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Flashcards in CN LANGE - Movement Disorders II Deck (104):

Progressive supranuclear palsy has much overlap with ...?

Corticobasal degeneration - Clinically and pathologically.


Progressive supranuclear palsy - The principal neuropathologic finding is ...?

Neuronal degeneration with the presence of neurofibrillary tangles in the midbrain, pons, basal ganglia, and dentate nuclei of the cerebellum.


Progressive supranuclear palsy - Associated neurochemical abnormalities include:

Decr. concentrations of dopamine and its metabolite homovanillic acid in the caudate nucleus and putamen.


Progressive supranuclear palsy - Pathogenesis:

Pathogenesis seems to relate to both a genetic predisposition and mt dysfunction.


Progressive supranuclear palsy - Epidemiology:

Men:Women 2:1.
--> 45-75yr.


Progressive supranuclear palsy - Classic clinical features:

1. Gait disturbance with early falls.
2. Supranuclear ophthalmoplegia.
3. Pseudobulbar palsy.
4. Axial dystonia +/- extrapyramidal rigidity of the limbs.
5. Dementia.


Supranuclear ophthalmoplegia:

1. Prominent failure of voluntary VERTICAL gaze with later paralysis of horizontal gaze.
2. Oculocephalic and oculovestibular reflexes are preserved.


PSP - Postural instability, marked akinesia, and unexplained falls also occur early and may ...?

PRECEDE vertical gaze palsies.


PSP - In addition, the neck often assumes an ...?

Extended postured (axial dystonia IN EXTENSION), with resistance to passive flexion.


PSP - Rigidity of the limbs and bradykinesia may mimic PD, but ...?

Tremor is less common or conspicuous.


PSP - A coexisting pseudobulbar palsy produces ...?

Facial weakness, dysarthria, dysphagia, and often exaggerated jaw jerk and gag reflexes --> There may also be exaggerated and inappropriate emotional responses (pseudobulbar affect).


The dementia of PSP:

1. Forgetfullness.
2. Slowed thought processes.
3. Alterations of mood and personality.
4. Impaired calculation and abstraction.


PSP - Sleep?

Insomnia is common.


PSP - Some patients with pathologically verified disease have:

1. Pure akinesia or a clinical phenotype resembling PD.
2. Others resemble corticobasal degeneration, with dystonia, apraxia and cortical sensory loss.



Midbrain atrophy --> Hummingbird sign.


PSP from PD:

PD differs from the classic form of PSP in that
1. Voluntary downward and horizontal gaze are NOT usually lost.
2. Axial posture tends to be characterized by flexion rather than extension.
3. Tremor is common.
4. The course is LESS fulminant.
5. Anti-PD drugs are MORE effective.


PSP - Prognosis:

The disorder typically follows a progressive course, with death from aspiration or inanition within 2 to 12 (usually 6-10) years.


Corticobasal degeneration (CBD):

Rare, NON familial, degenerative disorder - a TAUOPATHY - that occurs in middle-aged or elderly persons of EITHER sex.


CBD - Pathology:

Presence of abnormal intracellular filamentous deposits containing TAU protein.


CBD sometimes simulates PD:

When bradykinesia and rigidity are conspicuous features.


CBD - Postural-action tremor may also occur, but the usual cause of profound disability is ...?

LIMB ATAXIA + CLUMSINESS rather than extrapyramidal defects.


CBD - Other clinical features:

1. Speech disturbances (aphasic, apraxic, or dysarthric).
2. Acalculia.
3. Cortical sensory deficits (eg neglect syndromes).
4. Stimulus-sensitive myoclonus.
5. Alien-limb phenomenon.
6. Dysphagia.
7. Postural disturbances/dystonic features.
8. Cognitive decline and behavioral changes.


Alien-limb phenomenon:

The tendency for a limb to move semipurposefully, involuntarily, and without the knowledge of the owner.


CBD - Frontal release signs:

May be present, along with brisk tendon reflexes, and extensor plantar responses.
--> ALSO incr. saccadic latency, but saccades are of normal velocity.


CBD - Some pathologically verified cases present with a ...?

Frontal behavioral-spatial disorder, a nonfluent/agrammatic variant of primary progressive aphasia, or the phenotype of PSP.


CBD from PD:

1. Marked apraxia that often leads to a useless limb.
2. Difficulty in opening/closing the eyes.
3. Speech disturbances.
4. Presence of pyramidal and cortical deficits in addition to any extrapyramidal dysfunction also helps in this regard, but definitive diagnosis can be made only at autopsy.



Show cortical, callosal, and midbrain atrophy + 3rd ventricle enlargement.



Hypoperfusion in regions of the frontal and parietal lobes.


CBD - Treatment:

NO specific therapy exists and treatment is generally supportive.


