity of such patients to neuroleptic drugs, including increased confusion and greatly worsening parkinsonism or the development of the neuroleptic malignant syndrome.
Some patients also have orthostatic hypotension corresponding to cell loss and Lewy bodies in the intermediolateral cell column of the spinal cord or in the sympathetic ganglia, thereby simulating striatonigral degeneration or Shy-Drager syndrome.
מה לא מאפיין
Lewy body disease
1. הלוצינציות
2. רגישות לנורולפטיקה
3. רעד אסימטרי
4. הפרעות שינה בשלב מוקדם
רעד אסימטרי לא מאפיין לואי בודי.
-
LBD-
Ubiquitin and synuclein, main components of the Lewy body, by immunostaining. With this improved detection has come a better definition of the clinical syndrome and its distinctions from Alzheimer and other dementias. The disease in its typical form is marked by parkinsonian features, dementia, and a tendency to episodic delirium, especially nocturnally, and rapid eye movement (REM) sleep behavior disorder.
Diagnostic criteria requiring 2 of 3 of the following: - a parkinsonian syndrome (usually symmetric),
fluctuations in behavior and cognition
recurrent hallucinations. - REM sleep behavior disorder
-
severe neuroleptic sensitivity.
The parkinsonian features can respond favorably to L-dopa, but only for a limited time and sometimes at the expense of causing an agitated delirium or hallucinations. Others have commented on an extreme sensitivity of such patients to neuroleptic drugs, including increased confusion and greatly worsening parkinsonism or the development of the neuroleptic malignant syndrome.
Some patients also have orthostatic hypotension corresponding to cell loss and Lewy bodies in the intermediolateral cell column of the spinal cord or in the sympathetic ganglia, thereby simulating striatonigral degeneration or Shy-Drager syndrome.
בחצי שנה אחרונה בן 75 סובל מהתקפי בלבול, הזיות ראיה. בין ההתקפים מתנהג רגיל ביום וצועק וזז
הרבה תוך שינה. בבדיקה: ירידה קוגניטיבית קלה, בעיקר בזיכרון; איטיות וריגידיות סימטרית.
מהו קו טיפול ראשון לשיפור ההתנהגות?
א. Haloperidol
ב. Quetiapine
ג. Clonazepam
ד. Rivastigmine
ריבסטיגמין.
מדובר במטופל עם מחלת לואי בודי
מחלה מוגדרת ע”י מעורבות דיפוזית של משקעי גופיפי לואי – משקעים של סינוקלאין ויוביקויטין. למעשה מדובר בשקיעה של אלפא סינוקלאין. במחלה זו מבחינה פתולוגית אין שקיעה עמילואיד או חלבון טאו.
מאפיינים קלינים - למעשה הגדרת המחלה מבוססת על הימצאות 2/3 הקליניקות הבאות:
פרקינסוניזם (לרוב סימטרי)
פלקטואציה בהתנהגות וקוגניציה
הזיות חוזרות
למעשה ההתייצגות תיראה כך – מטופל עם פרקינסוניזם, דמנציה, ונטייה לדליריום התקפי (בעיקר בזמן הלילה),
REM sleep behaivour – מאפיין רביעי של המחלה.
כמו כן בחולים אלו ישנה רגישות מאוד גבוהה לנוירולפטיקה.
- Treatment This has proved to be difficult, both in managing motor symptoms as mentioned above and more so, in treating psychosis. If orthostatic hypotension or wide swings in blood pressure supervene, the picture becomes even more complicated. For the blood pressure changes, midodrine is often prescribed; we have had less success with mineralocorticoids. At least one randomized trial has described benefit from the anticholinesterase inhibitor, rivastigmine, in reducing delusions, hallucinations, and anxiety (McKeith and colleagues, 2000). Pimavanserin, a selective serotonin 5-HT2A inverse agonist used to treat psychosis in Parkinson disease, has shown some modest benefit for psychosis and hallucinations in a trial in Lewy body dementia without worsening motor symptoms (see Cummings et al). Antipsychotic drugs such as quetiapine and clozapine are also used but are limited by their risks and side effects.
בן 25, מגיע עקב תלונה של חולשת ידיים בזמן גילוח וקושי לעלות מדרגות. בבדיקה גופנית – גינקומסטיה, חולשה פרוקסימלית בגפיים, חולשה שרירי פנים ד”צ.
CK 1500.
מהי האבחנה הסבירה ביותר:
- Myasthenia
- Myotonic dystrophy
- FSH-D
- Kennedy syndrome
- Limb girdle muscular dystrophy
Kennedy syndrome
An unusual pattern of distal muscular atrophy with prominent bulbar signs and, less often, ocular palsies was described by Kennedy and coworkers. The onset has varied from childhood to adult age, but symptoms typically begin in the third decade. The condition has an X-linked pattern of inheritance; female carriers may occasionally be mildly symptomatic. The proximal shoulder and hip musculature are involved first by weakness and atrophy, followed in about half of patients by dysarthria and dysphagia. Muscle cramps or twitching often precedes weakness. Facial fasciculations and mild weakness are characteristic and may be striking. The tendon reflexes become depressed and may be absent; a mild sensory neuropathy is almost universal. In the family described by Kaeser, which is representative of the disease as described by others, 12 members in 5 generations were affected, the pattern of weakness was shoulder-shank, that is scapuloperoneal; it may therefore be mistaken for muscular dystrophy. Two-thirds of patients have gynecomastia, a feature that may first identify affected men in a kindred; oligospermia and diabetes are additional associations; therefore, the presence of genuine progeny virtually excludes the disease in a male. The CK level is elevated, sometimes tenfold, and physiologic studies reveal denervation and reinnervation as well as indications of a mild sensory neuropathy.
As in Huntington disease and certain of the spinocerebellar atrophies, the genetic defect is a CAG expansion, in this case in the gene (AR) that codes for the androgen receptor on the short arm of the X-chromosome (La Spada et al; see Table 38-7). Indeed, the first reported polyglutamine disease was Kennedy syndrome. Lengthened sequences correlate with an earlier age of onset (anticipation, as in Huntington disease) but have no relation to the severity of disease. Androgen receptors have been found on motor neurons of the spinal cord; the subpopulation of motor neurons that is susceptible to both Kennedy syndrome and ALS express abundant surface androgen receptors, but it is not clear whether this finding has direct pathogenic significance. Neuronal inclusions have been described, composed of aggregations of the abnormally long polyglutamine protein sequences that correspond to the CAG expansion. The diagnosis can be confirmed by genetic testing for the lengthened trinucleotide sequence. Prenatal diagnosis and identification of female carriers are also possible by this method.
בן 40 מתקשה להרים ידיים מעל לראשו, לעלות מדרגות, בבדיקה חולשה 4/5 בחגורת הכתפיים, שרירי האגן, פסיקולציות בולטות בסנטר, גניקומסטיה, מחלה דומה אצל אביב ושני דודיו מצד האם אך לא אצל אמו. היכן הפגיעה במחלה זו?
