Flashcards in CN LANGE - Movement Disorders I Deck (118):
Movement disorders result from dysfunction of ...?
Deep subcortical gray matter structures termed the basal ganglia.
The basic circuitry of the basal ganglia consists of 3 interacting neuronal loops:
1. Corticocortical loop.
2. Nigrostriatal loop.
3. Striatopallidal loop.
Cortex --> Caudate + Putamen --> GPi + Thalamus --> Cortex.
SN --> Caudate + putamen.
Caudate + putamen --> GPe --> STN --> GPi.
Categorizing an abnormal movement is generally the first step toward arriving at the neurologic diagnosis. Abnormal movements can be classified as:
A rhythmic oscillatory movement best characterized by its relationship to voluntary motor activity, that is, according to whether it occurs at rest, during maintenance of a particular posture, or during movement.
3 main types of tremor:
Causes of tremor - Postural tremor:
1. Physiologic tremor.
2. Enhanced physiologic tremor.
3. Familial (AD) or idiopathic (benign essential) tremor.
4. Dystonic tremor.
5. Cerebellar disorders.
6. Wilson disease.
Enhanced physiologic tremor:
1. Anxiety or fear.
2. Excessive physical activity or sleep deprivation.
3. Sedative drug or alcohol withdrawal.
4. Drug toxicity (eg Li, bronchodilators, sodium valproate, TCAs).
5. Heavy metal poisoning (eg mercury, lead, arsenic).
6. CO poisoning.
Causes of tremor - Intention tremor:
1. Brainstem or cerebellar disease.
2. Drug toxicity (eg alcohol, anticonvulsants, sedatives).
3. Wilson disease.
4. Dystonic tremor.
Causes of tremor - Rest tremor:
3. Heavy metal poisoning (eg mercury).
4. Dystonic tremor.
An 8- to 12-Hz tremor of the outstretched hands is a normal finding.
Its physiologic basis is uncertain.
MC type of abnormal postural tremor is ...?
Benign essential tremor - May be familial.
A postural tremor of the hands that is indistinguishable from essential tremor may occur in patients with ...?
--> Dystonic tremor refers to a postural or intention tremor that occurs in a part of the body already affected by dystonia.
--> It is a part of the dystonia and is most prominent when an attempt is made to oppose the dystonic posturing.
May be associated with postural tremor, but is itself more properly considered a form of MYOCLONUS, than tremor.
Intention (kinetic) tremor - Sometimes mistaken for ...?
Limb ataxia, but the latter has no rhythmic oscillatory component.
Intention tremor results from a lesion affecting the ...?
Superior cerebellar peduncle.
The word chorea denotes ...?
Rapid irregular muscle jerks that occur involuntarily + unpredictably in different parts of the body.
Chorea - What is the milkmaid grasp?
Power is full, but there may be difficulty in maintaining muscular contraction such that, for example, handgrip is relaxed intermittently.
Causes of chorea:
2. Static encephalopathy (cerebral palsy).
3. Sydenham chorea.
4. Chorea gravidarum.
6. Miscellaneous medical disorders.
7. Cerebrovascular disorders.
8. Structural lesions of the STN.
Causes of chorea - Hereditary:
1. Huntington disease (HD).
2. Huntington disease-like (HDL) disorders.
3. Dentatorubro-pallidoluysian atrophy.
4. Benign hereditary chorea.
6. Paroxysmal choreoathetosis.
7. Familial chorea with associated acanthocytosis.
Causes of chorea - Miscellaneous medical disorders:
1. Thyrotoxicosis, hypoparathyroidism, Addison.
2. Hypo-Ca, Mg, Na + HyperNa.
4. Polycythemia vera.
6. SLE/Primary anti-phospholipid syndrome.
8. Paraneoplastic syndrome.
Causes of chorea - Cerebrovascular disorders:
2. Ischemic/hemorrhagic stroke.
3. Subdural hematoma.
Hemiballismus is ...?
UNILATERAL CHOREA that is especially violent because the proximal muscles of the limbs are involved.