CBD - Prognosis:

The disorder follows a progressive course, leading to increasing disability and dependence. DEATH typically follows within 10years, often sooner, from ASPIRATION PNEUMONIA.


Huntington disease:

Hereditary disorder of the nervous system characterized by the gradual onset and subsequent progression of chorea and dementia.


HD - Epidemiology:

1. Throughout the world and in all ethnic groups.
2. 5/100.000.


HD - Genetics:

1. AD - Huntingtin gene (HTT).
2. Complete penetrance.
3. Anticipation and paternal descent.
4. CAG repeat --> Polyglutamine tract.


Paternal descent:

Refers to the tendency for anticipation to be most pronounced in individuals who inherit the disease from their father.
--> The CAG repeat can expand during gametogenesis, especially in the male germline.


Normal subjects have between ...-... CAG repeats.

Nearly ALL HD patients have >40.


HD - Pathology:

Postmortem examination reveals cell loss, particularly in the cerebral cortex and corpus striatum.
--> In the latter region --> Medium-sized spiny neurons that contain GABA and enkephalin and project to the GPe are affected EARLIEST, but other classes of neurons are eventually involved as well.


HD - Biochemical studies have shown:

Concentrations of the inhibitory neurotransmitter GABA + its biosynthetic enzyme GAD (glutamic acid decarboxylase), and ACh + its biosynthetic enzyme choline acetyltransferase --> ARE ALL REDUCED in the basal ganglia of HD patients.


HD - PET shows ...?

Reduced glucose utilization, even in an anatomically normal caudate nucleus.


HD - Initial symptoms:

Either abnormal movements or intellectual changes may be the initial symptom, but ultimately BOTH are present.


HD - Dementia:

1. Early --> Irritability, moodiness, and anti-social behavior, but a more obvious dementia subsequently develops.
2. Selective and progressive impairment of attention and executive function, consistent with FRONTOSTRIATAL pathology.


HD - Chorea:

Movement disturbance may be characterized initially by no more than an apparent fidgetiness or restlessness, but grossly abnormal choreiform or choreoathetoid movement are eventually seen.


HD - Atypical forms:

1. Especially in cases developing during CHILDHOOD --> Clinical picture is dominated by progressive akinesia and rigidity, with little or no chorea.
2. --> Westphal variant.
3. The correct diagnosis is suggested by the accompanying dementia + positive FHx.
4. EPILEPSY + CEREBELLAR ATAXIA are frequent features of the juvenile form but NOT of adult cases.


HD - Imaging:

CT/MRI demonstrates atrophy of the cortex + caudate nucleus in established cases.
PET --> Reduction in striatal metabolic rate may be demonstrated.


HD DDx - Huntington disease-like (HDL) disorders:

Resemble HD but are NOT associated with abnormal CAG trinucleotide repeat number of the huntingtin gene.


HDL disorders:

1. HDL-1, HDL-2 are AD.
2. HDL-3 is AR.


HDL-1 is associated with ...?

A 192-nt insertion --> Expanded octapeptide repeat, in the prion protein gene (PRNP).


HDL-2 is caused by ...?

An expanded CAG/CTG repeat in the junctophilin-3 gene (JPH3).


HD DDx - Benign hereditary chorea:

1. AD or de novo.
2. Choreiform movements that develop in early childhood.
3. NOT progressive.
4. NOT associated with dementia.


Benign hereditary chorea - In patients with mutations in the gene NKX2-1 ...?

Coding for thyroid transcription factor-1, hypothyroidism and pulm. abnormalities may also be present --> Brain-thyroid-lung syndrome.


HD DDx - Familial chorea sometimes occurs in association with circulating ...?

Acanthocytes (spiny RBCs), but examinaton of a wet blood film will clearly distinguish this disorder.


HD DDx - Other clinical features of chorea-acanthocytosis?

1. Orolingual ticlike dyskinesias.
2. Vocalizations.
3. Mild intellectual decline.
4. Seizures.
5. Peripheral neuropathy.
6. Muscle atrophy.
--> Parkinsonian features are sometimes present.


HD DDx - Unlike certain other disorders associated with circulating acanthocytes?

There is NO disturbance of beta-lipoprotein concentration in the peripheral blood.


HD DDx - Paroxysmal choreoathetosis:

1. May occur on a familial basis.
2. The intermittent nature of the symptoms and their relationship to movement or emotional stress usually distinguish this disorder from HD.


HD DDx - Dentatorubral-pallidoluysian atrophy:

Another dominantly inherited CAG repeat disorder that is clinically similar to HD --> Distinguished by genetic testing.


HD DDx - Neuroferritinopathy (NBIA2):

1. Progressive chorea + dystonia.
2. Adult onset with positive FHx.
3. Cognitive function is relatively preserved.
4. MRI is characteristically abnormal.
--> Mutant gene (FTL1) is distinct from the Huntingtin gene.