1. androgen receptor
2. achetyl choline receptor
3. dysferlin complex
4. sarcoglycogan complex
5. ryanodine receptor
androgen receptor- kennedy syndrome
Kennedy syndrome
An unusual pattern of distal muscular atrophy with prominent bulbar signs and, less often, ocular palsies was described by Kennedy and coworkers. The onset has varied from childhood to adult age, but symptoms typically begin in the third decade. The condition has an X-linked pattern of inheritance; female carriers may occasionally be mildly symptomatic. The proximal shoulder and hip musculature are involved first by weakness and atrophy, followed in about half of patients by dysarthria and dysphagia. Muscle cramps or twitching often precedes weakness. Facial fasciculations and mild weakness are characteristic and may be striking. The tendon reflexes become depressed and may be absent; a mild sensory neuropathy is almost universal. In the family described by Kaeser, which is representative of the disease as described by others, 12 members in 5 generations were affected, the pattern of weakness was shoulder-shank, that is scapuloperoneal; it may therefore be mistaken for muscular dystrophy. Two-thirds of patients have gynecomastia, a feature that may first identify affected men in a kindred; oligospermia and diabetes are additional associations; therefore, the presence of genuine progeny virtually excludes the disease in a male. The CK level is elevated, sometimes tenfold, and physiologic studies reveal denervation and reinnervation as well as indications of a mild sensory neuropathy.
As in Huntington disease and certain of the spinocerebellar atrophies, the genetic defect is a CAG expansion, in this case in the gene (AR) that codes for the androgen receptor on the short arm of the X-chromosome (La Spada et al; see Table 38-7). Indeed, the first reported polyglutamine disease was Kennedy syndrome. Lengthened sequences correlate with an earlier age of onset (anticipation, as in Huntington disease) but have no relation to the severity of disease. Androgen receptors have been found on motor neurons of the spinal cord; the subpopulation of motor neurons that is susceptible to both Kennedy syndrome and ALS express abundant surface androgen receptors, but it is not clear whether this finding has direct pathogenic significance. Neuronal inclusions have been described, composed of aggregations of the abnormally long polyglutamine protein sequences that correspond to the CAG expansion. The diagnosis can be confirmed by genetic testing for the lengthened trinucleotide sequence. Prenatal diagnosis and identification of female carriers are also possible by this method.
—–
כמה מילים על המסיחים האחרים:
* Sarcoglycan:
Hereditary polymyoclonus
LGMD2C-F – severe childhood AR muscular dystrophies
Another form of nonprogressive myoclonus, dominantly inherited, is associated with dystonia, which is due to a mutation in a sarcoglycan gene, SGCE.
* Ryanodine Receptor:
Hyperthermia is also part of the malignant hyperthermia syndrome, in which, in a limited number of cases, there is an inherited (autosomal dominant) susceptibility to develop hyperthermia and muscle rigidity in response to inhalation anesthetics and skeletal muscle relaxants (“Malignant Hyperthermia” in Chap 54). In some of these instances, it has been found to be caused by a defective ryanodine receptor.
* Dysferlin – Limb Girdle Muscular Dystrophy 2B And Myoshi Myopathy
involved in the distal form of Miyoshi
muscular dystrophy. Early involvement of the gastrocnemius muscle (inability to walk on tiptoe) and extraordinarily high levels of CK.
Kennedy-
X-linked Bulbospinal muscular atrophy
CAG expansion androgen Receptor
Gynaecomastia, oligospermia, diabetes
מה מהבאים אינו ממצא אופייני לאלצהיימר?
1. אטרופיה פרונטלית קשה בתחילת המחלה
2. ירידה בקליטה באונות הטמפורליות בבדיקת SPECT
3. הגדלת חדרים לטרלים וחדר שלישיבשלב מאוחר של המחלה
אטרופיה פרונטלית קשה בתחילת המחלה אינה אופיינית לאלצהיימר
Studies with CT and MRI are useful, but not definitive ancillary tests (Fig. 38-3). In patients with advanced Alzheimer disease, the lateral and third ventricles are enlarged to about twice the normal size and the cerebral sulci are proportionately widened, both as a result of cerebral atrophy. Coronal MRI of the medial temporal lobes shows a disproportionate atrophy of the hippocampi and a corresponding enlargement of the temporal horns of the lateral ventricles.
Early in the disease, however, the changes do not exceed those found in many mentally intact old persons. For this reason, one cannot rely solely on imaging procedures for diagnosis and CT and MRI are most valuable in excluding alternative causes of dementia such as brain tumor, subdural hematoma, cerebral infarction, and hydrocephalus.
מוטציות בכל אחד מן הגנים הבאים יכולה לגרום לאלצהיימר תורשתית פרט ל:
1. amyloid precursor protein
2. presenilin 2
3. apolipoprotein E
4. ubiquitin esterase
5. ubiquilin 1
ubiquitin esterase = PARK 5 of parkinsons disease
מה אינו נכון לגבי הפתולוגיה במחלת האלצהיימר?
1. קיימים פלאקים עמילואידיים בין תאים
amyloid plaques
2. יש בתוך תאי העצב אגרגטים חלבוניים הנקראים
neurofibrillary tangles
3. לא נראים תאים דלקתיים
4. יש פגיעה הן בחלבון הטאו והן איבוד הפרקורסר פרוטאין של עמילואיד. Amyloid precursor protein APP
5. נוירופטים דיסטרופים הם חלק מהפלאקים העמילואידיים
amyloid plaques
- יש פגיעה הן בחלבון הטאו והן איבוד הפרקורסר פרוטאין של עמילואיד. Amyloid precursor protein APP
זו התשובה שאינה נכונה לגבי הפתולוגיה במחלת אלצהיימר.
pathology of alzheimer-
* brain weight is usually reduced by 20 percent or more.
* atrophic process involves the frontal, temporal, and parietal lobes. The extreme atrophy of the hippocampus, is diagnostic.
* widespread loss of nerve cells. most pronounced in layer II of the entorhinal cortex.
* marked neuronal loss in the hippocampus parahippocampal gyri and subiculum—
anterior nuclei of the thalamus, septal nuclei, and diagonal band of Broca, amygdala, and particular brainstem parts of the monoaminergic systems are also depleted.
- The cholinergic neurons of the nucleus basalis of Meynert (the substantia innominata) and locus ceruleus are also reduced in number, Astrocytic hypertrophy (more than proliferation) is in evidence as a compensatory or reparative process.
- Three additional microscopic changes give this disease its distinctive character:
(1) The presence within the nerve cell cytoplasm of thick, fiber-like strands of silver-staining material, also in the form of loops, coils, or tangled masses (Alzheimer neurofibrillary changes or “tangles”). These strands are composed of a hyperphosphorylated form of the microtubular protein, tau, and appear as pairs of helical filaments when studied ultrastructurally.
(2) Spherical deposits of amorphous material scattered throughout the cerebral cortex and easily seen with periodic acid-Schiff (PAS); the core of the aggregates is the protein amyloid, surrounded by degenerating nerve terminals (neuritic plaques) that stains with silver. Amyloid is also scattered throughout the cerebral cortex in a nascent “diffuse” form, without organization or core formation and then is appreciated mainly by immunohistochemical methods, as well as deposition in the walls of small blood vessels near the plaques, so-called congophilic angiopathy.
