פרק 38 Chapter 38: Degenerative Diseases of the Nervous System Flashcards

Question

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

Answer 1

Beta secretase- part of amyloid in Alzheimer disease ## Footnote **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

Answer 2

thyrosine hydroxylase is the rate limiting step in Dopamine synthesis ## Footnote **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

Answer 3

**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.

Answer 4

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.

Answer 5

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..

Answer 6

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.

Answer 7

אנטקפון- מאריכה את ההשפעה של לבודופה, לא ניתנת לבד.

Answer 8

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.

Answer 9

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).***

Answer 10

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.**

Answer 11

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..

Answer 12

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. .

Answer 13

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. .

Answer 14

אמפליפיקציה של CAG

Answer 15

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 .

Answer 16

**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.) ## Footnote 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

Answer 17

משטח דם **Acanthocytosis with chorea** 1. ***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 2. ***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 3. **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 . ## Footnote 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

Answer 18

לא נראה ערות החזרים באקנטוציטוזיס. **Acanthocytosis with chorea** 1. ***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 2. ***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 3. **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** ## Footnote 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

Answer 19

לא נראה רעד באקנטוציטוזיס. לא נראה ערות החזרים באקנטוציטוזיס. **Acanthocytosis with chorea** 1. ***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 2. ***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 3. **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** ## Footnote 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

Answer 20

vitamin C deficiency is not a part of the syndrome. ***Abeta lipoproteinemia (Bassen-Kornzweig Syndrome)*** (See also Chap. 37) This rare **autosomal recessive** childhood disorder was described in Chap. 37 with the **inherited metabolic disorders** of the nervous system and commented upon with **neuroacanthocytosis** in Chap. 39, although there is **no relationship between the two processes**. It is mentioned here because the **brunt of the neurologic disorder falls upon the *peripheral nerves***. **Acanthocytosis** of red blood cells is its identifying feature. The **earliest neurologic finding is usually diminution or absence of tendon reflexes**, detected as early as the second year of life. Later, when the child is first able to cooperate in sensory testing, a **loss of vibratory and position sense** is found in the legs. **Cerebellar signs** (ataxia of gait, trunk, and extremities; titubation of the head; and dysarthria), **muscle weakness**, **ophthalmoparesis**, **Babinski signs**, and **loss of pain and temperature sense** are the other characteristic neurologic abnormalities, in more or less this order of frequency. **Developmental delay, usually mild, occurs in some patients**. Irregular progression occurs over a few years, and *many patients are unable to stand and walk by the time they reach adolescence*. **Skeletal abnormalities** include pes cavus and kyphoscoliosis, which are secondary to the early onset neuropathy. Constriction of the visual fields and ring scotomata are manifestations of the **macular degeneration and retinitis pigmentosa** in some cases. **Cardiac enlargement and congestive failure** are serious late complications. **Neuropathologic** findings consist of **demyelination of peripheral nerves and degeneration of nerve cells in the spinal gray matter and cerebellar cortex**. **Diagnosis** is confirmed by the finding of **red blood cell acanthocytes, low serum cholesterol, and 13 (low-density) lipoproteins**. The disease is caused by **defects in a triglyceride transfer protein**, as discussed in Chap. 37. A **deficiency of vitamin E, as a result of malabsorption**, may be a factor, and large doses of the vitamin should be tried as therapy. A closely related disease, also with familial hypobetalipoproteinemia, was described by van Buchem and coworkers. It, too, is associated with malabsorption syndrome, ill-defined weakness, ataxia, dysesthesia of the legs, and Babinski signs. There is no sensory loss.

Answer 21

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.

Answer 22

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.

Answer 23

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.

Answer 24

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.

Answer 25

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.

Answer 26

**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.

Answer 27

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. ## Footnote Kennedy- X-linked Bulbospinal muscular atrophy CAG expansion androgen Receptor Gynaecomastia, oligospermia, diabetes

Answer 28

האטה מפושטת בטווח הטטא. Diffuse Degenerative Diseases * **Alzheimer disease** and other degenerative diseases that cause serious impairment of cerebrocortical function are accompanied by **relatively slight degrees of diffuse slow-wave abnormality in the *theta (4- to 7-Hz) range***; many recordings are normal in the early and midstages of illness. * more rapidly progressive disorders—such as **subacute sclerosing panencephalitis (SSPE), Creutzfeldt-Jakob disease, and to a lesser extent the cerebral lipidoses**—often have, in addition, very **characteristic and almost pathognomonic EEG changes** consisting of **periodic bursts of high-amplitude sharp waves**, usually **bisynchronous and symmetrical** (Fig. 2-7K). * In a negative sense, a normal EEG in a patient who is profoundly apathetic is a point in favor of the diagnosis of hysteria, catatonia, or schizophrenia | Delta= coma, theta= old and demented

Answer 29

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.