Hemiballismus is most often due to ...?
Vascular disease in the contralateral STN - Commonly resolves spontaneously in the weeks after its onset.
Dystonia and athetosis:
The term athetosis generally denotes abnormal movements that are slow, sinuous, and writhing in character. When the movements are so sustained that they are better regarded as abnormal postures, the term DYSTONIA is used.
--> Many now use the terms interchangeably.
By international consensus, dystonia is now classified along:
1. A clinical axis - Includes age at onset, body distribution, temporal pattern, and associated features such as other movement disorders or neurologic features.
2. An etiologic axis - Includes nervous system pathology and inheritance.
Factors influencing dystonia:
1. Not present during sleep.
2. Generally enhanced by emotional stress and by voluntary activity.
MCC of dystonia:
1. Perinatal anoxia.
2. Birth trauma.
3. Kernicterus from hyperbilirubinemia.
Dystonic movements and postures are the cardinal features of:
Isolated torsion dystonia.
Torsion dystonia may also occur as a manifestation of:
3. Sequela of encephalitis.
Acute dystonic posturing may result from ...?
Treatment with dopamine receptor antagonist drugs.
Lateralized dystonia may occasionally relate to ...?
Focal intracranial disease, but the clinical context in which it occurs usually identifies the underlying cause.
Myoclonic jerks are sudden, rapid, twitchlike muscle contractions.
Myoclonus can be classified according to:
1. Distribution --> Generalized/focal,segmental.
2. Relationship to precipitating stimuli --> Spontaneous or can be brought on by sensory stimulation, arousal, or the initiation of movement (Action myoclonus).
3. May be physiologic --> Physiologic myoclonus.
4. May be isolated abnormality --> Essential myoclonus.
5. Manifestation of epilepsy --> Epileptic myoclonus.
Sudden loss of muscle activity --> Best seen in asterixis.
Physiologic myoclonus includes the myoclonus that occurs ...?
Upon falling asleep or awakening (nocturnal myoclonus) as well as hiccup.
Brainstem involvement of the dentatorubroolivary pathway --> By stroke, MS, tumors, etc.
--> Can produce palatal myoclonus which may be associated with an audible click or synchronous movements of ocular, facial, or other bulbar muscles.
Propriospinal myoclonus arises in the spinal cord and then spreads up and down the cord, leading to a brief bodily contraction.
Post anoxic myoclonus is remarkably responsive to ...?
5-hydroxytryptophan, the precursor neurotransmitter of 5-hydroxytryptamine (serotonin).
Localized myoclonus regardless of origin, may respond to ..?
Sudden + recurrent + quick + coordinated + abnormal movements that can usually by imitated without difficulty.
Tics tend to ...?
1. Worsen with stress.
2. Diminish during voluntary activity or mental concentration.
3. Disappear during sleep.
Tics - Can be classified into 4 groups depending on whether they are simple or multiple and transient/chronic:
1. Transient simple tics.
2. Chronic simple tics.
3. Persistent simple or multiple tics.
4. Chronic multiple motor and vocal tics --> Gilles de la Tourette syndrome.
Transient simple tics:
1. Common in children.
2. Usually terminate spontaneously within 1 year (often within a few weeks).
3. Generally require no treatment.
Chronic simple tics:
1. Can develop at any age but often begin in childhood.
2. Treatment is unnecessary in most cases.
3. The benign nature of them must be explained.
Persistent simple or multiple tics:
1. Before 15yr.
2. Single or multiple motor tics + vocal tics.
3. Complete remission occurs by the end of adolescence.
Bradykinesia - Manifestations include:
1. A fixity of facial expression, with reduced blinking, widened palpebral fissures, and an apparently impassive appearance.
2. A paucity of spontaneous movement of the limbs (eg a reduced atm swing on walking).
3. Some patients have "freezing", that is, a temporary inability to move.
Familial or essential tremor - Pathogenesis - Genetics:
2. 4 gene loci: ETM1, ETM2, ETM3 + ETM4 (using exome sequencing).