(3) Granulovacuolar degeneration of neurons, most evident in the pyramidal layer of the hippocampus. This last change is least important in diagnosis but there is uncertainty regarding its nature; it had been thought to be simply a reactive process but recent studies suggest it reflects a defect in phagocytosis of degraded proteins. - Neuritic plaques and neurofibrillary changes are found in all the association areas of the cerebral cortex, but it is the neurofibrillary tangles and quantitative neuronal loss, not the amyloid plaques, that correlate best with the severity of the dementia
the hippocampus, particularly the CA1 and CA2 zones and the entorhinal cortex, subiculum, and amygdala. - Only a few tangles and plaques are found in the hypothalamus, thalamus, periaqueductal region, pontine tegmentum, and granule-cell layer of the cerebellum.
- Several pieces of evidence favor the view that elevation of the levels of Aβ42 leads to aggregation of amyloid and then to neuronal toxicity. This is currently the most often cited hypothesis for the genesis of the disease. It appears that the diffuse deposition of Aβ42 precedes the formation of better-defined neurofibrils and plaques.
APP- amyloid precursor protein is not affected.
רעד ביד ימין מזה כשנתיים, חוסר יכולת להשתמש ביד הזו לחלוטין. מה הפתולוגיה?
1. Tau
2. Amyloid
3. Alfa synuclein
CBD= TAU
- The disease is now clearly considered to be related to
tau deposition in specific brain structures; however, the original authors were more impressed with ballooned and chromatolytic neurons with eccentric nuclei, a state that was called neuronal achromasia. The presence of these achromatic cells in posterior frontal and parietal neurons continues to be considered an essential feature of the disease, although the rounded areas within neurons stain for tau and resemble globose tangles that are found occasionally in Alzheimer disease (corticobasal bodies);
in this way, CBD is connected to the other tau-related neurodegenerative diseases, “tauopathies.” In addition, adjacent glia are filled with various configurations of tau protein, thereby linking the disease to frontotemporal lobar degeneration and PSP. - The most common early symptom was an asymmetrical clumsiness of the limbs with rigidity and, with tremor; these features are now considered to be the most characteristic early features of the process.
As the illness progressed, almost all the patients developed an asymmetric or unilateral akinetic-rigid syndrome, which may be considered the essential motor disorder of this disease, and various forms of gait disorder and dysarthria. Stimulus-induced or spontaneous myoclonus and pyramidal signs, limitations of vertical gaze and frontal lobe release signs eventually became apparent in half.
Eventually, although able to exert considerable muscle power, these patients cannot effectively direct their voluntary actions. Attempts to move a limb to accomplish some purposeful act might result in a totally inappropriate movement, always with great enhancement of rigidity in the limb and in other affected parts, or the limb may drift off and assume an odd posture, such as a persistent elevation of the arm without the patient’s awareness—a kind of catalepsy. The disorder of limb function has some of the attributes of a limb-kinetic or an ideomotor apraxia (see Chap. 3), but the hand postures, involuntary movements, and changes in tone are at times more of the type described as “alien hand.” Some patients exhibit anosognosia, Babinski signs, impaired eyelid or ocular motion (upgaze paresis or abnormal saccadic movements), lingual dyskinesias, frontal release signs, myoclonus, or dysarthria.
איזו מחלה מהבאות שייכת לקבוצת ה- tauopathies ?
א. Parkinson disease
ב. Multisystem atrophy
ג. Lewy body dementia
ד. Corticobasal degeneration
Corticobasal degeneration
- synucleinopathies- PD, DLBD, MSA
- Tauopathies: AD, PSP, FTD, CBD
תיאור של בחור צעיר עם דיסטוניה שמחמירה בערב, יש סיפור משפחתי. מה הטיפול הראשון?
1. טטרבנזין
2. טריהקילפנידין
3. L-DOPA
L-DOPA
Hereditary Dystonia-Parkinsonism (Segawa Syndrome, Juvenile Dopa-Responsive Dystonia, GCH1 Mutation)
main characteristic is a dystonia that is responsive to l-dopa, but most cases also have features of parkinsonism, The pattern of inheritance is autosomal dominant linkage to the gene on chromosome 14q for the protein GTP cyclohydrolase 1 (GCH1 gene) that is implicated in the synthesis of tetrahydrobiopterin, a cofactor for tyrosine hydroxylase. It is likely that the mutation impairs the generation of dopamine, a prediction that accords with responsiveness of the parkinsonian and dystonic features to l-dopa.
The dystonic manifestations usually become evident in childhood, usually between 4 and 8 years of age; females outnumber males in a ratio of 3:2. Often the legs are first affected by intermittent stiffening, with frequent falls and peculiar posturing, sometimes the feet assuming an equinovarus position. The arms become involved as well as the truncal muscles; retrocollis or torticollis may appear. Within 4 to 5 years, all parts of the body, including the bulbar muscles, are involved. Mild parkinsonian features (rigidity, bradykinesia, postural instability) can usually be detected early in the course of the illness, but more characteristically they are added to the clinical picture several years later.
The special feature of this juvenile dystonia-parkinsonism syndrome is the dramatic response of both the dystonic and parkinsonian symptoms to treatment with l-dopa. As little as 20-200 mg/d may eliminate the movement disorder and permit normal functioning. Unlike idiopathic Parkinson disease, the medication can be continued indefinitely without the development of tolerance, wearing-off effects, or dyskinesias. Segawa disease accounts for some cases that had in the past been reported as juvenile Parkinson disease. Another feature is the disappearance or marked subsidence of the symptoms after a period of sleep and worsening as the day progresses. This diurnal variation is shared with many of the inherited (and sporadic) forms of Parkinson disease listed in Table 38-3. Fluctuations of symptoms with exercise and menses and in the first month of pregnancy have been observed in some cases.
Dopa Repsonsive Dystonia
SEGAWA
Diurnal variation
Dopa Repsonsive
בת8עםקשייהליכה,הוריהמתאריםטונוסריגידיברגלימיןאשרמשתפרלאחרשינהומחמירבמהלךהיום.ישסיפורמשפחתי.מההטיפול?
1. בקלופןאינטרה-טקלי
2. דופה
3. טגרטול
4. בוטוקס
דופה
בת 8, מזה כשנה סובלת מדיסטוניה בגפיים וצוואר, שכמעט נעלמת בבוקר אחרי שינה ומחמירה במהלך היום. איזה טיפול מתאים?
א. Tetrabenazine
ב. Biperiden
ג. L-dopa
ד. Diazepam
L- DOPA
בן 60 , סבל מזה מספר חודשים מאירועי סינקופה. בבדיקתו, נמצאו סימנים אקסטרה-פירמידלים. ניסיון
טיפולי בלבודופה נכשל. במבחן אורטוסטטיזם נרשמה ירידה של 46 מ”מ כספית בלחץ הסיסטולי.
איפה נוצרים התהליכים הפתולוגים שגורמים לאורטוסטטיזם במחלה זו?