Answer 30

טמפורלי (וגם בקורטקס האסוציאטיבי הפריאטלי) Of some value have been studies of cerebral blood flow (single-photon emission computed tomography [SPECT]) nd metabolism (positron emission tomography [PET]), which *early in the illness often, but not always, show **diminished activity in the parietal association regions of the cortex and in the medial temporal lobes***. In most cases, when such changes are evident, the diagnosis was already obvious on clinical grounds. Newer PET ligand agents that bind to amyloid, such as “Pittsburgh compound” and tau-ligands are more sensitive in identifying and observing the course of Alzheimer disease. Their main utility may be in detecting changes before brain atrophy is evident and in identifying patients who have the earliest changes of Alzheimer disease, whose disease course may be amenable to alteration by medications. They are currently used as biomarkers in therapeutic trials of various agents that reduce or remove brain amyloid.

Answer 31

ubiquitin esterase = PARK 5 of parkinsons disease

Answer 32

4. 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.

Answer 33

ירידה בשטף הדיבור עקב חיפוש מילים Clinical features לרוב קשה מאוד לתארך את מועד התחלת הסימפטומים, לעיתים יוצאים החוצה לאחר חבלת ראש קלה, ניתוח, התחלת תרופה חדשה או מחלת חום. המטופל יתלונן על כאב ראש לא ספציפי, שכחה, דיזינס או עוד תלונות סומטיות לא ספציפיות. * **התפתחות הדרגתית של אובדן זיכרון הוא הסימפטום העיקרי**- שכחה לגבי פגישות שנקבעו ואובדן חפצים. מלים שכמעט ולא היו בשימוש או שמות שלרוב המטופל לא השתמש בהם ישכחו. למטופל נטייה לחזור על אותם שאלות בנושאים שדוינו עכשיו. בעבר הייתה מחשבה שאובדן זיכרון ריסנטי בולט יותר מזכרונות רחוקים (חוק ריבוט), אולם במחקרים אחרים נמצא שבסה"כ האובדן סימטרי לכל חייו של המטופל. * שפה - ברגע שהפרעת הזכרון נהייתה משמעותית, תופיע הפרעת שפה, **תחילה המטופל יצטרך לחשוב על שמות ועל כן הדיבור יעצר (למטופל קושי בשליפת המילה)**, אותה הפרעה תהיה גם בכתיבה. **אוצר המלים הולך ומצטמצם**. הבנה נראית שמורה עד לרגע המטופל נראה כאילו הוא מבין אך לא מבצע את הבקשה (טרם הובן האם זה מתרחש משנית לירידה בקשב או עקב פגיעה באוצר מילים). ככל שהמחלה מתקדמת הפרעת השפה מחמירה ו**אחרי שנים רבות של מחלה המטופל לא יצליח לדבר משפטים שלמים, יחזור על השאלה לפני שיענה על התשובה ולעיתים החזרה תהיה כל כך משמעותית עד שתופיע אקולליה**. ההדרדרות ממשיכה להתקדם עד לכדי **אנומיק אפזיה, מרכיבים של אפאזיה רצטיבית בשילוב עם אקספרסיבית**. לסיכום – ירידה משמעותית בתפקודי שפה ובתפקודים המנטליים. .

Answer 34

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.**

Answer 35

Corticobasal degeneration * synucleinopathies- PD, DLBD, MSA * Tauopathies: AD, PSP, FTD, CBD

Answer 36

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. ## Footnote Dopa Repsonsive Dystonia SEGAWA Diurnal variation Dopa Repsonsive

Answer 37

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**

Answer 38

MSA anterocollis or dystonia of the lower facial muscles is striking in a few cases

Answer 39

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

Answer 40

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.

Answer 41

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.

Answer 42

Primary lateral sclerosis **Primary Lateral Sclerosis** This entity, like ALS, can be a form of **motor neuron disease**, although most cases appear to be examples of a unique degenerative process. Approximately 20 percent of patients suspected of developing ALS, have a **slowly progressive corticospinal tract disorder** that begins with a **pure spastic paraparesis**; later, the **arms and oropharyngeal muscles become involved** and the disease remains one ***solely of the upper neurons***. These cases have distinctive neuropathologic features and are designated as primary lateral sclerosis (PLS) The typical case begins insidiously in the **fifth or sixth decade** with a **stiffness in one leg, then in the other**; there is a **slowing of gait**, with **spasticity** predominating over weakness as the years go on. Walking is still possible with the help of a cane for many years after the onset, but **eventually this condition acquires the characteristic features of a severe spastic paraparesis**. Over the years, **finger movements become slower, the arms become spastic, and, if the illness persists for decades, *speech takes on a pseudobulbar lilt***. There are **no sensory symptoms or signs**. The legs are often found to be **surprisingly strong**, the difficulty in locomotion being attributable to rigid spasticity. About half the patients eventually acquire **spasticity of the Bladder**. Pringle and associates suggest that a diagnostic criterion of the disease is progression for 3 years without evidence of lower motor neuron dysfunction. * **Pathologic studies** in a limited number of cases have disclosed a **relatively stereotyped pattern of *reduced numbers of Betz cells* in the *frontal and prefrontal motor cortex*, degeneration of the *corticospinal tracts*, and *preservation of motor neurons in the spinal cord and brainstem*** (Beal and Richardson; Fisher; Pringle et al). The corticospinal tract lesions are identical to those in typical ALS.