3. In some cases (ETM1) the disorder is related to a polymorphism in the D3 dopamine receptor gene (DRD3).
Familial or essential tremor - Pathogenesis - Other features:
1. Evidence of involvement of olivocerebellar and cerebello-thalamo-cortical pathways.
2. Decr. levels of GABAa/GABAb receptors have been found postmortem in the dentate nucleus.
Patients with essential tremor have a higher risk of developing ...?
Parkinson disease than the general population.
Familial tremor - Symptoms may develop in the ... years.
Teenage or early adult years - but often do not appear until later.
Familial tremor - Examination usually reveals ...?
No other gross abnormalities, but some patients may have mild ataxia or personality disturbances.
Familial tremor - A small quantity of ...?
Alcohol sometimes provides remarkable but transient relief - the mechanism is not known.
1. In all ethnic groups.
2. 1 to 2 per 1.000.
3. Males = Females.
Idiopathic PD is also called ...?
During a preclinical phase extending back for several years before the development of the motor deficit ...?
5. REM sleep behavior disorder may be present.
Multiple subcortical white-matter infarcts may lead to symptoms and signs suggestive of parkinsonism, usually accompanied by brisk tendon reflexes and extensor plantar responses.
Parkinsonism - Pathology - Idiopathic PD is ...?
A proteinopathy --> Misfolding and aggregation of alpha-synuclein (thus referred to as synucleinopathy).
PD - Histopathologic exam at advanced stages:
1. Loss of pigmentation and cells in the substantia nigra + other brainstem centers.
2. Cell loss in the globus pallidus and putamen.
3. Filamentous eosinophilic intraneural inclusion granules (Lewy bodies) --> Containing alpha-synuclein in the basal ganglia, brainstem, spinal cord, and SNS ganglia.
The distribution of Lewy bodies is more widespread than originally appreciated:
1. Early involvement of the lower brainstem (dorsal motor nucleus of X).
2. Olfactory bulb.
3. Enteric nervous system.
4. Subsequent spread to the locus ceruleus.
5. Substantia nigra.
6. Transentorhinal cortex, hippocampus, and neocortex.
Lewy bodies are NOT seen in ...?
Post-encephalitic parkinsonism --> Instead there may be nonspecific neurofibrillary degeneration in a number of diencephalic structures as well as changes in the substantia nigra.
The motor manifestations of PD appear to result from ...?
Altered patterns of inhibition and excitation within the basal ganglia and its connections via direct and indirect pathways.
PD - Other neurotransmitters ...?
Such as NE are also depleted in the brains of patients with parkinsonism, but the clinical relevance of this deficiency is less clear.
PD - Tremor:
2. Most conspicuous at rest.
3. Frequently involves the lower jaw and chin as well.
4. Although it may ultimately be present in all limbs, it is NOT uncommon for the tremor to be confined to one limb - or both limbs on one side - for months or years before it becomes generalized.
--> In some patients, tremor NEVER becomes prominent.
What is the reason for the flexed posture of many PD patients?
Rigidity --> Disturbance in muscle tone.
Rigidity vs spasticity?
The resistance is typically uniform throughout the range of movement at a particular joint and affects agonists and antagonists alike --> In contrast to spasticity, where it is often greatest at the beginning of the passive movement (clasp-knife phenomenon) + more marked in some muscles than others.
In some instances, the rigidity in parkinsonism is described as ...?
Cogwheel rigidity because of ratchet-like interruptions of passive movement that may be due, in part, to the presence of tremor.
The most disabling feature of parkinsonism is ...?
Hypokinesia (bradykinesia or akinesia).
--> Slowness of voluntary movement and a reduction in automatic movement, such as swinging the arms while walking.
PD - The patient's face is relatively ...?
IMMOBILE (hypomimia or mask-like facies), with widened palpebral fissures, infrequent blinking, a certain fixity of facial expression, and a smile that develops and fades slowly.
PD - The voice is ...?
Soft (hypophonia) and poorly modulated.
PD - Power is ...?
Not diminished if time is allowed for it to develop.