א. Dentate nucleus in the cerebellum
ב. Lateral nuclei of the hypothalamus
ג. Preganglionic lateral horn thoracic spinal cord
ד. Vagus cranial nerve
Preganglionic lateral horn thoracic spinal cord
Autonominc Failure:
This clinical state is now known to be caused by at least two conditions. One is a degenerative disease of middle and late adult life - idiopathic orthostatic hypotension /primary autonomic Failure. In this disorder, the lesions involve mainly the postganglionic sympathetic neurons; the parasympathetic system is relatively spared and the CNS is uninvolved. In the second more common disorder multiple system atrophy, the preganglionic lateral horn neurons of the thoracic spinal segments degenerate; these changes are responsible for the orthostatic hypotension. Later, signs of basal ganglionic or cerebellar disease or both are added. In both types of orthostatic hypotension, anhidrosis, erectile dysfunction and atonicity of the bladder may be conjoined, but orthostatic fainting is the main problem.
- Primary Orthostatic Hypotension: In the postganglionic type of autonomic failure, plasma levels of NE are subnormal while the patient is recumbent because of failure of the damaged nerve terminals to synthesize or release catecholamines. When the patient stands, the NE levels do not rise, as they do in a normal person. Also, in this type, there is denervation hypersensitivity to infused NE.
- In the central preganglionic MSA type, the resting NE levels in the plasma are normal but again, on standing, there is no Rise, and the response to exogenously administered NE is normal.
- In both types, the plasma levels of dopamine
f3-hydroxylase, the enzyme that converts dopamine to NE, are subnormal
למה מתאים אנטרוקוליס?
1. MSA
2. PSP
3. PD
4. DLBD
5. FTD
MSA
anterocollis or dystonia of the lower facial muscles is striking in a few cases
איזו מחלה יכולה להתחיל עם שיתוק מיתרי קול?
1. MSA
2. PD
3. DRPLA
4. PSP
MSA
vocal cord palsy is an important and sometimes initial manifestation of the disorder; it may cause dysphonia or stridor and airway obstruction requiring tracheostomy
חולה עם סימנים פרקינסונים ואורטוסטטיזם. מה יחזק אבחנה של
MSA
1. LP
2. MRI
3. tilt test
4. urodynamic testing
MRI= hot cross bun sign
Both MRI and CT scanning frequently show atrophy of the cerebellum and pons in those with cerebellar features. The putamina are hypointense on T2-weighted MRI and may show an increased deposition of iron in the parkinsonian form. In the cerebellar form, a “hot cross bun“ sign has been emphasized on MRI; it reflects atrophy of the pontocerebellar fibers that manifest high T2 signal intensity in an atrophic pons.
בן 70, מזה מספר חודשים הופעת הפרעות אוטונומיות (אורטוסטטיזם וכד’), ריגידיות סימטרית בבדיקה. מה המחלה הסבירה?
1. MSA
2. PD
3. PSP
4. DLBD
MSA
העדר תגובה לדופה, העדר רעד במנוחה, סימנים אוטונומיים בולטים בתחילת המחלה, העדר הגבלה בתנועות עיניים, מהלך מהיר ויחסית סימטרי תומך יותר ב
MSA
ולא בפרקינסון.
מה הבדיקה האבחנתית של מטופל עם
ALS
1. SF- EMG
2. repetitive stimulation
3. NCS
4. Needle EMG
Needle EMG
אישה בת 59 עם מהלך פרוגרסיבי של כמה חודשים המערב בהדרגה עצב 9 , 10, 11 ו-12 עם אטרופיה של הלשון. היתה חולשת צוואר שתוארה כסטרנוקליידומסטואיד וזוקפי צוואר. מה האבחנה הסבירה?
1. פולימיוזיטיס
2. מייסטניה
3. מחלת ALS
ALS
או יותר ספציפית-
progressive bulvar palsy
גבר בשנות ה-50 עם פאראפרזיס ספסטי, קושי בבליעה, דיבור ספסטי ואטרופיה בשרירי הידיים. מה נמצא בהדמיה?
א. Midbrain atrophy
ב. Hot cross-bun sign
ג. Bilateral internal capsule T2 hyperintensity
Bilateral internal capsule T2 hyperintensity
Laboratory features of motor neuron disease
* EMG, as expected, displays widespread fibrillations (evidence of active denervation) and fasciculations and enlarged motor units (denoting reinnervation).
Widespread denervation of the paraspinal muscles and of the genioglossus or facial muscles is also strongly suggestive.
A muscle biopsy is sometimes helpful in corroborating neurogenic denervation.
- MRI may show slight atrophy of the motor cortices and wallerian degeneration of the motor tracts These changes may be diagnostically useful and appear as increased FLAIR and T2 signal intensity in the posterior limb of the internal capsule, descending motor tracts of the brainstem, and spinal cord, all of which are subtle and may be missed.
- All these laboratory findings, particularly the degeneration of the lateral columns of the cord and changes in the internal capsules, pertain also to primary lateral sclerosis with the notable exception of EMG findings of denervation and of elevations of creatine kinase (CK).
גבר בן 70 עם נפילות לאחור בחודשיים האחרונים. בבדיקה עמידה זקופה, פרקינסוניזם סימטרי. מה עוד סביר שנמצא בבדיקתו?
1. אורטוסטטיזם
2. ירידה קוגניטיבית קשה
3. התקפי צחוק ובכי לא תואמים.
התקפי צחוק ובכי לא תואמים- פסאודובולבר אפקט כחלק מ
PSP.
The stiffness, slowness of movement, difficulty in
turning and sitting down, and hyopmima may suggest
a diagnosis of Parkinson disease. However, the facial
expression of the PSP patient is more a matter of tonic
Grimace than of lack of movement, and the lack of tremor, the erect rather than stooped posture, and prominence of oculomotor abnormalities serve to distinguish the 2 disorders. The signs of pseudobulbar palsy are eventually prominent, and this feature, along with the eye movements, distinguishes the process most conspicuously from other degenerative conditions. The face becomes less expressive (“masked“), speech is slurred in a slowed spastic fashion, the mouth tends to be held open, and swallowing is difficult. Forced laughing and crying, said to be infrequent, have been present in about half of our cases late in the course. Many patients complain of sleep disturbances.
מה הפתולוגיה שנראה בהדמייה של מטופל עם
PSP
1. אטרופיה בצורת מיקי מאוס במידבריין
2. אטרופיה של הפונס
3. Panda sign
4. Eye of the tiger sign
אטרופיה בצורת מיקי מאוס במידבריין
איזה סוג של הפרעת דיבור אופייני ל-
progressive supranuclear palsy ?