HD DDx - When the early symptoms constitute progressive intellectual failure ...?

It may not be possible to distinguish HD from other varieties of dementia, unless the family history is characteristic or the movement disorder becomes noticeable.


Dentatorubral-pallidoluysian atrophy:

AD --> Rare EXCEPT in JAPAN.
1. Dementia.
2. Choreoathetosis.
3. Ataxia.
4. Myoclonic epilepsy.


Dentatorubral-Pallidoluysian atrophy - Mutant gene:

Atrophin 1 (ATN1) --> Distinct from that in HD, despite the similarity of clinical phenotype.


Mutant ATN1 contains an expanded ...?

CAG repeat.


MCC of acute chorea in children?

Sydenham chorea.


Sydenham chorea - The underlying pathologic feature is probably ...?

An arteritis.


Sydenham chorea - In approx. ...% of cases, it appears 2 to 3 months after an episode of rheumatic fever or polyarthritis, but in other patients no such history can be obtained.



Sydenham chorea - Characterized by ...?

Abnormal choreiform movements that are sometimes UNILATERAL and, when mild, may be mistaken for restlessness or fidgetiness.


Sydenham chorea - PET/SPECT:

REVERSIBLE basal ganglia hypermetabolism.



Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections.


Isolated generalized torsion dystonia:

This disorder is characterized by dystonic movements and postures + an ABSENCE of neurologic signs.


Isolated generalized torsion dystonia - Inheritance:

Typically inherited as an AD disorder with variable penetrance of 30-40%.


Isolated generalized torsion dystonia - Molecular genetic techniques:

Permit identification of the responsible deletion in torsin 1A, an ATP-binding protein, but there is some evidence of genetic heterogeneity.


Isolated generalized torsion dystonia - Changes in the concentrations of ...?

NE, serotonin, and dopamine occur in a variety of brain regions, but their role in the pathogenesis of dystonia is UNCERTAIN.


IGTD - When onset is in childhood?

1. A family history is usually obtainable. Symptoms generally commence in the LEGS.
2. Progression is likely, and the disorder typically leads to severe disability from generalized dystonia.


IGTD - With onset in adult life:

1. Positive family history is less likely.
2. The initial symptoms are usually in the ARMS + AXIAL structures.
3. Generalized dystonia may ultimately develop in approx. 20% of patients with adult-onset dystonia, but severe disability does NOT usually occur.


IGTD - Examination - The disorder is characterized by ...?

Abnormal movements and postures that are typically exacerbated by voluntary activity.
1. Torticollis.
2. Blepharospasm.
3. Oromandibular dystonia.


The combination of blepharospasm and oromandibular dystonia is sometimes refered to as ...?

Meige syndrome.


IGTD - Treatment:

1. A dramatic response to levodopa suggest Dopa-responsive dystonia.
2. Anticholinergic drugs may be effective.


IGTD - Course and prognosis:

1. Approx. 1/3 of patients eventually become confined to chair or bed.
2. Another 1/3 are affected only mildly.
3. Severe disability is more likely to occur when the disorder commences in childhood.


Dopa-responsive dystonia:

Segawa syndrome --> Inherited in an AD manner with incomplete penetrance (GCH1 gene) or, rarely, as an AR trait (TH gene).


Dopa-responsive dystonia - Main clinical features:

1. Onset typically in childhood.
2. Girls more often.
3. Accompaniment by bradykinesia and rigidity may lead to mistaken diagnosis of juvenile PD.
4. Diurnal worsening of symptoms is common.


Dystonia-Parkinsonism - X-linked recessive form (sometimes called lubag) has been identified in men from ...?

Philippines and relates to mutations to TAF1 gene at Xq13.1.


Dystonia-Parkinsonism - Another variety with AD inheritance has been described in patients of different ethnic origin, with ...?

Rapid evolution of symptoms and signs over HOURS, days, or weeks, but slow progression thereafter.
--> A rostrocaudal (face, arm, leg) gradient of involvement may be noted.


Dystonia-Parkinsonism - AD variety - Mutation:

Gene encoding the alpha-3 subunit of N,K-ATPase (ATP1A3) on chromosome 19q13.


Myoclonic dystonia:

AD disorder with incomplete penetrance and variable expression, related to mutations in the DRD2 or SGCE gene.
--> Patients exhibit rapid jerks in addition to more sustained abnormal postures.


Myoclonic dystonia - The jerks may respond to ...?



Myoclonic dystonia appears to be distinct from classic isolated torsion dystonia:

1. Usually begins before 20yrs.
2. Benign, slowly progressive course over many years.


Genetic studies suggest that myoclonic dystonia and essential myoclonus are ...?