PD - The handwriting is ...?
Small (micrographia), tremulous, and hard to read.
Abnormal gait and posture:
1. The patient finds it difficult to get up from bed or an easy chair and adopts a flexed posture on standing.
2. Often difficult to start/stop walking.
3. Generally some unsteadiness on turning.
4. In advanced stages --> Patient tends to walk with increasing speed to prevent a fall (festinating gait) because of the altered center of gravity that results from the abnormal posture.
PD - Other motor abnormalities:
1. Mild blepharoclonus (fluttering of the closed eyelids).
2. Occasionally blepharospasm (involuntary closure of the eyelids).
3. There is typically no alteration in the tendon reflexes (although a mild hyperreflexia may occur on the affected side in asymmetric parkinsonism).
4. Repetitive tapping (appprox. 2 per second) over the bridge of the nose produces SUSTAINED blink response (Myerson sign).
PD - NON motor manifestations:
1. Anosmia is an early symptom (may arise from many other causes).
2. Cognitive decline, executive dysfunction, and personality changes are common, as are depression and anxiety.
3. Apathy may be conspicuous.
4. A sense of fatigue may be prominent, and some patients complain of pain or sensory disturbances.
5. Dysautonomic symptoms (urinary urgency, constipation, postural hypotension).
6. Sleep disorders including REM behavior disorder are common.
7. Seborrheic dermatitis may occur.
PD - DDx - 8 diagnoses:
2. Essential (benign familial) tremor.
3. Parkinson-plus syndromes.
Differentiate depression from PD:
1. May simulate PD - Expressionelss face, poorly modulated voice, and reduction in voluntary activity.
2. The 2 diseases may coexist.
3. A trial of anti-depressants may be helpful in some instances.
Differentiate essential (benign familial tremor) from PD:
1. Early age at onset.
2. Family history.
3. Relationship to activity.
4. Beneficial effect of alcohol.
5. Lack of other neurologic signs.
6. Essential tremor commonly affects the head (causing a nod or head shake) --> PD typically affects the lower jaw and chin.
Parkinsonism + clinical evidence of more widespread disease from degeneration in other neuronal systems.
--> Depending on the disorder, they are either:
Parkinson-plus syndromes typically have better or worse prognosis than PD?
4 Parkinson-plus syndromes:
1. Lewy body disease.
2. Multisystem atrophy (MSA).
3. Progressive supranuclear palsy.
4. Corticobasal degeneration.
Huntington disease may occasionally be mistaken for parkinsonism when it presents with ...?
Rigidity and akinesia --> Family history of HD or an accompanying dementia, if present, should suggest the correct diagnosis.
Does early parkinsonism require treatment?
Anticholinergic drugs - More helpful in ...?
Alleviating tremor and rigidity than hypokinesia but are generally less effective than dopaminergic drugs.
Anticholinergic drugs are best avoided in the ...?
Elderly because of their side effects, which include dry mouth, constipation, urinary retention, etc.
Amantadine can be given for ...?
MILD parkinsonism - Either alone or in combination with an anticholinergic agent.
Amantadine - mechanism of action:
Precise mechanism is unclear.
1. Blockade of NMDA-preferring glutamate and muscarinic cholinergic receptors.
2. Stimulates release of dopamine.
Pros and cons of amantadine:
Pros: Improves all the motor features of parkinsonism + its side effects are relatively uncommon + its effects are exerted rapidly + may be useful for the extreme fatigue.
Cons: Many patients fail to respond to this drug, or its benefit is short-lived.
Major plus of levodopa:
Ameliorates all the major clinical features of parkinsonism and, unlike the anticholinergic drugs, is often particularly helpful against hypokinesia.
MC side effects of levodopa:
4. Abnormal movements (dyskinesias).
Late complications of levodopa:
1. Response fluctuation such as the wearing-off effect, in which deterioration occurs shortly before the next dose is to be taken.
2. The on-off phenomenon, in which abrupt but transient fluctuations in the severity of parkinsonism occur at frequent intervals during the day.