א. Monotonic
ב. Spastic
ג. Scanning
ד. Tremulous
spastic
speech is slurred in a slowed spastic fashion, quite different from Parkinson disease, the mouth tends to be held open, and swallowing is difficult. Many patients complain of sleep disturbances.
scanning= cerebellar
monotonic= parknisons
Tremulous= Rigid (extrapyramidal) dysarthria
מטופל עם תסמונת פרקינסונית, דיסארתריה, בהדמייה נראה אטרופיה של המידבריין
1. CBD
2. PD
3. PSP
4. Alzheimer
PSP
בן 19 סובל מהתקפים חוזרים של חוסר שיווי משקל והפרעה בהליכה שנמשכים עד יממה. אביו סובל מהתקפים חוזרים של המיפרזיס מלווה בכאב ראש המיקרני עם פוטופוביה ואי סבילות לתנועות מהירות. איזה טיפול עשוי לעזור למנית התקפי הפרעת ההליכה ושיווי המשקל של הנער?
1. acetazolamide
2. amitryptilline
3. cinnarizine
4. propranolol
5. valproate
acetazolamide.
Two adult forms of hereditary cerebellar ataxia are paroxysmal in nature.
* In one (EA-2 for “episodic ataxia, type 2”), the episodes occur without explanation and last several hours; vertigo is the prominent feature of the attacks. Between attacks the patient is normal or has only minimal ataxia and nystagmus (Griggs et al). These ataxic episodes are prevented strikingly by the administration of oral acetazolamide. The disorder has been found to be a mutation of the calcium channel gene on chromosome 19
- A similar but physiologically and genetically unrelated
paroxysmal ataxia (EA-1) is characterized by episodes that may be precipitated by exercise and by the presence of muscle myokymia (rippling) between attacks. Vertigo does not occur and acetazolamide is less effective or not
effective at all. The disorder is caused by an abnormality of the potassium channel gene on chromosome 12 (see Table 38-5).
חולה עם התקפי אטאקסיה פריודית עם ורטיגו ללא טריגר. מה הטיפול?
1. אצטזולאמיד
2. בנזודיאזפינים
3. תרופה אנטי אפילפטית
acetazolamide.
Two adult forms of hereditary cerebellar ataxia are paroxysmal in nature.
* In one (EA-2 for “episodic ataxia, type 2”), the episodes occur without explanation and last several hours; vertigo is the prominent feature of the attacks. Between attacks the patient is normal or has only minimal ataxia and nystagmus (Griggs et al). These ataxic episodes are prevented strikingly by the administration of oral acetazolamide. The disorder has been found to be a mutation of the calcium channel gene on chromosome 19
- A similar but physiologically and genetically unrelated
paroxysmal ataxia (EA-1) is characterized by episodes that may be precipitated by exercise and by the presence of muscle myokymia (rippling) between attacks. Vertigo does not occur and acetazolamide is less effective or not
effective at all. The disorder is caused by an abnormality of the potassium channel gene on chromosome 12 (see Table 38-5).
לרוב התינוקות עם תסמונת
werding hoffman= infantile SMA
יש מטוציה ב:
1. gene encoding for frataxin on 9q chromosome
2. gene encoding for paraplegin on 16q chromosome
3. chromosome 14 with enhanced number of CAG repeats
4. chromosome 19 with enhanced number of CTG repeats
5. mutation in the “survival of motor neuron gene” on chromosme 5
mutation in the “survival of motor neuron gene” on chromosme 5
frataxin= friedreich ataxia
paraplegin- hereditary spastic paralysis
CAG- huntington’s disease
CTG- myotonic dystrophy
מה נמצא בהדמיה ב
-DYT1
א.Normal imaging
ב. hyperintensity in the MCP
ג. gross atrophy of the spinal cord
normal imaging
Dystonia Musculorum Deformans (Torsion Dystonia)
-
Genetic aspects
“dystonia-plus” as they encompass tremor, parkinsonism or myoclonus. The most important of these is an abnormal gene (DYT1, also known as TOR1A) on chromosome 9q, which codes for the protein, torsin A in both Jewish and non-Jewish families. The most common mutation in DYT1 is a deletion of a single glutamate from the torsin A peptide and accounts for most cases of dystonia musculorum deformans. This disease is inherited in an autosomal dominant pattern. Although the penetrance of the clinical trait in these families is low, PET demonstrates hypermetabolism in the cerebellum, lenticular nuclei, and supplementary motor cortex in all carriers of the mutated gene.
torsin A is not fully defined. It is present in neurons throughout the brain and has adenosine triphosphate (ATP) binding and nuclear localization. It may function as a chaperone protein that shuttles other proteins in and out of cells. A current speculation, shared with other degenerative disease, is that the absence of torsin A renders neurons unduly sensitive to oxidative stress (Some individuals in families affected with generalized dystonia will demonstrate only localized forms (e.g., writer’s cramp or torticollis).
The general rule stated above still holds, namely, that the inherited variety (dystonia musculorum deformans) related to DYT1 manifests early in life and begins in one limb and then spreads to most muscles of the body, while in the common dystonias (mostly sporadic but some heritable) the disease remains confined to the craniocervical or another region, does not generalize, and has an adult onset. -
Clinical features The first manifestations of the generalized disease may be rather subtle. Intermittently, and usually after activity (late in the day), the patient (usually a child between 6 and 14 years of age, less often an adolescent) begins to invert one foot, to extend one leg and foot in an unnatural way, or to hunch one shoulder, raising the question of a nervous tic. As time passes, the motor disturbance becomes more persistent and interferes increasingly with the patient’s activities. Soon the muscles of the spine and shoulder or pelvic girdle become implicated in involuntary spasmodic twisting movements. The cardinal feature of these severe dystonic muscle contractions is the simultaneous contraction of both agonists and antagonists at a joint.
finally, they are continuous and the body may become grotesquely contorted, Lateral and rotatory scoliosis uniformly results as secondary deformities. For a time, recumbency relieves the spasms, but later on position has no influence. The hands are seldom involved, although at times they may be held in a fisted posture. Cranial muscles do not escape, and in a few instances a slurring, staccato-type speech was the initial manifestation. Uncontrollable blepharospasm was the initial disorder in one of our patients; in two others, severe dysarthria and dysphagia were the first signs, caused by dystonia of the tongue, pharyngeal, and laryngeal muscles.
Other manifestations include torticollis, tortipelvis, dromedary gait, propulsive gait, action tremor, myoclonic jerks during voluntary movement, and mild choreoathetosis of the limbs. Excitement worsens the dystonia and sleep abolishes it. As the years pass the postural distortion may become fixed to the point where it does not disappear even in sleep.
Tendon reflexes are normal, corticospinal signs are absent, and there is no ataxia, sensory abnormality, convulsive disorder, or dementia. - The brain is grossly normal and ventricular size is not increased. no significant changes in the striatum, pallidum, or elsewhere.
- Treatment Early in the course of the illness, several drugs including l-dopa, bromocriptine, carbamazepine, diazepam, and tetrabenazine seem to be helpful, but only in a few patients, and the benefit is not lasting. Intrathecal baclofen has been somewhat more successful in children. The rare hereditary form of dystonia-parkinsonism (segawa) responds well to small doses of l-dopa and dopamine agonists and is exceptional in this respect. use of very high doses (up to 30 mg daily or more) of trihexyphenidyl (Artane). Apparently, dystonic children can tolerate these high doses if the medication is raised gradually, by 5-mg increments weekly. In adults, high-dose anticholinergic treatment is less successful but worthy of a trial. Clonazepam is beneficial in some patients with segmental myoclonus. Impressive results were obtained in the past by the use of stereotactic techniques that made lesions in the ventrolateral nuclei of the thalamus or in the pallidum-ansa lenticularis region. Some frightfully disabled children, unable to sit or stand, were restored to near normalcy for a time. The main risk of the operation was a corticospinal tract lesion, produced inadvertently by damaging the internal capsule. Bilateral lesions have sometimes been disastrous, causing pseudobulbar palsy. The production of lesions has been supplanted, with success over longer periods, by bilateral stimulation of the internal segments of the globus pallidus
מהי המוטציה ב
DYT1?