Combined dystonia:

Large group of disorders characterized by dystonia combined with other neurologic features, such as dementia, ataxia, dyskinesias, or parkinsonism.


Combined dystonias - Fahr disease:

Idiopathic basal ganglia calcification associated with dystonia, parkinsonism, and behavioral disturbances.
--> AD inheritance in some families.


Neurodegeneration with brain iron accumulation (NBIA) refers to a group of inherited disorders with ...?

Iron accumulation in the basal ganglia.


Neurodegeneration with brain iron accumulation (NBIA) - Clinical manifestations:

1. Extrapyramidal and pyramidal deficits.
2. Neuropsychiatric changes.
3. Ocular abnormalities.


Pantothenate kinase-associated neurodegeneration (NBIA1) is characterized by ...?

1. Gait abnormalities.
2. Dystonia.
3. Spasticity.
4. Hyperreflexia.
5. Extensor plantar responses.
6. Behavioral changes.
7. Dysarthria.
8. Dysphagia.
9. Ocular abnormalities (retinal degeneration, gaze palsies, optic atrophy).


Pantothenate kinase-associated neurodegeneration (NBIA1) - Deposition of iron and other pigments in the globus pallidus leads to a characteristic MRI appearance ...?

"Eye of the tiger".


Pantothenate kinase-associated neurodegeneration (NBIA1) - Mutation:

AR inheritance - Mutation in the gene for pantothenate kinase 2 (PANK2).


Neuroferritinopathy (NBIA2):

Rare, adult-onset, AD progressive disorder related to mutations in the ferritin light chain gene (FTL1).


Neuroferritinopathy (NBIA2) - Clinical features:

1. Chorea.
2. Dystonia (predominantly in the legs).
3. Parkinsonism.
or some combination of these.
--> An action-specific facial dystonia (involving symmetric frontalis and platysma contracion, giving a startled appearance) is characteristic.


Chorea-acanathocytosis is characterized by:

Some combination of:
1. Dystonia.
2. Chorea.
3. Orofacial dyskinesias.
4. Parkinsonism.
5. Tics.
6. Hyporeflexia.
7. Amyotrophy.
8. Cognitive abnormalities.


Chorea-acanthocytosis - Mutation:

AR inheritance with mutation in the VPS13A gene.


Certain mitochondrionopathies may also be associated with dystonia, such as ...?

Leber HOA.


Paroxysmal dyskinesias:

Group of disorders in which dystonia and dyskinesias occur episodically, often on a familial basis.


Paroxysmal dyskinesias may also occur with ...?

1. Basal ganglia pathology.
2. MS.
3. Cerebral palsy.
4. Thyroid dysfunction.
5. Idiopathic hypoparathyroidism.


Hypnogenic paroxysmal dyskinesia is a form of ...?

Frontal lobe EPILEPSY characterized by:
1. Intermittent dystonia.
2. Choreoathetoid movements during sleep.
--> Responds well to antiseizure medication.


Mention the 3 main paroxysmal dyskinesias:

1. Paroxysmal nonkinesigenic dyskinesia.
2. Paroxysmal kinesigenic choreoathetosis.
3. Paroxysmal exercise-induced dyskinesia.


Paroxysmal nonkinesigenic dyskinesia:

Gene: MR1.
Inheritance: AD.
Precipitants: Caffeine, alcohol, fatigue, stress, hunger, menstruation.
Onset: Before 30.
Duration of ep.: Min-Hr.
Frequency: 1-3/day - May be long episode-free intervals.
Manifestations: Choreoathetosis, dystonia - May be unilateral and then generalize.
Rx: Sleep, clonazepam.
2o causes: MS, trauma, endocrinopathy, vascular disease.


Paroxysmal kinesigenic choreoathetosis:

Gene: PRRT2.
Inheritance: AD or sporadic.
Precipitants: Sudden movement or startle.
Onset: Before 20.
Duration of ep.: Sec-min.
Frequency: Variable; may be many/day.
Manifestations: Choreoathetosis, dystonia, usually unilateral.
Rx: Anticonvulsants (carbamazepine, phenytoin).
2o causes: MS, trauma, endocrinopathy.


Paroxysmal exercise-induced dyskinesia:

Gene: SLC2A1.
Inheritance: Sporadic or AD?.
Precipitants: Exercise (eg walking for 30min) or physical exertion.
Onset: Before 30.
Duration of ep.: Min-Hr (commonly 5-30min).
Frequency: 1/day-1/month.
Manifestations: Dystonia in exercised limbs - may be unilateral.
Rx: Usually helpful.
2o causes: Trauma, insulinoma.


Progressive supranuclear palsy:

Idiopathic, usually sporadic, degenerative disorder, a TAUOPATHY, that primarily affects subcortical gray matter regions of the brain.