How can we control the fluctuations with levodopa therapy?
Only partly by:
1. Varying the dosing intervals.
2. Restricting protein intake.
3. Use of a controlled-release preparation of carbidopa/levodopa.
4. Addition of entacapone, MAOI-B, or dopamine agonists to the medication regimen.
5. Administration of carbidopa/levodopa via portable intraduodenal pump.
Levodopa - Contraindications:
1. Narrow-angle glaucoma.
2. Psychotic illness.
3. In patients receiving MAOI-A.
4. Used with care in patients with active peptic ulcers or suspected malignant melanomas.
Compared to levodopa, dopamine agonists are ...?
Slightly less effective, BUT less likely to cause dyskinesias.
What side effect has been associated with tolcapone?
Acute hepatic necrosis --> Prefer entacapone.
Which commercial preparation now available combines levodopa with both carbidopa and entacapone?
What is the problem with initiation of therapy with Stalevo rather than carbidopa/levodopa?
Fails to delay the time of onset or reduce the frequency of dyskinesia.
--> May occur sooner and with increased frequency.
Cellular therapies in PD:
Autologous or fetal adrenal medullary tissue or fetal substantia nigra has been transplanted to the putamen or caudate nucleus in the belief that the transplanted tissue would continue to synthesize and release dopamine --> FAILURE.
Lewy body disease - Epidemiology:
Up to 15% of all dementias.
--> Onset 50-85yr.
Lewy body disease - Main features:
1. Cognitive changes leading to dementia are conspicuous and usually precede or occur shortly after the appearance of parkinsonian deficits.
2. Cognitive function may fluctuate MARKEDLY over the 24h-period.
3. Visual hallucinations are common.
4. Many patients have unexplained periods of markedly increased confusion or delirium.
Lewy body disease - Parkinsonian deficits:
Become increasingly severe with time, but tremor is often relatively inconspicuous compared with bradykinesia and rigidity.
--> Postural hypotension and syncope are common.
Lewy body disease - Pathology:
Lewy bodies diffusely in cortical and subcortical structures.
--> In some instances, mutations in the alpha-synuclein or beta-synuclein genes have been described.
--> Also other mutations.
Differentiate Lewy body disease from PD:
PD differs in that cognitive function is preserved until a later stage + motor involvement is more likely to be ASYMMETRIC in onset, with more conspicuous tremor.
Differentiate Lewy body disease from Alzheimer:
The marked variability over short periods of time and the accompanying motor deficit differentiate Lewy body disease from Alzheimer.
Imaging in Lewy body disease reveals ...?
Generalized cortical atrophy.
Lewy body disease - Treatment:
Difficult because levodopa induces hallucinations and exacerbates the cognitive and behavioral disturbances while providing only limited benefit to the motor disturbance.
--> The dementia and behavioral abnormalities often respond favorably to cholinesterase inhibitors.
Multisystem atrophy (MSA):
Progressive neurodegenerative disorder (synucleinopathy) with multisystem motor abnormalities + often DYSAUTONOMIA.
MSA - Epidemiology:
More common in MEN 50-60.
One subtype of MSA, referred to as MSA-P, is associated with ...?
Neuronal loss in the putamen, globus pallidus, and caudate nucleus --> Presents with bradykinesia + rigidity.
--> Anterocollis is especially conspicuous.
MSA-C type is associated with ...?
MSA - When autonomic insufficiency is a conspicuous accompaniment, the eponymous designation is ...?
Shy-Drager syndrome is characterized by:
1. Parkinsonian features.
2. Autonomic insufficiency (postural hypotension, anhidrosis, disturbance of sphincter control, and impotence).
3. Signs of more widespread neurologic involvement (pyramidal or LMN signs + often a cerebellar deficit).
MSA - MRI:
Hypointense putamen with a hyperintense rim.
MSA from PD:
The autonomic and multisystem - often SYMMETRIC - motor findings with marked anterocollis distinguish the disorder from classic PD.
MSA - Prognosis:
The disease follows a progressive course leading to death over about 8 to 10 years.