Torsin
gene (DYT1, also known as TORlA) on chromosome 9q,
which codes for the protein, torsin A in both Jewish and
non-Jewish families
נער ממוצא אשכנזי (רוסיה- בלרוסיה) פנה לרופא המשפחה עם תלונה של ירידה בהישיגיו בספורט. בדיקתו תקינה, אך כשמתחיל ללכת הרגל מתעקמת פנימה. מה נראה בהדמיה?
1. הדמיה תקינה
2. hot cross buns sign
3. eye of the tiger sign
יכול להיות או הדמיה תקינה או
eye of the tiger.
—–
normal imaging
Dystonia Musculorum Deformans (Torsion Dystonia)
-
Genetic aspects
“dystonia-plus” as they encompass tremor, parkinsonism or myoclonus. The most important of these is an abnormal gene (DYT1, also known as TOR1A) on chromosome 9q, which codes for the protein, torsin A in both Jewish and non-Jewish families. The most common mutation in DYT1 is a deletion of a single glutamate from the torsin A peptide and accounts for most cases of dystonia musculorum deformans. This disease is inherited in an autosomal dominant pattern. Although the penetrance of the clinical trait in these families is low, PET demonstrates hypermetabolism in the cerebellum, lenticular nuclei, and supplementary motor cortex in all carriers of the mutated gene.
torsin A is not fully defined. It is present in neurons throughout the brain and has adenosine triphosphate (ATP) binding and nuclear localization. It may function as a chaperone protein that shuttles other proteins in and out of cells. A current speculation, shared with other degenerative disease, is that the absence of torsin A renders neurons unduly sensitive to oxidative stress (Some individuals in families affected with generalized dystonia will demonstrate only localized forms (e.g., writer’s cramp or torticollis).
The general rule stated above still holds, namely, that the inherited variety (dystonia musculorum deformans) related to DYT1 manifests early in life and begins in one limb and then spreads to most muscles of the body, while in the common dystonias (mostly sporadic but some heritable) the disease remains confined to the craniocervical or another region, does not generalize, and has an adult onset. -
Clinical features The first manifestations of the generalized disease may be rather subtle. Intermittently, and usually after activity (late in the day), the patient (usually a child between 6 and 14 years of age, less often an adolescent) begins to invert one foot, to extend one leg and foot in an unnatural way, or to hunch one shoulder, raising the question of a nervous tic. As time passes, the motor disturbance becomes more persistent and interferes increasingly with the patient’s activities. Soon the muscles of the spine and shoulder or pelvic girdle become implicated in involuntary spasmodic twisting movements. The cardinal feature of these severe dystonic muscle contractions is the simultaneous contraction of both agonists and antagonists at a joint.
finally, they are continuous and the body may become grotesquely contorted, Lateral and rotatory scoliosis uniformly results as secondary deformities. For a time, recumbency relieves the spasms, but later on position has no influence. The hands are seldom involved, although at times they may be held in a fisted posture. Cranial muscles do not escape, and in a few instances a slurring, staccato-type speech was the initial manifestation. Uncontrollable blepharospasm was the initial disorder in one of our patients; in two others, severe dysarthria and dysphagia were the first signs, caused by dystonia of the tongue, pharyngeal, and laryngeal muscles.
Other manifestations include torticollis, tortipelvis, dromedary gait, propulsive gait, action tremor, myoclonic jerks during voluntary movement, and mild choreoathetosis of the limbs. Excitement worsens the dystonia and sleep abolishes it. As the years pass the postural distortion may become fixed to the point where it does not disappear even in sleep.
Tendon reflexes are normal, corticospinal signs are absent, and there is no ataxia, sensory abnormality, convulsive disorder, or dementia. - The brain is grossly normal and ventricular size is not increased. no significant changes in the striatum, pallidum, or elsewhere.
- Treatment Early in the course of the illness, several drugs including l-dopa, bromocriptine, carbamazepine, diazepam, and tetrabenazine seem to be helpful, but only in a few patients, and the benefit is not lasting. Intrathecal baclofen has been somewhat more successful in children. The rare hereditary form of dystonia-parkinsonism (segawa) responds well to small doses of l-dopa and dopamine agonists and is exceptional in this respect. use of very high doses (up to 30 mg daily or more) of trihexyphenidyl (Artane). Apparently, dystonic children can tolerate these high doses if the medication is raised gradually, by 5-mg increments weekly. In adults, high-dose anticholinergic treatment is less successful but worthy of a trial. Clonazepam is beneficial in some patients with segmental myoclonus. Impressive results were obtained in the past by the use of stereotactic techniques that made lesions in the ventrolateral nuclei of the thalamus or in the pallidum-ansa lenticularis region. Some frightfully disabled children, unable to sit or stand, were restored to near normalcy for a time. The main risk of the operation was a corticospinal tract lesion, produced inadvertently by damaging the internal capsule. Bilateral lesions have sometimes been disastrous, causing pseudobulbar palsy. The production of lesions has been supplanted, with success over longer periods, by bilateral stimulation of the internal segments of the globus pallidus
Eye of the Tiger – Hallervorden Spatz
* PANK mutation – Hallervorden-Spatz
* AR disease
* Onset in childhood or early adolescence –
Slow progression
* Early signs variable: Predominantly motor
Corticospinal – spasticity, hypereflexia, Babinski
Extrapyramidal – rigidity, dystonia, choreoathetosis
Conjoined with general deterioration of intellect.
May affect bulbar muscles as well.
It is an autosomal recessive neurodegenerative
disorder presenting in childhood with the insidious
onset of dystonia and gait disorder. Rigidity, dysarthria, spasticity, dementia, retinitis pigmentosa, and optic atrophy develop and progress relentlessly until death in early childhood.
T2-weighted MRI brain scans show areas of reduced
attenuation in the GP surrounding an area of hyperintensity, the eye of the tiger sign
ילד אשכנזי. קושי בפעילות גופנית. במנוחה בדיקה תקינה. בזמן הליכה הופעה לסירוגין של כיפוף רגל שמאל הגורם לצליעה. היכן המוטציה?
א. Torsin-A
ב. Dysferlin
ג. Ataxin
ד. Dystrophin
Torsin- A
בחורה עם ירידה משמעותית בחדות הראיה בשתי העיניים, בבדיקתה היפרמיה של הרשתית, סקוטומות מרכזיות. נאמר לה שהפרוגנוזה לא טובה. מה נכון?