Answer 43

Needle EMG

Answer 44

ALS או יותר ספציפית- progressive bulvar palsy

Answer 45

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).**

Answer 46

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**.

Answer 47

אטרופיה בצורת מיקי מאוס במידבריין

Answer 48

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

Answer 49

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).

Answer 50

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).

Answer 51

mutation in the "survival of motor neuron gene" on chromosme 5 Familial spinal muscular atrophy that begins in infancy and childhood is inherited mainly as an **autosomal recessive trait**. All the SMA phenotypes in children have been mapped to mutations affecting the **“survival of motor neuron” (SMN1) gene.** ----- frataxin= friedreich ataxia paraplegin- hereditary spastic paralysis CAG- huntington's disease CTG- myotonic dystrophy

Answer 52

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**

Answer 53

Torsin gene (DYT1, also known as TORlA) on chromosome 9q, which codes for the protein, torsin A in both Jewish and non-Jewish families

Answer 54

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

Answer 55

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

Answer 56

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

Answer 57

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.

Answer 58

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

Answer 59

I. Syndrome of progressive dementia, other neurologic signs absent or inconspicuous A. Alzheimer disease B. Some cases of Lewy body disease C. Frontotemporal dementias—Pick disease, including behavioral variant, primary progressive aphasias (several types) D. Posterior cortical atrophy (visuospatial dementia)

Answer 60

II. Syndrome of progressive dementia in combination with other neurologic abnormalities A. Huntington disease (chorea) B. Lewy-body disease (parkinsonian features) C. Cortico-basal ganglionic degeneration (rigidity, dystonia) D. Cortical-striatal-spinal degeneration (spasticity) E. Frontotemporal dementia-amyotrophic lateral sclerosis complex F. Familial dementia with spastic paraparesis, amyotrophy, or myoclonus G. Polyglucosan body disease (neuropathy)

Answer 61

III. Syndrome of disordered posture and movement A. Parkinson disease B. Multiple system atrophy, MSAP (striato-nigral degeneration, autonomic failure) C. Progressive supranuclear palsy D. Dystonia musculorum deformans E. Huntington disease (chorea) F. Acanthocytosis with chorea G. Corticobasal ganglionic degeneration H. Lewy body disease I. Restricted dystonias, including spasmodic torticollis and Meige syndrome

Answer 62

IV. Syndrome of progressive ataxia A. Spinocerebellar ataxias 1. Friedreich ataxia 2. Non-Friedreich ataxia (retained reflexes, tremor, hypogonadism, myoclonus, and other disorders)

Answer 63

B. Cerebellar cortical ataxias 1. Holmes type of familial pure cerebellar-olivary atrophy 2. Late-onset cerebellar atrophy

Answer 64

C. Complicated hereditary and sporadic cerebellar ataxias (later onset ataxia with brainstem and other neurologic disorders) 1. Multiple system atrophies (MSAC) 2. Dentatorubral degeneration (Ramsay Hunt type) 3. Dentato-rubro-pallido-luysian atrophy (DRPLA) 4. Machado-Joseph disease; SCA3 (ataxia, basal ganglia features) 5. Other complicated late-onset, autosomal dominant ataxias with pigmentary retinopathy, ophthalmoplegia, slow eye movements, polyneuropathy, optic atrophy, deafness, extrapyramidal features, and dementia

Answer 65

V. Syndrome of slowly developing muscular weakness and atrophy A. Motor disorders with amyotrophy 1. Amyotrophic lateral sclerosis 2. Progressive spinal muscular atrophy 3. Progressive bulbar palsy 4. Kennedy syndrome and other hereditary forms of progressive muscular atrophy and spastic paraplegia 5. Motor neuron disease with frontotemporal dementia

Answer 66

B. Spastic paraplegia without amyotrophy 1. Primary lateral sclerosis 2. Hereditary spastic paraplegia (Strümpell-Lorrain)

Answer 67

VI. Sensory and sensorimotor disorders (neuropathies; see Chap. 43) A. Hereditary sensorimotor neuropathies—peroneal muscular atrophy (Charcot-Marie-Tooth); hypertrophic interstitial polyneuropathy (Dejerine-Sottas) B. Pure or predominantly sensory or motor neuropathic C. Riley-Day autonomic degeneration

Answer 68

VII. Syndrome of progressive blindness with or without other neurologic disorders (see Chap. 12) A. Pigmentary degeneration of retina (retinitis pigmentosa) B. Stargardt disease C. Age-related macular degeneration (ARMD)

Answer 69

VIII. Syndromes characterized by degenerative neurosensory deafness (see Chap. 14) A. Pure neurosensory deafness B. Hereditary hearing loss with retinal diseases C. Hereditary hearing loss with system atrophies of the nervous system

Answer 70

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.

Answer 71

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.

Answer 72

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.

פרק 38 Chapter 38: Degenerative Diseases of the Nervous System Flashcards

(109 cards)