1. תורשה אימהית
2. התבטאות שווה בבנים ובנות
3. שכיח שמתבטא רק בעין אחת
תורשה אימהית.
LEBER
Clinical features In most patients, the visual loss begins between 18 and 25 years of age,
Usually the visual loss rapid onset and a subacute evolution suggesting a retrobulbar neuritis;, aching in the eye or brow may accompany the visual loss.
Usually both eyes are affected simultaneously, although in many, one eye is affected first, followed by the other after an interval of several weeks or months. In practically all cases, the second eye is affected within a year of the first. In the unimpaired eye, abnormalities of visual evoked potentials may antedate impairment of visual acuity Once started, the visual loss progresses over a period of weeks to months. Characteristically, central vision is lost before peripheral, and there is a stage at which bilateral central scotomata are readily demonstrated. Early on, perception of blue-yellow is deficient, while that of red and green is relatively preserved. In the more advanced stages, however, the patients are totally color-blind. Constriction of the fields may be added later. At first there may be swelling and hyperemia of the discs, but soon they become atrophic. Peripapillary vasculopathy, consisting of tortuosity and arteriovenous shunting, is the primary structural change; this has been present also in asymptomatic offspring of carrier females.
Common to all cases is the presence of a pathogenic mitochondrial DNA abnormality (Riordan-Eva et al), but the defect may occur at one of several sites as discussed in Chap. 36. Thus, Leber optic atrophy has been added to the growing list of mitochondrial diseases.
* The disorder is said to be more prominent in males with a ratio of M:F 5:1
בת 20 סובלת מירידה מהירה בחדות הראייה. בבדיקה שנערכת חצי שנה אחרי תחילת הסימפטומים חדות הראייה היא 6/18 מימין ו6/24 משמאל. בבדיקת פונדוס נמצאו גודש והיפראמיה של עצבי הראייה. בשדות הראייה יש סקוטומות מרכזיות. נאמר למטופלת כי פרוגנוזת המחלה אינה טובה. איזה מהממצאים הבאים מאפיין את המחלה?
1. תורשה אימהית בלבד
2. המחלה יכולה להיות חד צצדית עד שלב מאוד מתקדם
3. פוגע בשני המינים במידה שווה
4. מאוחר במהלך המחלה רואים ניוון שלהאונות האוקסיפיטליות
5. מוחמרת עקב שימוש מוגזם של אלכוהול
תורשה אימהית בלבד (מיטוכונדריאלית)
LEBER
Clinical features In most patients, the visual loss begins between 18 and 25 years of age,
Usually the visual loss rapid onset and a subacute evolution suggesting a retrobulbar neuritis;, aching in the eye or brow may accompany the visual loss.
Usually both eyes are affected simultaneously, although in many, one eye is affected first, followed by the other after an interval of several weeks or months. In practically all cases, the second eye is affected within a year of the first. In the unimpaired eye, abnormalities of visual evoked potentials may antedate impairment of visual acuity Once started, the visual loss progresses over a period of weeks to months. Characteristically, central vision is lost before peripheral, and there is a stage at which bilateral central scotomata are readily demonstrated. Early on, perception of blue-yellow is deficient, while that of red and green is relatively preserved. In the more advanced stages, however, the patients are totally color-blind. Constriction of the fields may be added later. At first there may be swelling and hyperemia of the discs, but soon they become atrophic. Peripapillary vasculopathy, consisting of tortuosity and arteriovenous shunting, is the primary structural change; this has been present also in asymptomatic offspring of carrier females.
Common to all cases is the presence of a pathogenic mitochondrial DNA abnormality (Riordan-Eva et al), but the defect may occur at one of several sites as discussed in Chap. 36. Thus, Leber optic atrophy has been added to the growing list of mitochondrial diseases.
* The disorder is said to be more prominent in males with a ratio of M:F 5:1
תיאור של מטופל עם ארפלקסיה ואטקסיה. בבדיקתו
pes cavus, kiphoscoliosis,
מה הגן הפגוע?
1. frataxin
2. presenilin
3. laminin
4. sarcoglycan
Frataxin
מה לא מאפיין פרידריך אטקסיה?
1. החזרים ערים
2. קוגניציה שמורה
3. אטקסיה משולבת סנסורית וצרבלרית
4. קרדיומיופתיה
בפרידריך אטקסיה יש ארפלקסיה
Clinical features Ataxia of gait is nearly always the initial symptom. Difficulties in standing steadily and in running are early symptoms. hands become clumsy months or years after the gait disorder, dysarthric speech appears.
Exceptionally, the ataxia begins rather abruptly after a febrile illness, and one leg may become clumsy before the other. In some patients, pes cavus and kyphoscoliosis (scoliosis) are evident well before the neurologic symptoms; in others, they follow by several years. The characteristic foot deformity takes the form of a high plantar arch with retraction of the toes at the metatarsophalangeal joints and flexion at the interphalangeal joints (hammertoes).
In the fully developed syndrome, the abnormality of gait is of mixed sensory and cerebellar type, aptly called tabetocerebellar by Charcot. According to Mollaret, the author of an authoritative monograph on the disease, the cerebellar component predominates, but in our relatively small experience we have been as impressed almost as much with the sensory (tabetic) aspect. The patient stands with feet wide apart, constantly shifting position to maintain balance. Friedreich referred to the constant teetering and swaying on standing as static ataxia. In walking, as with all sensory ataxias, the movements of the legs tend to be brusque, the feet resounding unevenly and irregularly as they strike the floor, and closure of the eyes causes the patient to fall (Romberg sign). This is one component of the spinal aspect (posterior columns) of the disease. Attempts to correct the imbalance may result in abrupt, wild movements. Often there is a rhythmic tremor of the head. Eventually, the arms are grossly ataxic, and both action and intention tremors are manifest. Speech is slow, slurred, explosive, and, finally, almost incomprehensible. Breathing, speaking, swallowing, and laughing may be so incoordinated that the patient nearly chokes while speaking. Holmes (1907a) remarked on an ataxia of respiration that causes “curious short inspiratory whoops.” Facial, buccal, and arm muscles may display tremulous and sometimes choreiform movements.
Although mentation is generally preserved, emotional lability has been sufficiently prominent to provoke comment. Torsional and vertical nystagmus is rare but “square wave jerks” are seen in the early stages of disease. Horizontal nystagmus may be present late in the course of the illness, but not early, but it is slight in amplitude. Ocular movements usually remain full, and pupillary reflexes are normal. The facial muscles may seem slightly weak, and deglutition may become impaired. Amyotrophy occurs late in the illness and is usually mild, but it may be extreme in patients with an associated neuropathy (see in the following text).
The tendon reflexes are abolished in nearly every case; rarely, they may be obtainable when the patient is examined early in the illness (see in the following text). Plantar reflexes are extensor and flexor spasms may occur even with complete absence of tendon reflexes (another manifestation of the spinal component). The abdominal reflexes are usually retained until late in the illness. Loss of vibratory and position sense is invariable from the beginning; later, there may be some diminution of tactile, pain, and temperature sensation as well. Sphincter control is usually preserved.
A notable feature in more than half of patients is a cardiomyopathy. The myocardial fibers are hypertrophic and may contain iron-reactive granules (Koeppen). Many of the patients die as a result of cardiac arrhythmia or congestive heart failure. For this reason, it is essential that affected individuals have a cardiologic assessment including electrocardiography and echocardiography.
איזו לויקודיסטרופיה קשורה ל
trinucleotide repeats?
1. Dentatorubral-pallidoluysian atrophy
2. adrenoleukodystrophy
3. Fabry
4. metachromatic
Dentatorubral-pallidolusian atrophy DRPLA
DRPLA- ATROPHIN1 CAG repeat
The extrapyramidal manifestations include chorea, myoclonus, and rigidity, dementia, seizures, dystonia
Cerebellar ataxia couple with choreoathetosis. Parkinsonism, myoclonus, epilepsy and dementia.
Degeneration of dentatorubral, pallidoluysian systems.
AD inheritance with anticipation.
- Fabry alpha galactosidase – x linked – accumulation of cermide – lancinating pain worse with heat/ exercise/ HTN, renal damage, cardiomegaly, MI, CVA ischemic, , periumbilical angiokeratoma, enzyme replacment.
- Metachromatic – Arylsulfatase – AR inheritance, prevents myelin creation slowly evolving intellectual decline, spastic weakness, hyperreflexia, Babinski, polyneuropathy, dysarthria, dysphagia, optic atrophy , diagnosis – increased in sulfatide in urine and absence of arylsulfatase A in blood cells – bone Marrow if early.
-
ALD – LCFA – X linked, impairment of oxidation of long chain fatty acids, accumulation in brain and adrenal gland, ABCD1 gene, - adrenal insufficiency – bronzing of skin, vomiting plus cerebral : decline in performance, personality change, inappropriate giggling, ataxic gait, quadriparesis, dysarthria and dysphagia, . Spasticity commonly asymmetrical and and gait ataxia, cortical blindness,
Pathology – sudanophilic demyelination. Dx: excess of VLCFA. Adrenal replacement therapy and diet with monosaturated fatty acids, bone marrow transplantation
Figure 38-1.
Photomicrograph of Alzheimer amyloid plaques and neurofibrillary tangles. Bielschowsky silver stain.
fig 38-2 Formation of Aβ42 is promoted by mutations, either in the APP gene itself or in the presenilins. In Down syndrome, excess production of APP
and its product Aβ42 is caused by triplication of the long arm of chromosome 21, the location of the APP gene. The Apo E4 allele is associated with
inadequate clearance of Aβ42 and is another mechanism that promotes fibrillogenesis. (Modified by permission from Sisodia SS, St. George–Hyslop
PH: γSecretase,
notch, Aβ and Alzheimer disease: Where do the presenilins fit in? Nat Rev Neurosci 3:281–290, 2002.)
Several
Figure 38-3.
Top: Coronal- T1-weighted
MRI of a 74 year old man with moderate Alzheimer-type dementia. Diffuse cerebral and hippocampal atrophy with ex vacuo ventricular and cortical sulcal dilation is noted. Bottom: Coronal T1 weighted MRI of a 70 year old woman with behavioral variant frontotemporal lobar dementia. Atrophy of the right greater than left temporal lobes is out of proportion to atrophy of the frontal and parietal lobes.
Figure 38-3.
Top: Coronal- T1-weighted
MRI of a 74 year old man with moderate Alzheimer-type dementia. Diffuse cerebral and hippocampal atrophy with ex vacuo ventricular and cortical sulcal dilation is noted. Bottom: Coronal T1 weighted MRI of a 70 year old woman with behavioral variant frontotemporal lobar dementia. Atrophy of the right greater than left temporal lobes is out of proportion to atrophy of the frontal and parietal lobes.
Figure 38-4.
Axial CT from a 54 year-old
mildly demented woman with a 10 year history of Huntington chorea. The bulge in the inferolateral border of the lateral ventricle, normally created by the head of the caudate nucleus, is absent. There is also diffuse enlargement of the lateral ventricles.
Figure 38-4.
Axial CT from a 54 year-old
mildly demented woman with a 10 year history of Huntington chorea. The bulge in the inferolateral border of the lateral ventricle, normally created by the head of the caudate nucleus, is absent. There is also diffuse enlargement of the lateral ventricles.
Figure 38-5 Photomicrograph of a round Lewy body inclusion in the cytoplasm of a nigral neuron. (Hematoxylin and eosin [H&E] staining.) (From Frosch MP, et al:
The central nervous system. In Robbins SL, et al (eds): Robbins and Cotran Pathologic Basis of Disease, 8th ed. Philadelphia, Saunders/Elsevier, 2010.)
Figure 38- 6.
Schematic diagram of proposed mechanisms of αsynuclein
toxicity in Parkinson disease. In this model, α-synuclein levels are elevated by
(a) duplication of one copy of the α- synuclein gene;
(b) point mutations in the αsynuclein
gene that generate excessive accumulations of synuclein; or
(c) mutations in parkin and UCHL1
genes that reduce normal removal of synuclein by the proteosomes.
The excess of synuclein polymerizes to form protofibrils, a process that is enhanced by defects in heat shock proteins (Hsps) or by the action of dopamine, which binds to synuclein. In turn, this leads to formation of Lewy bodies. This model attributes the neurotoxicity to either the protofibrils or the Lewy bodies. (Adapted by permission from
Eriksen JL, Dawson TM, Dickson DW, Petrucelli L: Caught in the act: α- Synuclein
is the culprit in Parkinson’s disease. Neuron 40:453–456, 2003.)
Figure 38-7.
Progressive supranuclear palsy.
A. T2 weighted axial MRI showing the atrophic dorsal midbrain that gives rise to the “mouse ears” (also “Mickey
mouse”) appearance.
.
Figure 38-7.
Progressive supranuclear palsy.
B. Mid-sagittal image showing atrophy of the dorsal midbrain, giving the appearance of a hummingbird.
Figure 38-8.
Familial cortical cerebellar atrophy. T1 weighted MRI in the sagittal plane showing marked atrophy of vermis and enlargement of fourth ventricle. The brainstem is only mildly atrophic and the posterior fossa is normal is size. Compare with Fig. 38-9
in which the cerebellum and pons are atrophic.
Figure 38-8.
Familial cortical cerebellar atrophy. T1 weighted MRI in the sagittal plane showing marked atrophy of vermis and enlargement of fourth ventricle. The brainstem is only mildly atrophic and the posterior fossa is normal is size. Compare with Fig. 38-9
in which the cerebellum and pons are atrophic.
Figure 38-9.
MSA-C, formerly called
olivopontocerebellar atrophy. MRI in the sagittal plane demonstrating both vermian atrophy (black arrow) and smallness of the pons (white arrow). (Reproduced by permission from Bisese JH: Cranial MRI. New York, McGrawHill, 1991.)
Figure 38-10.
Axial T2 weighted MRI showing abnormal hyperintensity reflecting wallerian change in the corticospinal tracts at the level of the internal capsule (top, arrow) and the pons (bottom) in a patient with ALS.
